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Sample records for multiple myeloma correlate

  1. Multiple myeloma

    MedlinePlus

    Plasma cell dyscrasia; Plasma cell myeloma; Malignant plasmacytoma; Plasmacytoma of bone; Myeloma - multiple ... Multiple myeloma most commonly causes: Low red blood cell count ( anemia ), which can lead to fatigue and ...

  2. [Multiple myeloma].

    PubMed

    Abe, Masahiro; Miki, Hirokazu; Nakamura, Shingen

    2016-03-01

    Owing to the positive clinical benefits obtained with new agents, complete remission (CR) can be used as a surrogate for overall survival, and should be achieved. Although multiple myeloma is a heterogeneous disease in terms of myeloma cell- and patient-related risk factors, patients should receive the most effective combination therapy based on proteasome inhibitors and/or immunomodulatory drugs (IMiDs) as backbone medication irrespective of the risks encountered in the setting of induction therapy ("one-size-fits-all" therapy), followed by consolidation/maintenance therapy to achieve CR with the ultimate goal of extended survival. Myeloma-defining biomarkers have been established to identify high-risk smoldering myeloma requiring treatment. The development of salvage treatments yielding better outcomes for relapsed/refractory myeloma is urgently needed. Upcoming novel molecular targeting agents with different modes of action and immunotherapeutic agents will be integrated into myeloma treatment regimens with a great therapeutic impact, and further evolution of the treatment paradigm for multiple myeloma is eagerly anticipated. PMID:27076236

  3. Multiple myeloma

    PubMed Central

    Rajkumar, S. Vincent

    2008-01-01

    Multiple myeloma is a clonal plasma cell malignancy that accounts for slightly more than 10% of all hematologic cancers. In this paper, we present a historically focused review of the disease, from the description of the first case in 1844 to the present. The evolution of drug therapy and stem-cell transplantation for the treatment of myeloma, as well as the development of new agents, is discussed. We also provide an update on current concepts of diagnosis and therapy, with an emphasis on how treatments have emerged from a historical perspective after certain important discoveries and the results of experimental studies. PMID:18332230

  4. Myeloma (multiple)

    PubMed Central

    2006-01-01

    Introduction Multiple myeloma is the most common primary cancer of the bones in adults, representing about 1% of all cancers diagnosed in the US in 2004, and 14% of all haematological malignancies. In the UK, multiple myeloma accounts for 1% of all new cases of cancer diagnosed each year. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatment in people with asymptomatic early stage multiple myeloma (stage I)? What are the effects of first-line treatments in people with advanced stage multiple myeloma (stages II and III)? What are the effect of salvage treatments, or supportive therapy, in people with advanced stage multiple myeloma (stages II and III)? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2004 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: allogenic transplant (non-myeloablative), autologous stem cell transplant (early or late transplantation, double or single, purging of), bisphosphonates, bone marrow stem cells, bortezomib, chemotherapy (combination, conventional dose, intermediate dose plus stem cell rescue, high-dose plus stem cell rescue), combination chemotherapy plus corticosteroids, deferred treatment (in stage I disease), early chemotherapy plus corticosteroids (in stage I disease), epoetin alpha, first-line treatments, infection prophylaxis, interferon, maintenance therapy (in advanced multiple myeloma), melphalan (normal dose

  5. Correlation of proliferative and clonogenic tumor cells in multiple myeloma

    SciTech Connect

    Karp, J.E.; Burke, P.J.; Saylor, P.L.; Humphrey, R.L.

    1984-09-01

    To expand on the findings from previous clinical trials that the growth of residual tumor is increased at a predictable time following initial drug administration, malignant plasma cells from bone marrows of patients with multiple myeloma (MM) were examined for changes in proliferation and clonogenicity induced in vivo by cyclophosphamide and in vitro by drug-induced humoral stimulatory activity. Peak plasma cell (/sup 3/H)thymidine labeling index (LI) occurred predictably following drug and paralleled changes in agar colony formation by marrow cells obtained during therapy. Colony-forming capacity of pretreatment MM marrow populations was enhanced when those cells were cultured with humoral stimulatory activity, similar to the increased colony formation detected in Day 9 postcyclophosphamide marrows at the time of peak plasma cell LI. To further define a relationship between proliferative plasma cells and colony-forming tumor cells, MM marrows were fractionated by sedimentation on an isokinetic gradient. Enrichment of a proliferative tumor cell cohort was achieved, evidenced by (/sup 3/H)thymidine LI. Colony-forming cells were also enriched by isokinetic gradient sedimentation, and agar colony formation by MM marrow cell fractions correlated with the kinetic characteristics of the isolated subpopulations. These studies of whole and fractionated human MM marrow cell populations suggest that the kinetically active cells which are induced to proliferate in vivo and in vitro are closely related to the clonogenic tumor cells which produce colonies in agar and which, like those cells measured by (/sup 3/H)thymidine LI, respond to growth stimulation by drug-induced humoral stimulatory activity.

  6. Multiple Myeloma

    MedlinePlus

    ... myeloma is a cancer that begins in plasma cells, a type of white blood cell. These cells are part of your immune system, which helps ... germs and other harmful substances. In time, myeloma cells collect in the bone marrow and in the ...

  7. What Is Multiple Myeloma?

    MedlinePlus

    ... other tissues. If someone has only a single plasma cell tumor, the disease is called an isolated (or solitary ) plasmacytoma . If someone has more than one plasmacytoma, they have multiple myeloma . Multiple myeloma is ...

  8. Multiple Myeloma Symptoms

    MedlinePlus

    ... it is multiple myeloma . Stay on top of discoveries, trials, research and more. Click here to sign up for the MMRF Newsletter First name Last name E-mail address CLOSE News & Press Multiple Myeloma Knowledge Center Privacy Policy Donor Privacy Policy Terms of ...

  9. Pomalidomide for Multiple Myeloma

    Cancer.gov

    A summary of results from a phase III trial that compared the combination of pomalidomide (Pomalyst®) and low-dose dexamethasone versus high-dose dexamethasone alone in patients with multiple myeloma that has progressed despite other treatments.

  10. [Smoldering multiple myeloma].

    PubMed

    Fouquet, G; Guidez, S; Herbaux, C; Demarquette, H; Leleu, X

    2014-04-01

    Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell neoplasia, characterized by monoclonal plasma cell proliferation in the absence of end-organ damage, but with a high risk of progression to multiple myeloma. It has therefore to be distinguished from monoclonal gammapathy of undetermined significance (MGUS), which has a much lower risk of progression, but also from multiple myeloma, which remains an incurable disease and requires a specific treatment. The critical question in the management of SMM is whether an early therapeutic strategy could help delaying the progression to multiple myeloma, in order to lower the risk of serious complications related to this progression, or even to cure the disease. This early treatment could not be proposed to all SMM patients, who are indeed asymptomatic, and in whom the risk of toxicity could make it difficult to justify the potential benefit obtained. The challenge is to target early at diagnosis SMM patients with a high risk of progression, using available routine tests sufficiently reliable to warrant the therapeutic sanction which relies on it. Today however, apart from randomized studies, recommendations are to maintain therapeutic abstention in SMM patients. PMID:24050785

  11. Increased serum levels of MIP-1alpha correlate with bone disease and angiogenic cytokines in patients with multiple myeloma.

    PubMed

    Tsirakis, George; Roussou, Parascevi; Pappa, Constantina A; Kolovou, Anna; Vasilokonstantaki, Chrysoula; Miminas, Ioannis; Kyriakaki, Stavroula; Alegakis, Athanasios; Alexandrakis, Michael G

    2014-01-01

    Many cytokines possess variable roles in the pathogenesis of multiple myeloma. Macrophage inflammatory protein-1alpha (MIP-1alpha) is an osteoclast-activating factor with a major role in myeloma bone disease. The aim of the study was to examine its participation in the angiogenic process of the disease. We measured, by enzyme-linked immunosorbent assays, its serum levels in 56 newly diagnosed myeloma patients, in several skeletal grades and stages of the disease and in 25 healthy controls. Concurrently, we measured serum levels of the angiogenic cytokines basic-fibroblast growth factor, hepatocyte growth factor and interleukin-18. All the above cytokines were higher in myeloma patients (p < 0.001 for all cases) and were increasing in parallel with disease stage (p < 0.001 for all cases) and skeletal grade (p < 0.04 for MIP-1alpha and p < 0.001 for the other cases). Moreover, positive correlations between MIP-1alpha and all the angiogenic cytokines were noted (p < 0.001 for all cases). MIP-1alpha seems to be a predominant factor responsible for the enhancement of bone resorption and increased angiogenesis. The positive correlation between MIP-1alpha and the angiogenic chemoattractants supports the involvement of these factors in the biology of myeloma cell growth. Moreover, they could be used as possible therapeutic targets as well as markers of disease activity.

  12. Circulating plasma cells in multiple myeloma: characterization and correlation with disease stage.

    PubMed

    Rawstron, A C; Owen, R G; Davies, F E; Johnson, R J; Jones, R A; Richards, S J; Evans, P A; Child, J A; Smith, G M; Jack, A S; Morgan, G J

    1997-04-01

    The aim of this study was to develop a flow cytometric test to quantitate low levels of circulating myeloma plasma cells, and to determine the relationship of these cells with disease stage. Cells were characterized using five-parameter flow cytometric analysis with a panel of antibodies, and results were evaluated by comparison with fluorescent consensus-primer IgH-PCR. Bone marrow myeloma plasma cells, defined by high CD38 and Syndecan-1 expression, did not express CD10, 23, 30, 34 or 45RO, and demonstrated weak expression of CD37 and CD45. 65% of patients had CD19- 56+ plasma cells, 30% CD19- 56(low), and 5% CD19+ 56+, and these two antigens discriminated myeloma from normal plasma cells, which were all CD19+ 56(low). Peripheral blood myeloma plasma cells had the same composite phenotype, but expressed significantly lower levels of CD56 and Syndecan-1, and were detected in 75% (38/51) of patients at presentation, 92% (11/12) of patients in relapse, and 40% (4/10) of stem cell harvests. Circulating plasma cells were not detectable in patients in CR (n = 9) or normals (n = 10), at a sensitivity of up to 1 in 10,000 cells. There was good correlation between the flow cytometric test and IgH-PCR results: myeloma plasma cells were detectable by flow cytometry in all PCR positive samples, and samples with no detectable myeloma plasma cells were PCR negative. Absolute numbers decreased in patients responding to treatment, remained elevated in patients with refractory disease, and increased in patients undergoing relapse. We conclude that flow cytometry can provide an effective aternative to IgH-PCR that will allow quantitative assessment of low levels of residual disease.

  13. IRON IN MULTIPLE MYELOMA

    PubMed Central

    VanderWall, Kristina; Daniels-Wells, Tracy R; Penichet, Manuel; Lichtenstein, Alan

    2013-01-01

    Multiple myeloma is a non-curable B cell malignancy in which iron metabolism plays an important role. Patients with this disorder almost universally suffer from a clinically significant anemia, which is often symptomatic, and which is due to impaired iron utilization. Recent studies indicate that the proximal cause of dysregulated iron metabolism and anemia in these patients is cytokine-induced upregulation of hepcidin expression. Malignant myeloma cells are dependent on an increased influx of iron and therapeutic efforts are being made to target this requirement. The studies detailing the characteristics and biochemical abnormalities in iron metabolism causing anemia and the initial attempts to target iron therapeutically are described in this review. PMID:23879589

  14. Cytokine and chemokine profiles in multiple myeloma; significance of stromal interaction and correlation of IL-8 production with disease progression.

    PubMed

    Kline, Michael; Donovan, Kathleen; Wellik, Linda; Lust, Christopher; Jin, Wendy; Moon-Tasson, Laurie; Xiong, Yuning; Witzig, Thomas E; Kumar, Shaji; Rajkumar, S Vincent; Lust, John A

    2007-05-01

    Multiple myeloma (MM) is a product of interactions between tumor plasma cells and multiple cell types native to the bone marrow (BM). We have used antibody array technology to examine the proteins produced by BM stromal cells in response to stimulation by BM taken from patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and MM. We observed increased production of the chemokine IL-8 by stromal cells co-cultured with supernatants from bone marrow cells of patients with active myeloma. IL-8 production is correlated with active disease and is dependent upon IL-1beta and NF-kappaB signaling. Consistent with the pro-angiogenic activity of IL-8, increased BM microvessel density (MVD) correlated with stimulation of stromal cell IL-8 production. In addition, the majority of MM cell lines and MM patient plasma cells were found to express IL-8 receptors CXCR1 and CXCR2. We conclude that stromal cell IL-8 production parallels MM disease activity, is IL-1beta induced, and correlates with bone marrow angiogenesis. PMID:16879867

  15. Artifactual hypercalcemia in multiple myeloma

    SciTech Connect

    Annesley, T.M.; Burritt, M.F.; Kyle, R.A.

    1982-09-01

    A calcium-binding IgG K monoclonal protein in a patient with multiple myeloma and asymptomatic hypercalcemia was recognized, isolated, and characterized. In addition to binding by the whole IgG molecules, calcium was bound by purified Fab fragments and recombined heavy and light chains. In a competitive binding study, the isolated myeloma protein did not bind magnesium. Recognition of calcium-binding myeloma proteins is important in order to avoid therapy for hypercalcemia.

  16. Multiple myeloma and physical activity: a scoping review

    PubMed Central

    Smith, Lee; McCourt, Orla; Henrich, Malgorzata; Paton, Bruce; Yong, Kwee; Wardle, Jane; Fisher, Abigail

    2015-01-01

    Objectives Multiple myeloma is the second most common haematological cancer. A growing body of literature is emerging that investigates the role physical activity plays in all stages of multiple myeloma (prevention and survivorship) and to date no attempt has been made to collate and understand this literature. Therefore, this scoping review aims to (1) outline what is already known about physical activity in all stages of multiple myeloma (2) map the literature on physical activity and multiple myeloma and (3) identify future directions for research. Design Scoping Review. Data Sources Searches were carried out in May 2015. Searchers were conducted in PubMed, Web of Science, SPORTdiscus and MEDLINE. Eligibility criteria for selecting studies To be included studies had to report original data, investigate physical activity per se or physical activity correlates and multiple myeloma or smouldering multiple myeloma. Results A total of 19 papers received full screening, 5 of these papers were excluded. This review identified three journal articles relating to the role of physical activity in the prevention of multiple myeloma, nine papers were identified in the treatment of multiple myeloma and two on smouldering multiple myeloma. Conclusions The search identified that the literature surrounding multiple myeloma and physical activity is very limited. We encourage those designing new cohort studies to allow for future assessment of associations between physical activity and onset of multiple myeloma and smouldering multiple myeloma, as well as the potential role that physical activity plays in the progression from smouldering multiple myeloma to multiple myeloma. Second, we encourage the design and investigation of gender and treatment-specific physical activity interventions in patients with multiple myeloma. Finally, we highlight the need for more randomised controlled trials to evaluate the impact of different types, frequencies and intensities of physical activity

  17. Smoldering multiple myeloma.

    PubMed

    Gao, Minjie; Yang, Guang; Kong, Yuanyuan; Wu, Xiaosong; Shi, Jumei

    2015-01-01

    Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage of multiple myeloma (MM) characterized by clonal bone marrow plasma cells (BMPC) ≥ 10% and/or M protein level ≥ 30 g/L in the absence of end organ damage. It represents an intermediate stage between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic MM. The risk of progression to symptomatic MM is not uniform, and several parameters have been reported to predict the risk of progression. These include the level of M protein and the percentage of BMPC, the proportion of immunophenotypically aberrant plasma cells, and the presence of immunoparesis, free light-chain (FLC) ratio, peripheral blood plasma cells (PBPC), pattern of serum M protein evolution, abnormal magnetic resonance imaging (MRI), cytogenetic abnormalities, IgA isotype, and Bence Jones proteinuria. So far treatment is still not recommended for SMM, because several trials suggested that patients with SMM do not benefit from early treatment. However, the Mateos et al. trial showed a survival benefit after early treatment with lenalidomide plus dexamethasone in patients with high-risk SMM. This trial has prompted a reevaluation of early treatment in an asymptomatic patient population. PMID:26000300

  18. Smoldering Multiple Myeloma

    PubMed Central

    Gao, Minjie; Yang, Guang; Kong, Yuanyuan; Wu, Xiaosong; Shi, Jumei

    2015-01-01

    Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage of multiple myeloma (MM) characterized by clonal bone marrow plasma cells (BMPC) ≥ 10% and/or M protein level ≥ 30 g/L in the absence of end organ damage. It represents an intermediate stage between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic MM. The risk of progression to symptomatic MM is not uniform, and several parameters have been reported to predict the risk of progression. These include the level of M protein and the percentage of BMPC, the proportion of immunophenotypically aberrant plasma cells, and the presence of immunoparesis, free light-chain (FLC) ratio, peripheral blood plasma cells (PBPC), pattern of serum M protein evolution, abnormal magnetic resonance imaging (MRI), cytogenetic abnormalities, IgA isotype, and Bence Jones proteinuria. So far treatment is still not recommended for SMM, because several trials suggested that patients with SMM do not benefit from early treatment. However, the Mateos et al. trial showed a survival benefit after early treatment with lenalidomide plus dexamethasone in patients with high-risk SMM. This trial has prompted a reevaluation of early treatment in an asymptomatic patient population. PMID:26000300

  19. Smoldering multiple myeloma

    PubMed Central

    Landgren, Ola; Mateos, María-Victoria

    2015-01-01

    Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM. PMID:25838344

  20. Smoldering multiple myeloma.

    PubMed

    Rajkumar, S Vincent; Landgren, Ola; Mateos, María-Victoria

    2015-05-14

    Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM. PMID:25838344

  1. Multiple myeloma. Houses and spouses

    SciTech Connect

    Kyle, R.A.; Greipp, P.R.

    1983-02-15

    Two families in which successive spouses who lived in the same house developed multiple myeloma are reported. In the first instance, a man whose first wife died of multiple myeloma remarried, and his second wife also developed myeloma. In the second family, a woman's first husband died of multiple myeloma and her second husband did too. Radiation studies of the houses and yards showed no increased radioactivity. No evidence was found for excessive exposure to chemicals or other environmental agents, for contact with other patients having similar malignancies, or for exposure to viruses or other transmissible factors. The significance of the occurrence of multiple myeloma in subsequent spouses is unknown. It is hoped that this report will stimulate research for other instances and lead to careful epidemiologic, radiologic, and virologic studies.

  2. Multiple myeloma involving the orbit.

    PubMed

    Fay, A M; Leib, M L; Fountain, K S

    1998-01-01

    Multiple myeloma is a plasma cell malignancy often associated with destructive skeletal lesions. Orbital involvement in multiple myeloma is rare. Risk factors for orbital involvement have not been established, although risk may vary with immunoglobulin subtype. Early detection of orbital plasmacytoma may affect treatment and clinical course. A case is reported of multiple myeloma without elevated serum immunoglobulins that involves the orbit, and the implications of early detection are discussed. The patient was first examined by an ophthalmologist 13 months after multiple myeloma was diagnosed and 5 months after the external appearance of an orbital tumor. Urine protein electrophoresis demonstrated kappa light chains. Hypergammaglobulinemia was not detected. Plain-film roentgenography showed orbital involvement at the time of initial diagnosis. An impressive clinical response to external beam radiation therapy was seen. Attention to immunoprotein characteristics in multiple myeloma may help to identify risk factors for orbital involvement. Early detection may permit safer and equally effective treatment. All patients with multiple myeloma should undergo thorough ophthalmic examination at the time of initial diagnosis.

  3. Therapeutic advancements in multiple myeloma.

    PubMed

    Gozzetti, Alessandro; Candi, Veronica; Papini, Giulia; Bocchia, Monica

    2014-01-01

    Multiple myeloma survival has significantly improved in the latest years due to a broad spectrum of novel agents available for treatment. The introduction of thalidomide, bortezomib, and lenalidomide together with autologous stem-cell transplantation has considerably increased complete remission rate and progression-free survival resulting ultimately in prolonged survival in myeloma patients. Moreover, novel strategies of treatment such as consolidation and maintenance are being used to further implement responses. Finally, a number of new drugs such as carfilzomib and pomalidomide are already in clinical practice, making the future of myeloma patients brighter. PMID:25237651

  4. Therapeutic Advancements in Multiple Myeloma

    PubMed Central

    Gozzetti, Alessandro; Candi, Veronica; Papini, Giulia; Bocchia, Monica

    2014-01-01

    Multiple myeloma survival has significantly improved in the latest years due to a broad spectrum of novel agents available for treatment. The introduction of thalidomide, bortezomib, and lenalidomide together with autologous stem-cell transplantation has considerably increased complete remission rate and progression-free survival resulting ultimately in prolonged survival in myeloma patients. Moreover, novel strategies of treatment such as consolidation and maintenance are being used to further implement responses. Finally, a number of new drugs such as carfilzomib and pomalidomide are already in clinical practice, making the future of myeloma patients brighter. PMID:25237651

  5. Multiple Myeloma: Patient Handbook

    MedlinePlus

    ... way in which these agents cross-link the DNA of myeloma cells and block cell division. Amyloidosis: ... a cancer treatment regimen. Chromosome: A strand of DNA and proteins in the nucleus of a cell. ...

  6. Kidney Disease and Multiple Myeloma

    PubMed Central

    Rennke, Helmut G.; Laubach, Jacob P.; Richardson, Paul G.

    2013-01-01

    Summary Kidney injury is a common complication of multiple myeloma and other plasma cell dyscrasias, and it is associated with increased mortality. Multiple pathogenic mechanisms can contribute to kidney injury in the patient with myeloma, some of which are the result of nephrotoxic monoclonal Ig and some of which are independent of paraprotein deposition. The pathogenic mechanisms that underlie paraprotein-related kidney disease are increasingly well understood. A novel assay allowing the quantification of free light chains in the serum has aided the diagnosis of new onset disease and allowed for the earlier detection of relapse. Novel myeloma agents have shown considerable promise in reversing renal failure in some patients and improving outcomes. Stem cell transplantation remains a mainstay of management for younger patients with myeloma who are suitable candidates for intensive therapy, whereas the role of new drugs, plasma exchange, and kidney transplantation continues to evolve. PMID:23868898

  7. Multiple myeloma: evaluation by CT

    SciTech Connect

    Schreiman, J.S.; McLeod, R.A.; Kyle, R.A.; Beabout, J.W.

    1985-02-01

    Although patients who have multiple myeloma usually have straightforward clinical symptoms and corroborative radiographs, in some instances, these patients will present atypically, with symptoms suggesting active disease but radiographs that are normal or nonspecific. The authors reviewed the records of 32 patients who had documented multiple myeloma and had undergone CT examinations, assessing the value of those examinations. Although CT is not indicated in all patients who have multiple myeloma, it is especially useful in patients who have bone pain and normal or nonspecific radiographs. CT provided confirmatory information in all cases in which lesions were seen on radiographs. CT also frequently demonstrated a greater extent of disease than could be appreciated on the radiographs.

  8. Multiple Myeloma Cancer Stem Cells

    PubMed Central

    Huff, Carol Ann; Matsui, William

    2008-01-01

    Multiple myeloma is characterized by the clonal expansion of neoplastic plasma cells within the bone marrow, elevated serum immunoglobulin, and osteolytic bone disease. The disease is highly responsive to a wide variety of anticancer treatments including conventional cytotoxic chemotherapy, corticosteroids, radiation therapy, and a growing number of agents with novel mechanisms of action. However, few if any patients are cured with these modalities and relapse remains a critical issue. A better understanding of clonogenic multiple myleoma cells is essential to ultimately improving long-term outcomes, but the nature of the cells responsible for myeloma regrowth and disease relapse is unclear. We review evidence that functional heterogeneity exists in multiple myeloma and discuss potential strategies and clinical implications of the stem-cell model of cancer in this disease. PMID:18539970

  9. Polycythaemia: an unusual presentation of multiple myeloma.

    PubMed

    Hutchison, Elaine J; Taverna, Josephine A; Yu, Qi; Yeager, Andrew M

    2016-01-01

    In contrast to anaemia, polycythaemia is a distinctly uncommon finding in patients with multiple myeloma. We describe the presence of otherwise unexplained polycythaemia in a 57-year-old Caucasian man who was found to have IgG κ multiple myeloma. After treatment of myeloma, the polycythaemia resolved. We reviewed previous reports of polycythaemia associated with multiple myeloma and discuss potential pathophysiological mechanisms that link these 2 conditions. PMID:27651406

  10. Drugs Approved for Multiple Myeloma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for multiple myeloma and other plasma cell neoplasms. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  11. Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data.

    PubMed

    Waheed, Sarah; Mitchell, Alan; Usmani, Saad; Epstein, Joshua; Yaccoby, Shmuel; Nair, Bijay; van Hemert, Rudy; Angtuaco, Edgardo; Brown, Tracy; Bartel, Twyla; McDonald, James; Anaissie, Elias; van Rhee, Frits; Crowley, John; Barlogie, Bart

    2013-01-01

    Multiple myeloma causes major morbidity resulting from osteolytic lesions that can be detected by metastatic bone surveys. Magnetic resonance imaging and positron emission tomography can detect bone marrow focal lesions long before development of osteolytic lesions. Using data from patients enrolled in Total Therapy 3 for newly diagnosed myeloma (n=303), we analyzed associations of these imaging techniques with baseline standard laboratory variables assessed before initiating treatment. Of 270 patients with complete imaging data, 245 also had gene expression profiling data. Osteolytic lesions detected on metastatic bone surveys correlated with focal lesions detected by magnetic resonance imaging and positron emission tomography, although, in two-way comparisons, focal lesion counts based on both magnetic resonance imaging and positron emission tomography tended to be greater than those based on metastatic bone survey. Higher numbers of focal lesions detected by magnetic resonance imaging and positron emission tomography were positively linked to high serum concentrations of C-reactive protein, gene-expression-profiling-defined high risk, and the proliferation molecular subgroup. Positron emission tomography focal lesion maximum standardized unit values were significantly correlated with gene-expression-profiling-defined high risk and higher numbers of focal lesions detected by positron emission tomography. Interestingly, four genes associated with high-risk disease (related to cell cycle and metabolism) were linked to counts of focal lesions detected by magnetic resonance imaging and positron emission tomography. Collectively, our results demonstrate significant associations of all three imaging techniques with tumor burden and, especially, disease aggressiveness captured by gene-expression-profiling-risk designation. (Clinicaltrials.gov identifier: NCT00081939).

  12. Multiple myeloma imaging.

    PubMed

    Touzeau, C; Moreau, P

    2013-02-01

    Imaging myeloma is often performed when complications occur which may reveal the disease. Since the malignant plasma cell proliferation characteristic of this disease can affect the whole of the bony skeleton to various degrees, examination of the bones should be as complete as possible. The radiographic images must be studied for lytic lesions or signs of diffuse osteopenia, as well for fracture complications such as vertebral compression. Slice imaging has the advantage of being more sensitive and showing extra-osseous extension well. With a CT scan and MRI, spinal compression can be detected or a surgical procedure planned, while MRI or a PET scan can be used to assess extension of the disease and the response to treatment.

  13. Increased circulating VCAM-1 correlates with advanced disease and poor survival in patients with multiple myeloma: reduction by post-bortezomib and lenalidomide treatment

    PubMed Central

    Terpos, E; Migkou, M; Christoulas, D; Gavriatopoulou, M; Eleutherakis-Papaiakovou, E; Kanellias, N; Iakovaki, M; Panagiotidis, I; Ziogas, D C; Fotiou, D; Kastritis, E; Dimopoulos, M A

    2016-01-01

    Circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and selectins were prospectively measured in 145 newly-diagnosed patients with symptomatic myeloma (NDMM), 61 patients with asymptomatic/smoldering myeloma (SMM), 47 with monoclonal gammopathy of undetermined significance (MGUS) and 87 multiple myeloma (MM) patients at first relapse who received lenalidomide- or bortezomib-based treatment (RD, n=47; or VD, n=40). Patients with NDMM had increased VCAM-1 and ICAM-1 compared with MGUS and SMM patients. Elevated VCAM-1 correlated with ISS-3 and was independently associated with inferior overall survival (OS) (45 months for patients with VCAM-1 >median vs 75 months, P=0.001). MM patients at first relapse had increased levels of ICAM-1 and L-selectin, even compared with NDMM patients and had increased levels of VCAM-1 compared with MGUS and SMM. Both VD and RD reduced dramatically serum VCAM-1 after four cycles of therapy, but only VD reduced serum ICAM-1, irrespective of response to therapy. The reduction of VCAM-1 was more pronounced after RD than after VD. Our study provides evidence for the prognostic value of VCAM-1 in myeloma patients, suggesting that VCAM-1 could be a suitable target for the development of anti-myeloma therapies. Furthermore, the reduction of VCAM-1 and ICAM-1 by RD and VD supports the inhibitory effect of these drugs on the adhesion of MM cells to stromal cells. PMID:27232930

  14. Increased circulating VCAM-1 correlates with advanced disease and poor survival in patients with multiple myeloma: reduction by post-bortezomib and lenalidomide treatment.

    PubMed

    Terpos, E; Migkou, M; Christoulas, D; Gavriatopoulou, M; Eleutherakis-Papaiakovou, E; Kanellias, N; Iakovaki, M; Panagiotidis, I; Ziogas, D C; Fotiou, D; Kastritis, E; Dimopoulos, M A

    2016-01-01

    Circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and selectins were prospectively measured in 145 newly-diagnosed patients with symptomatic myeloma (NDMM), 61 patients with asymptomatic/smoldering myeloma (SMM), 47 with monoclonal gammopathy of undetermined significance (MGUS) and 87 multiple myeloma (MM) patients at first relapse who received lenalidomide- or bortezomib-based treatment (RD, n=47; or VD, n=40). Patients with NDMM had increased VCAM-1 and ICAM-1 compared with MGUS and SMM patients. Elevated VCAM-1 correlated with ISS-3 and was independently associated with inferior overall survival (OS) (45 months for patients with VCAM-1 >median vs 75 months, P=0.001). MM patients at first relapse had increased levels of ICAM-1 and L-selectin, even compared with NDMM patients and had increased levels of VCAM-1 compared with MGUS and SMM. Both VD and RD reduced dramatically serum VCAM-1 after four cycles of therapy, but only VD reduced serum ICAM-1, irrespective of response to therapy. The reduction of VCAM-1 was more pronounced after RD than after VD. Our study provides evidence for the prognostic value of VCAM-1 in myeloma patients, suggesting that VCAM-1 could be a suitable target for the development of anti-myeloma therapies. Furthermore, the reduction of VCAM-1 and ICAM-1 by RD and VD supports the inhibitory effect of these drugs on the adhesion of MM cells to stromal cells. PMID:27232930

  15. Poor Correlation between Pneumococcal IgG and IgM Titers and Opsonophagocytic Activity in Vaccinated Patients with Multiple Myeloma and Waldenstrom's Macroglobulinemia.

    PubMed

    Karlsson, Johanna; Roalfe, Lucy; Hogevik, Harriet; Zancolli, Marta; Andréasson, Björn; Goldblatt, David; Wennerås, Christine

    2016-04-01

    Patients with multiple myeloma and other B cell disorders respond poorly to pneumococcal vaccination. Vaccine responsiveness is commonly determined by measuring pneumococcal serotype-specific antibodies by enzyme-linked immunosorbent assay (ELISA), by a functional opsonophagocytosis assay (OPA), or by both assays. We compared the two methods in vaccinated elderly patients with multiple myeloma, Waldenstrom's macroglobulinemia, and monoclonal gammopathy of undetermined significance (MGUS). Postvaccination sera from 45 patients (n= 15 from each patient group) and 15 control subjects were analyzed by multiplexed OPA for pneumococcal serotypes 4, 6B, 14, and 23F, and the results were compared to IgG and IgM antibody titers measured by ELISA. While there were significant correlations between pneumococcal OPA and IgG titers for all serotypes among the control subjects (correlation coefficients [r] between 0.51 and 0.85), no significant correlations were seen for any of the investigated serotypes in the myeloma group (r= -0.18 to 0.21) or in the group with Waldenstrom's macroglobulinemia (borderline significant correlations for 2 of 4 serotypes). The MGUS group resembled the control group by having good agreement between the two test methods for 3 of 4 serotypes (r= 0.53 to 0.80). Pneumococcal postvaccination IgM titers were very low in the myeloma patients compared to the other groups and did not correlate with the OPA results. To summarize, our data indicate that ELISA measurements may overestimate antipneumococcal immunity in elderly subjects with B cell malignancies and that a functional antibody test should be used specifically for myeloma and Waldenstrom's macroglobulinemia patients. PMID:26912783

  16. Subclinical Peripheral Neuropathy in Patients With Multiple Myeloma Before Chemotherapy Is Correlated With Decreased Fingertip Innervation Density

    PubMed Central

    Kosturakis, Alyssa K.; He, Zijing; Li, Yan; Boyette-Davis, Jessica A.; Shah, Nina; Thomas, Sheeba K.; Zhang, Haijun; Vichaya, Elisabeth G.; Wang, Xin Shelley; Wendelschafer-Crabb, Gwen; Kennedy, William R.; Simone, Donald A.; Cleeland, Charles S.; Dougherty, Patrick M.

    2014-01-01

    Purpose The goal in this study was to determine the incidence of subclinical neuropathy in treatment-naive patients with multiple myeloma (MM) with no history of peripheral neuropathy using quantitative sensory tests (QSTs) and its correlation with innervation density of the extremities using noninvasive laser reflectance confocal microscopy. Patients and Methods QST results were collected for 27 patients with a diagnosis of MM and compared with data collected from 30 age- and sex-matched healthy volunteers. Skin temperature, sensorimotor function (grooved pegboard test), and detection thresholds for temperature, sharpness, and low-threshold mechanical stimuli (von Frey monofilaments and bumps detection test) were measured. Meissner's corpuscle (MC) density in the fingertips was assessed using in vivo laser reflectance confocal microscopy. Results Patients showed a high incidence (> 80%) of ≥ one subclinical QST deficit. These included increased von Frey, bumps, and warmth detection thresholds as compared with healthy volunteers. Patients also showed increases in cold pain, sensorimotor deficits (grooved pegboard test), and higher overall neuropathy scores. MC density was significantly lower in patients than controls and showed significant inverse correlation with bumps detection threshold. Conclusion Patients with MM commonly present with sensory and sensorimotor deficits before undergoing treatment, and these deficits seem to result from disease-related decreases in peripheral innervation density. PMID:25154818

  17. Novel Combination Treatments in Multiple Myeloma.

    PubMed

    Nooka, Ajay K; Lonial, Sagar

    2016-05-01

    The last decade has witnessed the identification of several novel druggable targets in multiple myeloma, leading to identification of novel therapies with clinically proven efficacy, both in the newly diagnosed and relapsed setting. More importantly, a common theme of good outcomes was observed among prospective randomized studies that have utilized combinations of agents with different mechanisms of action. The correlation between achieving a deeper response and the improvement in progression-free survival and overall survival has never been so clear. In this article, we elucidate the rationale for use of novel drug combinations in patients with myeloma, and review current evidence-based data supporting the use of specific combinations in various settings. We also attempt to craft a framework to guide clinicians in optimizing the use of combination therapies, to enable patients to derive maximal benefit. PMID:27188677

  18. Fucoidan inhibits angiogenesis induced by multiple myeloma cells.

    PubMed

    Liu, Fen; Luo, Guoping; Xiao, Qing; Chen, Liping; Luo, Xiaohua; Lv, Jinglong; Chen, Lixue

    2016-10-01

    Multiple myeloma (MM) remains an incurable hematological neoplasms. Our previous studies showed that Fucoidan possessed anti-myeloma effect by inducing apoptosis and inhibiting invasion of myeloma cells. In this study, we evaluated the effect of Fucoidan on angiogenesis induced by human myeloma cells and elucidated its possible mechanisms. Multiple myeloma cells were treated with Fucoidan at different concentrations, then the conditioned medium (CM) was collected. The levels of VEGF in the CM were tested by ELISA. The results showed that Fucoidan significantly decreased VEGF secretion by RPMI-8226 and U266 cells. The tube formation assay and migration test on human umbilical vein endothelial cells (HUVECs) were used to examine the effect of Fucoidan on angiogenesis induced by human myeloma cells. The results showed that Fucoidan decreased HUVECs formed tube structures and inhibited HUVECs migration, and suppressed the angiogenic ability of multiple myeloma RPMI-8226 and U266 cells in a dose-dependent manner. The study also showed that Fucoidan downregulated the expression of several kinds of proteins, which may be correlated with the reduction of angiogenesis induced by myeloma cells. Moreover, results were compared from normoxic and hypoxic conditions, they showed that Fucoidan had anti-angiogenic activity. Furthermore, in a multiple myeloma xenograft mouse model, it indicated that Fucoidan negatively affected tumor growth and angiogenesis in vivo. In conclusion, our results demonstrate that Fucoidan was able to interfere with angiogenesis of multiple myeloma cells both in vitro and in vivo and may have a substantial potential in the treatment of MM.

  19. Molecular aspects of multiple myeloma.

    PubMed

    Kastrinakis, N G; Gorgoulis, V G; Foukas, P G; Dimopoulos, M A; Kittas, C

    2000-10-01

    Multiple myeloma (MM) is a B-cell neoplasm characterized by bone marrow infiltration with malignant plasma cells, which synthesize and secrete monoclonal immunoglobulin (Ig) fragments. Despite the considerable progress in the understanding of MM biology, the molecular basis of the disease remains elusive. The initial transformation is thought to occur in a postgerminal center B-lineage cell, carrying a somatically hypermutated Ig heavy chain (IGH) gene. This plasmablastic precursor cell colonizes the bone marrow, propagates clonally and differentiates into a slowly proliferating myeloma cell population, all under the influence of specific cell adhesion molecules and cytokines. Production of interleukin-6 by stromal cells, osteoblasts and, in some cases, neoplastic cells is an essential element of myeloma cell growth, with the cytokine stimulus being delivered intracellularly via the Jack-STAT and ras signaling pathways. While karyotypic changes have been identified in up to 50% of MM patients, recent molecular cytogenetic techniques have revealed chromosomal abnormalities in the vast majority of examined cases. Translocations mostly involve illegal switch rearrangements of the IGH locus with various partner genes (CCND1, FGFR3, c-maf). Such events have been assigned a critical role in MM development. Mutations in coding and regulatory regions, as well as aberrant expression patterns of several oncogenes (c-myc, ras) and tumor suppressor genes (p16, p15) have been reported. Key regulators of programmed cell death (BCL-2, Fas), tumor expansion (metalloproteinases) and drug responsiveness (topoisomerase II alpha) have also been implicated in the pathogenesis of this hematologic malignancy. A tumorigenic role for human herpesvirus 8 (HHV8) was postulated recently, following the detection of viral sequences in bone marrow dendritic cells of MM patients. However, since several research groups were unable to confirm this observation, the role of HHV8 remains unclear

  20. [Relativity in multiple myeloma and KL-6].

    PubMed

    Matsuda, Chikashi; Miyake, Takaaki; Araki, Tuyoshi; Ishikawa, Noriyoshi; Taketani, Takeshi; Mishima, Seiji; Shibata, Hiroshi; Nagai, Atsushi

    2012-01-01

    KL-6 is a high-molecular-weight mucinous glycoprotein discovered as a pulmonary adenocaricinoma related antigen. Its levels are used as a biomarker of lung injury in interstitial pneumonia. We here report a case of multiple myeloma with Bence-Jones lambda type whose serum KL-6 level was revealed high at a concentration of 19,400 U/ml. Next, we analyzed the blood test profiles and the concentrations of KL-6 in 20 patients with multiple myeloma. CD19/CD56 double negative fraction on myeloma cells with high expression of CD38 was found in all 5 patients with multiple myeloma having elevated KL-6 level. Patients with interstitial pneumonia show high level of KL-6. We, therefore, need to differentiate the interstitial pneumonia and the above-mentioned multiple myeloma when serum KL-6 level is high.

  1. Clonal Evolution in Multiple Myeloma.

    PubMed

    Fakhri, Bita; Vij, Ravi

    2016-08-01

    Multiple myeloma (MM) is the second most common hematologic malignancy encountered among patients in the United States. The last decade has seen incremental improvements in the survival of patients with MM. These advances are, to a large extent, attributable to the addition of proteasome inhibitors and immunomodulatory drugs to the armamentarium of treatment options. The adoption of these drug classes was the result of an empiric research paradigm. However, with the application of next generation sequencing technologies, we are now starting to unravel the genomic landscape of MM. It is hoped that this will allow us to better disentangle the biology of the disease and allow for identification of new therapeutic targets. In this article, we review what we have learned to date about the mutational profile, clonal architecture, and evolution of the disease, and discuss the potential clinical implications of these findings. PMID:27521309

  2. Diagnostic Advances in Multiple Myeloma.

    PubMed

    Barley, Kevin; Chari, Ajai

    2016-04-01

    There have been several advances in the diagnosis of multiple myeloma (MM) in recent years. Serum free light chains have improved the ability to diagnose light chain MM; however, there are still difficulties in the serologic diagnosis of MM in some cases, particularly IgA MM. A novel heavy/light chain assay is able to improve the accuracy of diagnosis in these cases. Free light chains may also improve the diagnosis of extramedullary disease in difficult cases such as disease involving the central nervous system, pleura, or ascites. Advances in imaging such as whole body low-dose computed tomography (CT) whole body magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT) have improved sensitivity in identifying lytic bone lesions, which would enable earlier treatment, and monitoring of osseous disease particularly in non- or oligosecretory disease. New techniques such as fused PET/MRI may further enhance the diagnosis of both bone lesions and extramedullary disease.

  3. Novel therapy in multiple myeloma.

    PubMed

    Avilés, Agustin; Neri, Natividad; Nambo, M Jesús; Cleto, Sergio; Castañeda, Claudia; González, Martha; Talavera, Alejandra; Huerta-Guzmán, Judith

    2005-10-01

    Treatment in patients with multiple myeloma remain to be defined. Younger patients (defined as a cut-off level < 65 years old) will be treated with chemotherapy and transplant procedures. However, most patients > 65 years old are not candidates for this therapeutic approach and the use of intensive chemotherapy could be associated to severe toxicity. We developed an new, not-cytotoxic regimen with dexamethasone 30 mg/m(2), iv, days 1 to 4, all trans retinoic acid 45 mg/m(2), po, days 5 to 14 and interferon alfa 2a 4.5 MU, sc, daily, days 5 to 14 (DAI regimen) administered every 28 days in number of 6 cycles, at this point patients were restaging, if they showed complete response, objective response or partial response they were conducted to received thalidomide 100-200 mg po, daily and dexamethasone 10 mg/2, po days 1 to 4 at monthly intervals, for 18 months. Forty one patients were enrolled in an Phase II study. In an intent to treat analysis all patients were evaluable. Complete response was observed in 18 cases (43%), objective response in 10 patients (24%) and partial response in 5 patients (12%), overall response rate was 80%. Eight patients were considered failures. At an median of 36 months, no relapse of progression disease has been observed, thus actuarial curves at 3-years showed that event free survival is 100% and overall survival is 91%. Toxicity was mild, all patients received the planned dose in time. This regimen appear to be useful in older patients with multiple myeloma, the response rate is higher and toxicity was mild. Controlled clinical trials comparing with conventional chemotherapy will be conducted to define the role of this therapeutic approach. PMID:16133792

  4. Extramedullary (EMP) relapse in unusual locations in multiple myeloma: Is there an association with precedent thalidomide administration and a correlation of special biological features with treatment and outcome?

    PubMed

    Katodritou, E; Gastari, V; Verrou, E; Hadjiaggelidou, C; Varthaliti, M; Georgiadou, S; Laschos, K; Xirou, P; Yiannaki, E; Constantinou, N; Markala, D; Zervas, K

    2009-08-01

    Extramedullary relapse constitutes an uncommon manifestation of multiple myeloma (MM), characterized by highly malignant histology, special biological features, resistance to treatment and poor outcome. Its incidence has been increased during the last years, probably due to the introduction of novel strategies in the management of MM, including intensified treatment and immunomodulatory drugs. Here we report nine cases of extramedullary relapse of MM, presented in unusual locations, seven of which had previously been treated with thalidomide-containing regimens (TCR). Our aim was to explore the morphological, immunophenotypical, molecular and laboratory characteristics accompanying EMP-relapse and seek possible correlations with treatment and clinical outcome.

  5. The serological diagnostic challenges of multiple myeloma.

    PubMed

    Gu, Yisu; Hunter, Terrence; Offer, Mark

    2015-02-01

    Serological screening tests for multiple myeloma are commonly requested by physicians in both primary and secondary care to investigate patients presenting with anaemia or renal impairment of unknown cause. This article reviews the interpretation of these tests.

  6. Multiple myeloma presenting as gingival hyperplasia.

    PubMed

    Jain, Sanjeev; Kaur, Harjit; Kansal, Gaurav; Gupta, Parul

    2013-05-01

    Multiple myeloma is a malignant neoplasm that is characterized by a monoclonal proliferation of plasma cells. Oral and maxillofacial manifestations as an initial sign or symptom of multiple myeloma are rare. A 58-year-old male patient presented with generalized gingival enlargement for last 6 months. Based on clinical presentation, a diagnosis of gingival hyperplasia was made. After Phase I therapy, excisional biopsy was taken in anterior mandibular region and excised tissue was sent for histopathological examination. The histopathology report revealed a lining of stratified squamous epithelium with foci of ulceration. The subepithelial zone showed infiltration by sheets of mainly binucleate and multinucleate plasma cells, few cells being less differentiated. Rounded cytoplasmic inclusion bodies were identified in many of these cells. After a series of clinical investigations, a case of "multiple myeloma" was diagnosed. Patient presenting with generalized gingival hyperplasia should be worked up for systemic disease like multiple myeloma.

  7. Multiple Myeloma Gets Three New Drugs.

    PubMed

    Poh, Alissa

    2016-01-01

    In the last few weeks, the FDA approved three new therapies for multiple myeloma: ixazomib, the first oral proteasome inhibitor; and daratumumab and elotuzumab, two monoclonal antibodies that target CD38 and SLAMF7, respectively.

  8. NCI collaborates with Multiple Myeloma Research Foundation

    Cancer.gov

    The National Cancer Institute (NCI) announced a collaboration with the Multiple Myeloma Research Foundation (MMRF) to incorporate MMRF's wealth of genomic and clinical data on the disease into the NCI Genomic Data Commons (GDC), a publicly available datab

  9. Smoldering multiple myeloma: present position and potential promises.

    PubMed

    Tageja, Nishant; Manasanch, Elisabet E; Korde, Neha; Kwok, Mary; Mailankody, Sham; Bhutani, Manisha; Roschewski, Mark; Landgren, Ola

    2014-01-01

    Since smoldering multiple myeloma (SMM) was first described over three decades ago based on a case series of six patients, its definition and our understanding of the entity have evolved considerably. The risk of progression to symptomatic myeloma (MM) varies greatly among individuals diagnosed with myeloma precursor disease. Epidemiologic, molecular, flow cytometric and radiological techniques have demonstrated that this transformation to MM from precursor states is not sudden but rather a continuous overlapping series of events with evidence of end-organ damage that could manifest in the earliest stages of disease. Contemporary antimyeloma therapies can yield rapid, deep, and durable responses with manageable toxicities, and molecular-cell-based measures are now available to rule out minimal residual disease. With this information, clinical studies with correlative measures can now be developed to test the fundamental hypothesis that intervention in early myeloma may provide a measurable clinical benefit to patients by either delaying progression or eradicating plasma cell clones. PMID:24112232

  10. Multiple Myeloma and Kidney Disease

    PubMed Central

    Noiri, Eisei

    2013-01-01

    Multiple myeloma (MM) has a high incidence rate in the elderly. Responsiveness to treatments differs considerably among patients because of high heterogeneity of MM. Chronic kidney disease (CKD) is a common clinical feature in MM patients, and treatment-related mortality and morbidity are higher in MM patients with CKD than in patients with normal renal function. Recent advances in diagnostic tests, chemotherapy agents, and dialysis techniques are providing clinicians with novel approaches for the management of MM patients with CKD. Once reversible factors, such as hypercalcemia, have been corrected, the most common cause of severe acute kidney injury (AKI) in MM patients is tubulointerstitial nephropathy, which results from very high circulating concentrations of monoclonal immunoglobulin free light chains (FLC). In the setting of AKI, an early reduction of serum FLC concentration is related to kidney function recovery. The combination of extended high cutoff hemodialysis and chemotherapy results in sustained reductions in serum FLC concentration in the majority of patients and a high rate of independence from dialysis. PMID:24288486

  11. Molecular pathogenesis of multiple myeloma.

    PubMed

    Furukawa, Yusuke; Kikuchi, Jiro

    2015-06-01

    Multiple myeloma (MM), one of the most intractable malignancies, is characterized by the infiltration and growth of plasma cells, the most differentiated cells in the B-cell lineage, in the bone marrow. Despite the introduction of novel therapeutic agents, including proteasome inhibitors and immunomodulatory drugs, the prognosis of patients with MM is still worse than that of most hematological malignancies. A better understanding of the molecular pathogenesis of the disease is essential to achieve any improvement of treatment outcome of MM patients. All MM cases pass through the phase of asymptomatic expansion of clonal plasma cells, referred to as monoclonal gammopathy of undetermined significance (MGUS). It has long been believed that MM evolves linearly from MGUS to terminal phases, such as extramedullary tumors and plasma cell leukemia via the accumulation of novel mutations. However, recent studies using next-generation sequencing have disclosed the complex genomic architecture of the disease. At each step of progression, the acquisition of novel mutations is accompanied by subclonal evolution from reservoir clones with branching patterns. Each subclone may carry novel mutations and distinct phenotypes, including drug sensitivity. In addition, minor clones already exist at the MGUS stage, which could expand later in the clinical course, resulting in relapse and/or leukemic conversion. The ultimate goal of treatment is to eradicate all clones, including subclonal populations with distinct biological characteristics. This goal could be achieved by further improving treatment strategies that reflect the genomic landscape of the disease.

  12. Emerging therapies for multiple myeloma

    PubMed Central

    Podar, Klaus; Tai, Yu-Tzu; Hideshima, Teru; Vallet, Sonia; Richardson, Paul G; Anderson, Kenneth C

    2011-01-01

    Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 – 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents – small molecules as well as therapeutic antibodies – that hold promise to further improve outcome in MM. PMID:19249983

  13. The Genetic Architecture of Multiple Myeloma

    PubMed Central

    Prideaux, Steven M.; Conway O'Brien, Emma; Chevassut, Timothy J.

    2014-01-01

    Multiple myeloma is a malignant proliferation of monoclonal plasma cells leading to clinical features that include hypercalcaemia, renal dysfunction, anaemia, and bone disease (frequently referred to by the acronym CRAB) which represent evidence of end organ failure. Recent evidence has revealed myeloma to be a highly heterogeneous disease composed of multiple molecularly-defined subtypes each with varying clinicopathological features and disease outcomes. The major division within myeloma is between hyperdiploid and nonhyperdiploid subtypes. In this division, hyperdiploid myeloma is characterised by trisomies of certain odd numbered chromosomes, namely, 3, 5, 7, 9, 11, 15, 19, and 21 whereas nonhyperdiploid myeloma is characterised by translocations of the immunoglobulin heavy chain alleles at chromosome 14q32 with various partner chromosomes, the most important of which being 4, 6, 11, 16, and 20. Hyperdiploid and nonhyperdiploid changes appear to represent early or even initiating mutagenic events that are subsequently followed by secondary aberrations including copy number abnormalities, additional translocations, mutations, and epigenetic modifications which lead to plasma cell immortalisation and disease progression. The following review provides a comprehensive coverage of the genetic and epigenetic events contributing to the initiation and progression of multiple myeloma and where possible these abnormalities have been linked to disease prognosis. PMID:24803933

  14. Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma

    PubMed Central

    Calcinotto, Arianna; Ponzoni, Maurilio; Ria, Roberto; Grioni, Matteo; Cattaneo, Elena; Villa, Isabella; Sabrina Bertilaccio, Maria Teresa; Chesi, Marta; Rubinacci, Alessandro; Tonon, Giovanni; Bergsagel, P Leif; Vacca, Angelo; Bellone, Matteo

    2015-01-01

    While multiple myeloma (MM) is almost invariably preceded by asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM), the alterations of the bone marrow (BM) microenvironment that establish progression to symptomatic disease are circumstantial. Here we show that in Vk*MYC mice harboring oncogene-driven plasma cell proliferative disorder, disease appearance associated with substantial modifications of the BM microenvironment, including a progressive accumulation of both CD8+ and CD4+ T cells with a dominant T helper type 1 (Th1) response. Progression from asymptomatic to symptomatic MM was characterized by further BM accrual of T cells with reduced Th1 and persistently increased Th2 cytokine production, which associated with accumulation of CD206+Tie2+ macrophages, and increased pro-angiogenic cytokines and microvessel density (MVD). Notably, MVD was also increased at diagnosis in the BM of MGUS and SMM patients that subsequently progressed to MM when compared with MGUS and SMM that remained quiescent. These findings suggest a multistep pathogenic process in MM, in which the immune system may contribute to angiogenesis and disease progression. They also suggest initiating a large multicenter study to investigate MVD in asymptomatic patients as prognostic factor for the progression and outcome of this disease. PMID:26155424

  15. Multiple myeloma cancer stem cells

    PubMed Central

    Gao, Minjie; Kong, Yuanyuan; Yang, Guang; Gao, Lu; Shi, Jumei

    2016-01-01

    Multiple myeloma (MM) remains incurable despite much progress that has been made in the treatment of the disease. MM cancer stem cell (MMSC), a rare subpopulation of MM cells with the capacity for self-renewal and drug resistance, is considered to lead to disease relapse. Several markers such as side population (SP) and ALDH1+ have been used to identify MMSCs. However, ideally and more precisely, the identification of the MMSCs should rely on MMSCs phenotype. Unfortunately the MMSC phenotype has not been properly defined yet. Drug resistance is the most important property of MMSCs and contributes to disease relapse, but the mechanisms of drug resistance have not been fully understood. The major signaling pathways involved in the regulation of self-renewal and differentiation of MMSCs include Hedgehog (Hh), Wingless (Wnt), Notch and PI3K/Akt/mTOR. However, the precise role of these signaling pathways needs to be clarified. It has been reported that the microRNA profile of MMSCs is remarkably different than that of non-MMSCs. Therefore, the search for targeting MMSCs has also been focused on microRNAs. Complex and mutual interactions between the MMSC and the surrounding bone marrow (BM) microenvironment sustain self-renewal and survival of MMSC. However, the required molecules for the interaction of the MMSC and the surrounding BM microenvironment need to be further identified. In this review, we summarize the current state of knowledge of MMSCs regarding their phenotype, mechanisms of drug resistance, signaling pathways that regulate MMSCs self-renewal and differentiation, abnormal microRNAs expression, and their interactions with the BM microenvironment. PMID:27007154

  16. Drugs Approved for Multiple Myeloma and Other Plasma Cell Neoplasms

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Multiple Myeloma and Other Plasma Cell ... plasma cell neoplasms that are not listed here. Drugs Approved for Multiple Myeloma and Other Plasma Cell ...

  17. What's New in Multiple Myeloma Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for multiple myeloma What’s new in multiple myeloma research and treatment? Important research ... the disease and how to improve treatment. Many new drugs are being tested. Researchers have found that ...

  18. Multiple myeloma: diagnosis and orthopaedic implications.

    PubMed

    Scharschmidt, Thomas J; Lindsey, Joshua D; Becker, Pamela S; Conrad, Ernest U

    2011-07-01

    Multiple myeloma is a hematologic malignancy that commonly affects the skeletal system. The disease is primarily managed medically with chemotherapeutic agents. Pathologic fractures are common in patients with diagnosed and undiagnosed disease. The number of patients diagnosed with multiple myeloma is increasing, as is the incidence of associated pathologic fractures. Novel chemotherapeutic agents and radiation therapy protocols have been used to extend the average life span of patients with this disease. Various methods that allow for restoration of function and pain reduction can be used to stabilize and manage fractures associated with multiple myeloma. The orthopaedic surgeon and oncology team must work together to develop an individualized treatment plan to improve patient quality of life and provide pain relief.

  19. Recent advances in understanding multiple myeloma

    PubMed Central

    Dhakal, Binod; Girnius, Saulius; Hari, Parameswaran

    2016-01-01

    There have been major recent advancements in the understanding and management of multiple myeloma. Diagnostic criteria have been revised and former ultra-high-risk smoldering multiple myeloma is now considered multiple myeloma in need of treatment. Understanding clonal progression, evolution, and tides not only has helped elucidate the disease behavior but might help expand therapeutic choices in order to select appropriate treatment for patients. Unprecedented response rates with modern triplet induction therapies containing proteasome inhibitor and immunomodulators have made this approach standard for initial treatment. The US Food and Drug Administration approved four new drugs (two targeted antibodies and two oral agents) in 2015 in relapsed/refractory multiple myeloma and these drugs along with the other already-available drugs have now increased the choices of regimens. Even drugs without single-agent activity, such as panobinostat and elotuzumab, have an important role, especially in the proteasome inhibitor refractory setting. Recent studies done in the context of novel agent induction suggest that high-dose therapy followed by autologous transplant continues to improve response rates and progression-free survival, thus underscoring their role in transplant-eligible patients. Evolving paradigms in the treatment of multiple myeloma include newer promising immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations. Though multiple myeloma is still considered incurable, it is clear that with the improved understanding of disease biology and clonal architecture of relapse combined with the availability of multi-targeted approaches, we are ever closer to a lasting cure or transformation into indolent and long-lasting disease courses or both. PMID:27610224

  20. Recent advances in understanding multiple myeloma

    PubMed Central

    Dhakal, Binod; Girnius, Saulius; Hari, Parameswaran

    2016-01-01

    There have been major recent advancements in the understanding and management of multiple myeloma. Diagnostic criteria have been revised and former ultra-high-risk smoldering multiple myeloma is now considered multiple myeloma in need of treatment. Understanding clonal progression, evolution, and tides not only has helped elucidate the disease behavior but might help expand therapeutic choices in order to select appropriate treatment for patients. Unprecedented response rates with modern triplet induction therapies containing proteasome inhibitor and immunomodulators have made this approach standard for initial treatment. The US Food and Drug Administration approved four new drugs (two targeted antibodies and two oral agents) in 2015 in relapsed/refractory multiple myeloma and these drugs along with the other already-available drugs have now increased the choices of regimens. Even drugs without single-agent activity, such as panobinostat and elotuzumab, have an important role, especially in the proteasome inhibitor refractory setting. Recent studies done in the context of novel agent induction suggest that high-dose therapy followed by autologous transplant continues to improve response rates and progression-free survival, thus underscoring their role in transplant-eligible patients. Evolving paradigms in the treatment of multiple myeloma include newer promising immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations. Though multiple myeloma is still considered incurable, it is clear that with the improved understanding of disease biology and clonal architecture of relapse combined with the availability of multi-targeted approaches, we are ever closer to a lasting cure or transformation into indolent and long-lasting disease courses or both.

  1. Recent advances in understanding multiple myeloma.

    PubMed

    Dhakal, Binod; Girnius, Saulius; Hari, Parameswaran

    2016-01-01

    There have been major recent advancements in the understanding and management of multiple myeloma. Diagnostic criteria have been revised and former ultra-high-risk smoldering multiple myeloma is now considered multiple myeloma in need of treatment. Understanding clonal progression, evolution, and tides not only has helped elucidate the disease behavior but might help expand therapeutic choices in order to select appropriate treatment for patients. Unprecedented response rates with modern triplet induction therapies containing proteasome inhibitor and immunomodulators have made this approach standard for initial treatment. The US Food and Drug Administration approved four new drugs (two targeted antibodies and two oral agents) in 2015 in relapsed/refractory multiple myeloma and these drugs along with the other already-available drugs have now increased the choices of regimens. Even drugs without single-agent activity, such as panobinostat and elotuzumab, have an important role, especially in the proteasome inhibitor refractory setting. Recent studies done in the context of novel agent induction suggest that high-dose therapy followed by autologous transplant continues to improve response rates and progression-free survival, thus underscoring their role in transplant-eligible patients. Evolving paradigms in the treatment of multiple myeloma include newer promising immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations. Though multiple myeloma is still considered incurable, it is clear that with the improved understanding of disease biology and clonal architecture of relapse combined with the availability of multi-targeted approaches, we are ever closer to a lasting cure or transformation into indolent and long-lasting disease courses or both. PMID:27610224

  2. Insulin Autoimmune Syndrome Accompanied by Multiple Myeloma.

    PubMed

    Ito, Harumi; Miyake, Takafumi; Nakashima, Kazuo; Ito, Yuji; Tanahashi, Chisato; Uchigata, Yasuko

    2016-01-01

    In 1981, a 48-year old man was diagnosed with insulin autoimmune syndrome. In 2005, he experienced a substantial increase in his monoclonal insulin antibody levels; in 2006 and 2007, serum monoclonal gammopathy and an 11% marrow plasmacyte ratio were confirmed. In 2012, asymptomatic multiple myeloma was diagnosed based on an increased γ-globulin fraction and serum M-protein (IgG) levels. The insulin antibody binding rate was 75.4% in 2005 and 78.8% in 2012. In 2012, he was hospitalized for ileus and died. Autopsy identified multiple myeloma and no endocrinological tumors in the pancreas. PMID:27522998

  3. [The pathology of smoldering multiple myeloma].

    PubMed

    Shibayama, Hirohiko

    2015-01-01

    The precursor states (named as monoclonal gammopathy of undetermined significance [MGUS] and smoldering multiple myeloma [SMM]) consistently exist before symptomatic multiple myeloma is diagnosed. After approximately 30 years have passed since Kyle et al. advocated MGUS and SMM for the first time, the pathology and prognosis of these diseases have been clarified considerably. Recently, the safety and efficacy of the early treatment for the patients with high risk SMM are shown. In this article, the current understanding of the pathology of SMM as well as MGUS including the diagnosis, prognosis and treatment is reviewed. PMID:25626300

  4. Orbital Metastasis of Multiple Myeloma: Case Report

    PubMed Central

    Vatansever, Mustafa; Bozkurt, Fatma Merve; Dinç, Erdem; Yılmaz, Eda Bengi; Nayir, Erdinç; Sarı, Ayşe Ayça; Yıldırım, Özlem; Kara, Tuba

    2016-01-01

    A 68-year-old woman with a history of multiple myeloma presented to the clinic with pain and vision loss in her right eye. Proptosis was observed in her right eye and eye movements were restricted in all directions. Best corrected visual acuity was 3/10 in her right eye. On biomicroscopic examination, hyperemia and subconjunctival hemorrhage were present. Fundus examination of the right eye revealed optic disc edema and choroidal folds. In magnetic resonance imaging two orbital masses were detected. Based on the patient’s history and ocular examination, we evaluated the masses as orbital metastasis of multiple myeloma. Palliative radiotherapy was recommended. PMID:27800278

  5. Single cell functional analysis of multiple myeloma cell populations correlates with diffusion profiles in static microfluidic coculture systems.

    PubMed

    Moore, Thomas A; Young, Edmond W K

    2016-07-01

    Microfluidic cell culture systems are becoming increasingly useful for studying biology questions, particularly those involving small cell populations that are cultured within microscale geometries mimicking the complex cellular microenvironment. Depending on the geometry and spatial organization of these cell populations, however, paracrine signaling between cell types can depend critically on spatial concentration profiles of soluble factors generated by diffusive transport. In scenarios where single cell data are acquired to study cell population heterogeneities in functional response, uncertainty associated with concentration profiles can lead to interpretation bias. To address this issue and provide important evidence on how diffusion develops within typical microfluidic cell culture systems, a combination of experimental and computational approaches were applied to measure and predict concentration patterns within microfluidic geometries, and characterize the functional response of culture cells based on single-cell resolution transcription factor activation. Using a model coculture system consisting of multiple myeloma cells (MMCs) and neighboring bone marrow stromal cells (BMSCs), we measured concentrations of three cytokines (IL-6, VEGF, and TNF-α) in conditioned media collected from separate culture compartments using a multiplex ELISA system. A 3D numerical model was developed to predict biomolecular diffusion and resulting concentration profiles within the tested microsystems and compared with experimental diffusion of 20 kDa FITC-Dextran. Finally, diffusion was further characterized by controlling exogenous IL-6 diffusion and the coculture spatial configuration of BMSCs to stimulate STAT3 nuclear translocation in MMCs. Results showed agreement between numerical and experimental results, provided evidence of a shallow concentration gradient across the center well of the microsystem that did not lead to a bias in results, and demonstrated that

  6. Single cell functional analysis of multiple myeloma cell populations correlates with diffusion profiles in static microfluidic coculture systems.

    PubMed

    Moore, Thomas A; Young, Edmond W K

    2016-07-01

    Microfluidic cell culture systems are becoming increasingly useful for studying biology questions, particularly those involving small cell populations that are cultured within microscale geometries mimicking the complex cellular microenvironment. Depending on the geometry and spatial organization of these cell populations, however, paracrine signaling between cell types can depend critically on spatial concentration profiles of soluble factors generated by diffusive transport. In scenarios where single cell data are acquired to study cell population heterogeneities in functional response, uncertainty associated with concentration profiles can lead to interpretation bias. To address this issue and provide important evidence on how diffusion develops within typical microfluidic cell culture systems, a combination of experimental and computational approaches were applied to measure and predict concentration patterns within microfluidic geometries, and characterize the functional response of culture cells based on single-cell resolution transcription factor activation. Using a model coculture system consisting of multiple myeloma cells (MMCs) and neighboring bone marrow stromal cells (BMSCs), we measured concentrations of three cytokines (IL-6, VEGF, and TNF-α) in conditioned media collected from separate culture compartments using a multiplex ELISA system. A 3D numerical model was developed to predict biomolecular diffusion and resulting concentration profiles within the tested microsystems and compared with experimental diffusion of 20 kDa FITC-Dextran. Finally, diffusion was further characterized by controlling exogenous IL-6 diffusion and the coculture spatial configuration of BMSCs to stimulate STAT3 nuclear translocation in MMCs. Results showed agreement between numerical and experimental results, provided evidence of a shallow concentration gradient across the center well of the microsystem that did not lead to a bias in results, and demonstrated that

  7. Lung Involvement in Multiple Myeloma - Case Study

    PubMed Central

    NIŢU, MIMI; CRIȘAN, EMILIA; OLTEANU, M.; CĂLĂRAŞU, CRISTINA; OLTEANU, MĂDĂLINA; POPESCU, M.R.

    2014-01-01

    Introduction: Mutiple mieloma (MM) cells are rarely found in extramedullary sites. The sites of extramedullary dissemination reported in the literature are spleen, liver, lymph nodes, kidneys, thyroid gland, adrenal gland, ovary, tests, lung, pleura, pericardium, intestinal tract and skin. We report a case in which the myeloma was diagnosed after we discovered the presence of monoclonal plasma cells in the bronchoalveolar lavage fluid (BAL). Matherial and method: a case in which diagnosis was established from bronchoalveolar lavage (BAL) fluid demonstrating the presence of monoclonal plasma cells in Craiova Pneumology Departament. Results: Analysis of BAL fluid for the presence of plasma cells and for cytoplasmic immunoglobulin DNA provides a noninvasive means of establishing the diagnosis. Conclusions: Pulmonary parenchyma is an uncommon site of extramedullary involvement in multiple myeloma. Interstitial lung disease as pulmonary manifestation of multiple myeloma is even rarer; only isolated cases with histological proofs have been reported in the literature. PMID:26788357

  8. The expression of osteopontin and vascular endothelial growth factor in correlation with angiogenesis in monoclonal gammopathy of undetermined significance and multiple myeloma.

    PubMed

    Babarović, Emina; Valković, Toni; Budisavljević, Ivana; Balen, Ivan; Štifter, Sanja; Duletić-Načinović, Antica; Lučin, Ksenija; Jonjić, Nives

    2016-06-01

    Several studies have shown a gradual increase in the extent of bone marrow angiogenesis in various stages of proliferative plasma cell disorders, from monoclonal gammopathy of undetermined significance (MGUS) to active multiple myeloma (MM). The main aim of this study was to evaluate tumor angiogenesis parameters in detail and to correlate them with the expression of osteopontin (OPN) and vascular endothelial growth factor (VEGF) in the bone marrow of patients with MGUS and MM. In addition, we wanted to determine their prognostic significance in active MM. Ninety-five patients were enrolled in the study: 14 diagnosed with MGUS, 13 with asymptomatic myeloma (AMM) and 68 with active MM. Computer assisted image analysis was used to determine the angiogenesis parameters, the quantity of microvessels per 1mm(2) (MVD), the area occupied by microvessels per 1mm(2) and the percentage of microvessel area in total section area (TVA). Double immunohistochemical methods CD138+VEGF and CD138+OPN were used to evaluate expression of these proteins in plasma cells, and OPN was also analyzed for its interstitial expression (iOPN). A significant positive correlation was determined between VEGF and iOPN with angiogenic parameters in the MGUS stage of the disease. In advanced stages of the disease, a significant negative correlation was recorded between OPN and iOPN with parameters of angiogenesis. Overall survival was significantly shorter for patients with negative iOPN (p=0.002) and higher angiogenic parameters, MVD (p=0.009), TVA (p=0.008) and area of microvessels per 1mm(2) (p=0.02). Positive VEGF expression in our model predicted a better three-year survival of patients with active MM (OR: 5.25, p=0.03; HR: 0.44, p=0.04). The results of our study suggested a possible key role of VEGF and OPN in the induction of angiogenesis in early-stage disease. PMID:26997492

  9. Multiple Myeloma, Version 2.2016

    PubMed Central

    Anderson, Kenneth C.; Alsina, Melissa; Atanackovic, Djordje; Biermann, J. Sybil; Chandler, Jason C.; Costello, Caitlin; Djulbegovic, Benjamin; Fung, Henry C.; Gasparetto, Cristina; Godby, Kelly; Hofmeister, Craig; Holmberg, Leona; Holstein, Sarah; Huff, Carol Ann; Kassim, Adetola; Krishnan, Amrita Y.; Kumar, Shaji K.; Liedtke, Michaela; Lunning, Matthew; Raje, Noopur; Singhal, Seema; Smith, Clayton; Somlo, George; Stockerl-Goldstein, Keith; Treon, Steven P.; Weber, Donna; Yahalom, Joachim; Shead, Dorothy A.; Kumar, Rashmi

    2016-01-01

    Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM. PMID:26553768

  10. How I treat smoldering multiple myeloma

    PubMed Central

    Landgren, Ola

    2014-01-01

    Smoldering myeloma is a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as “early myeloma.” It is defined as either serum M-protein ≥3 g/L or ≥10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity. PMID:25298034

  11. The Role of Immunotherapy in Multiple Myeloma

    PubMed Central

    Kocoglu, Mehmet; Badros, Ashraf

    2016-01-01

    Multiple myeloma is the second most common hematologic malignancy. The treatment of this disease has changed considerably over the last two decades with the introduction to the clinical practice of novel agents such as proteasome inhibitors and immunomodulatory drugs. Basic research efforts towards better understanding of normal and missing immune surveillence in myeloma have led to development of new strategies and therapies that require the engagement of the immune system. Many of these treatments are under clinical development and have already started providing encouraging results. We, for the second time in the last two decades, are about to witness another shift of the paradigm in the management of this ailment. This review will summarize the major approaches in myeloma immunotherapies. PMID:26784207

  12. Implications of Heterogeneity in Multiple Myeloma

    PubMed Central

    de Mel, Sanjay; Lim, Su Hong; Tung, Moon Ley; Chng, Wee-Joo

    2014-01-01

    Multiple myeloma is the second most common hematologic malignancy in the world. Despite improvement in outcome, the disease is still incurable for most patients. However, not all myeloma are the same. With the same treatment, some patients can have very long survival whereas others can have very short survival. This suggests that there is underlying heterogeneity in myeloma. Studies over the years have revealed multiple layers of heterogeneity. First, clinical parameters such as age and tumor burden could significantly affect outcome. At the genetic level, there are also significant heterogeneity ranging for chromosome numbers, genetic translocations, and genetic mutations. At the clonal level, there appears to be significant clonal heterogeneity with multiple clones coexisting in the same patient. At the cell differentiation level, there appears to be a hierarchy of clonally related cells that have different clonogenic potential and sensitivity to therapies. These levels of complexities present challenges in terms of treatment and prognostication as well as monitoring of treatment. However, if we can clearly delineate and dissect this heterogeneity, we may also be presented with unique opportunities for precision and personalized treatment of myeloma. Some proof of concepts of such approaches has been demonstrated. PMID:25101266

  13. Bone marrow biopsy in monoclonal gammopathies: correlations between pathological findings and clinical data. The Cooperative Group for Study and Treatment of Multiple Myeloma.

    PubMed Central

    Riccardi, A; Ucci, G; Luoni, R; Castello, A; Coci, A; Magrini, U; Ascari, E

    1990-01-01

    Between January 1987 and October 1989, 561 consecutive untreated patients with monoclonal gammopathy of undetermined clinical importance (MGUS) (n = 295) or with multiple myeloma (n = 266) were evaluated in a multicentre trial. Both bone marrow biopsy and aspiration (performed at different anatomical sites) were required at presentation. Bone marrow biopsy data indicated that changes in bone marrow composition from MGUS to early multiple myeloma and to advanced multiple myeloma followed a precise pattern, including an increased percentage of bone marrow plasma cells (BMPC%), a shift from plasmocytic to plasmoblastic cytology, an increase in bone marrow cellularity and fibrosis, a change in bone marrow infiltration (becoming diffuse rather than interstitial), a decrease in residual haemopoiesis and an increase in osteoclasts. In multiple myeloma the BMPC% of biopsy specimens and aspirate were closely related, although in 5% of cases the difference between the two values was greater than 20%. Some histological features were remarkably associated with each other. For example, BMPC% was higher in cases with plasmoblastic cytology, heavy fibrosis, or reduced residual haemopoiesis. Anaemia was the clinical characteristic most influenced by bone marrow histology. The BMPC% was the only histological variable which affected the greatest number of clinical and laboratory characteristics, including, besides haemoglobin concentration, erythrocyte sedimentation rate, radiographic skeletal bone disease, and serum concentrations of monoclonal component, calcium, beta 2-microglobulin and thymidine kinase activity. These data indicate that comparative bone marrow histology in monoclonal gammopathies has clinical importance. Images PMID:2199532

  14. Multiple myeloma: managing a complex blood cancer.

    PubMed

    Dowling, Maura; Kelly, Mary; Meenaghan, Teresa

    2016-09-01

    This article gives a comprehensive overview of multiple myeloma (MM), a complex blood cancer involving overproduction of plasma cells. Although MM remains incurable, patients are living longer as a result of multiple treatment options. However, MM patients are also living with a higher symptom burden. The overall aims in managing MM are therefore to control disease progression, prolong survival and improve quality of life. PMID:27615537

  15. Aberrant glycosylation of Igg heavy chain in multiple myeloma.

    PubMed

    Aurer, Igor; Lauc, Gordan; Dumić, Jerka; Rendić, Dubravko; Matisić, Danica; Milos, Marija; Heffer-Lauc, Marija; Flogel, Mirna; Labar, Boris

    2007-03-01

    Although the majority of eukaryotic proteins are glycosylated, there is a dearth of knowledge regarding protein sugar moieties and their changes in disease. Most multiple myeloma cases are characterized by production of monoclonal immunoglobulins (Ig). We studied galactosylation and sialylation of IgG heavy chains in 16 patients with IgG myeloma using lectin blotting and densitometry. In comparison to age and sex matched controls, galactosylation was reduced in multiple myeloma (median 317 vs. 362, range 153-410 vs. 309-447 relative units, p = 0.015, Student's t-test). Sialylation was stage dependent; samples from patients with stage IIA had lowest amounts of sialic acid, IIIA intermediate and IIIB highest (142.6 vs. 185.9 vs. 248.5 relative units, correlation coefficient r = 0.55). Both galactosylation and sialylation levels were independent of age, sex, treatment type, response to treatment, disease duration and IgG and b2 microglobulin concentration. These data indicate that multiple myeloma is characterized by aberrant immunoglobulin glycosylation. PMID:17598409

  16. Aberrant glycosylation of Igg heavy chain in multiple myeloma.

    PubMed

    Aurer, Igor; Lauc, Gordan; Dumić, Jerka; Rendić, Dubravko; Matisić, Danica; Milos, Marija; Heffer-Lauc, Marija; Flogel, Mirna; Labar, Boris

    2007-03-01

    Although the majority of eukaryotic proteins are glycosylated, there is a dearth of knowledge regarding protein sugar moieties and their changes in disease. Most multiple myeloma cases are characterized by production of monoclonal immunoglobulins (Ig). We studied galactosylation and sialylation of IgG heavy chains in 16 patients with IgG myeloma using lectin blotting and densitometry. In comparison to age and sex matched controls, galactosylation was reduced in multiple myeloma (median 317 vs. 362, range 153-410 vs. 309-447 relative units, p = 0.015, Student's t-test). Sialylation was stage dependent; samples from patients with stage IIA had lowest amounts of sialic acid, IIIA intermediate and IIIB highest (142.6 vs. 185.9 vs. 248.5 relative units, correlation coefficient r = 0.55). Both galactosylation and sialylation levels were independent of age, sex, treatment type, response to treatment, disease duration and IgG and b2 microglobulin concentration. These data indicate that multiple myeloma is characterized by aberrant immunoglobulin glycosylation.

  17. Immunoregulatory T Cell Function in Multiple Myeloma

    PubMed Central

    Ozer, H.; Han, T.; Henderson, E. S.; Nussbaum, A.; Sheedy, D.

    1981-01-01

    Multiple myeloma is a malignancy characterized by uncontrolled monoclonal B cell differentiation and immunoglobulin production. In most instances, there is concomitant reduction in polyclonal differentiation and immunoglobulin synthesis both in vivo and in vitro. In in vitro pokeweed mitogen-induced B cell differentiation assays, proliferation and polyclonal immunoglobulin secretion optimally requires T cell help and can be inhibited both by monocytes and suppressor T cells. Helper function and monocyte-mediated suppression are relatively radio-resistant whereas T suppressor function is sensitive to 2,000 rad x-irradiation. We have examined myeloma T cell subset function in this assay using recombinations of isolated patient and normal B cells, T cells, and T cell subsets. Monocytes were removed by a carbonyl iron ingestion technique, normal and myeloma T cells were fractionated on the basis of Fc receptors for immunoglobulin (Ig) G (Tγ) or IgM (Tμ or T non-γ), and proliferation and IgG secretion after co-culture determined by [3H]thymidine incorporation and radio-immunoassay, respectively. Myeloma B cells demonstrate quantitatively and qualitatively normal blastogenic responses and are appropriately regulated by either autologous or allogeneic T helper and suppressor subsets. Despite normal proliferation, however, myeloma B cells remain deficient in subsequent differentiation and immunoglobulin secretion even when co-cultured in the absence of monocytes or suppressor T cells and the presence of normal helper cells. Myeloma T cell populations, in contrast, are entirely normal in helper capacity over a range of T:B ratios but are markedly deficient in radiosensitive and concanavalin A-induced suppressor activity. T suppressor cell dysfunction in multiple myeloma is apparently due to a deficit in the T non-γ suppressor subset, whereas Tγ cells, although proportionately reduced, are functionally normal. This unique T suppressor deficit reflects the heterogeneity

  18. Noninvasive imaging of multiple myeloma using near infrared fluorescent molecular probe

    NASA Astrophysics Data System (ADS)

    Hathi, Deep; Zhou, Haiying; Bollerman-Nowlis, Alex; Shokeen, Monica; Akers, Walter J.

    2016-03-01

    Multiple myeloma is a plasma cell malignancy characterized by monoclonal gammopathy and osteolytic bone lesions. Multiple myeloma is most commonly diagnosed in late disease stages, presenting with pathologic fracture. Early diagnosis and monitoring of disease status may improve quality of life and long-term survival for multiple myeloma patients from what is now a devastating and fatal disease. We have developed a near-infrared targeted fluorescent molecular probe with high affinity to the α4β1 integrin receptor (VLA-4)overexpressed by a majority of multiple myeloma cells as a non-radioactive analog to PET/CT tracer currently being developed for human diagnostics. A near-infrared dye that emits about 700 nm was conjugated to a high affinity peptidomimmetic. Binding affinity and specificity for multiple myeloma cells was investigated in vitro by tissue staining and flow cytometry. After demonstration of sensitivity and specificity, preclinical optical imaging studies were performed to evaluate tumor specificity in murine subcutaneous and metastatic multiple myeloma models. The VLA-4-targeted molecular probe showed high affinity for subcutaneous MM tumor xenografts. Importantly, tumor cells specific accumulation in the bone marrow of metastatic multiple myeloma correlated with GFP signal from transfected cells. Ex vivo flow cytometry of tumor tissue and bone marrow further corroborated in vivo imaging data, demonstrating the specificity of the novel agent and potential for quantitative imaging of multiple myeloma burden in these models.

  19. Bone marrow mast cell density correlates with serum levels of VEGF and CXC chemokines ENA-78 and GRO-α in multiple myeloma.

    PubMed

    Pappa, C A; Tsirakis, G; Devetzoglou, M; Zafeiri, M; Vyzoukaki, R; Androvitsanea, A; Xekalou, A; Sfiridaki, K; Alexandrakis, M G

    2014-06-01

    Angiogenesis is a crucial process in growth and progression of multiple myeloma (MM). Mast cells (MCs) play an important role in MM angiogenesis. Various angiogenic mediators secreted by MCs regulate endothelial cell proliferation and function. Among them, ELR(+) CXC chemokines, such as growth-related oncogen-alpha (GRO-α) and epithelial neutrophil activating protein-78 (ENA-78), have been described as potential mediators in regulation of angiogenesis. The purpose of the study was to quantify MCs in bone marrow (BM) biopsies of MM patients, expressed as MC density (MCD), and correlate it with serum concentrations of vascular endothelial factor (VEGF), GRO-α, ENA-78. Fifty-four newly diagnosed MM patients and 22 healthy controls were studied. Tryptase was used for the immunohistochemical stain of MCs. VEGF, GRO-α, and ENA-78 were measured in sera by ELISA. MCD and serum levels of GRO-α, ENA-78, and VEGF were significantly higher in MM patients compared to controls (p<0.001 in all cases). MCD was significantly increasing with increased stage of the disease (p<0.001). Furthermore, significant correlations were found between MCD with VEGF, GRO-α, and ENA-78. These findings support that MCs participate in the pathophysiology of MM and is implicated in the angiogenic process and disease progression.

  20. Multiple myeloma associated with acquired cutis laxa.

    PubMed

    Cho, S Y; Maguire, R F

    1980-08-01

    Acquired cutis laxa is a rare disorder characterized by diffuse laxity of the skin and loss of connective tissue support with involvement of the lungs, gastrointestinal tract, pelvic organs, and aorta. The case report presented herein describes a forty-six year old woman with multiple myeloma and cutis laxa. Her history included several severe allergic reactions and the gradual development of lax skin, loss of connective tissue support throughout the body, and emphysema. At autopsy, multiple myeloma, diffuse laxity of the skin, and panacinar emphysema were found. The amount of elastic fiber in the skin, lungs, and aorta was decreased and showed abnormal fragmentation. Results of direct immunofluorescence study demonstrated IgG bound to dermal elastic fibers. Speculation regarding an immunologic etiology of the elastic tissue abnormality is presented herein.

  1. Renal failure in patients with multiple myeloma.

    PubMed

    Almueilo, Samir H

    2015-01-01

    Renal dysfunction is encountered in 20-25% of patients with multiple myeloma (MM) at the time of diagnosis. There is often a precipitating event. Several biochemical and clinical correlations with renal failure in MM have been reported. Renal failure in MM is associated with worse outcome of the disease. We retrospectively analyzed the medical records of 64 patients with MM admitted to our institution during the period January 1992 to December 2012. Abnormal renal function was observed in 24 (37.5%) patients and 17 (26.6%) of them had renal failure; 14 of the 17 (82.4%) of patients with renal failure had Stage III MM. Urine Bence- Jones protein was positive in ten (58.8%) patients with renal failure versus ten (21.3%) patients without renal failure (P = 0.004). Potential precipitating factors of renal failure were determined in nine patients. Renal function normalized in 11 patients with simple measures, while six patients required hemodialysis; one remained dialysis dependent till time of death. Early mortality occurred in five (29.4%) patients with renal failure as compared with two (4.3%) patients in the group without renal failure (P = 0.005). In conclusion, renal failure is associated with a higher tumor burden and Bence-Jones proteinuria in patients with MM. It is reversible in the majority of patients; however, early mortality tends to be higher in patients with persistent renal failure.

  2. Elotuzumab for the treatment of multiple myeloma.

    PubMed

    Moreau, Philippe; Touzeau, Cyrille

    2014-05-01

    New agents are awaited for the treatment of multiple myeloma and research is ongoing for the development of monoclonal antibodies (MoAbs) targeting the tumor cells. One of the most promising MoAb is elotuzumab, the only humanized IgG1 MoAb specifically targeting CS1 (SLAMF7), a cell surface glycoprotein that is highly expressed in plasma cells. Preclinical and clinical data on elotuzumab will be presented in this article. PMID:24941981

  3. New prognostic biomarkers in multiple myeloma.

    PubMed

    Szudy-Szczyrek, Aneta; Szczyrek, Michał; Soroka-Wojtaszko, Maria; Hus, Marek

    2016-01-01

    Multiple myeloma is a malignant neoplastic disease, characterized by uncontrolled proliferation and accumulation of plasma cells in the bone marrow, which is usually connected with production of a monoclonal protein. It is the second most common hematologic malignancy. It constitutes approximately 1% of all cancers and 10% of hematological malignancies. Despite the huge progress that has been made in the treatment of multiple myeloma in the past 30 years including the introduction of new immunomodulatory drugs and proteasome inhibitors, it is still an incurable disease. According to current data, the five-year survival rate is 45%. Multiple myeloma is a very heterogeneous disease with a very diverse clinical course, which is expressed by differences in effectiveness of therapeutic strategies and ability to develop chemoresistance. This diversity implies the need to define risk stratification factors that would help to create personalized and optimized therapy and thereby improve treatment outcomes. Prognostic markers that aim to objectively evaluate the risk of a poor outcome, relapse and the patient's overall outcome are useful for this purpose. The existing, widely used prognostic classifications, such as the Salmon-Durie classification or ISS, do not allow for individualization of treatment. As a result of the development of diagnostic techniques, especially cytogenetics and molecular biology, we were able to discover a lot of new, more sensitive and specific prognostic factors. The paper presents recent reports on the role of molecular, cytogenetic and biochemical alterations in pathogenesis and prognosis of the disease. PMID:27463592

  4. Pathway-based network analysis of myeloma tumors: monoclonal gammopathy of unknown significance, smoldering multiple myeloma, and multiple myeloma.

    PubMed

    Dong, L; Chen, C Y; Ning, B; Xu, D L; Gao, J H; Wang, L L; Yan, S Y; Cheng, S

    2015-01-01

    Although many studies have been carried out on monoclonal gammopathy of unknown significances (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM), their classification and underlying pathogenesis are far from elucidated. To discover the relationships among MGUS, SMM, and MM at the transcriptome level, differentially expressed genes in MGUS, SMM, and MM were identified by the rank product method, and then co-expression networks were constructed by integrating the data. Finally, a pathway-network was constructed based on Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and the relationships between the pathways were identified. The results indicated that there were 55, 78, and 138 pathways involved in the myeloma tumor developmental stages of MGUS, SMM, and MM, respectively. The biological processes identified therein were found to have a close relationship with the immune system. Processes and pathways related to the abnormal activity of DNA and RNA were also present in SMM and MM. Six common pathways were found in the whole process of myeloma tumor development. Nine pathways were shown to participate in the progression of MGUS to SMM, and prostate cancer was the sole pathway that was involved only in MGUS and MM. Pathway-network analysis might provide a new indicator for the developmental stage diagnosis of myeloma tumors. PMID:26345890

  5. [Multiple myeloma with diffuse osteosclerosis: distinct from POEMS syndrome].

    PubMed

    Morán Blanco, L M; Encinas Rodríguez, C

    2014-01-01

    Diffuse osteosclerotic lesions are a very uncommon radiologic presentation in multiple myeloma. These lesions affect the axial skeleton and proximal limbs; they may be accompanied by osteolytic lesions in the course of the disease. In fact, in cases of diffuse osteosclerosis, the diagnosis of multiple myeloma is reached only after ruling out other, more common diseases. We present an exceptional case of multiple myeloma with diffuse osteosclerosis and highlight the differences between this entity and POEMS syndrome. PMID:23890791

  6. Deregulated microRNAs in multiple myeloma.

    PubMed

    Benetatos, Leonidas; Vartholomatos, George

    2012-02-15

    MicroRNAs are short noncoding RNAS involved in gene expression regulation under physiological and pathological situations. They bind to mRNA of target genes and are potential regulators of gene expression at a post-transcription level through the RNA interference pathway. They are estimated to represent 1% to 2% of the known eukaryotic genome, and it has been demonstrated that they are involved in the pathogenesis of neurodegenerative diseases, cancer, metabolism disorders, and heart disease. MicroRNAs are known to act as tumor suppressors or oncogenes in cancer biology. The authors describe the current knowledge on microRNA involvement in regulatory pathways that characterize multiple myeloma pathogenesis gained from in vitro and in vivo studies. These small molecules interact with important factors such as p53, SOCS1, IGF-1, IGF-1R, vascular endothelial growth factor, NF-κB, and others. As such, microRNAs represent an attractive therapeutic target in the context of multiple myeloma interfering with the myeloma regulatory networks. Further studies are needed to better understand their role in myelomagenesis and their therapeutic potential.

  7. Pharmacotherapy of multiple myeloma: an economic perspective.

    PubMed

    Messori, Andrea; Trippoli, Sabrina; Santarlasci, Benedetta

    2003-04-01

    Since new treatments have recently been proposed for patients with multiple myeloma, the aim of this article is to review the main innovations in this therapeutic area and to examine the cost-effectiveness ratio. Innovative approaches include autologous transplantation and thalidomide, which are both utilised as induction or salvage treatments. According to a randomised trial conducted in 1996, the survival after autologous transplantation seems to be better than that following standard therapy; however, this result has not been confirmed by a recent study. Thalidomide has been found to be effective for relapsed or refractory myeloma and, more recently, also as induction therapy. Preliminary cost-effectiveness assessments about autologous transplantation and thalidomide have given promising results; yet one regulatory problem with thalidomide is that, both in Europe and in the US, the drug has not yet been approved for this indication. PMID:12667114

  8. Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma

    PubMed Central

    Thomas, Alexandra L.; Coarfa, Cristian; Qian, Jun; Wilkerson, Joseph J.; Rajapakshe, Kimal; Krett, Nancy L.; Gunaratne, Preethi H.; Rosen, Steven T.

    2015-01-01

    Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3’-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death. PMID:26715915

  9. Prognostic factors and classification in multiple myeloma.

    PubMed Central

    San Miguel, J. F.; Sànchez, J.; Gonzalez, M.

    1989-01-01

    Analyses of prognostic factors have allowed the design of staging systems in different haematological disorders. In a series of 220 patients with multiple myeloma, univariate analysis showed that nine parameters had a significant adverse effect on survival; poor performance status (Karnowsky scaling system less than 70%), infections before diagnosis, renal impairment (assessed either by creatinine clearance greater than 2 mg dl-1 or urea greater than 40 mg dl-1), serum calcium (greater than 10 mg dl-1), severe anaemia (less than 8.5 g dl-1), the presence of Bence-Jones proteinuria, failure to achieve complete remission, more than 40% plasma cells in bone marrow and a low paraprotein index (monoclonal component/% plasma cells: P less than 0.09). In addition, this index correlated significantly with all the other prognostic factors except performance status. The best combination of disease characteristics selected by means of the Cox regression proportional hazards method were performance status and creatinine levels. Additionally, by factor analysis of principal components we obtained a regression equation that included creatinine levels, haemoglobin, performance status and paraprotein index. Using this it was possible to separate the series of patients into three risk categories: A (65 patients), B (69 patients) and C (65 patients) with a median survival of 41, 24 and 12 months, respectively. The model provided similar results to those of the British Medical Research Council, whereas the staging systems proposed by Durie and Salmon, Merlin et al. and Carbone et al. had a lower discriminant value in our series. PMID:2757917

  10. Pleural effusion as a manifestation of multiple myeloma.

    PubMed

    Iqbal, Nousheen; Tariq, Muhammad Usman; Shaikh, Mohammad Usman; Majid, Hashir

    2016-01-01

    Multiple myeloma is a clonal B-cell malignancy, characterised by proliferation of plasma cells and secretion of paraproteins. These plasma cells accumulate predominantly in the bone marrow; rarely, they invade other areas, especially the thorax. Myeloma presenting with a pleural effusion is rare and reported in only 6% of patients with myeloma. Such patients generally present late and have a poor prognosis. Here, we describe a patient presenting with a lung mass, renal failure and a massive unilateral pleural effusion due to multiple myeloma who was treated successfully. PMID:27520995

  11. [Therapy of multiple myeloma. What is confirmed?].

    PubMed

    Peest, D; Ganser, A; Einsele, H

    2013-12-01

    Multiple myeloma (MM) is a malignant plasma cell disorder with clonal development. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are precursor stages of MM and both have to be differentiated from MM which is characterized by organ complications. High-dose chemotherapy combined with autologous stem cell support is the therapy of choice for most patients in order to achieve long-lasting complete remission with few symptoms, prevention of new organ complications and survival prolongation. Patients who cannot be intensively treated due to advanced age and comorbidities should be treated with low-dose chemotherapy, normally alkylating agents, for improved quality of life and also survival prolongation. Including thalidomide, lenalidomide, pomalidomide, bortezomib or carfilzomib in both high-dose and low-dose chemotherapy concepts results in a significantly higher remission rate and longer survival. Allogeneic stem cell transplantation is associated with a relatively high mortality during the first year after transplantation which will be refined with the aim of healing in various trials and is an alternative treatment approach for selected patients. A treatment concept for MM patients has to be individually complemented by local irradiation, administration of bisphosphonates and supportive infusions of immunoglobulins. PMID:24201762

  12. Multiple Myeloma. Diagnostic challenges and standard therapy.

    PubMed

    Kyle, R A

    2001-04-01

    In the diagnosis of multiple myeloma (MM), the clinician must exclude other disorders in which a plasma cell reaction may occur such as rheumatoid arthritis and connective tissue disorders, or metastatic carcinoma where the patient may have osteolytic lesions associated with bone metastases. Patients with smoldering multiple myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS) have none of the complicating features of MM and do not require treatment with potentially toxic agents. The plasma cell labeling index can help make a differential diagnosis of MM from SMM. Patients with a high labeling index have a high risk of complications and should be monitored carefully. However, the labeling index can be low in active MM. In addition, SMM or MGUS patients have few or no circulating plasma cells. High-dose chemotherapy and stem cell support prolong overall survival in contrast to conventional therapy. If stem cell transplantation is considered, it is important to harvest the cells before using alkylating agents to obtain a sufficient number of cells. Supportive treatment consists of the occasional use of erythropoietin to maintain adequate hemoglobin levels and adequate hydration to protect renal function. Vaccination against pneumococcal infections and the prophylactic use of antibiotic therapy during the first 2 months of treatment can be beneficial. Recognizing the symptoms of spinal cord compression and initiating dexamethasone therapy promptly to prevent paraplegia are critical. PMID:11309703

  13. Treatment of multiple myeloma: 2009 update.

    PubMed

    2009-12-01

    (1) New marketing authorizations continue to be granted for treatments of multiple myeloma, and new trials and meta-analyses continue to be published. This review re-examines our previous conclusions based on data published between 2003 and 2008. We again used the standard Prescrire methodology to review the latest data; (2) In patients who are symptomatic but who do not qualify for haematopoietic stem cell transplantation (especially people aged over 65), the results of five comparative trials suggest that adding thalidomide to the melphalan-prednisone combination delays myeloma progression by an additional 5 to 10 months. There is possibly also an increase in overall survival time. This triple combination is therefore a first-line treatment option. There is no firm evidence that replacing thalidomide with bortezomib in this combination provides an advantage; (3) In symptomatic patients aged under 65, two meta-analyses have compared high-dose chemotherapy followed by autologous stem cell transplantation with conventional chemotherapy. Unlike early trials, these meta-analyses showed no overall survival benefit but only a delay in myeloma progression. Initial treatment with two successive transplantation procedures has a negative risk-benefit balance. (4) The optimal chemotherapy regimen prior to autologous stem cell transplantation is controversial. It is unclear which combination (vincristine + doxorubicin + dexamethasone, cyclophosphamide + dexamethasone, cyclophosphamide + dexamethasone, or bortezomib + dexamethasone, etc.) has a better risk-benefit balance in terms of survival and quality of life; (5) According to a meta-analysis of three clinical trials, thalidomide maintenance therapy appears to improve overall survival after Autologous stem cell transplantation; (6) Despite their inadequate evaluation, lenalidomide and pegylated liposomal doxorubicin are licensed for use in patients who relapse or who are refractory to initial treatment. In view of their

  14. Comparison of bone scintigraphy and radiography in multiple myeloma. [/sup 99m/Tc-phosphate complexes

    SciTech Connect

    Woolfenden, J.M.; Pitt, M.J.; Durie, B.G.M.; Moon, T.E.

    1980-03-01

    Radionuclide images and skeletal radiographs of 51 patients with multiple myeloma were compared to assess the sensitivity of scintigraphy in detecting radiographically evident disease. Comparable studies were available for 562 sites. The radionuclide image was relatively insensitive in detecting myeloma; it failed to show radiographically evident disease or underestimated its extent at 27% of the sites. On a limited number of serial images there were 7 sites at which a scintigraphic abnormality preceded the radiographic abnormality. No definite correlation was found between scintigraphic findings and hematologic parameters of myeloma activity. Although the radionuclide image may demonstrate a few sites of myeloma before the radiograph, radiography remains the primary method of evaluating skeletal involvement by myeloma.

  15. Relation of osteoclast activating factor production to extent of bone disease in multiple myeloma.

    PubMed

    Durie, B G; Salmon, S E; Mundy, G R

    1981-01-01

    Measurements of total body myeloma cell number and osteoclast activating factor (OAF) production by bone marrow myeloma cells in vitro were made in 33 patients with plasma cell myeloma. There was a highly significant correlation (P < 0.001) between the amount of OAF produced by bone marrow myeloma cells and the extent of skeletal destruction. Serial studies indicated reduction of OAF production with remission induction and high OAF production at the time of relapse with new bone destruction. Although hypercalcaemia occurred only in patients with the most extensive bone lesions, there was no direct relationship between OAF production and the serum calcium concentration. These data suggest that measurement of OAF production in multiple myeloma may predict those patients at risk for development of extensive skeletal destruction due to this neoplasm.

  16. Identify multiple myeloma stem cells: Utopia?

    PubMed Central

    Saltarella, Ilaria; Lamanuzzi, Aurelia; Reale, Antonia; Vacca, Angelo; Ria, Roberto

    2015-01-01

    Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs. PMID:25621108

  17. The road to treating smoldering multiple myeloma.

    PubMed

    Korde, Neha; Mailankody, Sham; Landgren, Ola

    2014-09-01

    The management of smoldering multiple myeloma (SMM) has been a challenge to clinicians, ever since the condition was first characterized in 1980. While the risk of progression to symptomatic myeloma is greater for SMM (10% per year) compared to MGUS (1% per year), several SMM patients remain asymptomatic for years without evidence of disease progression. Early clinical trials focusing on early treatment of SMM have been equivocal with no clear benefit. However, the last decade has seen a greater understanding of the pathogenesis of plasma cell disorders, including SMM, and development of better therapeutics. A recent randomized trial has provided evidence of clinical benefit with early treatment of high-risk SMM. In this review, we summarize issues related to the early treatment of SMM including risk stratification and possible outcomes with therapy initiation. In the context of reviewing recent clinical trial data supporting early treatment, we define challenges faced by clinicians and provide future directions to the road to treating SMM. PMID:25486957

  18. Identify multiple myeloma stem cells: Utopia?

    PubMed

    Saltarella, Ilaria; Lamanuzzi, Aurelia; Reale, Antonia; Vacca, Angelo; Ria, Roberto

    2015-01-26

    Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs. PMID:25621108

  19. Identify multiple myeloma stem cells: Utopia?

    PubMed

    Saltarella, Ilaria; Lamanuzzi, Aurelia; Reale, Antonia; Vacca, Angelo; Ria, Roberto

    2015-01-26

    Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.

  20. Development of Novel Immunotherapies for Multiple Myeloma

    PubMed Central

    Al-Hujaily, Ensaf M.; Oldham, Robyn A. A.; Hari, Parameswaran; Medin, Jeffrey A.

    2016-01-01

    Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM. PMID:27618026

  1. Molecular mechanisms in multiple myeloma drug resistance

    PubMed Central

    Nikesitch, Nicholas; Ling, Silvia C W

    2016-01-01

    Multiple myeloma (MM) is predominantly an incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. MM is a genetically heterogeneous disease and the complexity increases as the disease progresses to a more aggressive stage. MM arises from a plasma cell, which produces and secretes non-functioning immunoglobulins. Most MM cells are sensitive to proteasome inhibitors (PIs), which have become the main drug in the treatment of newly diagnosed and relapsed MM. However, not all MM is sensitive to PIs. This review summarises the literature regarding molecular biology of MM with a focus on the unfolded protein response and explores how this could affect drug sensitivity and progression of disease. PMID:26598624

  2. Staging and prognostication of multiple myeloma

    PubMed Central

    Fonseca, Rafael; Monge, Jorge; Dimopoulos, Meletios A

    2014-01-01

    Multiple myeloma (MM) is a heterogeneous disease that, over the past 15 years, has seen an increased understanding of its biology and of novel therapeutic options. Distinctive subtypes of the disease have been described, each with different outcomes and clinic-pathological features. Even though a detailed classification of MM into at least seven or eight major subtypes is possible, a more practical clinical approach can classify the disease into high-risk and non-high-risk MM. Such classification has permitted a more personalized approach to the management of the disease. Additionally, risk stratification should be included in outcome discussions with patients, as survival differs significantly by high-risk status. Nowadays, test for risk stratification are widely available and can be routinely used in the clinic. A greater understanding of the genetic abnormalities underlying the biology of MM will allow for the development of novel targeted therapies and better prognostic markers of the disease. PMID:24483346

  3. Dilemmas in Treating Smoldering Multiple Myeloma

    PubMed Central

    Ahn, Inhye E.; Mailankody, Sham; Korde, Neha; Landgren, Ola

    2015-01-01

    Novel therapies hold promise for high-risk smoldering multiple myeloma (SMM). Recent studies suggest that modern combination approaches can be options for high-risk SMM to obtain deep molecular responses with favorable toxicity profiles. Although pioneering treatment trials based on small numbers of patients suggest progression-free and overall survival benefits, application of the data to real-life practice remains to be validated. Therapeutic modulation of disease tempo, disease burden, clonal evolution, and tumor microenvironment in SMM remains to be understood and calls for reliable biomarkers reflective of disease biology. Here, we review studies that open a new management platform for SMM, address ongoing dilemmas in practice and under investigation, and highlight emerging scientific questions in the era of SMM treatment. PMID:25422486

  4. Immunological Dysregulation in Multiple Myeloma Microenvironment

    PubMed Central

    Romano, Alessandra; Conticello, Concetta; La Fauci, Alessia; Parrinello, Nunziatina Laura

    2014-01-01

    Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target. PMID:25013764

  5. Development of Novel Immunotherapies for Multiple Myeloma.

    PubMed

    Al-Hujaily, Ensaf M; Oldham, Robyn A A; Hari, Parameswaran; Medin, Jeffrey A

    2016-01-01

    Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM. PMID:27618026

  6. Effect of serum monoclonal protein concentration on haemostasis in patients with multiple myeloma.

    PubMed

    Huang, Heyu; Li, Huijun; Li, Dengju

    2015-07-01

    Abnormalities in haemostasis are often detected in patients with multiple myeloma and the fundamental factors that lead to these abnormities are worthy of exploration. The objective of this study was to investigate bleeding diathesis and coagulopathy in different multiple myeloma types or stages and assess how paraprotein concentration contributes to differences in these conditions. Haemostasis screening tests and serum monoclonal protein (M protein) concentration were retrospectively analysed in 101 patients newly diagnosed with multiple myeloma from January 2012 to April 2014. No significant differences were found between bleeding diathesis and types or International Staging System (ISS) stages of multiple myeloma; however, prolonged thrombin time (TT) was found in most of patients (77.7%) and was positively related to light-chain concentration (P ≤ 0.01). Prolonged prothrombin time (PT) was more obvious in IgA and IgG-type multiple myeloma than in the light-chain type (P ≤ 0.01). With increased clinical staging, PT remarkably increased (P ≤ 0.01). M protein concentration was significantly higher in patients with prolonged PT than in those with normal PT (P ≤ 0.01). The D-dimer mean was significantly higher than normal (>0.5 μg/ml) (P ≤ 0.01). Fibrinogen was negatively related to M protein levels (P ≤ 0.01); however, there was no correlation between activated partial thromboplastin time (APTT) and multiple myeloma stages or types, M protein levels and serum light-chain concentration (P ≥ 0.05). Patients with light-chain type multiple myeloma were more likely to have prolonged TT than patients with other types. M protein levels had an obvious effect on PT. Prolonged PT was more common in IgA and IgG-type multiple myeloma. Abnormal haemostasis test results are not always accompanied by clinically apparent haemostatic complications.

  7. Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis.

    PubMed

    Bouchnita, Anass; Eymard, Nathalie; Moyo, Tamara K; Koury, Mark J; Volpert, Vitaly

    2016-06-01

    Multiple myeloma (MM) infiltrates bone marrow and causes anemia by disrupting erythropoiesis, but the effects of marrow infiltration on anemia are difficult to quantify. Marrow biopsies of newly diagnosed MM patients were analyzed before and after four 28-day cycles of non-erythrotoxic remission induction chemotherapy. Complete blood cell counts and serum paraprotein concentrations were measured at diagnosis and before each chemotherapy cycle. At diagnosis, marrow area infiltrated by myeloma correlated negatively with hemoglobin, erythrocytes, and marrow erythroid cells. After successful chemotherapy, patients with less than 30% myeloma infiltration at diagnosis had no change in these parameters, whereas patients with more than 30% myeloma infiltration at diagnosis increased all three parameters. Clinical data were used to develop mathematical models of the effects of myeloma infiltration on the marrow niches of terminal erythropoiesis, the erythroblastic islands (EBIs). A hybrid discrete-continuous model of erythropoiesis based on EBI structure/function was extended to sections of marrow containing multiple EBIs. In the model, myeloma cells can kill erythroid cells by physically destroying EBIs and by producing proapoptotic cytokines. Following chemotherapy, changes in serum paraproteins as measures of myeloma cells and changes in erythrocyte numbers as measures of marrow erythroid cells allowed modeling of myeloma cell death and erythroid cell recovery, respectively. Simulations of marrow infiltration by myeloma and treatment with non-erythrotoxic chemotherapy demonstrate that myeloma-mediated destruction and subsequent reestablishment of EBIs and expansion of erythroid cell populations in EBIs following chemotherapy provide explanations for anemia development and its therapy-mediated recovery in MM patients.

  8. Oxidative stress and proteasome inhibitors in multiple myeloma.

    PubMed

    Lipchick, Brittany C; Fink, Emily E; Nikiforov, Mikhail A

    2016-03-01

    Multiple myeloma is a form of plasma cell neoplasm that accounts for approximately 10% of all hematological malignancies. Recently, several novel drugs have been discovered that almost doubled the overall survival of multiple myeloma patients. One of these drugs, the first-in-class proteasome inhibitor bortezomib (Velcade) has demonstrated remarkable response rates in multiple myeloma patients, and yet, currently this disease remains incurable. The major factor undermining the success of multiple myeloma treatment is a rapidly emerging resistance to the available therapy. Thus, the development of stand-alone or adjuvant anti-myeloma agents becomes of paramount importance. Overproduction of intracellular reactive oxygen species (ROS) often accompanies malignant transformation due to oncogene activation and/or enhanced metabolism in tumor cells. As a result, these cells possess higher levels of ROS and lower levels of antioxidant molecules compared to their normal counterparts. Unbalanced production of ROS leads to oxidative stress which, if left unchecked, could be toxic for the cell. In multiple myeloma cells where high rates of immunoglobulin synthesis is an additional factor contributing to overproduction of ROS, further induction of oxidative stress can be an effective strategy to cope with this disease. Here we will review the available data on the role of oxidative stress in the cytotoxicity of proteasome inhibitors and the use of ROS-inducing compounds as anti-myeloma agents. PMID:26827824

  9. Familial multiple myeloma. A review of thirty-seven families.

    PubMed Central

    Shoenfeld, Y.; Berliner, S.; Shaklai, M.; Gallant, L. A.; Pinkhas, J.

    1982-01-01

    The review of the pertinent literature disclosed 36 reports of familial multiple myeloma, described mostly in siblings, to which the authors add one more family. These patients did not differ significantly from those with non-familial myeloma with regard to sex, age, distribution of monoclonal proteins, clinical and laboratory data, and the course and prognosis of the disease. An increased incidence of immunoglobulin abnormalities was observed in healthy relatives of patients affected with familial myeloma. In most cases the time interval of the diagnosis of myeloma in a family member of a known patient was under 4 years. These observations, in conjunction with reports of myeloma occurring in clusters in a community and the appearance of myeloma in spouses raise the possibility of an environmental factor (virus?) which may contribute to the pathogenesis of myeloma in genetically predisposed individuals. Multiple myeloma should be added to the list of neoplastic diseases in which the family history is relevant and in which genetic and possibly environmental factors may be pathogenetically involved. PMID:7088752

  10. PD-1/PD-L1 expression in extra-medullary lesions of multiple myeloma.

    PubMed

    Crescenzi, Anna; Annibali, Ombretta; Bianchi, Antonella; Pagano, Anastasia; Donati, Michele; Grifoni, Alba; Avvisati, Giuseppe

    2016-10-01

    Multiple myeloma patients may develop extraosseous involvement in the course of the disease making prognosis very poor and new drugs clearly needed. The PD-1/PD-L1 axis has emerged as a master immune checkpoint in antitumor responses and recent studies investigated the role of PD-L1 in multiple myeloma cells; no data however are still available about PD-L1 expression in extramedullary localizations. We demonstrate PD-L1 expression in 4/12 cases of extraosseous myeloma suggesting that these lesions represent a specialized microenvironment. We found presence of PD-1+ infiltrating lymphocytes in all observed cases supporting the relevance of PD-1/PD-L1 checkpoint in extramedullary myeloma. We also investigated the correlation in PD1/PD-L1 staining between marrow staining and EMP lesions. PMID:27619200

  11. Evolving treatments in multiple myeloma patients with renal failure.

    PubMed

    Gozzetti, Alessandro; Papini, Giulia; Candi, Veronica; Bocchia, Monica

    2014-01-01

    The introduction of novel agents in multiple myeloma therapy has dramatically improved survival in latest years. Great progress has also been detected in particular poor clinical situation such as acute renal failure in which survival was dismal in the past. Treatment with bortezomib, thalidomide and dialysis associated with high cut-off (HCO) filters can recover more than two thirds of myeloma patients with an end stage renal failure. Novel proteasome inhibitors and immunomodulating agents (IMID's) are even more promising in this set of patients. Aim of this review is to provide an overview of treatments of multiple myeloma patients with acute renal failure coming from most recent clinical trials. PMID:25329484

  12. Three-Drug Combination for Relapsed Multiple Myeloma

    Cancer.gov

    A summary of Interim results from an international, randomized phase III trial that suggest that adding carfilzomib (Kyprolis®) to a standard treatment improves outcomes for patients with multiple myeloma whose cancer has relapsed.

  13. General Information about Plasma Cell Neoplasms (Including Multiple Myeloma)

    MedlinePlus

    ... Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  14. Reconstruction of multiple myeloma lesions around the pelvis and acetabulum.

    PubMed

    Sakellariou, Vasileios I; Mavrogenis, Andreas F; Savvidou, Olga; Sim, Franklin H; Papagelopoulos, Panayiotis J

    2015-05-01

    Multiple myeloma is a malignancy of monoclonal plasma cells (plasma cells are of B-lymphocyte lineage of the hematopoietic system). It is the second most prevalent blood malignancy after non-Hodgkin's lymphoma. It accounts for approximately 1 % of all malignancies and 2 % of all cancer deaths. Bony involvement is very common; the incidence of pelvic and periacetabular involvement in MM is reported to be around 6 %. Lytic lesions comprise a hallmark of multiple myeloma, which may be complicated with pathologic fractures in a substantial percentage of patients. Pelvic and periacetabular bony involvement of multiple myeloma is associated with some unique characteristics regarding the biomechanics of this specific anatomical region, the morbidity, the overall survival, and prognosis, which all reflect to impairment of quality of life. In this paper, we review the special features of multiple myeloma lesions around the pelvis and acetabulum and present an algorithm of management with the use of current surgical techniques.

  15. Maxillary Swelling as the First Evidence of Multiple Myeloma

    PubMed Central

    Kasamatsu, Atsushi; Kimura, Yasushi; Tsujimura, Hideki; Kanazawa, Harusachi; Koide, Nao; Miyamoto, Isao; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2015-01-01

    Multiple myeloma is a malignant neoplasm of plasma cells characterized by proliferation of a single clone of abnormal immunoglobulin-secreting plasma cells. Since the amount of hemopoietic bone marrow is decreased in the maxilla, oral manifestations of multiple myeloma are less common in the maxilla than in the mandible. We report the case of 33-year-old Japanese man who presented with a mass in the right maxillary alveolar region. Computed tomography and magnetic resonance images showed a soft tissue mass in the right maxilla eroding the anterior and lateral walls of the maxillary sinus and extending into the buccal space. The biopsy results, imaging, and laboratory investigations led to the diagnosis of multiple myeloma. This case report suggests that oral surgeons and dentists should properly address oral manifestations as first indications of multiple myeloma. PMID:26640721

  16. Prognostic Impact of Cytogenetic Abnormalities in Multiple Myeloma

    PubMed Central

    Jian, Yuan; Chen, Xiaolei; Zhou, Huixing; Zhu, Wanqiu; Liu, Nian; Geng, Chuanying; Chen, Wenming

    2016-01-01

    Abstract The identification of specific cytogenetic abnormalities by interphase fluorescence in situ hybridization (i-FISH) has become a routine procedure for prognostic stratification of multiple myeloma (MM) patients. In this study, the prognostic significance of cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH) in 229 newly diagnosed multiple myeloma patients was retrospectively analyzed. Results showed that del (17p), t(4;14), and 1q21 gain were adverse predictors of progression-free survival (PFS). Patients who carried these cytogenetic abnormalities were more likely to have more adverse biological parameters and lower response rate. Multivariate analysis showed that del (17p), t(4;14), and 1q21 gain were statistically independent predictors of PFS, whereas del (17p) was also adverse predictor of overall survival. Multiple coexisting cytogenetic abnormalities also had a negative correlation with PFS. Bortezomib-based therapy could improve the rate and depth of response in patients with t(4;14) translocation and 1q21 gain. Autologous stem cell transplantation could improve, but not overcome the adverse prognostic effect of high-risk cytogenetic abnormalities. These results demonstrate that MM patients with iFISH abnormalities, especially del (17p), are more likely to have a poor prognosis. PMID:27175647

  17. Pulmonary Embolism as the First Manifestation of Multiple Myeloma

    PubMed Central

    Vallianou, N.; Lazarou, V.; Tzangarakis, J.; Barounis, R.; Sioula, E.

    2013-01-01

    Multiple myeloma is considered a hypercoagulable state due to several mechanisms such as the increased IL-6 and immunoglobulins production, the defective fibrinolytic mechanism, and the acquired resistance to activated protein C that are involved in the pathogenesis and clinical futures of the disease. We describe a case of a female patient who presented to the hospital with pulmonary embolism as the first manifestation of the hypercoagulability of multiple myeloma. PMID:24151508

  18. Tretatment Approach of Nontransplant Patients with Multiple Myeloma

    PubMed Central

    Krstevska, Svetlana B.; Sotirova, Tatjana; Balkanov, Trajan; Genadieva-Stavric, Sonja

    2014-01-01

    Multiple myeloma is still an incurable disease with pattern of regression and remission followed by multiple relapses raising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. In recent years there is a huge improvement in treatment of patients with multiple myeloma. The milestones of these improvement are: autologous transplantation and high-dose melphalan, imunomodulating drugs (thalidomide, lenalidomide), proteosom inhibitors (bortesomib, carfilzomib). The most significant improvement in overall survival has been achieved in the patients younger than 65 years. So, the major challenge for hematologist is to translate this improvement in the elderly patients with multiple myeloma. Today, physicians are able to offer wider variety of treatment options for elderly patients with multiple myeloma. Therapeutic options should be tailored and personalized according to patient's characteristics by balancing efficacy and toxicity of each drug which is especially important for elderly patients. In the mode of sequencing treatment for elderly patients with multiple myeloma, our goal is to achieve and maintain maximal response while limiting treatment -related toxicities as much as possible. Second-generation novel agent, such as carfilzomib, pomalidomide, elotuzumab, bendamustine are currently being evaluated as an option to improve treatment outcome in elderly patients. PMID:25568637

  19. Tretatment approach of nontransplant patients with multiple myeloma.

    PubMed

    Krstevska, Svetlana B; Sotirova, Tatjana; Balkanov, Trajan; Genadieva-Stavric, Sonja

    2014-10-01

    Multiple myeloma is still an incurable disease with pattern of regression and remission followed by multiple relapses raising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. In recent years there is a huge improvement in treatment of patients with multiple myeloma. The milestones of these improvement are: autologous transplantation and high-dose melphalan, imunomodulating drugs (thalidomide, lenalidomide), proteosom inhibitors (bortesomib, carfilzomib). The most significant improvement in overall survival has been achieved in the patients younger than 65 years. So, the major challenge for hematologist is to translate this improvement in the elderly patients with multiple myeloma. Today, physicians are able to offer wider variety of treatment options for elderly patients with multiple myeloma. Therapeutic options should be tailored and personalized according to patient's characteristics by balancing efficacy and toxicity of each drug which is especially important for elderly patients. In the mode of sequencing treatment for elderly patients with multiple myeloma, our goal is to achieve and maintain maximal response while limiting treatment -related toxicities as much as possible. Second-generation novel agent, such as carfilzomib, pomalidomide, elotuzumab, bendamustine are currently being evaluated as an option to improve treatment outcome in elderly patients.

  20. [Multiple myeloma and HIV/AIDS infection. Three case reports].

    PubMed

    Elira Dokekias, A; Purhuence, M F; Malanda, F; Moyikoua, A; Moutschen, M

    2004-01-01

    HIV/AIDS infection rages at the endemic state in Sub Saharan African and especially in our country. We are reporting 3 observations of patients, all of females affected by HIV/AIDS and multiple's myeloma. They are all in-patients in the department of haematology, University hospital of Brazzaville, from 2000 to 2002. In two cases out of three, multiple's myeloma is discovered after the tracking of HIV/AIDS infection. In the other case, the tracking HIV/AIDS seems to be posterior to the multiple's myeloma diagnostisis. HIV/AIDS is symptomatic in the tree cases and under antiviral treatment. Multiple's Myeloma is diagnosed at an advanced stage. It is about IgG myeloma in two cases and IgA myeloma in the other. The rate of the T4 lymphocytes is noted spontaneously to 204 and 486 by mm3, and 390 by mm3 in a patient under antiviral treatment before her hospitalisation. The measure of the viral intensity is not achieved. The poly chemotherapy of type VMCP and VAMCP is driven without major complications and under anti-infectious prophylaxis. The receding is still insufficient to affirm the medium-term evolution and to determine the prognosis of the malign blood disease. The description of these three observations confirms the implication of the human retrovirus and in particular of the VIH/SIDA in the lymphoma genesis.

  1. Revisiting IL-6 antagonism in multiple myeloma.

    PubMed

    Matthes, Thomas; Manfroi, Benoit; Huard, Bertrand

    2016-09-01

    IL-6, a cytokine with broad functions in inflammation and immunity, has been extensively studied for its role on normal antibody-producing plasma cells. In addition, IL-6 is recognized as a proliferative factor for multiple myeloma (MM), a malignant plasma cell tumor developing in the bone marrow. Blocking IL-6 signaling was thus developed into a therapeutic approach for MM already early after its discovery, in 1991. Unfortunately, the first clinical trials did not demonstrate a clear benefit, but despite this apparent failure hopes on IL-6 antagonism are still high and trials ongoing. The cellular source of IL-6 has long been a matter of debate. IL-6 was first recognized as an autocrine factor produced by the malignant plasma cells themselves, but later reports clearly showed that IL-6 was a paracrine factor, produced by the microenvironment, mostly by cells from the myeloid lineage. Recently, we have confirmed that IL-6 originates from myeloid lineage cells, mainly from myeloid precursors. We have also demonstrated that IL-6 amplifies the pool of myeloid cells producing a second key factor for MM, a proliferation inducing ligand (APRIL). These findings form a new rationale for IL-6 inhibition in MM and for new ways to use IL-6 blocking in the clinics. PMID:27497026

  2. Multiple Myeloma in a Patient with Acromegaly

    PubMed Central

    Kang, Yu Mi; Choi, Jong Han; Lee, Min Jung; Ahn, Ari; Park, Chan-Jeoung; Chang, Kiju; Seo, Seyoung; Hong, Sun In

    2015-01-01

    Acromegaly is a slowly progressing condition resulting from excess growth hormone (GH), generally caused by a GH-secreting pituitary adenoma. Cancer is the third most common cause of mortality in patients with acromegaly, and insulin-like growth factor 1 (IGF-1) is known to influence tumor formation by increasing cell proliferation and inhibiting apoptosis. Multiple myeloma (MM) is a plasma cell neoplasm, and previous studies have suggested the possible role of IGF-1 in its development of MM. However, no cases of acromegaly accompanied with MM have been reported in Asia to date. We here report the case of a 58-year-old woman with acromegaly accompanied with MM who presented with longstanding acromegalic manifestations resulting from a GH-secreting pituitary adenoma and also exhibited anemia, a reversed albumin/globulin ratio, and plasmacytosis on bone marrow examination. Because IGF-1 has been suggested to play an important role in the development and progression of MM, the patient promptly underwent surgical removal of the pituitary adenoma via a transsphenoidal approach. Since there is currently no consensus on therapeutic guidelines and suggested prognosis for MM with acromegaly, long-term follow-up of such cases is needed. PMID:25491781

  3. New Cancers after Autotransplants for Multiple Myeloma

    PubMed Central

    Mahindra, Anuj; Raval, Girindra; Mehta, Paulette; Brazauskas, Ruta; Zhang, Mei-Jie; Zhong, Xiaobo; Bird, Jennifer M.; Freytes, César O.; Hale, Gregory A.; Herzig, Roger; Holmberg, Leona A.; Kamble, Rammurti T.; Kumar, Shaji; Lazarus, Hillard M.; Majhail, Navneet S.; Marks, David I.; Moreb, Jan S.; Olsson, Richard; Saber, Wael; Savani, Bipin N.; Schiller, Gary J.; Tay, Jason; Vogl, Dan T.; Waller, Edmund K.; Wiernik, Peter H.; Wirk, Baldeep; Lonial, Sagar; Krishnan, Amrita Y.; Dispenzieri, Angela; Brandenburg, Nancy A.; Gale, Robert Peter; Hari, Parameswaran

    2015-01-01

    We describe baseline incidence and risk-factors for new cancers in 4161 persons receiving autotransplants for multiple myeloma (MM) in the US during 1990- 2010. Observed incidence of invasive new cancers was compared with expected incidence relative to the US population. The cohort represented 13387 person years at-risk. 163 new cancers were observed for a crude incidence rate of 1.2 new cancers per 100 person-years and cumulative incidences of 2.6% (95% CI; 2.09-3.17), 4.2% (95% CI; 3.49-5.00) and 6.1% (95% CI; 5.08-7.24) at 3, 5 and 7 years. The incidence of new cancers in the autotransplant cohort was similar to age- race- and gender-adjusted comparison subjects with an observed/expected (O/E) ratio of 1.00 (99% CI; 0.81-1.22). However, acute myeloid leukemia (AML) and melanoma were observed at higher than expected rates with O/E ratios of 5.19 (99% CI; 1.67–12.04; P=0.0004), and 3.58 (99% CI, 1.82–6.29; P<0.0001). Obesity, older age and male gender were associated with increased risks of new cancers in multivariate analyses. This large dataset provides a baseline for comparison and defines the histologic type specific risk for new cancers in patients with MM receiving post autotransplant therapies such as maintenance. PMID:25555448

  4. Imaging of multiple myeloma: Current concepts

    PubMed Central

    Derlin, Thorsten; Bannas, Peter

    2014-01-01

    Medical imaging is of crucial importance for diagnosis and initial staging as well as for differentiation of multiple myeloma (MM) from other monoclonal plasma cell diseases. Conventional radiography represents the reference standard for diagnosis of MM due to its wide availability and low costs despite its known limitations such as low sensitivity, limited specificity and its inability to detect extraosseous lesions. Besides conventional radiography, newer cross-sectional imaging modalities such as whole-body low-dose computed tomography (CT), whole-body magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT are available for the diagnosis of osseous and extraosseous manifestations of MM. Whole-body low-dose CT is used increasingly, replacing conventional radiography at selected centers, due to its higher sensitivity for the detection of osseous lesions and its ability to diagnose extraosseous lesions. The highest sensitivity for both detection of bone marrow disease and extraosseous lesions can be achieved with whole-body MRI and 18F-FDG PET/CT. According to current evidence, MRI is the most sensitive method for initial staging while 18F-FDG PET/CT allows monitoring of treatment of MM. There is an evolving role for assessment of treatment response using newer MR imaging techniques. Future studies are needed to further define the exact role of the different imaging modalities for individual risk stratification and therapy monitoring. PMID:25035830

  5. Notch signaling drives multiple myeloma induced osteoclastogenesis

    PubMed Central

    Colombo, Michela; Thümmler, Katja; Mirandola, Leonardo; Garavelli, Silvia; Todoerti, Katia; Apicella, Luana; Lazzari, Elisa; Lancellotti, Marialuigia; Platonova, Natalia; Akbar, Moeed; Chiriva-Internati, Maurizio; Soutar, Richard; Neri, Antonino; Goodyear, Carl S.; Chiaramonte, Raffaella

    2014-01-01

    Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors. The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance. Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact. Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities. PMID:25257302

  6. Multiple myeloma, immunotherapy and minimal residual disease.

    PubMed

    Kusenda, J; Kovarikova, A

    2016-01-01

    Multiple myeloma (MM) is an incurable heterogeneous hematological malignancy in which relapse is characterized by re-growth of residual tumor and immune suppression with a complex biology that affects many aspects of the disease and its response to treatment. The bone marrow microenvironment, including immune cells, plays a central role in MM pathogenesis, survival, and drug resistance. The advances in basic and translational research, introduction of novel agents, particularly combination therapies, improved indicators of quality of life and survival. Minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) has revolutionized monitoring of treatment response in MM. The importance of MFC methodology will be further strengthened by the ongoing international standardization efforts. Results of MRD testing provide unique and clinically important information and demonstrated the prognostic significance of MRD in patients, leading to regulate treatment intensity in many contemporary protocols. In this review, we will summarize the principal approaches in MM immunotherapy, focusing how new agents have potential in the treatment of MM and application of MRD detection by MFC as a surrogate endpoint would allow quicker evaluation of treatment outcomes and rapid identification of effective new therapies.

  7. [Peripheral blood monocyte hepcidin in patients with multiple myeloma is associated with anemia of chronic disease].

    PubMed

    Han, Xiao; Zhou, Dao-Bin; Duan, Ming-Hui; Wang, Xuan; Zhang, Jie-Ping; Zhao, Yong-Qiang; Shen, Ti; Wu, Yong-Ji

    2013-04-01

    Disorders of iron utilization caused by abnormal elevation of hepcidin levels are the main mechanism of anemia of chronic disease. Hepcidin is mainly produced by the liver. Recently it has been found that monocytes are another source of hepcidin. The increased hepcidin in serum and urine of multiple myeloma patients may be one cause of anemia of chronic disease (ACD). However it is unclear whether the peripheral blood monocyte hepcidin is involved in the pathogenesis of anemia of chronic disease. This study was purposed to investigate the role of monocyte hepcidin in multiple myeloma patients with anemia of chronic disease. The clinical data and peripheral venous blood of multiple myeloma patients were collected.Serum concentration of IL-6 and TNF-α was detected by ELISA. Peripheral blood monocytes were isolated by CD14(+) magnetic beads. Hepcidin, IL-6 and TNF-α mRNA of monocytes were detected by real time quantitative PCR. The results showed that the expression level of monocyte hepcidin mRNA in myeloma patients was higher than that in normal controls. In untreated patients, the expression level of monocyte hepcidin mRNA was negatively correlated with hemoglobin, and positively correlated with serum ferritin and IL-6 levels, but unrelated with TNF-α levels.It is concluded that the increased monocyte hepcidin levels in multiple myeloma patients may play an etiologic role in ACD.

  8. Genomic analysis of high-risk smoldering multiple myeloma

    PubMed Central

    López-Corral, Lucía; Mateos, María Victoria; Corchete, Luis A.; Sarasquete, María Eugenia; de la Rubia, Javier; de Arriba, Felipe; Lahuerta, Juan-José; García-Sanz, Ramón; San Miguel, Jesús F.; Gutiérrez, Norma C.

    2012-01-01

    Smoldering myeloma is an asymptomatic plasma cell dyscrasia with a heterogeneous propensity to progress to active myeloma. In order to investigate the biology of smoldering myeloma patients with high risk of progression, we analyzed the genomic characteristics by FISH, SNP-arrays and gene expression profile of a group of patients with high-risk smoldering myeloma included in a multicenter randomized trial. Chromosomal abnormalities detected by FISH and SNP-arrays at diagnosis were not associated to risk of progression to symptomatic myeloma. However, the overexpression of four SNORD genes (SNORD25, SNORD27, SNORD30 and SNORD31) was correlated with shorter time to progression (P<0.03). When plasma cells from high-risk smoldering patients who progressed to symptomatic myeloma were sequentially analyzed, newly acquired lesions together with an increase in the proportion of plasma cells carrying a given abnormality were observed. These findings suggest that gene expression profiling is a valuable technique to identify smoldering myeloma patients with high risk of progression. (Clinical Trials NCT00443235) PMID:22331267

  9. Sexual dysfunction in multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board.

    PubMed

    Richards, Tiffany A; Bertolotti, Page A; Doss, Deborah; McCullagh, Emily J

    2011-08-01

    The World Health Organization describes sexuality as a "central aspect of being human throughout life and encompasses sex, gender identities and roles, sexual orientation, eroticism, pleasure, intimacy, and reproduction. Sexuality is influenced by the interaction of biological, psychological, social, economic, political, cultural, ethical, legal, historical, religious, and spiritual factors." Currently, no research has been conducted regarding sexual dysfunction in patients with multiple myeloma; therefore, information related to the assessment and evaluation of sexual dysfunction is gleaned from other malignancies and diseases. In this article, members of the International Myeloma Foundation's Nurse Leadership Board discuss the definition, presentation, and causes of sexual dysfunction; provide recommendations for sexual assessment practices; and promote discussion among patients with multiple myeloma, their healthcare providers, and their partners.

  10. Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy.

    PubMed

    Narita, T; Ri, M; Masaki, A; Mori, F; Ito, A; Kusumoto, S; Ishida, T; Komatsu, H; Iida, S

    2015-12-04

    Bortezomib (BTZ), a proteasome inhibitor, is widely used in the treatment of multiple myeloma (MM), but a fraction of patients respond poorly to this agent. To identify factors predicting the duration of progression-free survival (PFS) of MM patients on BTZ treatment, the expression of proteasome and endoplasmic reticulum (ER) stress-related genes was quantified in primary samples from patients receiving a combination of BTZ and dexamethasone (BD). Fifty-six MM patients were stratified into a group with PFS<6 months (n=33) and a second group with PFS⩾6 months (n=23). Of the 15 genes analyzed, the expression of activating transcription factor 3 (ATF3) and ATF4 was significantly lower in patients with shorter PFS (P=0.0157 and P=0.0085, respectively). Chromatin immunoprecipitation analysis showed that these ATFs bind each other and transactivate genes encoding the pro-apoptotic transcription factors, CHOP and Noxa, which promote ER stress-associated apoptosis. When either ATF3 or ATF4 expression was silenced, MM cells partially lost sensitivity to BTZ treatment. This was accompanied by lower levels of Noxa, CHOP and DR5. Thus low basal expression of ATF3 and ATF4 may attenuate BTZ-induced apoptosis. Hence, ATF3 and ATF4 could potentially be used as biomarkers to predict efficacy of BD therapy in patients with MM.

  11. Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics.

    PubMed

    Garcia-Gomez, Antonio; Sanchez-Guijo, Fermin; Del Cañizo, M Consuelo; San Miguel, Jesus F; Garayoa, Mercedes

    2014-07-26

    Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented.

  12. Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics

    PubMed Central

    Garcia-Gomez, Antonio; Sanchez-Guijo, Fermin; del Cañizo, M Consuelo; San Miguel, Jesus F; Garayoa, Mercedes

    2014-01-01

    Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented. PMID:25126382

  13. [Recent biological and therapeutic advances in multiple myeloma].

    PubMed

    Coppetelli, U; Avvisati, G; Tribalto, M; Cantonetti, M; La Verde, G; Petrucci, T; Stasi, R; Papa, G

    1992-09-01

    Multiple myeloma still remains a fatal disease. However, in the last months new biological and clinical informations have been provided about this disease. In particular, the immunophenotype of myeloma cells seems indicate, in some patients, a clonal involvement of a stem cell in the pathogenesis of mieloma. Moreover, new biological insights concerning the cytokine network, have revealed a probable effect of some cytokines, such as IL6, IL3, IL4. Finally, new insights in the biology of multiple myeloma have been provided by studies of molecular biology and flow cytometry. As for therapy, the best conventional induction treatment still remains to be defined. In the last years, the increased use of alpha Interferon and new therapeutic modalities, such as transplantation procedures in multiple myeloma, open new hopes toward a cure of this disease. Therefore, in the future a better knowledge of the multiple myeloma biology, associated with a wider use of new effective therapeutic approaches will certainly improve the natural course of this disease. PMID:1439122

  14. In anemia of multiple myeloma hepcidin is induced by increased bone-morphogenetic protein-2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hepcidin is the principal iron-regulatory hormone and pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contrib...

  15. Bone marrow invasion in multiple myeloma and metastatic disease.

    PubMed

    Vilanova, J C; Luna, A

    2016-04-01

    Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases. PMID:26767542

  16. Bone marrow invasion in multiple myeloma and metastatic disease.

    PubMed

    Vilanova, J C; Luna, A

    2016-04-01

    Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases.

  17. HSP90 inhibitors as therapy for multiple myeloma.

    PubMed

    Usmani, Saad Z; Chiosis, Gabriela

    2011-06-01

    The heat shock protein 90 (HSP90) family of proteins are ubiquitous molecular chaperones that are intricately involved in folding, activation, maturation, and assembly of many proteins that include essential mediators of signal transduction and cell cycle progression. They are abundant in eukaryotic cells and localized to the cytoplasm and mitochondria as well as the endoplasmic reticulum under normal conditions, making up 1% to 2% of all cellular proteins. HSP90 proteins have increased expression in a number of malignancies, including multiple myeloma. HSP90 inhibition can influence multiple oncogenic pathways and proteins involved in myeloma, therefore making it an attractive target for drug development in this disease. This article serves as an overview of the pre-clinical data and clinical trial data on HSP90 inhibitors in multiple myeloma.

  18. [Multiple myeloma and venous thrombosis. Which thromboprophylaxis should be given?].

    PubMed

    de Moreuil, C; Ianotto, J-C; Eveillard, J-R; Carrier, M; Delluc, A

    2016-07-01

    Multiple myeloma is a malignant plasma cells dyscrasia that mainly affects patients older than 65 years. These patients are at a higher risk for venous thromboembolism (VTE) because of cancer status, intrinsic risk factors, and exposure to prothrombotic therapies. The risk for VTE appears higher during the first months of myeloma treatment and decreases over time. Exposure to immunomodulatory drugs (IMIDs) such as thalidomide or lenalidomide in association with high doses of dexamethasone or anthracyclin-based chemotherapy is associated with a four-fold increased risk for VTE. Low-dose aspirin, preventive-dose of low molecular weight heparin (LMWH) or vitamin K antagonists were tested for primary prevention of VTE in myeloma patients receiving chemotherapy. The International Myeloma Working Group (IMWG) suggests stratifying VTE risk to decide which patients should receive VTE prevention. Then, the IMWG suggests giving low-dose aspirin to low VTE risk patients and LMWH or vitamin K antagonists to patients at high risk for VTE. For daily practice, it seems reasonable to start preventive doses of LMWH for 3 to 6 months in ambulatory myeloma patients receiving combined therapy with IMID and in all myeloma patients admitted to hospital. PMID:26833146

  19. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.

    PubMed

    Kumar, Shaji; Paiva, Bruno; Anderson, Kenneth C; Durie, Brian; Landgren, Ola; Moreau, Philippe; Munshi, Nikhil; Lonial, Sagar; Bladé, Joan; Mateos, Maria-Victoria; Dimopoulos, Meletios; Kastritis, Efstathios; Boccadoro, Mario; Orlowski, Robert; Goldschmidt, Hartmut; Spencer, Andrew; Hou, Jian; Chng, Wee Joo; Usmani, Saad Z; Zamagni, Elena; Shimizu, Kazuyuki; Jagannath, Sundar; Johnsen, Hans E; Terpos, Evangelos; Reiman, Anthony; Kyle, Robert A; Sonneveld, Pieter; Richardson, Paul G; McCarthy, Philip; Ludwig, Heinz; Chen, Wenming; Cavo, Michele; Harousseau, Jean-Luc; Lentzsch, Suzanne; Hillengass, Jens; Palumbo, Antonio; Orfao, Alberto; Rajkumar, S Vincent; San Miguel, Jesus; Avet-Loiseau, Herve

    2016-08-01

    Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments. PMID:27511158

  20. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.

    PubMed

    Kumar, Shaji; Paiva, Bruno; Anderson, Kenneth C; Durie, Brian; Landgren, Ola; Moreau, Philippe; Munshi, Nikhil; Lonial, Sagar; Bladé, Joan; Mateos, Maria-Victoria; Dimopoulos, Meletios; Kastritis, Efstathios; Boccadoro, Mario; Orlowski, Robert; Goldschmidt, Hartmut; Spencer, Andrew; Hou, Jian; Chng, Wee Joo; Usmani, Saad Z; Zamagni, Elena; Shimizu, Kazuyuki; Jagannath, Sundar; Johnsen, Hans E; Terpos, Evangelos; Reiman, Anthony; Kyle, Robert A; Sonneveld, Pieter; Richardson, Paul G; McCarthy, Philip; Ludwig, Heinz; Chen, Wenming; Cavo, Michele; Harousseau, Jean-Luc; Lentzsch, Suzanne; Hillengass, Jens; Palumbo, Antonio; Orfao, Alberto; Rajkumar, S Vincent; San Miguel, Jesus; Avet-Loiseau, Herve

    2016-08-01

    Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.

  1. Multiple myeloma and family history of lymphohaematopoietic cancers: Results from the International Multiple Myeloma Consortium.

    PubMed

    Schinasi, Leah H; Brown, Elizabeth E; Camp, Nicola J; Wang, Sophia S; Hofmann, Jonathan N; Chiu, Brian C; Miligi, Lucia; Beane Freeman, Laura E; de Sanjose, Silvia; Bernstein, Leslie; Monnereau, Alain; Clavel, Jacqueline; Tricot, Guido J; Atanackovic, Djordje; Cocco, Pierluigi; Orsi, Laurent; Dosman, James A; McLaughlin, John R; Purdue, Mark P; Cozen, Wendy; Spinelli, John J; de Roos, Anneclaire J

    2016-10-01

    Family clusters of multiple myeloma (MM) suggest disease heritability. Nevertheless, patterns of inheritance and the importance of genetic versus environmental risk factors in MM aetiology remain unclear. We pooled data from eleven case-control studies from the International Multiple Myeloma Consortium to characterize the association of MM risk with having a first-degree relative with a history of a lympho-haematapoietic cancer. Unconditional logistic regression models, adjusted for study, sex, age and education level, were used to estimate associations between MM risk and having a first-degree relative with a history of non-Hodgkin lymphoma, Hodgkin lymphoma, leukaemia or MM. Sex, African American race/ethnicity and age were explored as effect modifiers. A total of 2843 cases and 11 470 controls were included. MM risk was elevated in association with having a first-degree relative with any lympho-haematapoietic cancer (Odds Ratio (OR) = 1·29, 95% Confidence Interval (CI): 1·08-1·55). The association was particularly strong for having a first-degree relative with MM (OR = 1·90, 95% CI: 1·26-2·87), especially among men (OR = 4·13, 95% CI: 2·17-7·85) and African Americans (OR = 5·52, 95% CI: 1·87-16·27).These results support the hypothesis that genetic inheritance plays a role in MM aetiology. Future studies are warranted to characterize interactions of genetic markers with environmental exposures.

  2. [Thalidomide-associated hypothyroidism in a patient with multiple myeloma].

    PubMed

    Okamura, Ikue; Ikeda, Takashi; Sato, Ken; Kimura, Fumihiko

    2015-01-01

    Thalidomide is highly effective against multiple myeloma, but some patients must discontinue this medication due to adverse effects. We present herein an instructive case report on thalidomide-associated hypothyroidism in a patient with multiple myeloma. Thyroid hormone replacement therapy allowed us to restart administration of thalidomide, a potentially life-saving therapy. Known adverse effects of thalidomide, such as lethargy, constipation, and bradycardia, are potential symptoms of hypothyroidism, but we tend to overlook drug-associated hypothyroidism. Our case highlights the importance of routinely testing thyroid function in patients receiving thalidomide therapy.

  3. Multiple Myeloma: A Review of Imaging Features and Radiological Techniques

    PubMed Central

    Healy, C. F.; Murray, J. G.; Eustace, S. J.; Madewell, J.; O'Gorman, P. J.; O'Sullivan, P.

    2011-01-01

    The recently updated Durie/Salmon PLUS staging system published in 2006 highlights the many advances that have been made in the imaging of multiple myeloma, a common malignancy of plasma cells. In this article, we shall focus primarily on the more sensitive and specific whole-body imaging techniques, including whole-body computed tomography, whole-body magnetic resonance imaging, and positron emission computed tomography. We shall also discuss new and emerging imaging techniques and future developments in the radiological assessment of multiple myeloma. PMID:22046568

  4. Multiple myeloma: a review of imaging features and radiological techniques.

    PubMed

    Healy, C F; Murray, J G; Eustace, S J; Madewell, J; O'Gorman, P J; O'Sullivan, P

    2011-01-01

    The recently updated Durie/Salmon PLUS staging system published in 2006 highlights the many advances that have been made in the imaging of multiple myeloma, a common malignancy of plasma cells. In this article, we shall focus primarily on the more sensitive and specific whole-body imaging techniques, including whole-body computed tomography, whole-body magnetic resonance imaging, and positron emission computed tomography. We shall also discuss new and emerging imaging techniques and future developments in the radiological assessment of multiple myeloma.

  5. Identification of the source of elevated hepatocyte growth factor levels in multiple myeloma patients

    PubMed Central

    2014-01-01

    Background Hepatocyte growth factor (HGF) is a pleiotropic cytokine which can lead to cancer cell proliferation, migration and metastasis. In multiple myeloma (MM) patients it is an abundant component of the bone marrow. HGF levels are elevated in 50% of patients and associated with poor prognosis. Here we aim to investigate its source in myeloma. Methods HGF mRNA levels in bone marrow core biopsies from healthy individuals and myeloma patients were quantified by real-time PCR. HGF gene expression profiling in CD138+ cells isolated from bone marrow aspirates of healthy individuals and MM patients was performed by microarray analysis. HGF protein concentrations present in peripheral blood of MM patients were measured by enzyme-linked immunosorbent assay (ELISA). Cytogenetic status of CD138+ cells was determined by fluorescence in situ hybridization (FISH) and DNA sequencing of the HGF gene promoter. HGF secretion in co-cultures of human myeloma cell lines and bone marrow stromal cells was measured by ELISA. Results HGF gene expression profiling in both bone marrow core biopsies and CD138+ cells showed elevated HGF mRNA levels in myeloma patients. HGF mRNA levels in biopsies and in myeloma cells correlated. Quantification of HGF protein levels in serum also correlated with HGF mRNA levels in CD138+ cells from corresponding patients. Cytogenetic analysis showed myeloma cell clones with HGF copy numbers between 1 and 3 copies. There was no correlation between HGF copy number and HGF mRNA levels. Co-cultivation of the human myeloma cell lines ANBL-6 and JJN3 with bone marrow stromal cells or the HS-5 cell line resulted in a significant increase in secreted HGF. Conclusions We here show that in myeloma patients HGF is primarily produced by malignant plasma cells, and that HGF production by these cells might be supported by the bone marrow microenvironment. Considering the fact that elevated HGF serum and plasma levels predict poor prognosis, these findings are of

  6. Genetics of multiple myeloma: another heterogeneity level?

    PubMed Central

    Corre, Jill; Munshi, Nikhil

    2015-01-01

    Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies because of the inherent difficulties in generating metaphases within the malignant plasma cell clone. With the development of molecular techniques (microarrays and next-generation sequencing), our understanding has been highly improved in the past 5 years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution. PMID:25628468

  7. [Palmar-plantar fasciitis and multiple myeloma].

    PubMed

    Rammeh, Nadia; Elleuch, Mohamed; Meddeb, Nihel; Sahli, Héla; Cheour, Elhem; Sellami, Slaheddine

    2003-11-01

    Palmar fasciitis and arthritis was reported in association with several neoplasms and in particular with the cancers of the ovary. We report the case of a 37 year old patient who was hospitalized in our service for investigation of sever palmar fasciitis and to whom various investigations allowed to make the diagnosis of a light chains myeloma. Through the study of the various cases of the literature, we remind the various characteristics of this syndrome.

  8. Survivorship Care Guidelines for Patients Living With Multiple Myeloma: Consensus Statements of the International Myeloma Foundation Nurse Leadership Board

    PubMed Central

    Bilotti, Elizabeth; Faiman, Beth M.; Richards, Tiffany A.; Tariman, Joseph D.; Miceli, Teresa S.; Rome, Sandra I.

    2012-01-01

    Novel therapies approved over the past decade for the management of multiple myeloma have contributed to improved overall survival in patients with newly diagnosed and relapsed disease. Nurses play a key role in educating, advocating for, and supporting patients throughout the continuum of care. Identifying potential and actual comorbid conditions associated directly with multiple myeloma and its treatment is important, as is confirming those that are patient specific so that prompt intervention can take place; therefore, the International Myeloma Foundation Nurse Leadership Board identified the most significant needs of patients diagnosed with multiple myeloma as bone health, health maintenance, mobility and safety, sexual dysfunction, and renal health. The Nurse Leadership Board then developed a survivorship care plan to assist healthcare providers and patients with multiple myeloma, their partners, and their caregivers to identify these needs. PMID:21816706

  9. Sarcoidosis and multiple myeloma: Concurrent presentation of an unusual association.

    PubMed

    Nair, Vidya; Prajapat, Deepak; Talwar, Deepak

    2016-01-01

    Literature on concurrent association of sarcoidosis with lymphoproliferative malignancies other than lymphoma e.g. multiple myeloma is meager. The rarity of the situation prompted us to report this patient who was a 51-year-old woman with a 2-years history of breathlessness, cough with expectoration, chest pain and backache. Initial evaluation revealed mild anemia, increased alkaline phosphatase with chest skiagram showing both lower zone non homogenous opacities with calcified hilar lymph nodes. CECT chest showed mediastinal with bilateral hilar lymphadenopathy, parenchymal fibrosis, traction bronchiectasis, ground glass opacities, septal and peribronchovascular thickening affecting mid and lower lung zones bilaterally. MRI Dorsolumbar spine was suggestive of marrow infiltrative disorder. EBUS FNA of intrathoracic nodes, EBB and TBLB confirmed sarcoidosis. PET CT revealed hyper metabolic activity in lung, multiple lymph nodes and lytic bone lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin IgG kappa type. Bone marrow biopsy revealed an increase in plasma cells (15%), but no granulomas. Diagnosis of Indolent or multiple myeloma with sarcoidosis was established. 12 cases of sarcoidosis and multiple myeloma have been reported in literature, and mostly preceding the onset of multiple myeloma by many years, in our case both were diagnosed concurrently. PMID:26933313

  10. Sarcoidosis and multiple myeloma: Concurrent presentation of an unusual association

    PubMed Central

    Nair, Vidya; Prajapat, Deepak; Talwar, Deepak

    2016-01-01

    Literature on concurrent association of sarcoidosis with lymphoproliferative malignancies other than lymphoma e.g. multiple myeloma is meager. The rarity of the situation prompted us to report this patient who was a 51-year-old woman with a 2-years history of breathlessness, cough with expectoration, chest pain and backache. Initial evaluation revealed mild anemia, increased alkaline phosphatase with chest skiagram showing both lower zone non homogenous opacities with calcified hilar lymph nodes. CECT chest showed mediastinal with bilateral hilar lymphadenopathy, parenchymal fibrosis, traction bronchiectasis, ground glass opacities, septal and peribronchovascular thickening affecting mid and lower lung zones bilaterally. MRI Dorsolumbar spine was suggestive of marrow infiltrative disorder. EBUS FNA of intrathoracic nodes, EBB and TBLB confirmed sarcoidosis. PET CT revealed hyper metabolic activity in lung, multiple lymph nodes and lytic bone lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin IgG kappa type. Bone marrow biopsy revealed an increase in plasma cells (15%), but no granulomas. Diagnosis of Indolent or multiple myeloma with sarcoidosis was established. 12 cases of sarcoidosis and multiple myeloma have been reported in literature, and mostly preceding the onset of multiple myeloma by many years, in our case both were diagnosed concurrently. PMID:26933313

  11. Plasma cell morphology in multiple myeloma and related disorders.

    PubMed

    Ribourtout, B; Zandecki, M

    2015-06-01

    Normal and reactive plasma cells (PC) are easy to ascertain on human bone marrow films, due to their small mature-appearing nucleus and large cytoplasm, the latter usually deep blue after Giemsa staining. Cytoplasm is filled with long strands of rough endoplasmic reticulum and one large Golgi apparatus (paranuclear hof), demonstrating that PC are dedicated mainly to protein synthesis and excretion (immunoglobulin). Deregulation of the genome may induce clonal expansion of one PC that will lead to immunoglobulin overproduction and eventually to one among the so-called PC neoplasms. In multiple myeloma (MM), the number of PC is over 10% in most patients studied. Changes in the morphology of myeloma PC may be inconspicuous as compared to normal PC (30-50% patients). In other instances PC show one or several morphological changes. One is related to low amount of cytoplasm, defining lymphoplasmacytoid myeloma (10-15% patients). In other cases (40-50% patients), named immature myeloma cases, nuclear-cytoplasmic asynchrony is observed: presence of one nucleolus, finely dispersed chromatin and/or irregular nuclear contour contrast with a still large and blue (mature) cytoplasm. A peculiar morphological change, corresponding to the presence of very immature PC named plasmablasts, is observed in 10-15% cases. Several prognostic morphological classifications have been published, as mature myeloma is related to favorable outcome and immature myeloma, peculiarly plasmablastic myeloma, is related to dismal prognosis. However, such classifications are no longer included in current prognostic schemes. Changes related to the nucleus are very rare in monoclonal gammopathy of unknown significance (MGUS). In contrast, anomalies related to the cytoplasm of PC, including color (flaming cells), round inclusions (Mott cells, Russell bodies), Auer rod-like or crystalline inclusions, are reported in myeloma cases as well as in MGUS and at times in reactive disorders. They do not correspond

  12. Membranous glomerulonephritis after haematopoietic cell transplantation for multiple myeloma.

    PubMed

    Rossi, L; Cardarelli, F; Vampa, M L; Buzio, C; Olivetti, G

    2001-07-01

    Renal involvement during graft-versus-host disease following haematopoietic cell transplantation for multiple myeloma has never been described. We report a case of a recipient who developed nephrotic syndrome and membranous glomerulonephritis 22 months after the graft and 6 months after cyclosporine withdrawal. Symptoms resolved when immunosuppressive therapy was reinstituted.

  13. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.

    PubMed

    Rajkumar, S Vincent; Lacy, Martha Q; Kyle, Robert A

    2007-09-01

    Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic disorders characterized by monoclonal plasma cell proliferation in the bone marrow in the absence of end-organ damage. Updated diagnostic criteria for these disorders, risk-stratification models to determine prognosis, and the current management of these two entities are discussed in this review. PMID:17367905

  14. [Secondary cutaneous plasmacytoma revealing multiple myeloma: about a case].

    PubMed

    Ngolet, Lydie Ocini; N'soundhat, Norbert Lamini; Ndounga, Eliane; Kocko, Innocent; Kidédé, Daphtone Chabel Nkouala; Ntsiba, Honoré

    2016-01-01

    Secondary metastatic cutaneous plasmacytoma is a multiple extramedullary plasma cell proliferation involving skin. Its diagnosis is based on the identification of malignant plasma cells proliferation in the bone marrow and in the skin. Its occurrence is associated with advanced myeloma and a poor prognosis. PMID:27642385

  15. Type B lactic acidosis associated with multiple myeloma.

    PubMed

    Sia, Patrick; Plumb, Troy J; Fillaus, Jennifer A

    2013-09-01

    We present a 58-year-old man with recurrent multiple myeloma treated with 2 autologous stem cell transplantations. He was admitted for dyspnea and found to have severe type B lactic acidosis with serum lactate level of 193.6 mg/dL. This case reviews malignancy-associated type B lactic acidosis and discusses its etiology, pathogenesis, and management.

  16. Multiple myeloma on polycythemia vera following radioactive phosphorus therapy.

    PubMed

    West, W O

    1976-11-01

    A 74-year-old white man with established polycythemia vera was treated with radioactive phosphorus after phlebotomies alone failed to control his disease. About 2 3/4 years later he died of multiple myeloma. The mutagenic effect of radioactive phosphorus may have caused or possibly accelerated preexisting myeloma. Basic nonmalignant disease deserves careful consideration before radiation or radiomimetic agents are used. One might consider a probably less mutagenic drug such as hydroxyurea in patients with polycythemia vera when phlebotomy alone does not give good control of red cell mass and thrombocytosis.

  17. Hypoxia inducible factor-1 alpha and multiple myeloma

    PubMed Central

    Tiwary, Bhupendra Nath

    2016-01-01

    Rapid tumor growth creates a state of hypoxia in the tumor microenvironment and results in release of hypoxia inducible factor-1 alpha (HiF-1α) in the local milieu. Hypoxia inducible factor activity is deregulated in many human cancers, especially those that are highly hypoxic. In multiple myeloma (MM) in initial stages of disease establishment, the hypoxic bone marrow microenvironment supports the initial survival and growth of the myeloma cells. Hypoxic tumour cells are usually resistant to radiotherapy and most conventional chemotherapeutic agents, rendering them highly aggressive and metastatic. Therefore, HIF is an attractive, although challenging, therapeutic target in MM directly or indirectly in recent years. PMID:26900575

  18. Targeting IL-17A in Multiple Myeloma: A Potential Novel Therapeutic Approach in Myeloma

    PubMed Central

    Prabhala, Rao H.; Fulciniti, Mariateresa; Pelluru, Dheeraj; Rashid, Naim; Nigroiu, Andreea; Nanjappa, Puru; Pai, Christine; Lee, Saem; Prabhala, Nithya S.; Bandi, Rajya Lakshmi; Smith, Robert; Lazo-Kallanian, Suzan B.; Valet, Sonia; Raje, Noopur; Gold, Jason S.; Richardson, Paul G.; Daley, John F.; Anderson, Kenneth C.; Ettenberg, Seth A.; Di Padova, Franco; Munshi, Nikhil C.

    2015-01-01

    We have previously demonstrated that interleukin-17A (IL-17) producing Th17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and absence of BM stromal cells (BMSC). While IL-17A induces IL-6 production, AIN457 significantly down-regulated IL-6 production and MM cell-adhesion in MM-BMSC co-culture. AIN-457 also significantly inhibited osteoclast cell–differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN-457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared to isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report here, that MM cells express IL-17A. We also observed that IL-17A knock-down inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN 457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease. PMID:26293646

  19. Sclerostin is overexpressed by plasma cells from multiple myeloma patients.

    PubMed

    Brunetti, Giacomina; Oranger, Angela; Mori, Giorgio; Specchia, Giorgina; Rinaldi, Erminia; Curci, Paola; Zallone, Alberta; Rizzi, Rita; Grano, Maria; Colucci, Silvia

    2011-11-01

    Sclerostin, an osteocyte-expressed negative regulator of bone formation, is one of the inhibitors of Wnt signaling that is a critical pathway in the correct process of osteoblast differentiation. It has been demonstrated that Wnt signaling through the secretion of Wnt inhibitors, such as DKK1, sFRP-2, and sFRP-3, plays a key role in the decreased osteoblast activity associated with multiple myeloma (MM) bone disease. We provide evidence that sclerostin is expressed by myeloma cells that are human myeloma cell lines and plasma cells (CD138(+) cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. Moreover, we show that there are no differences in sclerostin serum levels between MM patients and controls. Thus, our data indicate that MM cells, as a sclerostin source in the BM, could create a microenvironment with high sclerostin concentration that could contribute toward inhibiting osteoblast differentiation.

  20. Proteasome inhibition and its therapeutic potential in multiple myeloma

    PubMed Central

    Chari, Ajai; Mazumder, Amitabha; Jagannath, Sundar

    2010-01-01

    Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma. PMID:21116326

  1. European Myeloma Network Guidelines for the Management of Multiple Myeloma-related Complications

    PubMed Central

    Terpos, Evangelos; Kleber, Martina; Engelhardt, Monika; Zweegman, Sonja; Gay, Francesca; Kastritis, Efstathios; van de Donk, Niels W.C.J.; Bruno, Benedetto; Sezer, Orhan; Broijl, Annemiek; Bringhen, Sara; Beksac, Meral; Larocca, Alessandra; Hajek, Roman; Musto, Pellegrino; Johnsen, Hans Erik; Morabito, Fortunato; Ludwig, Heinz; Cavo, Michele; Einsele, Hermann; Sonneveld, Pieter; Dimopoulos, Meletios A.; Palumbo, Antonio

    2015-01-01

    The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6–8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A). PMID:26432383

  2. European Myeloma Network guidelines for the management of multiple myeloma-related complications.

    PubMed

    Terpos, Evangelos; Kleber, Martina; Engelhardt, Monika; Zweegman, Sonja; Gay, Francesca; Kastritis, Efstathios; van de Donk, Niels W C J; Bruno, Benedetto; Sezer, Orhan; Broijl, Annemiek; Bringhen, Sara; Beksac, Meral; Larocca, Alessandra; Hajek, Roman; Musto, Pellegrino; Johnsen, Hans Erik; Morabito, Fortunato; Ludwig, Heinz; Cavo, Michele; Einsele, Hermann; Sonneveld, Pieter; Dimopoulos, Meletios A; Palumbo, Antonio

    2015-10-01

    The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A). PMID:26432383

  3. Pancytopenia in Multiple Myeloma- An Enigma: Our Experience from Tertiary Care Hospital

    PubMed Central

    Sridevi, Hanaganahalli B; Rai, Sharada; Somesh, Meludurgamutt S; Minal, Jessica

    2015-01-01

    Introduction Multiple myeloma is a plasma cell neoplasm that is characterized by clonal proliferation of malignant plasma cell in the bone marrow along with M-protein in the serum and/or urine. Pancytopenia as a initial presentation of multiple myeloma is quite unusual. We are presenting a case series having pancytopenia as the presenting complaint. Materials and Methods A retrospective study was conducted for a period of 30 months, wherein all the cases of multiple myeloma presenting with pancytopenia were included. The complete blood picture, peripheral smear examination, bone marrow aspirate & protein electrophoresis of all the cases were reviewed & analysed. Results During the study period, 10 cases presented with pancytopenia with a mean age of 66.3 years (range: 59-72 years) at presentation with male: female ratio being 8:2. Fatigue and weakness was the most common symptom (100%) & average ESR was 104 mm/hour. High-resolution serum electrophoresis, showed a dense, sharp to wide M band in the gamma globulin region. Bone marrow plasma cell percentage was increased with an average of 63.1%. Bone marrow biopsy correlation was obtained in 100% cases. Conclusion Diagnosing multiple myeloma, presenting as pancytopenia requires a high degree of suspicion to avoid delay in initiation of treatment. PMID:26673280

  4. Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma.

    PubMed

    Corre, Jill; Labat, Elodie; Espagnolle, Nicolas; Hébraud, Benjamin; Avet-Loiseau, Hervé; Roussel, Murielle; Huynh, Anne; Gadelorge, Mélanie; Cordelier, Pierre; Klein, Bernard; Moreau, Philippe; Facon, Thierry; Fournié, Jean-Jacques; Attal, Michel; Bourin, Philippe

    2012-03-15

    Overexpression of growth differentiation factor 15 (GDF15) by bone marrow mesenchymal stem cells occurs widely in patients with multiple myeloma, but the pathophysiologic effects of GDF15 in this setting remain undefined. GDF15 has been described in numerous solid tumors but never in hematologic malignancies. In this study, we report that GDF15 significantly increases survival of stroma-dependent multiple myeloma cells including primary multiple myeloma cells. In particular, GDF15 conferred resistance to melphalan, bortezomib, and to a lesser extent, lenalidomide in both stroma-dependent and stroma-independent multiple myeloma cells. Akt-dependent signaling was critical to mediate the effects of GDF15, whereas Src and extracellular signal-regulated kinase 1/2 signaling pathways were not involved. Given these results, we tested the clinical significance of plasma concentrations of GDF15 (pGDF15) in 131 patients with multiple myeloma and found that it correlated with disease prognosis. Specifically, patients with high levels of pGDF15 had lower probabilities of event-free and overall survival 30 months after diagnosis than patients with low pGDF15 levels. Our findings suggest that tumor microenvironment-derived GDF15 is a key survival and chemoprotective factor for multiple myeloma cells, which is pathophysiologically linked to both initial parameters of the disease as well as patient survival.

  5. Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma

    PubMed Central

    Kervoëlen, Charlotte; Ménoret, Emmanuelle; Gomez-Bougie, Patricia; Bataille, Régis; Godon, Catherine; Marionneau-Lambot, Séverine; Moreau, Philippe; Pellat-Deceunynck, Catherine; Amiot, Martine

    2015-01-01

    Due to its cytotoxic effect in lymphoid cells, dexamethasone is widely used in the treatment of multiple myeloma (MM). However, only a subset of myeloma patients responds to high-dose dexamethasone. Despite the undeniable anti-myeloma benefits of dexamethasone, significant adverse effects have been reported. We re-evaluate the anti-tumor effect of dexamethasone according to the molecular heterogeneity of MM. We demonstrated that the pro-death effect of dexamethasone is related to the genetic heterogeneity of MM because sensitive cell lines were restricted to MAF and MMSET signature subgroups, whereas all CCND1 cell lines (n = 10) were resistant to dexamethasone. We demonstrated that the glucocorticoid receptor expression was an important limiting factor for dexamethasone-induced cell death and we found a correlation between glucocorticoid receptor levels and the induction of glucocorticoid-induced leucine zipper (GILZ) under dexamethasone treatment. By silencing GILZ, we next demonstrated that GILZ is necessary for Dex induced apoptosis while triggering an imbalance between anti- and pro-apoptotic Bcl-2 proteins. Finally, the heterogeneity of the dexamethasone response was further confirmed in vivo using myeloma xenograft models. Our findings suggested that the effect of dexamethasone should be re-evaluated within molecular subgroups of myeloma patients to improve its efficacy and reduce its adverse effects. PMID:26323097

  6. Proteasome Inhibitors in the Treatment of Multiple Myeloma

    PubMed Central

    Shah, Jatin J.; Orlowski, Robert Z.

    2016-01-01

    Targeting intracellular protein turnover by inhibiting the ubiquitin-proteasome pathway as a strategy for cancer therapy is a new addition to our chemotherapeutic armamentarium, and has seen its greatest successes against multiple myeloma. The first-in-class proteasome inhibitor bortezomib was initially approved for treatment of patients in the relapsed/refractory setting as a single agent, and was recently shown to induce even greater benefits as part of rationally-designed combinations that overcome chemoresistance. Modulation of proteasome function is also a rational approach to achieve chemosensitization to other anti-myeloma agents, and bortezomib has now been incorporated into the front-line setting. Bortezomib-based induction regimens are able to achieve higher overall response rates and response qualities than was the case with prior standards of care, and unlike these older approaches, maintain efficacy in patients with clinically- and molecularly-defined high-risk disease. Second-generation proteasome inhibitors with novel properties, such as NPI-0052 and carfilzomib, are entering the clinical arena, and showing evidence of anti-myeloma activity. In this spotlight review, we provide an overview of the current state of the art use of bortezomib and other proteasome inhibitors against multiple myeloma, and highlight areas for future study that will further optimize our ability to benefit patients with this disease. PMID:19741722

  7. Pathogenesis beyond the cancer clone(s) in multiple myeloma

    PubMed Central

    Bianchi, Giada

    2015-01-01

    Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment. PMID:25838343

  8. Pathogenesis beyond the cancer clone(s) in multiple myeloma.

    PubMed

    Bianchi, Giada; Munshi, Nikhil C

    2015-05-14

    Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment. PMID:25838343

  9. Notch signaling deregulation in multiple myeloma: A rational molecular target

    PubMed Central

    Garavelli, Silvia; Platonova, Natalia; Paoli, Alessandro; Basile, Andrea; Taiana, Elisa; Neri, Antonino; Chiaramonte, Raffaella

    2015-01-01

    Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches. PMID:26308486

  10. B-Lymphocyte stimulator: a new biomarker for multiple myeloma.

    PubMed

    Jiang, Pu; Yueguo, Wang; Huiming, Huang; Hongxiang, Yuan; Mei, Wang; Ju, Shaoqing

    2009-04-01

    Multiple myeloma (MM) is a common malignant tumor, characterized by unlimited proliferation of abnormal plasmocytes in bone marrow. Considering the biological function of B-Lymphocyte stimulator (BLyS) and its receptors in B cell, we examined BLyS and its receptors expression in MM cells. Our studies confirmed that BLyS and its receptors are expressed in MM cells, including KM3, CZ-1, and primary MM cells, playing an important role in the survival and proliferation of MM cells. Additionally, we provide evidence that BLyS protein is located in the MM cell plasma membrane. We also found that IFN-gamma and IL-6 can induce BLyS expression on MM cells, while after the treatment of BAY11-7082, an IkB-alpha phosphorylation inhibitor, IFN-gamma induced up regulation of BLyS was completely inhibited, suggesting that nuclear factor kappaB (NF-kappaB) might be involved in the mechanism of the regulation of BLyS levels in response to cytokines. Finally, linear correlation analysis of the Lactate Dehydrogenase concentration and beta 2-microglobulin level with BLyS, and expressions of BLyS mRNA in MM patients revealed a significant correlation between them (P < 0.01 in all case), showing that BLyS could be a biomarker for the diagnosis and treatment of MM.

  11. Smoldering multiple myeloma and monoclonal gammopathy of undetermined significance.

    PubMed

    Bladé, Joan; Rosiñol, Laura

    2006-05-01

    Smoldering multiple myeloma (SMM) consists of the presence of a serum M protein of 30 g/L or more and/or 10% or more bone marrow plasma cells (BMPCs), with no clinical manifestations or symptoms of myeloma. It accounts for approximately 10% of all myelomas, and the median time to progression to a symptomatic multiple myeloma ranges from 2 to 3 years. The main factors for progression are the plasma cell mass (M-protein size and percent of BMPCs), the spinal MRI pattern, the plasma cell proliferative index, and the variant of SMM ("evolving" vs "nonevolving"). Although treatment with thalidomide is promising (based on the results of two phase II trials), outside the context of a clinical trial, a watch-and-wait approach with clinical evaluation every 4 months is recommended until evident symptomatic disease progression occurs. Patients with monoclonal gammopathy of undetermined significance (MGUS) have a serum M protein lower than 30 g/L and a proportion of BMPCs of less than 10%, with no clinical findings or symptoms attributable to the monoclonal gammopathy. MGUS has a high prevalence, and its annual rate of malignant transformation is 1%, such that the actuarial probability of progression to a symptomatic monoclonal gammopathy at 25 years of follow-up is as high as 40%. The factors associated with a higher probability of malignant transformation are a relatively high plasma cell mass, immunoglobulin A M-protein type, and the "evolving" variant. It is recommended that patients with MGUS are monitored annually. Importantly, patients with asymptomatic monoclonal gammopathies must not be treated before the development of overt multiple myeloma. PMID:16615879

  12. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies.

    PubMed

    Landgren, Ola

    2013-01-01

    After decades of virtually no progress, multiple myeloma survival has improved significantly in the past 10 years. Indeed, multiple myeloma has perhaps seen more remarkable progress in treatment and patient outcomes than any other cancer during the last decade. Recent data show that multiple myeloma is consistently preceded by a precursor state (monoclonal gammopathy of undetermined significance [MGUS]/smoldering multiple myeloma [SMM]). This observation provides a framework for prospective studies focusing on transformation from precursor disease to multiple myeloma and for the development of treatment strategies targeting "early myeloma." This review discusses current biological insights in MGUS/SMM, provides an update on clinical management, and discusses how the integration of novel biological markers, molecular imaging, and clinical monitoring of MGUS/SMM could facilitate the development of early treatment strategies for high-risk SMM (early myeloma) patients in the future. PMID:24319222

  13. Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma.

    PubMed

    Ludwig, Heinz; Milosavljevic, Dejan; Berlanga, Oscar; Zojer, Niklas; Hübl, Wolfgang; Fritz, Veronique; Harding, Stephen

    2016-03-01

    Heavy light chain (HLC) assays allow precise measurement of the monoclonal and of the noninvolved polyclonal immunoglobulins of the same isotype as the M-protein (e.g., monoclonal IgAκ and polyclonal IgAλ in case of an IgAκ myeloma), which was not possible before. The noninvolved polyclonal immunoglobulin is termed 'HLC-matched pair'. We investigated the impact of the suppression of the HLC-matched pair on outcome in 203 patients with multiple myeloma, a phenomenon that likely reflects the host's attempt to control the myeloma clone. Severe (>50%) HLC-matched pair suppression was identified in 54.5% of the 156 newly diagnosed patients and was associated with significantly shorter survival (45.4 vs. 71.9 months, P = 0.019). This correlation was statistically significant in IgG patients (46.4 vs. 105.1 months, P = 0.017), but not in patients with IgA myelomas (32.9 vs. 54.1 months, P = 0.498). At best response, HLC-matched pair suppression improved only in patients with ≥VGPR, indicating partial or complete humoral immune reconstitution during remission in those with excellent response. Severe HLC-matched pair suppression retained its prognostic impact also during follow-up after first response. In the 47 pretreated patients with relapsed/refractory disease, a similar correlation between severe HLC suppression and survival was noted (22.8 vs. not reached, P = 0.028). Suppression of the polyclonal immunoglobulins of the other isotypes than the myeloma protein correlated neither with HLC-matched pair suppression, nor with outcome. Multivariate analysis identified severe HLC-matched pair suppression as independent risk factor for shorter survival, highlighting the impact of isotype specific immune dysregulation on outcome in multiple myeloma.

  14. Whole bone marrow irradiation for the treatment of multiple myeloma

    SciTech Connect

    Coleman, M.; Saletan, S.; Wolf, D.; Nisce, L.; Wasser, J.; McIntyre, O.R.; Tulloh, M.

    1982-04-01

    Nine patients with multiple myeloma were treated with whole bone marrow irradiation. Six had heavily pretreated disease refractory to chemotherapy. Three had stable disease lightly pretreated by chemotherapy. A modification of the ''three and two'' total nodal radiation technique was employed. Although varying and often severe treatment related cytopenia occurred, infectious complications, clinical bleeding, and nonhematalogic complications were minimal. Five of nine patients showed a decrease in monoclonal protein components, and one showed an increase during treatment. These preliminary results indicate that a reduction of tumor cell burden may occur in patients following whole bone marrow irradiation and that the technique is feasible. Whole bone marrow irradiation combined with chemotherapy represents a new conceptual therapeutic approach for multiple myeloma.

  15. Mandibular destructive radiolucent lesion: The first sign of multiple myeloma

    PubMed Central

    Fregnani, Eduardo-Rodrigues; Leite, Amanda-Almeida; Parahyba, Claudia-Joffily; Nesrallah, Ana-Cristina-Alo; Ramos-Perez, Flávia-Maria-de Moraes

    2016-01-01

    The occurrence of a mandibular lesion as the first sign of multiple myeloma (MM) is uncommon. This report describes a case of MM diagnosed because of a mandibular lesion. A 62-year-old woman presented a destructive radiolucent lesion in the right mandibular ramus. The lesion caused rupture of the anterior cortical bone and extended from the retromolar area to the coronoid process. An incisional biopsy was performed. Histopathological examination revealed numerous pleomorphic plasma cells, some with binucleated nuclei. The tumor cells showed kappa light-chain restriction. Bone marrow biopsy showed findings of massive infiltration of neoplastic plasma cells, besides lesions in the vertebrae. The diagnosis of MM was established. The patient underwent autologous hematopoietic stem-cell transplantation. Currently, the patient is under regular follow up after 40 months of initial treatment. In conclusion, MM should be considered in the differential diagnosis of destructive mandibular lesions. Key words:Mandible, multiple myeloma, radiolucent lesion. PMID:27703618

  16. Multiple myeloma: clinical features and indications for therapy.

    PubMed

    Dispenzieri, Angela; Kyle, Robert A

    2005-01-01

    Multiple myeloma is a malignant plasma-cell proliferative disease with an expected 15,270 new cases and 11,070 deaths in the USA in 2004 alone. This accounts for 1% of all malignancies and slightly more than 10% of all hematologic malignancies in Caucasians and 20% in African Americans. The diagnosis is based on the presence of bone pain, anemia, and plasma-cell infiltrate in the bone marrow or within bone lesions. It is essential that the spectrum of plasma-cell proliferative disorders be recognized: monoclonal gammopathy of undetermined significance (MGUS), smoldering (asymptomatic) multiple myeloma (SMM), and active (symptomatic) MM. These distinctions affect important management decisions. Other related disorders include primary systemic amyloidosis, POEMS syndrome, and acquired Fanconi syndrome. PMID:16026737

  17. Interpretation of cytogenetic results in multiple myeloma for clinical practice

    PubMed Central

    Rajan, A M; Rajkumar, S V

    2015-01-01

    The interpretation of cytogenetic abnormalities in multiple myeloma (MM) is often a challenging task. MM is characterized by several cytogenetic abnormalities that occur at various time points in the disease course. The interpretation of cytogenetic results in MM is complicated by the number and complexity of the abnormalities, the methods used to detect them and the disease stage at which they are detected. Specific cytogenetic abnormalities affect clinical presentation, progression of smoldering multiple myeloma (SMM) to MM, prognosis of MM and management strategies. The goal of this paper is to provide a review of how MM is classified into specific subtypes based on primary cytogenetic abnormalities and to provide a concise overview of how to interpret cytogenetic abnormalities based on the disease stage to aid clinical practice and patient management. PMID:26517360

  18. Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma without Cryopreservation

    PubMed Central

    Al-Anazi, Khalid Ahmed

    2012-01-01

    High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation is considered the standard of care for multiple myeloma patients who are eligible for transplantation. The process of autografting comprises the following steps: control of the primary disease by using a certain induction therapeutic protocol, mobilization of stem cells, collection of mobilized stem cells by apheresis, cryopreservation of the apheresis product, administration of high-dose pretransplant conditioning therapy, and finally infusion of the cryopreserved stem cells after thawing. However, in cancer centers that treat patients with multiple myeloma and have transplantation capabilities but lack or are in the process of acquiring cryopreservation facilities, alternatively noncryopreserved autologous stem cell therapy has been performed with remarkable success as the pretransplant conditioning therapy is usually brief. PMID:22693672

  19. Management of multiple myeloma in Asia: resource-stratified guidelines.

    PubMed

    Tan, Daryl; Chng, Wee Joo; Chou, Takaaki; Nawarawong, Weerasak; Hwang, Shang-Yi; Chim, Chor Sang; Chen, Wenming; Durie, Brian G M; Lee, Jae Hoon

    2013-11-01

    Treatment of multiple myeloma has undergone substantial developments in the past 10 years. The introduction of novel drugs has changed the treatment of the disease and substantially improved survival outcomes. Clinical practice guidelines based on evidence have been developed to provide recommendations on standard treatment approaches. However, the guidelines do not take into account resource limitations encountered by developing countries. The huge disparities in economy, health-care infrastructure, and access to novel drugs in Asian countries hinder the delivery of optimum care to every patient with multiple myeloma in Asia. In this Review we outline the guidelines that correspond with different levels of health-care resources and expertise, with the aim to unify diagnostic and therapeutic guidelines and help with the design of future studies in Asia.

  20. Multiple myeloma in the United States, 1950--1975

    SciTech Connect

    Blattner, W.A.; Blair, A.; Mason, T.J.

    1981-12-01

    A total of 68,400 whites and 10,533 nonwhites were reported to have died from multiple myeloma (MM) in the continental United States between 1950 and 1975 (excluding 1972 because of incomplete case ascertainment). Age-adjusted mortality rates for nonwhites were approximately twice as high as for whites. During the 25-year period of this survey, there was a twofold to threefold increase in MM mortality. The increase was seen in both races, but was greater in nonwhites than whites and primarily occurred in people over 55 years of age. The increases were uniform in all geographic regions and urban/rural categories. MM mortality from 1950--1969 was correlated with geographic, demographic, and occupational factors at the county level. The rates were highest in the far west and mid-central regions for whites and in the northeast for nonwhites. Urban areas had the highest rates and rural areas had the lowest, and positive associations were seen with indices of socioeconomic level and the percentage of residents with Scandinavian ancestry. For white males, MM mortality rates were elevated in areas with high petroleum and paper production, and a slight increase was seen in furniture manufacturing areas.

  1. Sacroplasty for Local or Massive Localization of Multiple Myeloma

    SciTech Connect

    Basile, Antonio; Tsetis, Dimitrios; Cavalli, Maide; Fiumara, Paolo; Raimondo, Francesco Di; Coppolino, Francesco; Coppolino, Carmelo; Mundo, Elena; Desiderio, Carla; Granata, Antonio; Patti, Maria Teresa

    2010-12-15

    The purpose of this study was to assess the efficacy of cementoplasty in the treatment of sacral multiple myelomas. We retrospectively reviewed the records of eight patients (four women and four men; age range 47-68 years; mean age 57.8) who underwent cementoplasty for painful osteolytic localization of multiple myeloma between April 2007 and May 2009. The patients had difficulty walking because of increasing pain. Six patients had persistent pain despite other cementoplasties for vertebral and femoral localization, whereas two patients referred at the time of diagnosis had only sacral lesions. The clinical indication for treatment was (1) a pain intensity score {>=}5 on visual analogue scale (VAS) and (2) pain totally or partially refractory to analgesic treatment in patients with a life expectancy >3 months. Technical planning was based on computed tomography and/or magnetic resonance imaging. Six patients had previously undergone radiotherapy or chemotherapy and were receiving varying doses of analgesics, whereas sacroplasty represented the first treatment for two patients. Five patients had monolateral local involvement, and the other patients had massive involvement of the sacrum; Technical success was achieved in all cases. We had only one small and asymptomatic foraminal leak. All patients experienced improvement in symptoms after the procedure, as demonstrated by improved VAS scores and performance status (PS) and decreased analgesic dose constant during follow-up. In our experience, percutaneous stabilization can be used effectively and safely in patients with focal or extensive involvement of the sacrum by multiple myeloma.

  2. Monoclonal gammopathy and smoldering multiple myeloma: diagnosis, staging, prognosis, management.

    PubMed

    Hillengass, Jens; Moehler, Thomas; Hundemer, Michael

    2011-01-01

    Monoclonal gammopathy of unknown significance (MGUS) as one of the most common premalignant disorders and smoldering multiple myeloma (sMM) are both caused by a proliferation of monoclonal plasma cells leading to a detectable serum monoclonal protein and/or excess of plasma cells in the bone marrow. Prerequisite for the diagnosis is that plasma cell disease does not cause clinical symptoms. Cytogenetic aberrations are detectable in the majority of patient in the clonally expanded plasma cells. MGUS consistently proceeds symptomatic MM. The lifetime risk of progression into symptomatic multiple myeloma lies between 15% and 59% for patients with MGUS or sMM. Prognostic parameters for development of symptomatic multiple myeloma from MGUS or sMM are concentration of monoclonal protein, bone marrow plasmocytosis, a non- IgG subtype and an abnormal free-light chain ratio. Detection of more than 1 focal lesion in whole body MRI, 95% or more of bone marrow plasma cells displaying an aberrant phenotype in flow cytometry and an evolving clinical course in two consecutive follow-up visits are additional prognostic parameters for sMM. Currently there is no accepted secondary prevention strategy available for sMM and MGUS progression. Future studies are required to combine increasing knowledge on risk factors and molecular pathogenesis with targeted agents to prevent progression. PMID:21509683

  3. Smoldering multiple myeloma requiring treatment: time for a new definition?

    PubMed Central

    Stewart, A. Keith; Chanan-Khan, Asher; Rajkumar, S. Vincent; Kyle, Robert A.; Fonseca, Rafael; Kapoor, Prashant; Bergsagel, P. Leif; McCurdy, Arleigh; Gertz, Morie A.; Lacy, Martha Q.; Lust, John A.; Russell, Stephen J.; Zeldenrust, Steven R.; Reeder, Craig; Roy, Vivek; Buadi, Francis; Dingli, David; Hayman, Suzanne R.; Leung, Nelson; Lin, Yi; Mikhael, Joseph; Kumar, Shaji K.

    2013-01-01

    Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved. PMID:24144641

  4. Smoldering multiple myeloma requiring treatment: time for a new definition?

    PubMed

    Dispenzieri, Angela; Stewart, A Keith; Chanan-Khan, Asher; Rajkumar, S Vincent; Kyle, Robert A; Fonseca, Rafael; Kapoor, Prashant; Bergsagel, P Leif; McCurdy, Arleigh; Gertz, Morie A; Lacy, Martha Q; Lust, John A; Russell, Stephen J; Zeldenrust, Steven R; Reeder, Craig; Roy, Vivek; Buadi, Francis; Dingli, David; Hayman, Suzanne R; Leung, Nelson; Lin, Yi; Mikhael, Joseph; Kumar, Shaji K

    2013-12-19

    Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved. PMID:24144641

  5. Ellipticine derivative NSC 338258 represents a potential new antineoplastic agent for the treatment of multiple myeloma.

    PubMed

    Tian, Erming; Landowski, Terry H; Stephens, Owen W; Yaccoby, Shmuel; Barlogie, Bart; Shaughnessy, John D

    2008-03-01

    High-risk multiple myeloma can be correlated with amplification and overexpression of the cell cycle regulator CKS1B. Herein, we used the COMPARE algorithm to correlate high expression of CKS1B mRNA in the NCI-60 cell line panel with the concentration causing 50% growth inhibition (GI(50)) of >40,000 synthetic compounds. This led to the identification of NSC 338258 (EPED3), a highly stable, hydrophilic derivative of the plant alkaloid ellipticine. In vitro, this synthetic anticancer compound exhibits dramatic cytotoxic activity against myeloma cells grown in suspension or in coculture with stromal cells. EPED3-induced cell cycle arrest and an apoptotic progression that appear to be a consequence of the instantaneous effect of the drug on cytoplasmic organelles, particularly mitochondria. Disruption of mitochondria and cytoplasmic distribution of cytochrome c initiated the intracellular proteolytic cascade through the intrinsic apoptotic pathway. EPED3 is able to induce apoptosis in myeloma cells with de novo or acquired resistance to commonly administered antimyeloma agents. Collectively, our data suggest that EPED3 targets mitochondrial function to rapidly deplete chemical energy and initiate apoptosis in myeloma cells at nanomolar concentrations while leaving stromal cells unharmed.

  6. The effects of cold atmospheric plasma on cell adhesion, differentiation, migration, apoptosis and drug sensitivity of multiple myeloma.

    PubMed

    Xu, Dehui; Luo, Xiaohui; Xu, Yujing; Cui, Qingjie; Yang, Yanjie; Liu, Dingxin; Chen, Hailan; Kong, Michael G

    2016-05-13

    Cold atmospheric plasma was shown to induce cell apoptosis in numerous tumor cells. Recently, some other biological effects, such as induction of membrane permeation and suppression of migration, were discovered by plasma treatment in some types of tumor cells. In this study, we investigated the biological effects of plasma treatment on multiple myeloma cells. We detected the detachment of adherent myeloma cells by plasma, and the detachment area was correlated with higher density of hydroxyl radical in the gas phase of the plasma. Meanwhile, plasma could promote myeloma differentiation by up-regulating Blimp-1 and XBP-1 expression. The migration ability was suppressed by plasma treatment through decreasing of MMP-2 and MMP-9 secretion. In addition, plasma could increase bortezomib sensitivity and induce myeloma cell apoptosis. Taking together, combination with plasma treatment may enhance current chemotherapy and probably improve the outcomes. PMID:27067049

  7. The effects of cold atmospheric plasma on cell adhesion, differentiation, migration, apoptosis and drug sensitivity of multiple myeloma.

    PubMed

    Xu, Dehui; Luo, Xiaohui; Xu, Yujing; Cui, Qingjie; Yang, Yanjie; Liu, Dingxin; Chen, Hailan; Kong, Michael G

    2016-05-13

    Cold atmospheric plasma was shown to induce cell apoptosis in numerous tumor cells. Recently, some other biological effects, such as induction of membrane permeation and suppression of migration, were discovered by plasma treatment in some types of tumor cells. In this study, we investigated the biological effects of plasma treatment on multiple myeloma cells. We detected the detachment of adherent myeloma cells by plasma, and the detachment area was correlated with higher density of hydroxyl radical in the gas phase of the plasma. Meanwhile, plasma could promote myeloma differentiation by up-regulating Blimp-1 and XBP-1 expression. The migration ability was suppressed by plasma treatment through decreasing of MMP-2 and MMP-9 secretion. In addition, plasma could increase bortezomib sensitivity and induce myeloma cell apoptosis. Taking together, combination with plasma treatment may enhance current chemotherapy and probably improve the outcomes.

  8. Bone disease in multiple myeloma: pathophysiology and management.

    PubMed

    Hameed, Abdul; Brady, Jennifer J; Dowling, Paul; Clynes, Martin; O'Gorman, Peter

    2014-01-01

    Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM). More than 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also increases the cost of management. Bone destruction and lack of bone formation are main factors in the development of MBD. Some novel factors are found to be involved in the pathogenesis of MBD, eg, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) system (RANKL/OPG), Wingless (Wnt), dickkopf-1 (Wnt/DKK1) pathway. The addition of novel agents in the treatment of MM, use of bisphosphonates and other supportive modalities such as radiotherapy, vertebroplasty/kyphoplasty, and surgical interventions, all have significant roles in the treatment of MBD. This review provides an overview on the pathophysiology and management of MBD.

  9. Recurrent Plasmacytomas after Allografting in a Patient with Multiple Myeloma

    PubMed Central

    Stawis, Allen N.; Maennle, Diane; Festuccia, Moreno; Uddin, Zia; Bruno, Benedetto

    2012-01-01

    Extramedullary recurrence in multiple myeloma patients has been reported after both autologous and allogeneic hematopoietic cell transplantation and, more recently, after treatment with so-called new drugs with potent antimyeloma activity. Only a very few sizable reports focused on its clinical presentation and its incidence, which may be highly underestimated, and most observations are based on single patients reported from several institutions. Given the unusual sites of recurrence, diagnosis may be rather difficult and delayed treatment may play a relevant role in prognosis. Here we report a case of a myeloma patient, initially treated with an allograft, who enjoyed an eleven-year disease-free remission with very good quality of life. She eventually relapsed first with an extramedullary plasmacytoma in the breast and, two years later, with a right atrial cardiac mass. PMID:23326271

  10. IMWG consensus on risk stratification in multiple myeloma.

    PubMed

    Chng, W J; Dispenzieri, A; Chim, C-S; Fonseca, R; Goldschmidt, H; Lentzsch, S; Munshi, N; Palumbo, A; Miguel, J S; Sonneveld, P; Cavo, M; Usmani, S; Durie, B G M; Avet-Loiseau, H

    2014-02-01

    Multiple myeloma is characterized by underlying clinical and biological heterogeneity, which translates to variable response to treatment and outcome. With the recent increase in treatment armamentarium and the projected further increase in approved therapeutic agents in the coming years, the issue of having some mechanism to dissect this heterogeneity and rationally apply treatment is coming to the fore. A number of robustly validated prognostic markers have been identified and the use of these markers in stratifying patients into different risk groups has been proposed. In this consensus statement, the International Myeloma Working Group propose well-defined and easily applicable risk categories based on current available information and suggests the use of this set of prognostic factors as gold standards in all clinical trials and form the basis of subsequent development of more complex prognostic system or better prognostic factors. At the same time, these risk categories serve as a framework to rationalize the use of therapies. PMID:23974982

  11. Immunoglobulin heavy/light chain ratios improve paraprotein detection and monitoring, identify residual disease and correlate with survival in multiple myeloma patients

    PubMed Central

    Ludwig, H; Milosavljevic, D; Zojer, N; Faint, J M; Bradwell, A R; Hübl, W; Harding, S J

    2013-01-01

    The novel heavy/light chain (HLC) assay was used for the detection and measurement of monoclonal immunoglobulins, response evaluation and prognostication. This test allows identification and quantification of the different light chain types of each immunoglobulin class (for example, IgGκ and IgGλ) and enables calculation of ratios of monoclonal/polyclonal immunoglobulin (HLC ratio). Sequential sera of 156 patients with IgG or IgA myeloma started on first-line therapy and followed for a median of 46.1 months were analyzed. Results were compared with those obtained with conventional techniques (serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE), nephelometry (NEPH), and the free light chain test (FLC)). Our data show that the HLC assay allowed quantification of monoclonal proteins not accurately measurable by SPEP or NEPH. When both HLC and FLC testing were applied for response assessment, clonal excess was noted in 14/31 patients with complete response (CR). HLC ratio indicated presence of disease in 8/31 patients who achieved CR and, in sequential studies indicated evolving relapse in three patients before IFE became positive. Highly abnormal HLC ratios at presentation were significantly associated with shorter overall survival (40.5 months vs median not reached, P=0.016). Multivariate analysis revealed HLC ratio (P=0.03) and β2-microglobulin (P<0.01) as independent risk factors for survival. PMID:22955329

  12. Increasing multiple myeloma mortality among the elderly: a manifestation of aging and differential survival.

    PubMed

    Riggs, J E

    1995-01-13

    Increasing multiple myeloma incidence and mortality among the elderly in industrialized nations has been attributed to associated environmental carcinogens. Age-specific multiple myeloma mortality rates in the United States from 1968 to 1989 were analyzed using the Strehler-Mildvan modification of the Gompertz relationship between aging and mortality. The results suggest that worsening environmental influences are not responsible for increasing multiple myeloma mortality among the elderly. Differential survival, a concept originally popularized by Charles Darwin, and its effect upon the surviving gene pool in an aging population is an alternative explanation for increasing multiple myeloma incidence and mortality in the elderly.

  13. Dynamic Interplay between Bone and Multiple Myeloma: Emerging Roles of the Osteoblast

    PubMed Central

    Reagan, Michaela R.; Liaw, Lucy; Rosen, Clifford J.; Ghobrial, Irene M.

    2015-01-01

    Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist, and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e. any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast. PMID:25725265

  14. Multiple Myeloma Treatment (Beyond the Basics)

    MedlinePlus

    ... the Licensed Materials from any location via the Internet. b. STANDALONE WORKSTATION: A standalone subscription permits multiple ... computer. A Standalone Workstation license does not include Internet access to the Licensed Materials. c. INSTITUTIONAL SUBSCRIPTION: ...

  15. CYT997 causes apoptosis in human multiple myeloma.

    PubMed

    Monaghan, Katherine; Khong, Tiffany; Smith, Gregg; Spencer, Andrew

    2011-04-01

    Multiple Myeloma (MM) is an incurable malignancy of mature plasma cells. Microtubule targeting agents (MTAs) are an established class of drug that include many conventional and some novel compounds. MTAs function by inhibiting the polymerisation or depolymerisation of microtubules (MTs) within the cell, disrupting various important cellular functions. We have investigated pre-clinically the novel tubulin polymerisation inhibitor CYT997 for the potential treatment of MM. Here we demonstrate the promising anti-myeloma activity of CYT997 as evidenced by tubulin disruption, inhibition of growth and proliferation, cell cycle arrest and most importantly apoptosis of both human myeloma cell lines (HMCLs) and primary MM cells using nanomolar drug concentrations. CYT997 also synergises with bortezomib to produce more potent anti-MM activity. These in vitro observations were validated in vivo by the ability of CYT997 to significantly prolong survival in a murine model of aggressive systemic myelomatosis. These findings provide a basis for continuing pre-clinical and clinical investigations into the anti-MM effects of CYT997.

  16. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma.

    PubMed

    Corre, J; Mahtouk, K; Attal, M; Gadelorge, M; Huynh, A; Fleury-Cappellesso, S; Danho, C; Laharrague, P; Klein, B; Rème, T; Bourin, P

    2007-05-01

    Recent literature suggested that cells of the microenvironment of tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression profiling and phenotypic and functional studies in three groups of individuals: patients with MM, patients with monoclonal gamopathy of undefined significance (MGUS) and healthy age-matched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in an MM group. MGUS BMMSCs were interspersed between these two groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs, 46% may account for a tumor-microenvironment cross-talk. Known soluble factors implicated in MM pathophysiologic features (i.e. IL (interleukin)-6, DKK1) were revealed and new ones were found which are involved in angiogenesis, osteogenic differentiation or tumor growth. In particular, GDF15 was found to induce dose-dependent growth of MOLP-6, a stromal cell-dependent myeloma cell line. Functionally, MM BMMSCs induced an overgrowth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, MM BMMSCs are abnormal and could create a very efficient niche to support the survival and proliferation of the myeloma cells.

  17. Panobinostat for the treatment of multiple myeloma: the evidence to date.

    PubMed

    Bailey, Hanna; Stenehjem, David D; Sharma, Sunil

    2015-01-01

    Multiple myeloma is a malignancy involving plasma cell proliferation within the bone marrow. Survival of patients diagnosed with myeloma has significantly improved in the last decade, following the approval of novel agents. Despite great strides achieved in the management of multiple myeloma, it is still considered an incurable disease as the majority of patients relapse after initiation of therapy. Additionally, the duration of response generally decreases with an increasing number of therapy lines. The need to overcome resistance to therapy dictates research into more potent agents and those with novel mechanisms of action. A therapeutic option for relapsed/refractory myeloma includes histone deacetylase inhibition. Various histone deacetylase inhibitors, including the newly approved panobinostat, are currently under evaluation in this setting. Panobinostat for multiple myeloma is used in combination with other potent therapeutic agents, such as proteasome inhibitors and steroids. Ongoing research evaluating other panobinostat-containing regimens will provide additional insight into its place in myeloma management. PMID:26504410

  18. Radiation therapy for the palliation of multiple myeloma

    SciTech Connect

    Leigh, B.R.; Kurtts, T.A.; Mack, C.F.; Matzner, M.B.; Shimm, D.S. )

    1993-04-02

    This study reviews the experience at the University of Arizona in an effort to define the minimum effective radiation dose for durable pain relief in the majority of patients with symptomatic multiple myeloma. The records of 101 patients with multiple myeloma irradiated for palliation at the University of Arizona between 1975 and 1990 were reviewed. Three hundred sixteen sites were treated. Ten sites were asymptomatic, including six hemibody fields with advanced disease unresponsive to chemotherapy and four local fields with impending pathological fractures. Three hundred six evaluable symptomatic sites remained. The most common symptom was bone pain. Other symptoms included neurological impairment with a palpable mass. Total tumor dose ranged from 3.0 to 60 Gy, with a mean of 25 Gy. Symptom relief was obtained in 297 of 306 evaluable symptomatic sites (97%). Complete relief of symptoms was obtained in 26% and partial relief in 71%. Symptom relief was obtained in 92% of sites receiving a total dose less than 10 Gy (n = 13) and 98% of sites receiving 10 Gy or more (n = 293). No dose-response could be demonstrated. The likelihood of symptom relief was not influenced by the location of the lesion or the use of concurrent chemotherapy. Of the 297 responding sites, 6% (n = 19) relapsed after a median symptom-free interval of 16 months. Neither the probability of relapse nor the time to relapse was related to the radiation dose. Retreatment of relapsing sites provided effective palliation in all cases. Radiation therapy is effective in palliating local symptoms in multiple myeloma. A total dose of 10 Gy should provide durable symptom relief in the majority of patients. 16 refs., 3 figs., 4 tabs.

  19. Case-control study of multiple myeloma and farming.

    PubMed Central

    Pearce, N. E.; Smith, A. H.; Howard, J. K.; Sheppard, R. A.; Giles, H. J.; Teague, C. A.

    1986-01-01

    A previous case-control study which utilised the occupational information available on the New Zealand Cancer Registry found an increased risk of multiple myeloma in agricultural workers consistent with previous findings in the United States. The findings are now presented for the second phase of the study which involved interviewing 76 cases of multiple myeloma (who had been included in the previous study) together with 315 controls with other types of cancer. The previous finding on an excess of farmers in the case group was confirmed by the interview data (odds ratio = 1.7, 95% confidence limits 1.0-2.9, P = 0.04). There were no significant differences between cases and controls regarding potential exposure to phenoxy herbicides or chlorophenols. There were also no significant differences regarding activities involving potential exposure to other agricultural chemicals, although the odds ratio for fencing work, which may involve exposure to arsenic and sodium pentachlorophenate, was 1.6 (95% confidence limits 0.9-2.7, P = 0.11). The odds ratios were significantly elevated for sheep farming (odds ratio = 1.9, 95% confidence limits 1.0-3.6, P = 0.04) and exposure to beef cattle (odds ratio = 1.7, 95% confidence limits 1.0-2.9, P = 0.05). The odds ratio was also elevated for persons reporting a history of hay fever (odds ratio = 1.9, 95% confidence limits 1.0-3.5, P = 0.05). Overall, these findings suggest that the search for the causes of elevated mortality in farmers from multiple myeloma should be directed to potential causes other than pesticide exposure. PMID:3756085

  20. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

    PubMed

    Laubach, J; Garderet, L; Mahindra, A; Gahrton, G; Caers, J; Sezer, O; Voorhees, P; Leleu, X; Johnsen, H E; Streetly, M; Jurczyszyn, A; Ludwig, H; Mellqvist, U-H; Chng, W-J; Pilarski, L; Einsele, H; Hou, J; Turesson, I; Zamagni, E; Chim, C S; Mazumder, A; Westin, J; Lu, J; Reiman, T; Kristinsson, S; Joshua, D; Roussel, M; O'Gorman, P; Terpos, E; McCarthy, P; Dimopoulos, M; Moreau, P; Orlowski, R Z; Miguel, J S; Anderson, K C; Palumbo, A; Kumar, S; Rajkumar, V; Durie, B; Richardson, P G

    2016-05-01

    The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM. PMID:26710887

  1. Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma.

    PubMed

    Yang, Wen-Chi; Lin, Sheng-Fung

    2015-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM.

  2. Multiple Myeloma: Biology, Standard Therapy, and Transplant Therapy

    PubMed Central

    Gertz, Morie A.; Ghobrial, Irene; Luc-Harousseau, Jean

    2011-01-01

    The understanding of the pathogenesis of multiple myeloma has undergone a major transformation over the past eight years. New insights into the microenvironment of the plasma cell as well as elucidation of signaling pathways that prevent plasma cell apoptosis are leading to rapid new drug development. The introduction of novel agents has led to a significant increase in survival. Combinations of novel agents are expected to provide higher complete response rate with anticipated prolongation of relapse free and overall survival. Autologous and allogeneic stem cell transplantation remains an integral part of therapy further improving the outcomes following induction with novel agents. PMID:19147078

  3. Spotlight on ixazomib: potential in the treatment of multiple myeloma

    PubMed Central

    Muz, Barbara; Ghazarian, Rachel Nicole; Ou, Monica; Luderer, Micah John; Kusdono, Hubert Daniel; Azab, Abdel Kareem

    2016-01-01

    Despite the significant therapeutic advances achieved with proteasome inhibitors (PIs) such as bortezomib and carfilzomib in prolonging the survival of patients with multiple myeloma, the development of drug resistance, peripheral neuropathy, and pharmacokinetic limitations continue to pose major challenges when using these compounds. Ixazomib is a second-generation PI with improved activity over other PIs. Unlike bortezomib and carfilzomib, which are administered by injection, ixazomib is the first oral PI approved by US Food and Drug Administration. This review discusses the biochemical properties, mechanisms of action, preclinical efficacy, and clinical trial results leading to the US Food and Drug Administration approval of ixazomib. PMID:26811670

  4. Morganella morganii Pericarditis in a Patient with Multiple Myeloma.

    PubMed

    Nakao, Takafumi; Yoshida, Masahiro; Kanashima, Hiroshi; Yamane, Takahisa

    2013-01-01

    Purulent pericarditis caused by Morganella morganii is extremely rare. We report herein a case of a 61-year-old man who presented with chest pain and dyspnea fourteen days after chemotherapy for multiple myeloma. Echocardiogram and computed tomography revealed a massive pericardial effusion and associated cardiac tamponade. Pericardiocentesis was performed. Pericardial fluid was found to be purulent, and Morganella morganii was isolated from the fluid. The patient was successfully treated with antibiotic therapy and surgical drainage of the fluid. Morganella morganii should be considered a possible pathogen when immunocompromised patients develop purulent pericarditis.

  5. Erythrocyte membrane fatty acids in multiple myeloma patients.

    PubMed

    Jurczyszyn, Artur; Czepiel, Jacek; Gdula-Argasińska, Joanna; Czapkiewicz, Anna; Biesiada, Grażyna; Dróżdż, Mirosław; Perucki, William; Castillo, Jorge J

    2014-10-01

    Mounting data show that fatty acids (FA) and fatty acid synthase (FAS) function could be potential targets for multiple myeloma (MM) therapy. Our study aimed at comparing the FA composition of erythrocyte membranes of MM patients and healthy controls. MM patients had higher saturated FA and n-6 polyunsaturated FA (PUFA) and lower monounsaturated, n-3 PUFA and trans-FA indices than controls. The n-3/n-6 PUFA ratio was lower in MM patients and there was distinct clustering of variants of individual FA in MM patients. The FA content of erythrocyte membrane could serve as a diagnostic and/or predictive biomarker in MM.

  6. Role of hematopoietic stem cell transplantation in multiple myeloma.

    PubMed

    Garcia, Ima N

    2015-02-01

    High-dose therapy followed by autologous stem cell transplantation (ASCT) has been the standard frontline consolidative therapy for patients with newly diagnosed multiple myeloma (MM) for > 2 decades. This approach has resulted in higher complete response (CR) rates and increased event-free survival and overall survival (OS) compared with conventional chemotherapy. The emergence of novel agent-based therapy combined with ASCT has revolutionized MM therapy by improving the CR rates and OS, raising questions concerning the role of hematopoietic stem cell transplantation in this setting.

  7. [New drugs in the treatment of multiple myeloma].

    PubMed

    Oriol, Albert; Motlló, Cristina

    2014-09-15

    Progress in the treatment of multiple myeloma in the last decade has been able to delay, but ultimately not to prevent, the development of resistances and most patients still die of the disease or its related complications. New drugs have been developed including new alkylating agents, proteasome inhibitors and immunomodulators but also monoclonal antibodies and drugs with new mechanisms of action. Hopefully, this new generation of targeted agents will improve the results of the initial therapy, avoid relapses and development of resistances and provide better and less toxic options for the relapsed and refractory patient. PMID:24342015

  8. MRI in multiple myeloma: a pictorial review of diagnostic and post-treatment findings.

    PubMed

    Dutoit, Julie C; Verstraete, Koenraad L

    2016-08-01

    Magnetic resonance imaging (MRI) is increasingly being used in the diagnostic work-up of patients with multiple myeloma. Since 2014, MRI findings are included in the new diagnostic criteria proposed by the International Myeloma Working Group. Patients with smouldering myeloma presenting with more than one unequivocal focal lesion in the bone marrow on MRI are considered having symptomatic myeloma requiring treatment, regardless of the presence of lytic bone lesions. However, bone marrow evaluation with MRI offers more than only morphological information regarding the detection of focal lesions in patients with MM. The overall performance of MRI is enhanced by applying dynamic contrast-enhanced MRI and diffusion weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity.This pictorial review provides an overview of the most important imaging findings in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma, by performing a 'total' MRI investigation with implications for the diagnosis, staging and response assessment. Main message • Conventional MRI diagnoses multiple myeloma by assessing the infiltration pattern. • Dynamic contrast-enhanced MRI diagnoses multiple myeloma by assessing vascularization and perfusion. • Diffusion weighted imaging evaluates bone marrow composition and cellularity in multiple myeloma. • Combined morphological and functional MRI provides optimal bone marrow assessment for staging. • Combined morphological and functional MRI is of considerable value in treatment follow-up. PMID:27164915

  9. Molecular analysis of immunoglobulin genes in multiple myeloma.

    PubMed

    Kosmas, C; Stamatopoulos, K; Stavroyianni, N; Belessi, C; Viniou, N; Yataganas, X

    1999-04-01

    The study of immunoglobulin genes in multiple myeloma over the last five years has provided important information regarding biology, ontogenetic location, disease evolution, pathogenic consequences and tumor-specific therapeutic intervention with idiotypic vaccination. Detailed analysis of V(H) genes has revealed clonal relationship between switch variants expressed by the bone marrow plasma cell and myeloma progenitors in the marrow and peripheral blood. V(H) gene usage is biased against V4-34 (encoding antibodies with cold agglutinin specificity; anti-l/i) explaining the absence of autoimmune phenomena in myeloma compared to other B-cell lymphoproliferative disorders. V(H) genes accumulate somatic hypermutations following a distribution compatible with antigen selection, but with no intraclonal heterogeneity. V(L) genes indicate a bias in usage of VkappaI family members and somatic hypermutation, in line with antigen selection, of the expressed Vkappa genes is higher than any other B-cell lymphoid disorder. A complementary imprint of antigen selection as evidenced by somatic hypermutation of either the V(H) or V(L) clonogenic genes has been observed. The absence of ongoing somatic mutations in either V(H) or V(L) genes gives rise to the notion that the cell of origin in myeloma is a post-germinal center memory B-cell. Clinical application of sensitive PCR methods in order to detect clonal immunoglobulin gene rearrangements has made relevant the monitoring and follow-up of minimal residual disease in stem cell autografts and after myeloablative therapy. The fact that surface immunoglobulin V(H) and V(L) sequences constitute unique tumor-specific antigenic determinants has stimulated investigators to devise strategies aiming to generate active specific immunity against the idiotype of malignant B-cells in myeloma by constructing vaccines based on expressed single-chain Fv fragments, DNA plasmids carrying V(H)+V(L) clonogenic genes for naked DNA vaccination, or

  10. Multiple myeloma: from front-line to relapsed therapies.

    PubMed

    Moreau, Philippe; Touzeau, Cyrille

    2015-01-01

    Recent developments in the treatment of multiple myeloma (MM) have led to improvements in response rates and to increased survival. A major advance in the last decade has been the introduction of the novel agents thalidomide, bortezomib, and lenalidomide as part of front-line treatment in both the transplant and nontransplant settings. However, disease relapse is inevitable for the majority of patients and myeloma typically recurs more aggressively with each relapse, eventually leading to the development of treatment-refractory disease. Several phase II and III trials have demonstrated the efficacy of recently approved agents in the setting of relapsed and relapsed and refractory MM, including pomalidomide and carfilzomib. Ixazomib, an oral proteasome inhibitor, and multiple other novel classes of agents are being investigated. These include monoclonal antibodies and histone deacetylase inhibitors, which may further add to the therapeutic armamentarium for this malignancy. Therefore, in a disease characterized by multiple relapses, the optimal sequencing of the different effective options is an important consideration in attempting to prolong survival. PMID:25993216

  11. [Meningococcal Septicemia Revealing Multiple Myeloma: A Case Report].

    PubMed

    Arakawa, Risturo; Mori, Nobuaki; Kagawa, Narito; Higuchi, Akiko; Tanaka, Masashi; Aoki, Yasuko; Seki, Shiko; Suzuki, Ryo

    2016-05-01

    Meningococcal infection is among the most devastating diseases. It is rarely seen in Japan. However, several environmental and host factors have been associated with increased risks of Neisseria meningitidis infection. We present a case of invasive N. meningitidis infection that revealed the presence of multiple myeloma. A 55-year-old Japanese man was admitted with fever and altered consciousness. He was sent to the intensive care unit for septic shock and disseminated intravascular coagulation. In addition to standard septic shock and multiple organ failure treatment, polymyxin-B immobilized column direct hemoperfusion was performed. His blood culture was positive for N. meningitidis. The patient gradually improved and was discharged on day 35. We evaluated the risk factors for the development of meningococcal infection. A laboratory examination showed that the patient was negative for human immunodeficiency virus antibody and had a normal total complement function. However, his serum immunoglobulin G level was high, and serum and urine protein electrophoresis detected a monoclonal gammopathy. A bone marrow examination led to the diagnosis of multiple myeloma. Because N. meningitidis bacteria spreads between individuals in close contact through the exchange of oral secretions, droplet precautions and antimicrobial chemoprophylaxis (ciprofloxacin, 500 mg) were implemented to prevent the spread of the meningococcal infection. Sporadic meningococcal infection warrants an evaluation for immunodeficiency and the prevention of secondary infection. PMID:27529971

  12. Advances in the medical imaging of multiple myeloma and related clinical significance.

    PubMed

    Zhang, Hai-Bo; Xue, Hua-Dan; Li, Shuo

    2014-12-01

    Multiple myeloma is an incurable malignancy developed in the bone marrow plasma cell system. It usually consists of focal lesions of the bone,soft tissue lesions,and diffuse bone marrow infiltration. Currently,the diagnosis and follow-up of multiple myeloma are highly dependent on various medical imaging techniques.

  13. The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective.

    PubMed

    Caers, Jo; Fernández de Larrea, Carlos; Leleu, Xavier; Heusschen, Roy; Zojer, Niklas; Decaux, Olivier; Kastritis, Efstathios; Minnema, Monique; Jurczyszyn, Artur; Beguin, Yves; Wäsch, Ralph; Palumbo, Antonio; Dimopoulos, Meletios; Mateos, Maria Victoria; Ludwig, Heinz; Engelhardt, Monika

    2016-03-01

    Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathy of undetermined significance to multiple myeloma (MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with high-risk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention, although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group as MM, and thus will require optimal MM treatment, based on biomarkers that identify patients with a >80% risk of progression. The number of these redefined patients is small (∼10%), but important to unravel, because their risk of progression to overt MM is substantial (≥80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-high-risk SMM are now considered as MM and may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be performed, and clinical judgment and careful discussion of pros and cons of treatment initiation need to be undertaken. For the majority of SMM patients, the standard of care remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in

  14. Multiple myeloma: new staging systems for diagnosis, prognosis and response evaluation.

    PubMed

    Rajkumar, S Vincent; Buadi, Francis

    2007-12-01

    Multiple myeloma must be distinguished from monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and several other closely related plasma-cell disorders. In recent years, new systems have emerged for diagnosis, staging, and risk stratification of myeloma. The criteria recommended are primarily derived from the International Myeloma Working Group, with certain updates and clarifications. The International Staging System (ISS) is the standard for staging of myeloma. However, for therapeutic purposes, a risk-stratification model is used to define high-risk patients who can benefit from novel therapeutic strategies. The International Myeloma Working Group uniform response criteria have been developed as the standard for response assessment in current and future clinical trials. The criteria incorporate the category 'very good partial response' (VGPR) which, given its importance in predicting outcome following therapy, should be reported in all trials; such reporting will also enable better comparisons between therapies. PMID:18070712

  15. Myeloma

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 30,330 % of All New Cancer Cases 1.8% Estimated Deaths in 2016 12,650 % of All Cancer ... of This Cancer : In 2013, there were an estimated 95,688 people living with myeloma in the ...

  16. Antithyroid drugs induced agranulocytosis and multiple myeloma: case report and general considerations

    PubMed Central

    Dănciulescu Miulescu, R; Carșote, M; Trifănescu, R; Ferechide, D; Poiană, C

    2013-01-01

    Antithyroid drugs as thionamides are largely used in the treatment of the thyrotoxicosis. Side effects were reported in less than 10% of the cases, especially hematological, hepatic or skin allergies. One of the most severe manifestations is agranulocytosis, probably based on an immune mechanism that is exacerbated by the presence of the thyroid autoimmune disease itself. If the presence of the severe leucopenia is actually an epiphenomenon of a preexisting hematological disturbance as multiple myeloma is debated. The myeloma may also be correlated with an autoimmune predisposition. We present the case of a 56 years old female patient diagnosed with Graves’ disease, who developed agranulocytosis after 8 months of therapy with thiamazole. Two months after antithyroid drug’s withdrawal, the granulocytes number increased and she received therapy with radioiodine. Two years later she came back for diffuse bone pain that turned out to be caused by a multiple myeloma, confirmed by bone marrow biopsy. It might be a connection between the severe form of leucopenia that the patient developed and the medullar malignancy. PMID:24155785

  17. Feasibility of exercise during treatment for multiple myeloma.

    PubMed

    Coleman, Elizabeth Ann; Coon, Sharon; Hall-Barrow, Julie; Richards, Kathy; Gaylor, David; Stewart, Beth

    2003-10-01

    Fatigue and insomnia are problems for patients with cancer. Research findings show that aerobic exercise decreases cancer-related fatigue. Because patients with cancer who have skeletal muscle wasting may not obtain maximum benefit from aerobic exercise training, exercise programs may need to include resistance training. Thus far, testing exercise as an intervention for fatigue has focused on patients with breast cancer and excluded patients with bone metastasis. There is a need to test the feasibility and effectiveness of exercise for patients with other types of cancer and with bone involvement. The effect of aerobic and strength resistance training on the sleep of patients with cancer has not been tested. A pilot/feasibility study with a randomized controlled design was conducted to investigate home-based exercise therapy for 24 patients receiving high-dose chemotherapy and autologous peripheral blood stem cell transplantation as treatment for multiple myeloma. None of the patients injured themselves. Because of the small sample size in the feasibility study, the effect of exercise on lean body weight was the only end point that obtained statistical significance. However, the results suggest that an individualized exercise program for patients receiving aggressive treatment for multiple myeloma is feasible and may be effective for decreasing fatigue and mood disturbance, and for improving sleep.

  18. Cement augmentation for vertebral fractures in patients with multiple myeloma.

    PubMed

    Majeed, Haroon; Bommireddy, Rajendranath; Klezl, Zdenek

    2014-12-01

    Objective of our study was to assess the outcome of cement augmentation in patients with multiple myeloma. We reviewed 12 patients with 48 vertebral fractures. Mean age was 62.5 years. Average length of follow-up was 27.5 months. Expected survival was less than 12 months in 2 patients and more than 12 months in the remaining patients. After surgery mean survival was 32.5 months. Mean correction in vertebral angle was 3.6°. Karnofsky score was more than 70 in 5 patients, 50-70 in 6 and less than 50 in 1 patient preoperatively, while it was more than 70 in all patients postoperatively. Preoperative mean ODI was 72%. After surgery it was 46% at 6 weeks and 14% at 12 months. All patients reported improvement in their pain status after surgery. Cement augmentation is a safe and effective way of treating symptoms of multiple myeloma, which occur due to vertebral metastases. It results in excellent pain control and improvement in quality of life. PMID:26280729

  19. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.

    PubMed

    Kyle, Robert A; Rajkumar, S Vincent

    2010-04-01

    Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a serum monoclonal (M) protein level less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of hypercalcemia, renal insufficiency, anemia, or bone lesions attributable to a clonal plasma cell disorder. Patients may be tested for a monoclonal gammopathy by serum protein electrophoresis, immunofixation, and the free light chain (FLC) assay. The prevalence of MGUS is 3% for persons more than 50 years of age and 5% in those more than 70 years of age. The risk of progression to multiple myeloma or a related disorder is 1% per year. The size and type of M protein, the number of bone marrow plasma cells, and the results of the FLC ratio are independent risk factors for progression. Smoldering multiple myeloma (SMM) is a more advanced premalignant phase than MGUS and is characterized by more than 3 g/dL of serum M protein, more than 10% clonal plasma cells in the bone marrow, or both, with no evidence of end-organ damage. PMID:20425398

  20. Elotuzumab: the first approved monoclonal antibody for multiple myeloma treatment

    PubMed Central

    Magen, Hila; Muchtar, Eli

    2016-01-01

    Elotuzumab is a monoclonal antibody directed against the SLAMF7 receptor, expressed on normal and malignant plasma cells with a lower expression on other lymphoid cells such as natural killer (NK) cells. Elotuzumab has no significant antimyeloma activity when given as a single agent to patients with relapsed or refractory multiple myeloma (RRMM). However, when combined with other antimyeloma agents, it results in improved response and outcome. Owing to the results from the landmark ELOQUENT-2 phase III clinical trial, which compared lenalidomide and dexamethasone with or without elotuzumab in patients with RRMM, elotuzumab in combination with lenalidomide and dexamethasone was approved by the American Food and Drug Administration (FDA) in November 2015 for multiple myeloma (MM) patients who received one to three prior lines of therapy. This review will give a brief description of the signaling lymphocytic activation molecule (SLAM) family receptors, the unique SLAMF7 receptor and the mechanism of action of elotuzumab. Thereafter, we will give an overview on its antimyeloma activity in preclinical and clinical trials, including its toxicity profile and management thereof. PMID:27493709

  1. CD200 is a new prognostic factor in multiple myeloma.

    PubMed

    Moreaux, Jerome; Hose, Dirk; Reme, Thierry; Jourdan, Eric; Hundemer, Michael; Legouffe, Eric; Moine, Philippe; Bourin, Philippe; Moos, Marion; Corre, Jill; Möhler, Thomas; De Vos, John; Rossi, Jean Francois; Goldschmidt, Hartmut; Klein, Bernard

    2006-12-15

    Using Affymetrix microarrays, we identified the expression of the CD200 gene in multiple myeloma cells (MMCs) of 112 patients with newly diagnosed multiple myeloma (MM). The CD200 gene was either absent or present (Affymetrix call) in 22% and 78% of MMCs, respectively. The CD200 gene is not expressed in cells of the patients' bone marrow (BM). CD200 is a membrane glycoprotein that imparts an immunoregulatory signal through CD200R, leading to the suppression of T-cell-mediated immune responses. Patients with CD200(absent) MMCs have an increased event-free survival (EFS; 24 months) compared with patients with CD200(present) MMCs (14 months), after high-dose therapy and stem cell transplantation. In a Cox proportional-hazard model, the absence or presence of CD200 expression in MMCs is predictive for EFS for patients independently of ISS stage or beta2M serum levels. Thus, CD200 is an independent prognosis factor for patients with MM that could represent a new therapeutic target in MM.

  2. Emergence of therapy resistance in multiple myeloma in heterogeneous microenvironment

    NASA Astrophysics Data System (ADS)

    Wu, Amy; Zhang, Qiucen; Lambert, Guillaume; Khin, Zayar; Silva, Ariosto; Gatenby, Robert; Kim, Hyungsung; Pourmand, Nader; Austin, Robert; Sturm, James

    2014-03-01

    Cancer chemotherapy resistance is always a problem that is not clear considering spatial heterogeneity in the tumor microenvironment. We culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region in a microfluidic device which mimics the tumor microenvironment with a chemotherapy drug gradient and microhabitats. Resistance of the multiple myeloma cells to doxorubicin emerged within two weeks. For the resistant cells evolved from the devices, the doxorubicin concentration that inhibits 50% of the controlled population increased by 16-fold than the parental cells. Whole transcriptome sequencing revealed that 39% of newly acquired mutational hotspots (the genes with more than 3 non-synonymous point mutation) of the resistant cells are involved in apoptosis and DNA repair. On the other hand, 40% of the non-mutated genes that are abnormally regulated in the resistant cells, are involved in metabolism, biosynthesis, and biomolecular transport. Among them, metabolic drug efflux pumps and oxidative stress scavengers are up-regulated to reduce the cytotoxicity of doxorubicin and further result in the resistance. The roles of the spatial drug gradients and microhabitats in rapid emergence of cancer resistance will be discussed. The project described was supported by the National Science Foundation and the National Cancer Institute.

  3. A Very Rare Presentation of Multiple Myeloma: Unilateral Raccoon Eye.

    PubMed

    Varım, Ceyhun; Ergenc, Hasan; Uyanık, Mehmet Sevki; Kaya, Tezcan; Nalbant, Ahmet; Karacaer, Cengiz; Sunu, Cenk; Tamer, Ali

    2015-09-15

    Multiple myeloma (MM), the second most common hematological malignancy, is caused by the accumulation of monoclonal plasma cells in bone marrow. It accounts for 10-15% of deaths from hematological malignancies and approximately 2% of deaths from cancer. The median age at presentation is 70 years old. The diagnosis is incidental in 30% of cases. MM is often discovered through routine blood screening with a large gap between the total protein and the albumin levels. Two thirds of patients complain of bone pain, especially lower back pain. MM could be diagnosed after a pathologic fracture occurs in one third of patients. Presentation with symptoms related to hyperviscosity, hypercalcemia and bleeding tendency could also be observed. A rare presentation of MM is peri-orbital ecchymotic lesion (raccoon eye). Here, we report a 64 years old, male patient presented with unilateral raccoon eye and high erythrocyte sedimentation rate (ESR) to internal medicine outpatient. The patient was referred to hematology outpatient and was diagnosed with multiple myeloma. PMID:27275266

  4. Prognostic significance of serum cystatin C in multiple myeloma.

    PubMed

    Nückel, Holger; Langer, Christian; Herget-Rosenthal, Stefan; Wichert, Marc; Assert, Roland; Döhner, Hartmut; Dührsen, Ulrich; Liebisch, Peter

    2012-05-01

    Multiple myeloma (MM) is frequently complicated by renal insufficiency, which is associated with an unfavorable prognosis. Serum cystatin C is a new and accurate marker of glomerular filtration rate. Global gene expression analysis has revealed serum cystatin C as one of the most highly upregulated genes in MM. Recent data have shown serum cystatin C as an independent prognostic marker in MM. To further elucidate the prognostic significance of serum cystatin C, we investigated pretreatment serum cystatin C levels in 68 newly diagnosed patients homogeneously treated with high-dose melphalan followed by autologous stem cell transplantation. Median serum cystatin C level in MM patients was significantly higher than in the 66 healthy controls (1.07 vs. 0.74 mg/L [p = 0.002]). Median serum cystatin C levels significantly increased with higher International Staging System (ISS) stages (stage I 0.72 mg/L; stage II 0.89 mg/L; stage III 1.28 mg/L; p < 0.0001). Higher serum cystatin C was positively correlated with higher serum levels of creatinine (r = 0.84; p < 0.0001), β2-microglobulin (r = 0.72; p < 0.0001), LDH (r = 0.43; p = 0.0003), white blood cell counts (r = 0.61; p < 0.0001) and calcium (r = 0.29; p = 0.016), and negatively correlated with lower serum albumin levels (r = 0.44; p < 0.0001) and hemoglobin levels (r = 0.31; p = 0.01). Using ROC analysis, patients with serum cystatin C levels ≥0.95 mg/L (n = 24) had a significantly shorter event-free survival (EFS) and overall survival (OS) than patients with serum cystatin C levels <0.95 mg/L (median EFS: 26 vs. 44 months, p < 0.0001; median OS: 54 vs. 68 months, p = 0.05). Moreover, the combination of serum cystatin C level and genomic aberrations further refined the prognostic information (EFS and OS) provided by either one of the factors. The level of serum cystatin C is not only a sensitive marker of renal function, but also reflects tumor burden and delivers prognostic information in MM.

  5. Multiple myeloma in a dog with multiple concurrent infectious diseases and persistent polyclonal gammopathy.

    PubMed

    Geigy, Caroline; Riond, Barbara; Bley, Carla Rohrer; Grest, Paula; Kircher, Patrick; Lutz, Hans

    2013-03-01

    A 12-year-old, spayed female, mixed-breed dog was presented for acute hematuria, stranguria, polyuria, and polydipsia, as well as lameness for 8 days. Previous medical history included treatment for infection with Ehrlichia canis, Anaplasma phagocytophilum, Leishmania infantum, and Dirofilaria immitis 6.5 years prior to presentation. Besides persistently increased antibody titers to E canis and A phagocytophilum, polyclonal gammopathy with a monoclonal spike and moderate hypercalcemia were observed. There was marked hematuria, and Staphylococcus aureus was cultured from urine. Two weeks after successful treatment of the urinary tract infection, radiographs showed an extensive destructive monostotic lesion of the right humerus. Cytologic examination of fine-needle aspirates of this lesion revealed a neoplastic round cell population suggestive of multiple myeloma. The dog was treated with melphalan and prednisolone for suspected multiple myeloma and doxycycline for suspected ehrlichiosis and anaplasmosis. Treatments lead to resolution of the clinical signs, hypercalcemia, and monoclonal gammopathy, and there was radiographic improvement of bone lesions; polyclonal gammopathy persisted. About one year after presentation the dog was still in clinical remission. This is a rare report of a dog with suspected multiple myeloma and a history of multiple chronic infectious diseases, suggesting that chronic infection and uncontrolled long-term stimulation of the immune system could contribute to the pathogenesis of multiple myeloma. PMID:23278475

  6. Immunoglobulin D Multiple Myeloma With Rapidly Progressing Renal Failure.

    PubMed

    Modi, Jwalant; Kamal, Jeanne; Eter, Ahmad; El-Sayegh, Suzanne; El-Charabaty, Elie

    2015-08-01

    Immunoglobulin D (IgD) multiple myeloma (MM) is a very rare form of myeloma affecting less than 2% of all myeloma patients. It has a multiorgan involvement with renal failure being the key feature. We present here a case of IgD MM in a 62-year-old white male, smoker with past medical history of hypertension, who presented to emergency department with complaints of lower abdominal pain, constipation and decreased urination. Physical exam was unremarkable. Laboratory investigation showed S.Cr 5.99 mg/dL, hemoglobin 8.7 g/dL and corrected S.Ca 10.6 mg/dL. Urine dipstick showed 100 protein and TP/Cr ratio was 23. Serology was positive for serum free lambda chain level of 8,947.6 mg/L as well with free κ/λ ratio < 0.01. The results of serum and urine electrophoresis and immunofixation were also supportive of diagnosis of IgD MM. IgD level was remarkably elevated (27,300 mg/L) too. CT scan of abdomen/pelvis was negative for obstructive uropathy. Skeletal survey showed a solitary lytic lesion in the iliac crest. His kidney function deteriorated next day requiring hemodialysis. The bone marrow biopsy was positive for plasma cell hypercellularity (70-80%) and flow cytometry showed 8% monoclonal IgD lambda plasma cells. The patient was started on bortezomib and dexamethasone and he underwent bone marrow transplant 6 months later. He is doing well hematologically now but he remains dialysis-dependent. IgD MM is a very rare disease affecting younger population with poor prognosis; patients often end up on hemodialysis despite better control of the hematological component. PMID:26124916

  7. Cross-talk between two antioxidants, thioredoxin reductase and heme oxygenase-1, and therapeutic implications for multiple myeloma

    PubMed Central

    Raninga, Prahlad V.; Di Trapani, Giovanna; Vuckovic, Slavica; Tonissen, Kathryn F.

    2016-01-01

    Multiple myeloma (MM) is characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Despite recent advancements in anti-myeloma therapies, MM remains an incurable disease. Antioxidant molecules are upregulated in many cancers, correlating with tumor proliferation, survival, and chemoresistance and therefore, have been suggested as potential therapeutic targets. This study investigated the cross-talk between two antioxidant molecules, thioredoxin reductase (TrxR) and heme oxygenase-1 (HO-1), and their therapeutic implications in MM. We found that although auranofin, a TrxR inhibitor, significantly inhibited TrxR activity by more than 50% at lower concentrations, myeloma cell proliferation was only inhibited at higher concentrations of auranofin. Inhibition of TrxR using lower auranofin concentrations induced HO-1 protein expression in myeloma cells. Using a sub-lethal concentration of auranofin to inhibit TrxR activity in conjunction with HO-1 inhibition significantly decreased myeloma cell growth and induced apoptosis. TrxR was shown to regulate HO-1 via the Nrf2 signaling pathway in a ROS-dependent manner. Increased HO-1 mRNA levels were observed in bortezomib-resistant myeloma cells compared to parent cells and HO-1 inhibition restored the sensitivity to bortezomib in bortezomib-resistant myeloma cells. These findings indicate that concurrent inhibition of HO-1 with either a TrxR inhibitor or with bortezomib would improve therapeutic outcomes in MM patients. Hence, our findings further support the need to target multiple antioxidant systems alone or in combination with other therapeutics to improve therapeutic outcomes in MM patients. PMID:26795735

  8. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

    PubMed Central

    Engelhardt, Monika; Terpos, Evangelos; Kleber, Martina; Gay, Francesca; Wäsch, Ralph; Morgan, Gareth; Cavo, Michele; van de Donk, Niels; Beilhack, Andreas; Bruno, Benedetto; Johnsen, Hans Erik; Hajek, Roman; Driessen, Christoph; Ludwig, Heinz; Beksac, Meral; Boccadoro, Mario; Straka, Christian; Brighen, Sara; Gramatzki, Martin; Larocca, Alessandra; Lokhorst, Henk; Magarotto, Valeria; Morabito, Fortunato; Dimopoulos, Meletios A.; Einsele, Hermann; Sonneveld, Pieter; Palumbo, Antonio

    2014-01-01

    Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B). PMID:24497560

  9. IMWG consensus on maintenance therapy in multiple myeloma

    PubMed Central

    Durie, Brian G. M.; McCarthy, Philip; Palumbo, Antonio; San Miguel, Jésus; Barlogie, Bart; Morgan, Gareth; Sonneveld, Pieter; Spencer, Andrew; Andersen, Kenneth C.; Facon, Thierry; Stewart, Keith A.; Einsele, Hermann; Mateos, Maria-Victoria; Wijermans, Pierre; Waage, Anders; Beksac, Meral; Richardson, Paul G.; Hulin, Cyrille; Niesvizky, Ruben; Lokhorst, Henk; Landgren, Ola; Bergsagel, P. Leif; Orlowski, Robert; Hinke, Axel; Cavo, Michele; Attal, Michel

    2012-01-01

    Maintaining results of successful induction therapy is an important goal in multiple myeloma. Here, members of the International Myeloma Working Group review the relevant data. Thalidomide maintenance therapy after autologous stem cell transplantation improved the quality of response and increased progression-free survival (PFS) significantly in all 6 studies and overall survival (OS) in 3 of them. In elderly patients, 2 trials showed a significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed a significant risk reduction for PFS/event-free survival and death. The role of thalidomide maintenance after melphalan, prednisone, and thalidomide is not well established. Two trials with lenalidomide maintenance treatment after autologous stem cell transplantation and one study after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction for PFS and an increase in OS in one of the transplant trials. Maintenance therapy with single-agent bortezomib or in combination with thalidomide or prednisone has been studied. One trial revealed a significantly increased OS with a bortezomib-based induction and bortezomib maintenance therapy compared with conventional induction and thalidomide maintenance treatment. Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established. PMID:22271445

  10. Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

    PubMed Central

    Ohta, Eri; Takeda, Shu; Sunamura, Satoko; Ishibashi, Mariko; Tamura, Hideto; Wang, Yan-hua; Deguchi, Atsuko; Tanaka, Junji; Maru, Yoshiro; Motoji, Toshiko

    2016-01-01

    Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of PPP3CA, a catalytic subunit of calcineurin, was high in advanced patients. Panobinostat degraded PPP3CA, a degradation that should have been induced by inhibition of the chaperone function of heat shock protein 90 (HSP90). Cotreatment with HDAC inhibitors and FK506 led to an enhanced antimyeloma effect with a greater PPP3CA reduction compared with HDAC inhibitors alone both in vitro and in vivo. In addition, this combination treatment efficiently blocked osteoclast formation, which results in osteolytic lesions. The poor response and short PFS duration observed in the bortezomib-containing therapies of patients with high PPP3CA suggested its relevance to bortezomib resistance. Moreover, bortezomib and HDAC inhibitors synergistically suppressed MM cell viability through PPP3CA inhibition. Our findings underscore the usefulness of calcineurin-targeted therapy in MM patients, including patients who are resistant to bortezomib. PMID:27699258

  11. Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

    PubMed Central

    Ohta, Eri; Takeda, Shu; Sunamura, Satoko; Ishibashi, Mariko; Tamura, Hideto; Wang, Yan-hua; Deguchi, Atsuko; Tanaka, Junji; Maru, Yoshiro; Motoji, Toshiko

    2016-01-01

    Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of PPP3CA, a catalytic subunit of calcineurin, was high in advanced patients. Panobinostat degraded PPP3CA, a degradation that should have been induced by inhibition of the chaperone function of heat shock protein 90 (HSP90). Cotreatment with HDAC inhibitors and FK506 led to an enhanced antimyeloma effect with a greater PPP3CA reduction compared with HDAC inhibitors alone both in vitro and in vivo. In addition, this combination treatment efficiently blocked osteoclast formation, which results in osteolytic lesions. The poor response and short PFS duration observed in the bortezomib-containing therapies of patients with high PPP3CA suggested its relevance to bortezomib resistance. Moreover, bortezomib and HDAC inhibitors synergistically suppressed MM cell viability through PPP3CA inhibition. Our findings underscore the usefulness of calcineurin-targeted therapy in MM patients, including patients who are resistant to bortezomib.

  12. Recent advances in multiple myeloma: a Korean perspective.

    PubMed

    Hong, Junshik; Lee, Jae Hoon

    2016-09-01

    Epidemiologically, multiple myeloma (MM) is a malignant disorder of plasma cells with a higher incidence among Western populations than among Asians. However, there is growing evidence of a recent increase in the age-standardized incidence rate (ASR) of MM in Asian countries, particularly Korea. Application of novel agents has resulted in significant improvement of treatment outcomes, and the advances are ongoing with the recent introduction and U.S. Food and Drug Administration's approval of newer agents, including carfilzomib, ixazomib, elotuzumab, and daratumumab. In concert with the technical advances in the cytogenetic and molecular diagnostics of MM, modifications of its diagnosis and staging system have been attempted for better risk stratification. The modified diagnostic criteria from the International Myeloma Working Group in 2014 enabled a strategy of more active treatment for some patients with smoldering MM, with an ultra-high risk of progression, and fine-tuned the definition of end-organ damage, known as CRAB (hypercalcemia, renal insufficiency, anemia, and bone lesions). Considering Korea's trend of aging at an unprecedented rate, we can expect that the ASR of MM will maintain a gradual increase for many years to come; therefore, MM will be a cancer of critical importance from both medical and socioeconomic perspectives in Korea. PMID:27604794

  13. Nephrogenic diabetes insipidus--prodromal phase of multiple myeloma.

    PubMed

    Goranov, S; Hristova, I; Pencheva, K

    1994-01-01

    We report on a 65-year-old female patient with an A-kappa multiple myeloma diagnosed on the grounds of bone pain, anemia and extremely elevated erythrocyte sedimentation rate (ESR). Eight years prior to admission to the Clinic of Haematology the patient started to excrete a considerable amount of urine (4-6 liters per 24 hrs) with low specific gravity and to experience hardly controllable thirst. The disorder was specified in a specialised endocrinologic clinic as diabetes inspidus with ambiguous aetiology. The administered treatment with adiuretin had a small effect. A course of cyclophosphamide and glucocorticosteroids was started after myeloma was diagnosed--this had a considerable effect on the polyuria and polydipsia; the specific gravity of the urine increased. This effect, as well as the proven light chain proteinuria in the patient, leads to the interpretation of the early complaints of the patient as onset of the underlying disease in the form of nephrogenic diabetes insipidus--a rare light chain tubular syndrome.

  14. Recent advances in multiple myeloma: a Korean perspective.

    PubMed

    Hong, Junshik; Lee, Jae Hoon

    2016-09-01

    Epidemiologically, multiple myeloma (MM) is a malignant disorder of plasma cells with a higher incidence among Western populations than among Asians. However, there is growing evidence of a recent increase in the age-standardized incidence rate (ASR) of MM in Asian countries, particularly Korea. Application of novel agents has resulted in significant improvement of treatment outcomes, and the advances are ongoing with the recent introduction and U.S. Food and Drug Administration's approval of newer agents, including carfilzomib, ixazomib, elotuzumab, and daratumumab. In concert with the technical advances in the cytogenetic and molecular diagnostics of MM, modifications of its diagnosis and staging system have been attempted for better risk stratification. The modified diagnostic criteria from the International Myeloma Working Group in 2014 enabled a strategy of more active treatment for some patients with smoldering MM, with an ultra-high risk of progression, and fine-tuned the definition of end-organ damage, known as CRAB (hypercalcemia, renal insufficiency, anemia, and bone lesions). Considering Korea's trend of aging at an unprecedented rate, we can expect that the ASR of MM will maintain a gradual increase for many years to come; therefore, MM will be a cancer of critical importance from both medical and socioeconomic perspectives in Korea.

  15. Recent advances in multiple myeloma: a Korean perspective

    PubMed Central

    Hong, Junshik; Lee, Jae Hoon

    2016-01-01

    Epidemiologically, multiple myeloma (MM) is a malignant disorder of plasma cells with a higher incidence among Western populations than among Asians. However, there is growing evidence of a recent increase in the age-standardized incidence rate (ASR) of MM in Asian countries, particularly Korea. Application of novel agents has resulted in significant improvement of treatment outcomes, and the advances are ongoing with the recent introduction and U.S. Food and Drug Administration’s approval of newer agents, including carfilzomib, ixazomib, elotuzumab, and daratumumab. In concert with the technical advances in the cytogenetic and molecular diagnostics of MM, modifications of its diagnosis and staging system have been attempted for better risk stratification. The modified diagnostic criteria from the International Myeloma Working Group in 2014 enabled a strategy of more active treatment for some patients with smoldering MM, with an ultra-high risk of progression, and fine-tuned the definition of end-organ damage, known as CRAB (hypercalcemia, renal insufficiency, anemia, and bone lesions). Considering Korea’s trend of aging at an unprecedented rate, we can expect that the ASR of MM will maintain a gradual increase for many years to come; therefore, MM will be a cancer of critical importance from both medical and socioeconomic perspectives in Korea. PMID:27604794

  16. Notch-directed microenvironment reprogramming in myeloma: a single path to multiple outcomes.

    PubMed

    Colombo, M; Mirandola, L; Platonova, N; Apicella, L; Basile, A; Figueroa, A J; Cobos, E; Chiriva-Internati, M; Chiaramonte, R

    2013-04-01

    Multiple myeloma is a deadly hematopoietic malignancy. Despite therapeutic advances such as autologous stem cell transplantation and novel chemotherapeutics, multiple myeloma remains incurable. Multiple myeloma cell localization in the bone marrow and the cross-talk with the bone niche trigger dramatic alterations in the bone marrow microenvironment critical for tumor progression, resistance to therapies and osteolytic bone destruction. It does not surprise that the molecular bases of such fatal interaction are under examination as source of novel potential pharmacological targets. Among these, the Notch family of receptors and ligands has gained growing interest in the recent years because of their early deregulation in multiple myeloma and their ability to affect multiple features of the disease, including tumor cell growth, drug resistance, angiogenesis and bone lesions. This review will explore the evidences of Notch deregulation in multiple myeloma, the state of the art of the currently known roles of its signaling in the fatal interaction between multiple myeloma cells, extracellular matrix and cells in the bone marrow stroma. Finally, we will present recent findings concerning the arguments for or against a therapy addressed to Notch signaling inhibition in the cure of multiple myeloma.

  17. Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma

    PubMed Central

    Milosavljevic, Dejan; Berlanga, Oscar; Zojer, Niklas; Hübl, Wolfgang; Fritz, Veronique; Harding, Stephen

    2016-01-01

    Heavy light chain (HLC) assays allow precise measurement of the monoclonal and of the noninvolved polyclonal immunoglobulins of the same isotype as the M‐protein (e.g., monoclonal IgAκ and polyclonal IgAλ in case of an IgAκ myeloma), which was not possible before. The noninvolved polyclonal immunoglobulin is termed ‘HLC‐matched pair’. We investigated the impact of the suppression of the HLC‐matched pair on outcome in 203 patients with multiple myeloma, a phenomenon that likely reflects the host's attempt to control the myeloma clone. Severe (>50%) HLC‐matched pair suppression was identified in 54.5% of the 156 newly diagnosed patients and was associated with significantly shorter survival (45.4 vs. 71.9 months, P = 0.019). This correlation was statistically significant in IgG patients (46.4 vs. 105.1 months, P = 0.017), but not in patients with IgA myelomas (32.9 vs. 54.1 months, P = 0.498). At best response, HLC‐matched pair suppression improved only in patients with ≥VGPR, indicating partial or complete humoral immune reconstitution during remission in those with excellent response. Severe HLC‐matched pair suppression retained its prognostic impact also during follow‐up after first response. In the 47 pretreated patients with relapsed/refractory disease, a similar correlation between severe HLC suppression and survival was noted (22.8 vs. not reached, P = 0.028). Suppression of the polyclonal immunoglobulins of the other isotypes than the myeloma protein correlated neither with HLC‐matched pair suppression, nor with outcome. Multivariate analysis identified severe HLC‐matched pair suppression as independent risk factor for shorter survival, highlighting the impact of isotype specific immune dysregulation on outcome in multiple myeloma. Am. J. Hematol. 91:295–301, 2016. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc. PMID:26662888

  18. The ubiquitin-proteasomal system is critical for multiple myeloma: implications in drug discovery

    PubMed Central

    Cao, Biyin; Mao, Xinliang

    2011-01-01

    Bortezomib is a specific inhibitor of proteasomes, the most important protease complexes in protein degradation. Bortezomib can induce apoptosis of a variety of cancer cells, including leukemia, lymphoma, multiple myeloma, breast cancers, prostate cancers, lung cancers, and so on. However, extensive studies and overall evaluation suggested that multiple myeloma is the most sensitive and the best responsive disease which was later approved by Food and Drug Administration for bortezomib treatment. Because proteasomes are an essential component in the ubiquitin-proteasomal protein degradation pathway, the discovery of bortezomib implicates that the UPS is critical for myeloma pathophysiology. The UPS also contains ubiquitin, ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin ligases (E3) and deubiquitinases (Dubs). In this review, we examined and analyzed the recent advancements of the UPS components in multiple myeloma and its implications in drug discovery for myeloma treatment. PMID:22432065

  19. Epstein-Barr virus-positive multiple myeloma following an ABO incompatible second renal transplantation.

    PubMed

    Kirushnan, B; Subbarao, B; Prabhu, P

    2016-01-01

    ABO incompatible kidney transplant recipients receive higher dose of immunosuppression. Previous data indicate that the incidence of malignancy is not higher in these patients. Compared to the general population, renal transplant recipients are at 4.4-fold higher risk of developing myeloma. We describe a case of posttransplant multiple myeloma in an ABO incompatible renal transplant recipient of a second graft. PMID:27512301

  20. Steroid-resistant nephrotic syndrome secondary to primary focal segmental glomerulosclerosis and smoldering multiple myeloma

    PubMed Central

    Shah, Rupin; Shah, Nishi; Shah, Arun

    2014-01-01

    We present a patient with steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis along with smoldering multiple myeloma. While investigating the cause of proteinuria, a monoclonal gammopathy with a negative kidney biopsy for myeloma-related pathology was discovered. PMID:24381395

  1. Epstein-Barr virus-positive multiple myeloma following an ABO incompatible second renal transplantation

    PubMed Central

    Kirushnan, B.; Subbarao, B.; Prabhu, P.

    2016-01-01

    ABO incompatible kidney transplant recipients receive higher dose of immunosuppression. Previous data indicate that the incidence of malignancy is not higher in these patients. Compared to the general population, renal transplant recipients are at 4.4-fold higher risk of developing myeloma. We describe a case of posttransplant multiple myeloma in an ABO incompatible renal transplant recipient of a second graft. PMID:27512301

  2. Modeling Cell–Cell Interactions in Regulating Multiple Myeloma Initiating Cell Fate

    PubMed Central

    Peng, Tao; Peng, Huiming; Choi, Dong Soon; Su, Jing; (Jeff) Chang, Chung-Che

    2014-01-01

    Cancer initiating cells have been documented in multiple myeloma and believed to be a key factor that initiates and drives tumor growth, differentiation, metastasis, and recurrence of the diseases. Although myeloma initiating cells (MICs) are likely to share many properties of normal stem cells, the underlying mechanisms regulating the fate of MICs are largely unknown. Studies designed to explore such communication are urgently needed to enhance our ability to predict the fate decisions of MICs (self-renewal, differentiation, and proliferation). In this study, we developed a novel system to understand the intercellular communication between MICs and their niche by seamlessly integrating experimental data and mathematical model. We first designed dynamic cell culture experiments and collected three types of cells (side population cells, progenitor cells, and mature myeloma cells) under various cultural conditions with flow cytometry. Then we developed a lineage model with ordinary differential equations by considering secreted factors, self-renewal, differentiation, and other biological functions of those cells, to model the cell–cell interactions among the three cell types. Particle swarm optimization was employed to estimate the model parameters by fitting the experimental data to the lineage model. The theoretical results show that the correlation coefficient analysis can reflect the feedback loops among the three cell types, the intercellular feedback signaling can regulate cell population dynamics, and the culture strategies can decide cell growth. This study provides a basic framework of studying cell–cell interactions in regulating MICs fate. PMID:24058033

  3. Does benzene cause multiple myeloma? An analysis of the published case-control literature

    SciTech Connect

    Bezabeh, S.; Engel, A.; Morris, C.B.; Lamm, S.H.

    1996-12-01

    Two case series and two epidemiological studies in the 1970s and 1980s suggested that benzene exposure might be a risk factor for multiple myeloma. An analysis has now been conducted of the published population-based and hospital-based case-control studies published through mid-1995 that permit examination of the relationship between multiple myeloma and benzene exposure or surrogates for benzene exposure. No increased association was found between multiple myeloma and benzene exposure or exposure to chemical groups that included benzene. The odds ratios from these analyses approximated 1.0. Exposures to petroleum products and employment in petroleum-related occupations did not appear to be risk factors for multiple myeloma. Cigarette smoking, as a surrogate of benzene exposure, was not found to be associated with multiple myeloma, while some studies of products of combustion described as {open_quotes}engine exhaust{close_quotes} did show a significant association with multiple myeloma. In toto, the population-based and hospital-based case-control literature indicated that benzene exposure was not a likely causal factor for multiple myeloma. 28 refs., 3 figs., 1 tab.

  4. Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma.

    PubMed

    Yang, J; He, J; Wang, J; Cao, Y; Ling, J; Qian, J; Lu, Y; Li, H; Zheng, Y; Lan, Y; Hong, S; Matthews, J; Starbuck, M W; Navone, N M; Orlowski, R Z; Lin, P; Kwak, L W; Yi, Q

    2012-09-01

    Bone destruction is a hallmark of multiple myeloma and affects more than 80% of patients. However, current therapy is unable to completely cure and/or prevent bone lesions. Although it is accepted that myeloma cells mediate bone destruction by inhibition of osteoblasts and activation of osteoclasts, the underlying mechanism is still poorly understood. This study demonstrates that constitutive activation of p38 mitogen-activated protein kinase in myeloma cells is responsible for myeloma-induced osteolysis. Our results show that p38 is constitutively activated in most myeloma cell lines and primary myeloma cells from patients. Myeloma cells with high/detectable p38 activity, but not those with low/undetectable p38 activity, injected into severe combined immunodeficient (SCID) or SCID-hu mice caused bone destruction. Inhibition or knockdown of p38 in human myeloma reduced or prevented myeloma-induced osteolytic bone lesions without affecting tumor growth, survival, or homing to bone. Mechanistic studies showed that myeloma cell p38 activity inhibited osteoblastogenesis and bone formation and activated osteoclastogenesis and bone resorption in myeloma-bearing SCID mice. This study elucidates a novel molecular mechanism-activation of p38 signaling in myeloma cells-by which myeloma cells induce osteolytic bone lesions, and indicates that targeting myeloma cell p38 may be a viable approach to treating or preventing myeloma bone disease. PMID:22425892

  5. Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma

    PubMed Central

    Yang, Jing; He, Jin; Wang, Ji; Cao, Yabing; Ling, Jianhua; Qian, Jianfei; Lu, Yong; Li, Haiyan; Zheng, Yuhuan; Lan, Yongsheng; Hong, Sungyoul; Matthews, Jairo; Starbuck, Michael W; Navone, Nora M; Orlowski, Robert Z.; Lin, Pei; Kwak, Larry W.; Yi, Qing

    2012-01-01

    Bone destruction is a hallmark of multiple myeloma and affects more than 80% of patients. However, current therapy is unable to completely cure and/or prevent bone lesions. Although it is accepted that myeloma cells mediate bone destruction by inhibition of osteoblasts and activation of osteoclasts, the underlying mechanism is still poorly understood. This study demonstrates that constitutive activation of p38 mitogen-activated protein kinase in myeloma cells is responsible for myeloma-induced osteolysis. Our results show that p38 is constitutively activated in most myeloma cell lines and primary myeloma cells from patients. Myeloma cells with high/detectable p38 activity, but not those with low/undetectable p38 activity, injected into SCID or SCID-hu mice caused bone destruction. Inhibition or knockdown of p38 in human myeloma reduced or prevented myeloma-induced osteolytic bone lesions without affecting tumor growth, survival, or homing to bone. Mechanistic studies showed that myeloma cell p38 activity inhibited osteoblastogenesis and bone formation and activated osteoclastogenesis and bone resorption in myeloma-bearing SCID mice. This study elucidates a novel molecular mechanism—sactivation of p38 signaling in myeloma cells—by which myeloma cells induce osteolytic bone lesions and indicates that targeting myeloma cell p38 may be a viable approach to treating or preventing myeloma bone disease. PMID:22425892

  6. Does benzene cause multiple myeloma? An analysis of the published case-control literature.

    PubMed

    Bezabeh, S; Engel, A; Morris, C B; Lamm, S H

    1996-12-01

    Two case series and two epidemiological studies in the 1970s and 1980s suggested that benzene exposure might be a risk factor for multiple myeloma. An analysis has now been conducted of the published population-based and hospital-based case-control studies published through mid-1995 that permit examination of the relationship between multiple myeloma and benzene exposure or surrogates for benzene exposure. No increased association was found between multiple myeloma and benzene exposure or exposure to chemical groups that included benzene. The odds ratios from these analyses approximated 1.0. Exposures to petroleum products and employment in petroleum-related occupations did not appear to be risk factors for multiple myeloma. Cigarette smoking, as a surrogate of benzene exposure, was not found to be associated with myeloma, while some studies of products of combustion described as "engine exhaust" did show a significant association with multiple myeloma. In toto, the population-based and hospital-based case-control literature indicated that benzene exposure was not a likely causal factor for multiple myeloma.

  7. Biclonal gammopathy in multiple myeloma: a case report.

    PubMed

    Bakta, I M; Sutarka, I N

    2000-05-01

    Monoclonal gammopathy is a group of B-cell disorders which result in the production of a specific and unique monoclonal immunoglobulin (M-component). Biclonal gammopathy is characterized by the simultaneous appearance of two different M-components. The incidence is about 1% of all monoclonal gammopathy. This paper reports on a 48-year-old male who had a chief complaint of back-pain beginning 7 months earlier. A physical examination was unremarkable, except for anemia and tenderness in the back. Hemoglobin was 5.4 g/dl, white blood cells 4.5 x 10(3)/microliter, platelets 157 x 10(3)/microliter, and reticulocytes 0.9%. Serum iron was 79 mg/dl, and total iron-binding capacity was 210 mg/dl. A blood smear showed the formation of rouleaux, but no plasma cells were found. Serum creatinine was 5.4 mg/dl, with a creatinine clearance of 18.1 ml/min. Serum electrolytes were normal except for serum calcium which was 14.4 mg/dl. The urinalysis showed strongly positive proteinuria (+2), with negative Bence Jones protein. Serum protein electrophoresis showed an increase and a spike pattern of beta-2 globulin (2.8 g/dl) and alpha-2 globulin (1.5 g/dl), with normal gamma globulin. By nephelometry technique, serum IgG was normal (1388 mg/dl), IgA was high (900 mg/dl), and IgM was also high (517 mg/dl). Advanced and extensive osteolytic lesions were found in the clavicle, ribs, skull, humerus, femur, and columna vertebralis. Plasma cells (myeloma cells) in bone marrow were 32%. The clinical diagnosis was multiple myeloma (biclonal gammopathy) stage IIIB (Durie and Salmon staging system). Clinical response was good after two series of conventional chemotherapy, with normal serum electrophoresis, decreasing serum creatinine and serum calcium. Based on the above data, the diagnosis of multiple myeloma with biclonal gammopathy was confirmed. This is a rare case with a combination of IgA and IgM M-components.

  8. Multiple myeloma involving mandible: In an elderly female.

    PubMed

    Sreeja, C; Vijayabanu, B; Vijayalakshmi, D; Devi, M; Ramakrishnan, K; Dhivya, K

    2015-08-01

    Multiple myeloma (MM) is a malignancy of plasma cell origin. It often has a multicentric origin within the bone. It makes about 1% of all malignancies and 15% of all hematologic malignancies. There is a monoclonal proliferation of abnormal plasma cells in this disease that arise from a single malignant precursor that has undergone uncontrolled mitotic division. These cells in turn produce one type of immunoglobulin light chain, either kappa or lambda. Unifocal, monoclonal proliferation of plasma cells is called plasmacytoma. Hereby, we present a case of a 65-year-old female patient who presented with a swelling of the mandible. The uniform sheets of plasma cells in the histopathology punched out radiolucencies in skull radiograph and the blood picture of anemia and hypercalcemia, confirmed the case as MM.

  9. A rare case of listeriosis, acute cholecystitis and multiple myeloma

    PubMed Central

    Polanco, Thais O.; Alothman, Sara; Depaz, Hector; Ramcharan, Alexius

    2016-01-01

    Listeria monocytogenes (LM) is an aerobic, motile, intracellular gram-positive bacterium. Most invasive systemic infections caused by LM are commonly seen in patients at both extremes of age, during pregnancy or in immunocompromised hosts. Common clinical manifestations of LM infection in immunocompromised adults are bacteremia, infections of central nervous system, such as meningitis, and self-limiting febrile gastroenteritis. Focal infections of listeria are rare, especially cholecystitis, with only few cases reported in the last 33 years. A 62-year-old man presented with multiple myeloma, cholecystitis and LM bacteremia. Due to prompt surgical treatment and antibiotics (amoxicillin plus clavulanic acid and gentamycin), this high-risk patient recovered without any complications. PMID:27170703

  10. [Molecular Mechanism and Malignant Clonal Evolution of Multiple Myeloma].

    PubMed

    Ding, Fei; Zhu, Ping; Wu, Xue-Qiang

    2015-10-01

    Almost all patients with multiple myeloma (MM) have chromosomal translocation which can result in genetic variation. There are mainly five types of chromosomal translocations, involving the IGH gene translocation to 11q13 (CCND1), 4p16 (FGFR/MMSET), 16q23 (MAF), 6p21 (CCND3) and 20q11 (MAFB). It is possible that all IGH translocations converge on a common cell cycle signal pathway. Some MM develops through a multistep transformation from monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM (SMM) and eventually to MM and plasma cell leukemia (PCL). Similarly to what Darwin proposed in the mid-19th century-random genetic variation and natural selection in the context of limited resources, MM clonal evolution follow branching and nonlinear mode. The failure of MM treatment is usually related with the minimal subclone which is hardly found at newlydiagnosed. PMID:26524068

  11. Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma

    PubMed Central

    Yang, Wen-Chi; Lin, Sheng-Fung

    2015-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM. PMID:26649299

  12. Multiple myeloma developing in a patient with immune thrombocytopenia.

    PubMed

    Itoh, Toshio

    2016-05-01

    A female diagnosed as having immune thrombocytopenic purpura (ITP) was found to be simultaneously suffering from monoclonal gammopathy of undetermined significance (IgGλ). Urine Bence-Jones protein was negative. During the course, plasma cells accounted for 21.6% of the bone marrow. Based on these clinical features in our case, the second disease was diagnosed as multiple myeloma (MM). Both ITP and MM were successfully treated with corticosteroids, bortezomib, lenalidomide with dexamethasone and eltrombopag olamine. MM with ITP may show the following features: 1) the great majority are IgG types, 2) λ chain types show marked light chain predominance when these two diseases appear simultaneously, 3) κ chain types are predominant in the cases with MM followed by ITP, and 4) MM cases with ITP are more often seen in Japan. PMID:27263790

  13. Multiple myeloma involving mandible: In an elderly female

    PubMed Central

    Sreeja, C.; Vijayabanu, B.; Vijayalakshmi, D.; Devi, M.; Ramakrishnan, K.; Dhivya, K.

    2015-01-01

    Multiple myeloma (MM) is a malignancy of plasma cell origin. It often has a multicentric origin within the bone. It makes about 1% of all malignancies and 15% of all hematologic malignancies. There is a monoclonal proliferation of abnormal plasma cells in this disease that arise from a single malignant precursor that has undergone uncontrolled mitotic division. These cells in turn produce one type of immunoglobulin light chain, either kappa or lambda. Unifocal, monoclonal proliferation of plasma cells is called plasmacytoma. Hereby, we present a case of a 65-year-old female patient who presented with a swelling of the mandible. The uniform sheets of plasma cells in the histopathology punched out radiolucencies in skull radiograph and the blood picture of anemia and hypercalcemia, confirmed the case as MM. PMID:26538963

  14. Multiple myeloma involving mandible: In an elderly female.

    PubMed

    Sreeja, C; Vijayabanu, B; Vijayalakshmi, D; Devi, M; Ramakrishnan, K; Dhivya, K

    2015-08-01

    Multiple myeloma (MM) is a malignancy of plasma cell origin. It often has a multicentric origin within the bone. It makes about 1% of all malignancies and 15% of all hematologic malignancies. There is a monoclonal proliferation of abnormal plasma cells in this disease that arise from a single malignant precursor that has undergone uncontrolled mitotic division. These cells in turn produce one type of immunoglobulin light chain, either kappa or lambda. Unifocal, monoclonal proliferation of plasma cells is called plasmacytoma. Hereby, we present a case of a 65-year-old female patient who presented with a swelling of the mandible. The uniform sheets of plasma cells in the histopathology punched out radiolucencies in skull radiograph and the blood picture of anemia and hypercalcemia, confirmed the case as MM. PMID:26538963

  15. [Prognostic value of minimal residual disease detection in multiple myeloma].

    PubMed

    Takamatsu, Hiroyuki

    2015-01-01

    Minimal residual disease (MRD) detection methods are important for diagnosis, treatment, and prognosis in multiple myeloma (MM), and include serum free-light chain assay, multiparametric flow cytometry (with ≥ 4 colors; sensitivity ≤ 10(-4)), allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR; sensitivity 10(-5)), and next-generation sequencing (NGS; sensitivity ≤ 10(-6)). Although molecular complete remission in MM can be assessed by ASO-PCR, this technique requires preparation of clonotype-pecific primers for each individual, which is both labor- and time-consuming. The use of NGS for MRD detection in MM provides increased sensitivity and specificity, while overcoming the challenges associated with ASO-PCR. Furthermore, MRD-negativity revealed by NGS is more closely associated with durable remission of MM than that revealed by ASO -PCR.

  16. Deep Response in Multiple Myeloma: A Critical Review

    PubMed Central

    Fulciniti, Mariateresa; Munshi, Nikhil C.; Martinez-Lopez, Joaquin

    2015-01-01

    Novel and more effective treatment strategies against multiple myeloma (MM) have significantly prolonged patients' survival and raised interest in the depth of response and its association with clinical outcome. Minimal residual disease (MRD) has emerged as one of the most relevant prognostic factors in MM and should be included in a new definition of complete response (CR). Although further standardization is still required, MRD monitoring should be applied in prospective clinical trials as a sensitive tool to compare and evaluate the efficacy of different treatment strategies, particularly in the consolidation and maintenance settings, and implement individualized therapy-monitoring approaches. Here, we review current definition of deep response in MM, advantages and limitations of current MRD assessment assays, clinical evidences for MRD monitoring as a prognostic tool for therapeutic decisions in MM, and challenges to develop uniform criteria for MRD monitoring. PMID:26783530

  17. Streptococcus pneumoniae bacteraemia leading to the diagnosis of multiple myeloma

    PubMed Central

    Shahani, Savita; Shahani, Lokesh

    2014-01-01

    Multiple myeloma (MM) is a malignant plasma cell disorder characterised by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Anaemia, bone pain from lytic lesions, hypercalcaemia and renal failure are the most common presentations at diagnosis; however, the presence of infection at the time of diagnosis is rarely reported. The author reports an elderly male presenting with isolated fever and initial blood cultures positive for Streptococcus pneumoniae. Investigating the patient's underlying immunodeficient state predisposing him to this infection, serum and urine immunofixation electrophoresis identified monoclonal IgG λ and bone marrow biopsy revealed diffuse plasma cell infiltration that comprised 35% of the cellular elements, which were all consistent with MM. This case report highlights the importance of considering MM in asymptomatic elderly patients who present with acute pneumococcal infection without an apparent predisposing factor. PMID:25239987

  18. [Role of Biology Based on Epigenetics in Multiple Myeloma].

    PubMed

    Wang, Bin-Bin; Wu, Tao

    2016-06-01

    Multiple myeloma (MM) is a malignant tumor, characterized by dysplasia of clonal plasma cells in the bone marrow secreting large amounts of monoclonal immunoglobulin or fragments (M protein), resulting in damage in relevant organs or tissues. The biological complexity of MM is based on disrupted cancer pathways. Except the central role of cytogenetic abnormalities, epigenetic aberrations have also been shown to be involved in the occurrence and development of MM. Epigenetics of MM is mainly concentrated in the ways of DNA methylation, histone modifications and noncoding RNA, which have generated abnormal signaling pathways to regulate cell cycle and apoptosis of MM. In this article, advances of research on epigenetics of development, clinical diagnosis and treatments of MM are reviewed. PMID:27342538

  19. Simvastatin Protects Osteoblasts from the Deleterious Effects of the Liquid Milieu of Multiple Myeloma

    PubMed Central

    Jitumori, R; Fernandes, D; Jitumori, C; Favero, GM

    2015-01-01

    ABSTRACT Lytic bone lesions are the main clinical manifestation of multiple myeloma. The intense variety in this cell microenvironment, composed mainly of fibroblasts, osteoblasts, osteoclasts, immune cells and mesenchymal cells, is influenced by the massive presence of neoplastic plasma cells. Studies with statins have reported their action in stimulating the formation and reducing bone resorption. The aim of this study was to verify the in vitro response of human osteoblasts exposed to the supernatant (liquid milieu) of multiple myeloma. The data obtained indicate that simvastatin has positive effects on the growth of osteoblasts and protection against the anti-proliferative effects of multiple myeloma supernatant. PMID:26426180

  20. Levels of uninvolved immunoglobulins predict clinical status and progression-free survival for multiple myeloma patients.

    PubMed

    Harutyunyan, Nika M; Vardanyan, Suzie; Ghermezi, Michael; Gottlieb, Jillian; Berenson, Ariana; Andreu-Vieyra, Claudia; Berenson, James R

    2016-07-01

    Multiple myeloma (MM) is characterized by the enhanced production of the same monoclonal immunoglobulin (M-Ig or M protein). Techniques such as serum protein electrophoresis and nephelometry are routinely used to quantify levels of this protein in the serum of MM patients. However, these methods are not without their shortcomings and problems accurately quantifying M proteins remain. Precise quantification of the types and levels of M-Ig present is critical to monitoring patient response to therapy. In this study, we investigated the ability of the HevyLite (HLC) immunoassay to correlate with clinical status based on levels of involved and uninvolved antibodies. In our cohort of MM patients, we observed that significantly higher ratios and greater differences of involved HLC levels compared to uninvolved HLC levels correlated with a worse clinical status. Similarly, higher absolute levels of involved HLC antibodies and lower levels of uninvolved HLC antibodies also correlated with a worse clinical status and a shorter progression-free survival. These findings suggest that the HLC assay is a useful and a promising tool for determining the clinical status and survival time for patients with multiple myeloma.

  1. Refractory IgD Multiple Myeloma Treated with Daratumumab: A Case Report and Literature Review

    PubMed Central

    Husnain, Muhammad; Kurtin, Sandra; Barkett, Nikki; bin Riaz, Irbaz

    2016-01-01

    Patients with relapsed and refractory multiple myeloma have poor prognosis. A recent analysis of patients with relapsed and refractory multiple myeloma who were refractory to both proteasome inhibitors and immunomodulatory drugs showed the median overall survival of 9 months only. Daratumumab is the first-in-class human monoclonal antibody against CD38 cells which was studied in phase I/II trials for treatment of these patients with relapsed refractory multiple myeloma. It showed an overall response rate of 36% and a median overall survival (OS) of 17 months in these patients. We report a case of 40-year-old man with immunoglobulin D (IgD) multiple myeloma whose disease was refractory to at least 5 different chemotherapy regimens including proteasome inhibitors and immunomodulatory drugs. The clinical studies assessing daratumumab did not include any patients with IgD myeloma which is a rare form of multiple myeloma and to our knowledge is the first study reporting use of daratumumab in IgD myeloma. PMID:27752376

  2. Role of Histone Deacetylase Inhibitors in Relapsed Refractory Multiple Myeloma: A Focus on Vorinostat and Panobinostat

    PubMed Central

    Afifi, Salma; Michael, Angela; Azimi, Mahshid; Rodriguez, Mabel; Lendvai, Nikoletta; Landgren, Ola

    2016-01-01

    Multiple myeloma is a neoplastic plasma cell disorder that is characterized by clonal proliferation of plasma cells in the bone marrow, monoclonal protein in the blood and/or urine, and associated organ dysfunction and biomarkers. There have been multiple recent advances in the relapsed and refractory setting. Major steps forward include the introduction of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide) in various combinations. These drugs have changed the management of multiple myeloma and have extended overall survival in the past decade. Established curative therapy is not yet available for patients diagnosed with multiple myeloma, supporting the development of new treatment targets. Histone deacetylase inhibitors have multiple proposed mechanisms of action in the treatment of multiple myeloma. Both vorinostat and panobinostat have demonstrated some activity against multiple myeloma, and due to the benefits reported with panobinostat, the U.S. Food and Drug Administration has recently approved the drug for the treatment of relapsed and refractory multiple myeloma. In this article, we describe the pharmacology, efficacy, and toxicity profile of vorinostat and panobinostat and their possible place in therapy. PMID:26684557

  3. Role of Histone Deacetylase Inhibitors in Relapsed Refractory Multiple Myeloma: A Focus on Vorinostat and Panobinostat.

    PubMed

    Afifi, Salma; Michael, Angela; Azimi, Mahshid; Rodriguez, Mabel; Lendvai, Nikoletta; Landgren, Ola

    2015-12-01

    Multiple myeloma is a neoplastic plasma cell disorder that is characterized by clonal proliferation of plasma cells in the bone marrow, monoclonal protein in the blood and/or urine, and associated organ dysfunction and biomarkers. There have been multiple recent advances in the relapsed and refractory setting. Major steps forward include the introduction of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide) in various combinations. These drugs have changed the management of multiple myeloma and have extended overall survival in the past decade. Established curative therapy is not yet available for patients diagnosed with multiple myeloma, supporting the development of new treatment targets. Histone deacetylase inhibitors have multiple proposed mechanisms of action in the treatment of multiple myeloma. Both vorinostat and panobinostat have demonstrated some activity against multiple myeloma, and due to the benefits reported with panobinostat, the U.S. Food and Drug Administration has recently approved the drug for the treatment of relapsed and refractory multiple myeloma. In this article, we describe the pharmacology, efficacy, and toxicity profile of vorinostat and panobinostat and their possible place in therapy.

  4. European perspective on multiple myeloma treatment strategies in 2014.

    PubMed

    Ludwig, Heinz; Sonneveld, Pieter; Davies, Faith; Bladé, Joan; Boccadoro, Mario; Cavo, Michele; Morgan, Gareth; de la Rubia, Javier; Delforge, Michel; Dimopoulos, Meletios; Einsele, Hermann; Facon, Thierry; Goldschmidt, Hartmut; Moreau, Philippe; Nahi, Hareth; Plesner, Torben; San-Miguel, Jesús; Hajek, Roman; Sondergeld, Pia; Palumbo, Antonio

    2014-08-01

    The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition, nowadays it is possible to categorize patients more precisely into different risk groups, thus allowing the evaluation of therapies in different settings and enabling a better comparison of results across trials. Here, we review the evidence from clinical studies, which forms the basis for our recommendations for the management of patients with myeloma. Treatment approaches depend on "fitness," with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT) remains the preferred option. Consolidation and maintenance therapy are attractive strategies not yet approved by the European Medicines Agency, and a decision regarding post-ASCT therapy should only be made after detailed discussion of the pros and cons with the individual patient. Two- and three-drug combinations are recommended for patients not eligible for transplantation. Treatment should be administered for at least nine cycles, although different durations of initial therapy have only rarely been compared so far. Comorbidity and frailty should be thoroughly assessed in elderly patients, and treatment must be adapted to individual needs, carefully selecting appropriate drugs and doses. A substantial number of new drugs and novel drug classes in early clinical development have shown promising activity. Their introduction into clinical practice will most likely further improve treatment results.

  5. Spotlight on elotuzumab in the treatment of multiple myeloma: the evidence to date

    PubMed Central

    Weisel, Katja

    2016-01-01

    Despite advances in the treatment of multiple myeloma, it remains an incurable disease, with relapses and resistances frequently observed. Recently, immunotherapies, in particular, monoclonal antibodies, have become important treatment options in anticancer therapies. Elotuzumab is a humanized monoclonal antibody to signaling lymphocytic activation molecule F7, which is highly expressed on myeloma cells and, to a lower extent, on selected leukocyte subsets such as natural killer cells. By directly activating natural killer cells and by antibody-dependent cell-mediated cytotoxicity, elotuzumab exhibits a dual mechanism of action leading to myeloma cell death with minimal effects on normal tissue. In several nonclinical models of multiple myeloma, elotuzumab was effective as a single agent and in combination with standard myeloma treatments, supporting the use of elotuzumab in patients. In combination with lenalidomide and dexamethasone, elotuzumab showed a significant increase in tumor response rates and progression-free survival in patients with relapsed and/or refractory multiple myeloma. This review summarizes the nonclinical and clinical development of elotuzumab as a single agent and in combination with established therapies for the treatment of multiple myeloma. PMID:27785050

  6. [Histone deacetylase inhibitors: new synergistic third-line option in multiple myeloma].

    PubMed

    Stegmann, Danielle A

    2016-04-01

    Despite advances in drug therapy of the orphan disease multiple myeloma, patients relapse or become refractory to first-line therapy, and the disease remains incurable. Therefore, histone deacetylase inhibitors have emerged as a new class of anti-myeloma drugs, with synergistic results on progression free survival when given in combination to current first-line therapy. Histone deacetylase inhibitors influence gene expression of target genes. Based on results of an extensive multicenter phase III trial, panobinostat was approved by the FDA in February 2015 as the first histone deacetylase inhibitor for the treatment of multiple myeloma. In Europe, panobinostat received marketing authorization by August 2015. PMID:27209894

  7. Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

    ClinicalTrials.gov

    2016-06-27

    Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Waldenström Macroglobulinemia

  8. Endogenous Panophthalmitis in a case of Multiple Myeloma and Diabetes Mellitus.

    PubMed

    Nayak, Madhurima K; Singh, Neha

    2016-07-01

    Multiple myeloma cripples the human body in many ways, one of them being decreased immunity. Infections occurring spontaneously can increase the morbidity. We report a case of an elderly lady with multiple myeloma on treatment and uncontrolled diabetes, who developed loss of vision, swelling and redness of left eye of 4 days duration. There was no history of injury or entry of a foreign body. She also had left arm cellulitis. Ocular examination revealed visual acuity of 6/36 in right eye and no perception of light in left eye. Anterior segment of the right eye was insignificant while the left eye showed features suggestive of panophthalmitis. B scan revealed choroidal detachment and confirmed panophthalmitis. She underwent evisceration of the left eye. The cause of spontaneous infections is an immunocompromised state due to multiple myeloma and uncontrolled diabetes. This case report highlights the propensity of multiple myeloma to cause infections of the eye debilitating enough to cause severe visual morbidity. PMID:27630876

  9. Endogenous Panophthalmitis in a case of Multiple Myeloma and Diabetes Mellitus

    PubMed Central

    Nayak, Madhurima K.

    2016-01-01

    Multiple myeloma cripples the human body in many ways, one of them being decreased immunity. Infections occurring spontaneously can increase the morbidity. We report a case of an elderly lady with multiple myeloma on treatment and uncontrolled diabetes, who developed loss of vision, swelling and redness of left eye of 4 days duration. There was no history of injury or entry of a foreign body. She also had left arm cellulitis. Ocular examination revealed visual acuity of 6/36 in right eye and no perception of light in left eye. Anterior segment of the right eye was insignificant while the left eye showed features suggestive of panophthalmitis. B scan revealed choroidal detachment and confirmed panophthalmitis. She underwent evisceration of the left eye. The cause of spontaneous infections is an immunocompromised state due to multiple myeloma and uncontrolled diabetes. This case report highlights the propensity of multiple myeloma to cause infections of the eye debilitating enough to cause severe visual morbidity. PMID:27630876

  10. Pomalidomide Plus Low-Dose Dexamethasone Improves Survival for Patients with Multiple Myeloma

    MedlinePlus

    ... Patients with Multiple Myeloma Summary Results from a randomized phase III trial show that the combination of ... condition of accelerated approval for the drug. That randomized phase III clinical trial ( CC-4047-MM-007 ) ...

  11. Multiple myeloma in the very elderly patient: challenges and solutions

    PubMed Central

    Willan, John; Eyre, Toby A; Sharpley, Faye; Watson, Caroline; King, Andrew J; Ramasamy, Karthik

    2016-01-01

    Diagnosis and management of myeloma in the very elderly patient is challenging. Treatment options have vastly improved for elderly myeloma patients but still require the clinician to personalize therapy. In this paper, we offer evidence-based, pragmatic advice on how to overcome six of the main challenges likely to arise: 1) diagnosis of myeloma in this age group, 2) assessment of the need for treatment, and the fitness for combination chemotherapy, 3) provision of the best quality of supportive care, 4) choice of combination chemotherapy in those fit enough for it, 5) treatment of relapsed myeloma, and 6) provision of end of life care. With an increased burden of comorbidities and a reduced resilience to treatment and its associated toxicities, the management of myeloma in this age group requires a different approach to that in younger patients to maximize both quality and length of life. PMID:27143866

  12. Steven's Johnson syndrome with toxic epidermal necrolysis due to thalidomide in a case of multiple myeloma.

    PubMed

    Das, Anupam; Sil, Amrita; Mishra, Vivek; Das, Nilay Kanti

    2014-01-01

    Thalidomide developed in 1954 for morning sickness had proven to be a teratogen and hence was withdrawn from market. Resurgence of thalidomide began as an immunomodulator when it was shown to be effective in the management of multiple myeloma and many conditions like erythema nodosum leprosum, graft versus host disease, recurrent aphthous ulcers etc. We report a case of Stevens Johnson syndrome-toxic epidermal necrolysis developing in an elderly male who was prescribed thalidomide after being diagnosed with multiple myeloma.

  13. Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma.

    PubMed

    Rosean, Timothy R; Tompkins, Van S; Tricot, Guido; Holman, Carol J; Olivier, Alicia K; Zhan, Fenghuang; Janz, Siegfried

    2014-08-01

    Studies on the biologic and molecular genetic underpinnings of multiple myeloma (MM) have identified the pleiotropic, pro-inflammatory cytokine, interleukin-6 (IL-6), as a factor crucial to the growth, proliferation and survival of myeloma cells. IL-6 is also a potent stimulator of osteoclastogenesis and a sculptor of the tumor microenvironment in the bone marrow of patients with myeloma. This knowledge has engendered considerable interest in targeting IL-6 for therapeutic purposes, using a variety of antibody- and small-molecule-based therapies. However, despite the early recognition of the importance of IL-6 for myeloma and the steady progress in our knowledge of IL-6 in normal and malignant development of plasma cells, additional efforts will be required to translate the promise of IL-6 as a target for new myeloma therapies into significant clinical benefits for patients with myeloma. This review summarizes published research on the role of IL-6 in myeloma development and describes ongoing efforts by the University of Iowa Myeloma Multidisciplinary Oncology Group to develop new approaches to the design and testing of IL-6-targeted therapies and preventions of MM.

  14. NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

    PubMed Central

    Xia, Jiliang; Gu, Zhimin; Wendlandt, Erik; Zhan, Xin; Janz, Siegfried; Tricot, Guido; Zhan, Fenghuang

    2014-01-01

    We reported previously that increased expression of aldehyde dehydrogenase 1 (ALDH1) in multiple myeloma (MM) is a marker of tumor-initiating cells (TICs) that is further associated with chromosomal instability (CIN). Here we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, is most abundantly expressed in myeloma. Enforced expression of ALDH1A1 in myeloma cells led to increased clonogenicity, tumor formation in mice, and resistance to myeloma drugs in vitro and in vivo. The mechanism underlying these phenotypes included the ALDH1A1-dependent activation of drug-efflux pump, ABCB1, and survival proteins, AKT and BCL2. Over expression of ALDH1A1 in myeloma cells led to increased mRNA and protein levels of NIMA-related kinase 2 (NEK2), whereas shRNA-mediated knock down of NEK2 decreased drug efflux pump activity and drug resistance. The activation of NEK2 in myeloma cells relied on the ALDH1A1-dependent generation of the retinoid X receptor α (RXRα) ligand, 9-cis retinoic acid (9CRA) – not the retinoic acid receptor α (RARα) ligand, all-trans retinoic acid (ATRA). These findings implicate the ALDH1A1-RXRα-NEK2 pathway in drug resistance and disease relapse in myeloma and suggest that specific inhibitors of ALDH1A1 are worthy of consideration for clinical development of new approaches to overcome drug resistance in myeloma. PMID:25230277

  15. Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120)

    PubMed Central

    Khan, Rashid; Dhodapkar, Madhav; Rosenthal, Adam; Heuck, Christoph; Papanikolaou, Xenofon; Qu, Pingping; van Rhee, Frits; Zangari, Maurizio; Jethava, Yogesh; Epstein, Joshua; Yaccoby, Shmuel; Hoering, Antje; Crowley, John; Petty, Nathan; Bailey, Clyde; Morgan, Gareth; Barlogie, Bart

    2015-01-01

    Multiple myeloma is preceded by an asymptomatic phase, comprising monoclonal gammopathy of uncertain significance and smoldering myeloma. Compared to the former, smoldering myeloma has a higher and non-uniform rate of progression to clinical myeloma, reflecting a subset of patients with higher risk. We evaluated the gene expression profile of smoldering myeloma plasma cells among 105 patients enrolled in a prospective observational trial at our institution, with a view to identifying a high-risk signature. Baseline clinical, bone marrow, cytogenetic and radiologic data were evaluated for their potential to predict time to therapy for symptomatic myeloma. A gene signature derived from four genes, at an optimal binary cut-point of 9.28, identified 14 patients (13%) with a 2-year therapy risk of 85.7%. Conversely, a low four-gene score (<9.28) combined with baseline monoclonal protein <3 g/dL and albumin ≥3.5 g/dL identified 61 patients with low-risk smoldering myeloma with a 5.0% chance of progression at 2 years. The top 40 probe sets showed concordance with indices of chromosome instability. These data demonstrate high discriminatory power of a gene-based assay and suggest a role for dysregulation of mitotic checkpoints in the context of genomic instability as a hallmark of high-risk smoldering myeloma. PMID:26022710

  16. Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma

    PubMed Central

    Rosean, Timothy R.; Tompkins, Van S.; Tricot, Guido; Holman, Carol J.; Olivier, Alicia K.; Zhan, Fenghuang; Janz, Siegfried

    2014-01-01

    Studies on the biologic and molecular genetic underpinnings of multiple myeloma (MM) have identified the pleiotropic, pro-inflammatory cytokine, interleukin-6 (IL-6), as a factor crucial to the growth, proliferation and survival of myeloma cells. IL-6 is also a potent stimulator of osteoclastogenesis and a sculptor of the tumor microenvironment in the bone marrow of patients with myeloma. This knowledge has engendered considerable interest in targeting IL-6 for therapeutic purposes, using a variety of antibody- and small-molecule-based therapies. However, despite the early recognition of the importance of IL-6 for myeloma and the steady progress in our knowledge of IL-6 in normal and malignant development of plasma cells, additional efforts will be required to translate the promise of IL-6 as a target for new myeloma therapies into significant clinical benefits for patients with myeloma. This review summarizes published research on the role of IL-6 in myeloma development and describes ongoing efforts by the University of Iowa Myeloma Multidisciplinary Oncology Group to develop new approaches to the design and testing of IL-6-targeted therapies and preventions of MM. PMID:24845460

  17. Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma.

    PubMed

    Hose, Dirk; Rème, Thierry; Meissner, Tobias; Moreaux, Jérôme; Seckinger, Anja; Lewis, Joe; Benes, Vladimir; Benner, Axel; Hundemer, Michael; Hielscher, Thomas; Shaughnessy, John D; Barlogie, Bart; Neben, Kai; Krämer, Alwin; Hillengass, Jens; Bertsch, Uta; Jauch, Anna; De Vos, John; Rossi, Jean-François; Möhler, Thomas; Blake, Jonathon; Zimmermann, Jürgen; Klein, Bernard; Goldschmidt, Hartmut

    2009-04-30

    Genetic instability and cellular proliferation have been associated with aurora kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of aurora-A, -B, and -C was determined by Affymetrix DNA microarrays in 784 samples including 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.

  18. How we manage autologous stem cell transplantation for patients with multiple myeloma

    PubMed Central

    Dingli, David

    2014-01-01

    An estimated 22 350 patients had multiple myeloma diagnosed in 2013, representing 1.3% of all new cancers; 10 710 deaths are projected, representing 1.8% of cancer deaths. Approximately 0.7% of US men and women will have a myeloma diagnosis in their lifetime, and with advances in therapy, 77 600 US patients are living with myeloma. The 5-year survival rate was 25.6% in 1989 and was 44.9% in 2005. The median age at diagnosis is 69 years, with 62.4% of patients aged 65 or older at diagnosis. Median age at death is 75 years. The rate of new myeloma cases has been rising 0.7% per year during the past decade. The most common indication for autologous stem cell transplantation in the United States is multiple myeloma, and this article is designed to provide the specifics of organizing a transplant program for multiple myeloma. We review the data justifying use of stem cell transplantation as initial management in myeloma patients. We provide selection criteria that minimize the risks of transplantation. Specific guidelines on mobilization and supportive care through the transplant course, as done at Mayo Clinic, are given. A review of the data on tandem vs sequential autologous transplants is provided. PMID:24973360

  19. Targeting Proliferating Cell Nuclear Antigen and Its Protein Interactions Induces Apoptosis in Multiple Myeloma Cells

    PubMed Central

    Müller, Rebekka; Bachke, Siri; Gilljam, Karin M.; Våtsveen, Thea K.; Rø, Torstein B.; Bellacchio, Emanuele; Sundan, Anders; Otterlei, Marit

    2013-01-01

    Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA) is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM). Thus inhibiting PCNA’s protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell-penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells’ sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX-101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment. PMID:23936203

  20. Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma.

    PubMed

    Vatolin, Sergei; Phillips, James G; Jha, Babal K; Govindgari, Shravya; Hu, Jennifer; Grabowski, Dale; Parker, Yvonne; Lindner, Daniel J; Zhong, Fei; Distelhorst, Clark W; Smith, Mitchell R; Cotta, Claudiu; Xu, Yan; Chilakala, Sujatha; Kuang, Rebecca R; Tall, Samantha; Reu, Frederic J

    2016-06-01

    Multiple myeloma cells secrete more disulfide bond-rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell-based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow-sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma. Cancer Res; 76(11); 3340-50. ©2016 AACR. PMID:27197150

  1. Maintaining Bone Health in Patients With Multiple Myeloma: Survivorship Care Plan of the International Myeloma Foundation Nurse Leadership Board

    PubMed Central

    Miceli, Teresa S.; Colson, Kathleen; Faiman, Beth M.; Miller, Kena; Tariman, Joseph D.

    2014-01-01

    About 90% of individuals with multiple myeloma will develop osteolytic bone lesions from increased osteoclastic and decreased osteoblastic activity. Severe morbidities from pathologic fractures and other skeletal events can lead to poor circulation, blood clots, muscle wasting, compromised performance status, and overall poor survival. Supportive care targeting bone disease is an essential adjunct to antimyeloma therapy. In addition, the maintenance of bone health in patients with multiple myeloma can significantly improve quality of life. Oncology nurses and other healthcare providers play a central role in the management of bone disease and maintenance throughout the course of treatment. Safe administration of bisphosphonates, promotion of exercise, maintenance of adequate nutrition, vitamin and mineral supplementation, scheduled radiographic examinations, and monitoring of bone complications are among the important functions that oncology nurses and healthcare providers perform in clinical practice. PMID:21816707

  2. Immunophenotyping in multiple myeloma and related plasma cell disorders

    PubMed Central

    Kumar, Shaji; Kimlinger, Teresa; Morice, William

    2010-01-01

    SUMMARY Plasma cell disorders form a spectrum ranging from the asymptomatic presence of small monoclonal populations of plasma cells to conditions like plasma cell leukemia and multiple myeloma, in which the bone marrow can be replaced by the accumulation of neoplastic plasma cells. Immunophenotyping has become an invaluable tool in the management of hematological malignancies and is increasingly finding a role in the diagnosis and monitoring of plasma cell disorders. Multiparameter flow cytometry has evolved considerably during the past decade with an increasing ability to screen large numbers of events and to detect multiple antigens at the same time. This, along with a better understanding of the phenotypic heterogeneity of the clonal plasma cells in different disorders, has made immunophenotyping an indispensible tool in the diagnosis, prognostic classification and management of plasma cell disorders. This book chapter addresses the approaches taken to evaluate monoclonal plasma cell disorders, and the different markers and techniques that are important for the study of these diseases. PMID:21112041

  3. A Rare Case of Nonsecretory Multiple Myeloma in Lagos, Nigeria: A Case Report and Literature Review

    PubMed Central

    Uche, Ebele; Akinbami, Akinsegun; John-Olabode, Sarah; Dosunmu, Adedoyin; Odesanya, Majeed

    2015-01-01

    Multiple myeloma (MM) is a plasma cell disorder associated with clonal proliferation of plasma cells. Nonsecretory multiple myeloma (NSMM) is a rare variant of MM and accounts for approximately 1% to 5% of all cases. It is defined as symptomatic myeloma without detectable monoclonal immunoglobulin on serum or urine electrophoresis. This variant usually poses a diagnostic challenge to the clinician. We present a 60-year-old Nigerian man who was investigated extensively for bone pain, weight loss, and anaemia. He was eventually diagnosed as having nonsecretory multiple myeloma based on histology and immunohistochemistry results of bone marrow trephine biopsy. He is currently being managed with bortezomib, doxorubicin, and thalidomide, as well as zoledronic acid. He is also on anticoagulation. He continues to show remarkable clinical improvement. We describe this case report and literature review for better awareness amongst medical practitioners and pathologists. PMID:26649043

  4. A Rare Case of Nonsecretory Multiple Myeloma in Lagos, Nigeria: A Case Report and Literature Review.

    PubMed

    Uche, Ebele; Akinbami, Akinsegun; John-Olabode, Sarah; Dosunmu, Adedoyin; Odesanya, Majeed

    2015-01-01

    Multiple myeloma (MM) is a plasma cell disorder associated with clonal proliferation of plasma cells. Nonsecretory multiple myeloma (NSMM) is a rare variant of MM and accounts for approximately 1% to 5% of all cases. It is defined as symptomatic myeloma without detectable monoclonal immunoglobulin on serum or urine electrophoresis. This variant usually poses a diagnostic challenge to the clinician. We present a 60-year-old Nigerian man who was investigated extensively for bone pain, weight loss, and anaemia. He was eventually diagnosed as having nonsecretory multiple myeloma based on histology and immunohistochemistry results of bone marrow trephine biopsy. He is currently being managed with bortezomib, doxorubicin, and thalidomide, as well as zoledronic acid. He is also on anticoagulation. He continues to show remarkable clinical improvement. We describe this case report and literature review for better awareness amongst medical practitioners and pathologists. PMID:26649043

  5. Total cost comparison in relapsed/refractory multiple myeloma

    PubMed Central

    Durie, Brian; Binder, Gary; Pashos, Chris; Khan, Zeba; Hussein, Mohamad; Borrello, Ivan

    2013-01-01

    Objectives Advances in survival in multiple myeloma have focused payer attention on the cost of care. An assessment was conducted to compare the costs of two recent treatments for relapsed/refractory multiple myeloma (rrMM), from the perspective of a US payer. Methods An economic model estimated the total costs of care for two guideline-recommended therapies in rrMM patients: bortezomib (BORT) and lenalidomide plus dexamethasone (LEN/DEX). To evaluate total treatment costs, the costs associated with drug treatment, medical resource utilization, and adverse event (AE) management were determined for each regimen over a common 1-year period. Medical costs and grade 3/4 AE costs were based on rates from published literature, package inserts, and fee schedules (US dollars). To evaluate cost per outcome, assessments determined the monthly costs without disease progression based on pivotal clinical trials (APEX [BORT] and MM-009/MM-010 [LEN/DEX]). Univariate sensitivity analyses and alternative scenarios were also conducted. Results Drug costs for the treatments were very similar, differing by under $10 per day. Medical and AE management costs for BORT were higher by more than $40 per day. Treatment with BORT had annual excess total costs of >$17,000 compared with LEN/DEX. A cost advantage for LEN/DEX was maintained across a variety of sensitivity analyses. Total cost per month without progression was 11% lower with LEN/DEX. Limitations This analysis relied on separate studies having similar comparators, populations, and end-points. Actual treatment patterns and costs pre- and post-relapse may vary from the base scenario and sensitivities modeled. The 12-month time frame captures the preponderance of costs for a relapse line of therapy, yet may not reflect the entirety of costs. There is insufficient evidence to determine whether, or how, a difference in the lifetime costs of the two regimens would vary from the 1-year cost difference. Conclusion While rrMM treatment with

  6. Angiogenic cytokines profile in smoldering multiple myeloma: No difference compared to MGUS but altered compared to symptomatic myeloma

    PubMed Central

    Gkotzamanidou, Maria; Christoulas, Dimitrios; Souliotis, Vassilis L.; Papatheodorou, Athanasios; Dimopoulos, Meletios A.; Terpos, Evangelos

    2013-01-01

    Background Symptomatic multiple myeloma (MM) evolves from an asymptomatic precursor state termed monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Angiogenesis plays a key role in the pathogenesis of MM but there are very limited data for angiogenesis in SMM. Material/Methods We measured the circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), and angiogenin in 54 patients with SMM. The results were compared with those of 27 MGUS patients, 55 MM patients, and 22 healthy controls. The expression of VEGF-A gene was also evaluated in 10 patients with SMM, 10 with symptomatic MM, and 10 with MGUS. Results The ratio of circulating Ang-1/Ang-2 was reduced in MM patients with symptomatic disease due to a dramatic increase of Ang-2 (p<0.001), but not in patients with SMM or MGUS, in whom it did not differ compared to controls. VEGF and angiogenin were increased in all patients compared to controls. However, circulating VEGF was higher in symptomatic MM compared to SMM and MGUS, while angiogenin was reduced. There were no differences in the expression of VEGF-A among the 3 patients categories. Conclusions SMM has a circulating angiogenic cytokine profile similar to that of MGUS, but has altered profile compared to symptomatic MM. Thus, in the progression of MGUS to SMM, circulating angiogenic cytokines seem to be the same. On the contrary, in symptomatic myeloma, the alterations of angiopoietins along with VEGF contribute to myeloma cell growth, supporting the target of these molecules for the development of novel anti-myeloma agents. PMID:24355943

  7. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group

    PubMed Central

    Palumbo, Antonio; Avet-Loiseau, Hervé; Oliva, Stefania; Lokhorst, Henk M.; Goldschmidt, Hartmut; Rosinol, Laura; Richardson, Paul; Caltagirone, Simona; Lahuerta, Juan José; Facon, Thierry; Bringhen, Sara; Gay, Francesca; Attal, Michel; Passera, Roberto; Spencer, Andrew; Offidani, Massimo; Kumar, Shaji; Musto, Pellegrino; Lonial, Sagar; Petrucci, Maria T.; Orlowski, Robert Z.; Zamagni, Elena; Morgan, Gareth; Dimopoulos, Meletios A.; Durie, Brian G.M.; Anderson, Kenneth C.; Sonneveld, Pieter; San Miguel, Jésus; Cavo, Michele; Rajkumar, S. Vincent; Moreau, Philippe

    2015-01-01

    Purpose The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Patients and Methods Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. Results ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum β2-microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. Conclusion The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival. PMID:26240224

  8. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review

    PubMed Central

    Fonseca, R; Bergsagel, PL; Drach, J; Shaughnessy, J.; Gutierrez, N; Stewart, AK; Morgan, G; Van Ness, B; Chesi, M; Minvielle, S; Neri, A; Barlogie, B; Kuehl, WM; Liebisch, P; Davies, F; Chen-Kiang, S; Durie, BGM; Carrasco, R; Sezer, Orhan; Reiman, Tony; Pilarski, Linda; Avet-Loiseau, H

    2010-01-01

    Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinico-pathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor- B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials. PMID:19798094

  9. What Are the Risk Factors for Multiple Myeloma?

    MedlinePlus

    ... a person’s risk of developing myeloma. Having other plasma cell diseases Many people with monoclonal gammopathy of ... American Cancer Society is a qualified 501(c)(3) tax-exempt organization. Cancer.org is provided courtesy ...

  10. Facilitating exercise adherence for patients with multiple myeloma.

    PubMed

    Coleman, Elizabeth Ann; Hall-Barrow, Julie; Coon, Sharon; Stewart, Carol Beth

    2003-01-01

    Physical exercise is becoming an accepted part of therapy for many patients with cancer. Exercise may alleviate patients' fatigue and improve physical performance and psychological outlook. Much of the research is limited to women with breast cancer and excludes patients with bone metastases. This article reports on the authors' work in facilitating exercise adherence for patients with multiple myeloma (MM) and bone lesions while they were enrolled in a feasibility/pilot exercise study as they were receiving treatment for their disease in an outpatient treatment program. The exercise program for these patients receiving high-dose chemotherapy and stem cell transplantation consisted of aerobic and strength-building components. The program was home based, and patients performed exercises without direct supervision. On average, the patients completed the six-month exercise prescription 75% of the time. Overall trends showed that all 14 patients in the exercise group improved in several areas of testing, and the test results of all 10 patients in the usual-care group declined. Flexibility and simplicity are essential when designing exercise programs for patients, and encouragement and support also are needed to help patients adhere to prescribed exercise.

  11. Multiple Myeloma Mortality in Relation to Obesity Among African Americans.

    PubMed

    Sonderman, Jennifer S; Bethea, Traci N; Kitahara, Cari M; Patel, Alpa V; Harvey, Chinonye; Knutsen, Synnøve F; Park, Yikyung; Park, Song-Yi; Fraser, Gary E; Teras, Lauren R; Purdue, Mark P; Stolzenberg-Solomon, Rachael Z; Gillanders, Elizabeth M; Palmer, Julie R; Kolonel, Laurence N; Blot, William J

    2016-10-01

    Multiple myeloma (MM) incidence and mortality are higher among African Americans (AAs) than among other population groups. The prevalence of obesity is also elevated among AAs, but few studies have examined risk of this cancer in relation to body size among AAs. We combined data from seven prospective cohorts tracking mortality among 239 597 AA adults and used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for death because of MM according to body mass index (BMI) at cohort entry, adjusted for age (as time-scale) and sex. Relative to those with normal BMIs (18.5-25 kg/m(2)), mortality increased monotonically as BMI increased, with hazard ratios reaching 1.43 (95% CI = 1.03 to 1.97) for BMIs of 35 kg/m(2) or greater. The findings suggest that obesity is a risk factor for MM and a contributor to the elevated rates and rising incidence trends of MM among AAs in the United States. PMID:27147231

  12. Model of translational cancer research in multiple myeloma

    PubMed Central

    Yasui, Hiroshi; Ishida, Tadao; Maruyama, Reo; Nojima, Masanori; Ikeda, Hiroshi; Suzuki, Hiromu; Hayashi, Toshiaki; Shinomura, Yasuhisa; Imai, Kohzoh

    2012-01-01

    Recently, intensive laboratory and preclinical studies have identified and validated therapeutic molecular targets in multiple myeloma (MM). The introduction of novel agents such as the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide, which were rapidly translated from preclinical studies at the Dana-Farber Cancer Institute into clinical trials, has changed the treatment paradigm and markedly extended overall survival; MM has therefore become a remarkable example of translational cancer research in new drug development. In this article, with the aim of determining the key factors underlying success in translational research, we focus on our studies of MM at Dana-Farber Cancer Institute as well as at our institutes. The identification of these key factors will help to promote translational cancer research not only in MM but also in other hematologic malignancies and solid tumors, to develop novel therapies, to overcome drug resistance, and to thereby improve the prognosis of cancer patients. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02384.x, 2012) PMID:22809142

  13. Multiple Myeloma Mortality in Relation to Obesity Among African Americans.

    PubMed

    Sonderman, Jennifer S; Bethea, Traci N; Kitahara, Cari M; Patel, Alpa V; Harvey, Chinonye; Knutsen, Synnøve F; Park, Yikyung; Park, Song-Yi; Fraser, Gary E; Teras, Lauren R; Purdue, Mark P; Stolzenberg-Solomon, Rachael Z; Gillanders, Elizabeth M; Palmer, Julie R; Kolonel, Laurence N; Blot, William J

    2016-10-01

    Multiple myeloma (MM) incidence and mortality are higher among African Americans (AAs) than among other population groups. The prevalence of obesity is also elevated among AAs, but few studies have examined risk of this cancer in relation to body size among AAs. We combined data from seven prospective cohorts tracking mortality among 239 597 AA adults and used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for death because of MM according to body mass index (BMI) at cohort entry, adjusted for age (as time-scale) and sex. Relative to those with normal BMIs (18.5-25 kg/m(2)), mortality increased monotonically as BMI increased, with hazard ratios reaching 1.43 (95% CI = 1.03 to 1.97) for BMIs of 35 kg/m(2) or greater. The findings suggest that obesity is a risk factor for MM and a contributor to the elevated rates and rising incidence trends of MM among AAs in the United States.

  14. A Mendelian Randomization Study of Plasma Homocysteine and Multiple Myeloma

    PubMed Central

    Xuan, Yang; Li, Xiao-Hong; Hu, Zhong-Qian; Teng, Zhi-Mei; Hu, Dao-Jun

    2016-01-01

    Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12–6.38; P = 2.7 × 10−2). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs). PMID:27126524

  15. Multiple myeloma in the marrow: pathogenesis and treatments.

    PubMed

    Fairfield, Heather; Falank, Carolyne; Avery, Lindsey; Reagan, Michaela R

    2016-01-01

    Multiple myeloma (MM) is a B cell malignancy resulting in osteolytic lesions and fractures. In the disease state, bone healing is limited owing to increased osteoclastic and decreased osteoblastic activity, as well as an MM-induced forward-feedback cycle where bone-embedded growth factors further enhance tumor progression as bone is resorbed. Recent work on somatic mutation in MM tumors has provided insight into cytogenetic changes associated with this disease; the initiating driver mutations causing MM are diverse because of the complexity and multitude of mutations inherent in MM tumor cells. This manuscript provides an overview of MM pathogenesis by summarizing cytogenic changes related to oncogenes and tumor suppressors associated with MM, reviewing risk factors, and describing the disease progression from monoclonal gammopathy of undetermined significance to overt MM. It also highlights the importance of the bone marrow microenvironment (BMM) in the establishment and progression of MM, as well as associated MM-induced bone disease, and the relationship of the bone marrow to current and future therapeutics. This review highlights why understanding the basic biology of the healthy and diseased BMM is crucial in the quest for better treatments and work toward a cure for genetically diverse diseases such as MM. PMID:27002787

  16. Efficacy and safety of denosumab in multiple myeloma.

    PubMed

    Kitagawa, Junichi; Shibata, Yuhei; Matsumoto, Takuro; Nakamura, Nobuhiko; Nakamura, Hiroshi; Ninomiya, Soranobu; Nannya, Yasuhito; Hara, Takeshi; Tsurumi, Hisashi

    2016-05-01

    We analyzed 11 patients with multiple myeloma (MM) treated using denosumab in our institute. The median age was 69 years (range, 54-76 years), and 7 patients were male. Seven patients had presented with newly diagnosed MM. Four patients were initially treated with zoledronic acid, which was then later switched to denosumab. The median number of injections was 15 (range, 1-27). No patients developed skeletal-related events (SRE) during denosumab treatment. Hypocalcemia was defined as serum calcium levels below the baseline in all patients. To prevent hypocalcemia, 8 patients were administered oral calcium. The first course of denosumab injections in 9 patients resulted in more marked decreases in serum calcium concentrations than subsequent courses. Two patients discontinued denosumab after osteonecrosis of the jaw (ONJ) was suspected, but squamous cell carcinoma was later identified in one of these cases. Denosumab might be effective and safe for preventing SRE. Cautionary measurement of serum calcium concentrations and prophylactic supplementation with oral calcium are warranted to avoid hypocalcemia after the first denosumab injection. The possibility of ONJ also merits attention. The clinical diagnosis of ONJ should be considered based on performing appropriate histological analyses. PMID:27263783

  17. Multiple myeloma in the very old: an IASIA conference report.

    PubMed

    Tuchman, Sascha A; Shapiro, Gary R; Ershler, William B; Badros, Ashraf; Cohen, Harvey J; Dispenzieri, Angela; Flores, Irene Q; Kanapuru, Bindu; Jurivich, Donald; Longo, Dan L; Nourbakhsh, Ali; Palumbo, Antonio; Walston, Jeremy; Yates, Jerome W

    2014-05-01

    Multiple myeloma (MM) in patients aged greater than 80 years poses an increasingly common challenge for oncology providers. A multidisciplinary workshop was held in which MM-focused hematologists/oncologists, geriatricians, and associated health-care team members discussed the state of research for MM therapy, as well as themes from geriatric medicine that pertain directly to this patient population. A summary statement of our discussions is presented here, in which we highlight several topics. MM disproportionately affects senior adults, and demographic trends indicate that this trend will accelerate. Complex issues impact cancer in seniors, and although factors such as social environment, comorbidities, and frailty have been well characterized in nononcological geriatric medicine, these themes have been inadequately explored in cancers such as MM, despite their clear relevance to this field. Therapeutically, novel agents have improved survival for MM patients of all ages, but less so for seniors than younger patients for a variety of reasons. Lastly, both MM- and treatment-related symptoms and toxicities require special attention in senior adults. Existing research provides limited insight into how best to manage these often complex patients, who are often not reflected in typical clinical trial populations. We hence offer suggestions for clinical trials that address knowledge gaps in how to manage very old and/or frail patients with MM, given the complicated issues that often surround this patient population.

  18. Proteasome inhibitors in multiple myeloma: 10 years later

    PubMed Central

    Richardson, Paul G.; Cavo, Michele; Orlowski, Robert Z.; San Miguel, Jesús F.; Palumbo, Antonio; Harousseau, Jean-Luc

    2012-01-01

    Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these “second-generation” PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade. PMID:22645181

  19. Systemic Mastocytosis with Smoldering Multiple Myeloma: Report of a Case

    PubMed Central

    Garcia, Gwenalyn; Ying, Liu; Hurford, Matthew; Odaimi, Marcel

    2016-01-01

    Systemic mastocytosis (SM) is a disease characterized by a clonal infiltration of mast cells affecting various tissues of the body. It is grouped into six different subtypes according to the World Health Organization classification. It is called indolent systemic mastocytosis (ISM) when there is no evidence of end organ dysfunction, while the presence of end organ dysfunction defines aggressive systemic mastocytosis (ASM). When SM coexists with a clonal hematological disorder, it is classified as systemic mastocytosis with associated clonal hematological nonmast cell lineage disease (SM-AHNMD). Over 80% of SM-AHNMD cases involve disorders of the myeloid cell lines. To our knowledge, there are only 8 reported cases to date of SM associated with a plasma cell disorder. We report a patient with ISM who was found to have concomitant smoldering multiple myeloma. His disease later progressed to ASM. We discuss this rare association between SM and a plasma cell disorder, and potential common pathophysiologic mechanisms linking the two disorders will be reviewed. We also discuss prognostic factors in SM as well as the management options considered during the evolution of the patient's disease. PMID:27293930

  20. Multiple myeloma in the very old: an IASIA conference report.

    PubMed

    Tuchman, Sascha A; Shapiro, Gary R; Ershler, William B; Badros, Ashraf; Cohen, Harvey J; Dispenzieri, Angela; Flores, Irene Q; Kanapuru, Bindu; Jurivich, Donald; Longo, Dan L; Nourbakhsh, Ali; Palumbo, Antonio; Walston, Jeremy; Yates, Jerome W

    2014-05-01

    Multiple myeloma (MM) in patients aged greater than 80 years poses an increasingly common challenge for oncology providers. A multidisciplinary workshop was held in which MM-focused hematologists/oncologists, geriatricians, and associated health-care team members discussed the state of research for MM therapy, as well as themes from geriatric medicine that pertain directly to this patient population. A summary statement of our discussions is presented here, in which we highlight several topics. MM disproportionately affects senior adults, and demographic trends indicate that this trend will accelerate. Complex issues impact cancer in seniors, and although factors such as social environment, comorbidities, and frailty have been well characterized in nononcological geriatric medicine, these themes have been inadequately explored in cancers such as MM, despite their clear relevance to this field. Therapeutically, novel agents have improved survival for MM patients of all ages, but less so for seniors than younger patients for a variety of reasons. Lastly, both MM- and treatment-related symptoms and toxicities require special attention in senior adults. Existing research provides limited insight into how best to manage these often complex patients, who are often not reflected in typical clinical trial populations. We hence offer suggestions for clinical trials that address knowledge gaps in how to manage very old and/or frail patients with MM, given the complicated issues that often surround this patient population. PMID:24700806

  1. Total therapy with tandem transplants for newly diagnosed multiple myeloma.

    PubMed

    Barlogie, B; Jagannath, S; Desikan, K R; Mattox, S; Vesole, D; Siegel, D; Tricot, G; Munshi, N; Fassas, A; Singhal, S; Mehta, J; Anaissie, E; Dhodapkar, D; Naucke, S; Cromer, J; Sawyer, J; Epstein, J; Spoon, D; Ayers, D; Cheson, B; Crowley, J

    1999-01-01

    Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum beta-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy ("Total Therapy"). Remission induction utilized non-cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low beta-2-microglobulin at diagnosis

  2. The Role of Imaging in the Treatment of Patients With Multiple Myeloma in 2016.

    PubMed

    Terpos, Evangelos; Dimopoulos, Meletios A; Moulopoulos, Lia A

    2016-01-01

    The novel criteria for the diagnosis of symptomatic multiple myeloma have revealed the value of modern imaging for the management of patients with myeloma. Whole-body low-dose CT (LDCT) has increased sensitivity over conventional radiography for the detection of osteolytic lesions, and several myeloma organizations and institutions have suggested that whole-body LDCT should replace conventional radiography for the work-up of patients with myeloma. MRI is the best imaging method for the depiction of marrow infiltration by myeloma cells. Whole-body MRI (or at least MRI of the spine and pelvis if whole-body MRI is not available) should be performed for all patients with smoldering multiple myeloma with no lytic lesions to look for occult disease, which may justify treatment. In addition, MRI accurately illustrates the presence of plasmacytomas, spinal cord, and/or nerve compression for surgical intervention or radiation therapy; it is also recommended for the work-up of solitary bone plasmacytoma, and it may distinguish malignant from benign fractures (which is very important in cases of patients in biochemical remission with no other signs of progression). Diffusion weighted imaging (DWI) seems to improve MRI diagnosis in patients with myeloma. PET/CT is a functional imaging technique, more sensitive than conventional radiography for the detection of lytic lesions, which probably allows better definition of complete response and minimal residual disease compared with all other imaging methods. PET/CT has shown the best results in the follow-up of patients with myeloma and has an independent prognostic value both at diagnosis and following treatment. PET/CT can also be used for the work-up of solitary bone plasmacytoma and nonsecretory myeloma. PMID:27249748

  3. Extensive skeletal involvement detected by gallium-67 citrate in a patient with multiple myeloma

    SciTech Connect

    Nishiyama, H.; Morand, T.M.; Seiwert, V.J.

    1988-03-01

    Extensive skeletal involvement of multiple myeloma was detected by Ga-67 citrate imaging while searching for infectious foci. The case was unique in that a radiographic skeletal survey showed typical lytic lesions only in the skull, and extensive myeloma involvement in the skeletal system was an incidental finding. A high tumor cell burden was presumed to be present, which led to a rapid and fulminant clinical course in this patient.

  4. Marine compounds inhibit growth of multiple myeloma in vitro and in vivo

    PubMed Central

    Steiner, Normann; Ribatti, Domenico; Willenbacher, Wolfgang; Jöhrer, Karin; Kern, Johann; Marinaccio, Christian; Aracil, Miguel; García-Fernández, Luis F.; Gastl, Guenther

    2015-01-01

    Purpose The prognosis of patients with multiple myeloma (MM) is still dismal despite recent improvements achieved by introducing new therapeutic agents. However, there remains an urgent need for progress in myeloma drug development. We here show that novel marine-derived compounds can exert potent anti-myeloma activity. Experimental Design Nine marine-derived compounds were applied at low nM concentrations (0.1-100 nM) to MM cell lines (OPM-2, NCI-H929, U266, RPMI-8226), to primary human myeloma cells and to peripheral blood mononuclear cells. Apoptosis was determined by flow cytometry. In addition, eGFP-transgenic MM cell lines growing with mesenchymal cells from bone marrow were used to visualize tumors by fluorescence stereomicroscopy. Anti-myelomaactivities were studied in vitro in 3D spheroids and in vivo in myeloma xenografts on chicken embryos. Tumor size was analyzed by measuring GFP content with a GFP ELISA. Anti-angiogenic activities of compounds were tested in an in vivo gelatin sponge assay with conditioned media from primary bone marrow-derived endothelial cells. Results We identified a subset of marine compounds with strong anti-myeloma activity in vitro and in vivo. Moreover, some of the compounds inhibited myeloma-related angiogenesis in the in vivo gelatin sponge assay. They merit further drug development to improve treatment options for MM. PMID:25860931

  5. FOXM1 is a therapeutic target for high-risk multiple myeloma

    PubMed Central

    Gu, Chunyan; Yang, Ye; Sompallae, Ramakrishna; Xu, Hongwei; Tompkins, Van S.; Holman, Carol; Hose, Dirk; Goldschmidt, Hartmut; Tricot, Guido; Zhan, Fenghuang; Janz, Siegfried

    2016-01-01

    The transcription factor forkhead box M1 (FOXM1) is a validated oncoprotein in solid cancers, but its role in malignant plasma cell tumors such as multiple myeloma (MM) is unknown. We analyzed publicly available MM datasets and found that overexpression of FOXM1 prognosticates inferior outcome in a subset (~15%) of newly diagnosed cases, particularly patients with high-risk disease based on global gene expression changes. Follow-up studies using human myeloma cell lines (HMCLs) as the principal experimental model system demonstrated that enforced expression of FOXM1 increased growth, survival and clonogenicity of myeloma cells, whereas knockdown of FOXM1 abolished these features. In agreement with that, constitutive up-regulation of FOXM1 promoted HMCL xenografts in laboratory mice, whereas inducible knockdown of FOXM1 led to growth inhibition. Expression of cyclin dependent kinase 6 (CDK6) and NIMA-related kinase 2 (NEK2) was co-regulated with FOXM1 in both HMCLs and myeloma patient samples, suggesting interaction of these 3 genes in a genetic network that may lend itself to targeting with small-drug inhibitors for new approaches to myeloma therapy and prevention. These results establish FOXM1 as high-risk myeloma gene and provide support for the design and testing of FOXM1-targeted therapies specifically for the FOXM1High subset of myeloma. PMID:26648534

  6. FOXM1 is a therapeutic target for high-risk multiple myeloma.

    PubMed

    Gu, C; Yang, Y; Sompallae, R; Xu, H; Tompkins, V S; Holman, C; Hose, D; Goldschmidt, H; Tricot, G; Zhan, F; Janz, S

    2016-04-01

    The transcription factor forkhead box M1 (FOXM1) is a validated oncoprotein in solid cancers, but its role in malignant plasma cell tumors such as multiple myeloma (MM) is unknown. We analyzed publicly available MM data sets and found that overexpression of FOXM1 prognosticates inferior outcome in a subset (~15%) of newly diagnosed cases, particularly patients with high-risk disease based on global gene expression changes. Follow-up studies using human myeloma cell lines (HMCLs) as the principal experimental model system demonstrated that enforced expression of FOXM1 increased growth, survival and clonogenicity of myeloma cells, whereas knockdown of FOXM1 abolished these features. In agreement with that, constitutive upregulation of FOXM1 promoted HMCL xenografts in laboratory mice, whereas inducible knockdown of FOXM1 led to growth inhibition. Expression of cyclin-dependent kinase 6 (CDK6) and NIMA-related kinase 2 (NEK2) was coregulated with FOXM1 in both HMCLs and myeloma patient samples, suggesting interaction of these three genes in a genetic network that may lend itself to targeting with small-drug inhibitors for new approaches to myeloma therapy and prevention. These results establish FOXM1 as high-risk myeloma gene and provide support for the design and testing of FOXM1-targeted therapies specifically for the FOXM1(High) subset of myeloma. PMID:26648534

  7. Tetraspanin 7 (TSPAN7) expression is upregulated in multiple myeloma patients and inhibits myeloma tumour development in vivo

    SciTech Connect

    Cheong, Chee Man; Chow, Annie W.S.; Fitter, Stephen; Hewett, Duncan R.; Martin, Sally K.; Williams, Sharon A.; To, L. Bik; and others

    2015-03-01

    Background: Increased expression of the tetraspanin TSPAN7 has been observed in a number of cancers; however, it is unclear how TSPAN7 plays a role in cancer progression. Methods: We investigated the expression of TSPAN7 in the haematological malignancy multiple myleoma (MM) and assessed the consequences of TSPAN7 expression in the adhesion, migration and growth of MM plasma cells (PC) in vitro and in bone marrow (BM) homing and tumour growth in vivo. Finally, we characterised the association of TSPAN7 with cell surface partner molecules in vitro. Results: TSPAN7 was found to be highly expressed at the RNA and protein level in CD138{sup +} MM PC from approximately 50% of MM patients. TSPAN7 overexpression in the murine myeloma cell line 5TGM1 significantly reduced tumour burden in 5TGM1/KaLwRij mice 4 weeks after intravenous adminstration of 5TGM1 cells. While TSPAN7 overexpression did not affect cell proliferation in vitro, TSPAN7 increased 5TGM1 cell adhesion to BM stromal cells and transendothelial migration. In addition, TSPAN7 was found to associate with the molecular chaperone calnexin on the cell surface. Conclusion: These results suggest that elevated TSPAN7 may be associated with better outcomes for up to 50% of MM patients. - Highlights: • TSPAN7 expression is upregulated in newly-diagnosed patients with active multiple myeloma. • Overexpression of TSPAN7 inhibits myeloma tumour development in vivo. • TSPAN7 interacts with calnexin at the plasma membrane in a myeloma cell line.

  8. Frequent expression of multiple myeloma 1/interferon regulatory factor 4 in Burkitt lymphoma.

    PubMed

    Gualco, Gabriela; Queiroga, Eduardo M; Weiss, Lawrence M; Klumb, Claudete E N; Harrington, William J; Bacchi, Carlos E

    2009-04-01

    Burkitt lymphoma is a highly aggressive non-Hodgkin lymphoma with endemic, sporadic, and immunodeficiency-associated clinical variants composed of monomorphic medium-sized B cells with a high proliferation rate and a translocation involving the C-MYC locus. Classically, the immunophenotype of Burkitt lymphoma has been considered to be the germinal center type. In most reports, all cases of Burkitt lymphoma are reported to be multiple myeloma 1-negative. multiple myeloma 1 expression is seen in plasma cells and in a small fraction of B cells located in the light zone of germinal centers corresponding to the final step of intra-germinal center B-cell differentiation, and in activated T cells. Therefore, multiple myeloma 1 expression may denote the final step of intra-germinal center B-cell differentiation at the centrocyte stage, as well as the subsequent steps of B-cell maturation toward plasma cells. Unlike most normal germinal center B cells, in which the expression of multiple myeloma 1 and bcl-6 are mutually exclusive, the tumor cells in approximately 50% of multiple myeloma 1-positive DLBCL show coexpression of bcl-6, suggesting that the expression of these proteins may be deregulated. Twenty-five Burkitt lymphoma cases, including 19 associated with HIV, were reported in one of the few studies in the literature; 2 of these cases showed occasional multiple myeloma 1-positive cells, less than the 20% cutoff for positivity. We studied 222 cases of well-characterized Burkitt lymphoma with the classic phenotype and C-MYC translocation and found 90 cases (40.5%) with multiple myeloma 1 nuclear expression, suggesting a late germinal center stage of differentiation.

  9. Bortezomib plus melphalan and prednisone (VMP regimen) as the initial treatment for IgE multiple myeloma: a case study.

    PubMed

    Sato, Hiroyuki; Komiya, Yusuke; Hoshino, Shigeru

    2014-06-01

    Patients with IgE multiple myeloma have poor prognosis. Due to the rarity of this condition, no standard treatment has been developed. As the VMP regimen (bortezomib plus melphalan and prednisone) has been reported to be highly effective in the treatment of other types of myeloma, we treated a patient with newly diagnosed IgE myeloma using the VMP regimen. Her myeloma responded well to VMP regimen. The results of this case report thus suggest that physicians may consider VMP regimen for use as the initial treatment for IgE myeloma.

  10. Geriatric assessment in multiple myeloma patients: validation of the International Myeloma Working Group (IMWG) score and comparison with other common comorbidity scores.

    PubMed

    Engelhardt, Monika; Dold, Sandra Maria; Ihorst, Gabriele; Zober, Alexander; Möller, Mandy; Reinhardt, Heike; Hieke, Stefanie; Schumacher, Martin; Wäsch, Ralph

    2016-09-01

    This first validation of the International Myeloma Working Group geriatric assessment in 125 newly diagnosed multiple myeloma patients was performed using the International Myeloma Working Group score based on age, the Charlson Comorbidity Index and cognitive and physical conditions (Activities of Daily Living / Instrumental Activities of Daily Living) to classify patients as fit, intermediate-fit or frail. We verified the International Myeloma Working Group score's impact on outcome, and whether additional tools complement it. Since our prior analyses determined renal, lung and Karnofsky performance impairment as multivariate risks, and the inclusion of frailty, age and cytogenetics complements this, we included the revised myeloma comorbidity index, the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index and the Kaplan-Feinstein Index in this assessment. Multivariate analysis confirmed cytogenetics, Activities of Daily Living, Instrumental Activities of Daily Living and the Charlson Comorbidity Index as risks: 3-year overall survival for fit, intermediate-fit and frail patients was 91%, 77% and 47%, respectively. Using the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index, the Kaplan-Feinstein Index and the revised Myeloma Comorbidity Index allowed us to define fit and frail patients with distinct progression-free and overall survival rates, with the most pronounced differences evidenced via the International Myeloma Working Group score, the Charlson Comorbidity Index and the revised Myeloma Comorbidity Index. Since the Charlson Comorbidity Index is included in the International Myeloma Working Group score, we propose the latter and the revised Myeloma Comorbidity Index for future frailty measurements. Both are useful instruments for identifying myeloma patients with a geriatric risk profile and have a strong prognostic value for functional decline and overall survival. The study was registered

  11. Geriatric assessment in multiple myeloma patients: validation of the International Myeloma Working Group (IMWG) score and comparison with other common comorbidity scores

    PubMed Central

    Engelhardt, Monika; Dold, Sandra Maria; Ihorst, Gabriele; Zober, Alexander; Möller, Mandy; Reinhardt, Heike; Hieke, Stefanie; Schumacher, Martin; Wäsch, Ralph

    2016-01-01

    This first validation of the International Myeloma Working Group geriatric assessment in 125 newly diagnosed multiple myeloma patients was performed using the International Myeloma Working Group score based on age, the Charlson Comorbidity Index and cognitive and physical conditions (Activities of Daily Living / Instrumental Activities of Daily Living) to classify patients as fit, intermediate-fit or frail. We verified the International Myeloma Working Group score’s impact on outcome, and whether additional tools complement it. Since our prior analyses determined renal, lung and Karnofsky performance impairment as multivariate risks, and the inclusion of frailty, age and cytogenetics complements this, we included the revised myeloma comorbidity index, the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index and the Kaplan-Feinstein Index in this assessment. Multivariate analysis confirmed cytogenetics, Activities of Daily Living, Instrumental Activities of Daily Living and the Charlson Comorbidity Index as risks: 3-year overall survival for fit, intermediate-fit and frail patients was 91%, 77% and 47%, respectively. Using the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index, the Kaplan-Feinstein Index and the revised Myeloma Comorbidity Index allowed us to define fit and frail patients with distinct progression-free and overall survival rates, with the most pronounced differences evidenced via the International Myeloma Working Group score, the Charlson Comorbidity Index and the revised Myeloma Comorbidity Index. Since the Charlson Comorbidity Index is included in the International Myeloma Working Group score, we propose the latter and the revised Myeloma Comorbidity Index for future frailty measurements. Both are useful instruments for identifying myeloma patients with a geriatric risk profile and have a strong prognostic value for functional decline and overall survival. The study was registered

  12. Non Secretory Multiple Myeloma With Extensive Extramedullary Plasmacytoma: A Diagnostic Dilemma

    PubMed Central

    Low, Soo Fin; Mohd Tap, Nor Hanani; Kew, Thean Yean; Ngiu, Chai Soon; Sridharan, Radhika

    2015-01-01

    Multiple myeloma (MM) is characterized by progressive proliferation of malignant plasma cells, usually initiating in the bone marrow. MM can affect any organ; a total of 7 - 18% of patients with MM demonstrate extramedullary involvement at diagnosis. Non-secretory multiple myeloma (NSMM) is a rare variant that accounts for 1 - 5% of all cases of multiple myeloma. The disease is characterized by the absence of monoclonal gammopathy in serum and urine electrophoresis. Our case report highlights the diagnostic challenge of a case of NSMM with extensive extramedullary involvement in a young female patient who initially presented with right shoulder pain and bilateral breasts lumps. Skeletal survey showed multiple lytic bony lesions. The initial diagnosis was primary breast carcinoma with osseous metastases. No monoclonal gammopathy was found in the serum or urine electrophoresis. Bone marrow and breast biopsies revealed marked plasmacytosis. The diagnosis was delayed for a month in view of the lack of clinical suspicion of multiple myeloma in a young patient and scant biochemical expression of non-secretory type of multiple myeloma. PMID:26528383

  13. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma

    PubMed Central

    Lonial, Sagar; Waller, Edmund K.; Richardson, Paul G.; Jagannath, Sundar; Orlowski, Robert Z.; Giver, Cynthia R.; Jaye, David L.; Francis, Dixil; Giusti, Sara; Torre, Claire; Barlogie, Bart; Berenson, James R.; Singhal, Seema; Schenkein, David P.; Esseltine, Dixie-Lee W.; Anderson, Jessica; Xiao, Hugh; Heffner, Leonard T.; Anderson, Kenneth C.

    2005-01-01

    Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m2 in 228 patients with relapsed and/or refractory myeloma in 2 phase 2 trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclic fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Plasma thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production. PMID:16099887

  14. Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers

    PubMed Central

    Castellano, Giancarlo; Pascual, Marien; Heath, Simon; Kulis, Marta; Segura, Victor; Bergmann, Anke; Esteve, Anna; Merkel, Angelika; Raineri, Emanuele; Agueda, Lidia; Blanc, Julie; Richardson, David; Clarke, Laura; Datta, Avik; Russiñol, Nuria; Queirós, Ana C.; Beekman, Renée; Rodríguez-Madoz, Juan R.; José-Enériz, Edurne San; Fang, Fang; Gutiérrez, Norma C.; García-Verdugo, José M.; Robson, Michael I.; Schirmer, Eric C.; Guruceaga, Elisabeth; Martens, Joost H.A.; Gut, Marta; Calasanz, Maria J.; Flicek, Paul; Siebert, Reiner; Campo, Elías; Miguel, Jesús F. San; Melnick, Ari; Stunnenberg, Hendrik G.; Gut, Ivo G.

    2015-01-01

    While analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with down-regulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cell-specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation, suggesting that MM cells either reacquire epigenetic features of undifferentiated cells or maintain an epigenetic signature of a putative myeloma stem cell progenitor. Overall, we have identified DNA hypermethylation of developmentally regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM. PMID:25644835

  15. A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma.

    PubMed

    Shiheido, Hirokazu; Terada, Fukiko; Tabata, Noriko; Hayakawa, Ichigo; Matsumura, Nobutaka; Takashima, Hideaki; Ogawa, Yoko; Du, Wenlin; Yamada, Taketo; Shoji, Mitsuru; Sugai, Takeshi; Doi, Nobuhide; Iijima, Shiro; Hattori, Yutaka; Yanagawa, Hiroshi

    2012-01-01

    Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9. This compound also showed in vivo activity against multiple myeloma cell line KMS34 tumor xenografts in ICR/SCID mice. By means of mRNA display selection on a microfluidic chip, the target protein of TC11 was identified as nucleophosmin 1 (NPM). Binding of TC11 and NPM monomer was confirmed by surface plasmon resonance. Immunofluorescence and NPM knockdown studies in HeLa cells suggested that TC11 inhibits centrosomal clustering by inhibiting the centrosomal-regulatory function of NPM, thereby inducing multipolar mitotic cells, which undergo apoptosis. NPM may become a novel target for development of antitumor drugs active against multiple myeloma.

  16. Concomitant multiple myeloma spectrum diagnosis in a central retinal vein occlusion: a case report and review.

    PubMed

    Borgman, Christopher J

    2016-07-01

    Multiple myeloma is a neoplastic plasma-cell disorder resulting from malignant plasma cells in the bone marrow. It can cause a hyperviscosity syndrome secondary to the paraproteinaemia associated with the disease. The increased hyperviscosity can lead to retinal vein occlusions and other ocular problems that may challenge clinicians. In patients with multiple myeloma and hypertension and/or diabetes mellitus, retinal changes appear similar and changes due to one disease or the other may be difficult to determine. A 48-year-old white female presented to the clinic with a complaint of blurry vision in her left eye. A full comprehensive ocular examination revealed a central retinal vein occlusion presumably from the patient's history of hypertension, diabetes mellitus and hypercholesterolaemia. Further bloodwork revealed monoclonal protein in the patient's serum and an increased percentage of plasma cells in the bone marrow. She was diagnosed with monoclonal gammopathy of undetermined significance, part of the multiple myeloma disease spectrum. She was referred to a retinal specialist for initiation of intravitreal injections of anti-vascular endothelial growth factor. Multiple myeloma has been implicated in younger patients as an underlying cause of retinal vein occlusions. Multiple myeloma should be considered as a differential diagnosis in young patients with retinal vein occlusions, even if other risk factors for venous occlusion like hypertension, diabetes mellitus and hypercholesterolaemia are present. Timely referral to the patient's primary care physician and haematologist is important for appropriate treatment and control of underlying systemic conditions. PMID:27079282

  17. EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

    SciTech Connect

    Huang, Er-Wen; Xue, Sheng-Jiang; Li, Xiao-Yan; Xu, Suo-Wen; Cheng, Jian-Ding; Zheng, Jin-Xiang; Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong; Li, Jie; Liu, Chao

    2014-05-02

    Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.

  18. Gene expression profiling defines a high-risk entity of multiple myeloma.

    PubMed

    Zhan, Feng-Huang; Barlogie, Bart; John D, Shaughnessy

    2007-04-01

    Multiple myeloma (MM) is the second most common hematological malignancy and remains incurable. The marked variation in survival of patients with symptomatic myeloma ranging from few months to more than 15 years can be explained by differences in tumor mass, proliferative activity and, more recently, by cytogenetic and molecular genetic characteristics of the myeloma clone. Oligonucleotide microarray-based gene expression analysis was applied to CD138-enriched plasma cells from newly diagnosed patients with symptomatic or progressive multiple myeloma treated with melphalan-based high-dose therapy. Here we discuss recent progress made in the development of molecular-based diagnostics and prognostics for MM from Myeloma Institute for Research and Therapy of University Arkansas for Medical Sciences, where we treat more patients with myeloma than anywhere else in the world. Seven distinct entities of myeloma were elucidated by genomic profiling. Expression extremes of 70 genes from a high-risk signature profile,30% of which were derived from chromosome 1, were strongly linked to disease-related survival. CKS1B located on chromosome 1q21, responsible for promoting cell cycle progression by inducing the degradation of p27Kip1, represented a strong candidate gene related to rapid patient death and was studied in detail. The data suggest that CKS1B influences myeloma cell growth and survival through SKP2j and P27(Kip1) -dependent and independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking.

  19. Multiple Myeloma and lifetime occupation: results from the EPILYMPH study

    PubMed Central

    2012-01-01

    Background The EPILYMPH study applied a detailed occupational exposure assessment approach to a large multi-centre case–control study conducted in six European countries. This paper analysed multiple myeloma (MM) risk associated with level of education, and lifetime occupational history and occupational exposures, based on the EPILYMPH data set. Methods 277 MM cases and four matched controls per each case were included. Controls were randomly selected, matching for age (+/− 5 years), centre and gender. Lifetime occupations and lifetime exposure to specific workplace agents was obtained through a detailed questionnaire. Local industrial hygienists assessed likelihood and intensity for specific exposures. The odds ratio and 95% confidence intervals (OR, 95% CI) were calculated for level of education, individual occupations and specific exposures. Unconditional logistic regression models were run for individual occupations and exposures. Results A low level of education was associated with MM OR=1.68 (95% CI 1.02-2.76). An increased risk was observed for general farmers (OR=1.77; 95% CI 1.05-2.99) and cleaning workers (OR=1.69; 95% CI 1.04-2.72) adjusting for level of education. Risk was also elevated, although not significant, for printers (OR=2.06; 95% CI 0.97-4.34). Pesticide exposure over a period of ten years or more increased MM risk (OR=1.62; 95% CI 1.01-2.58). Conclusion These results confirm an association of MM with farm work, and indicate its association with printing and cleaning. While prolonged exposure to pesticides seems to be a risk factor for MM, an excess risk associated with exposure to organic solvents could not be confirmed. PMID:23241100

  20. Effects of survivin on FVADT chemotherapy for refractory multiple myeloma

    PubMed Central

    Yang, Hua; Du, Xingjun; Xi, Yuren

    2016-01-01

    The present study aimed to investigate the effects of survivin, an apoptosis inhibitor protein, on the efficacy of the fludarabine, vincristine, epirubicin, dexamethasone and thalidomide (FVADT) chemotherapy regime for the treatment of refractory multiple myeloma (MM). A total of 82 patients with MM were selected from the Hematology Inpatient Department at The Second Affiliated Hospital of Zhengzhou University (Zhengzhou, China). The initial treatment group consisted of 40 patients with MM, who received the vincristine, epirubicin and dexamethasone (VAD) chemotherapy regime. The refractory group consisted of 42 patients with refractory MM, who received the FVADT chemotherapy regime. Bone marrow biopsies were collected via marrow aspirations, and the protein expression of survivin was analyzed by immunohistochemistry. In addition, the Kaplan-Meier method was used for survival analyses. Intergroup differences in the protein expression levels of survivin were compared, and the association between survivin expression and the short- and long-term effects of FVADT chemotherapy were analyzed. The positive expression rate of survivin was significantly higher in the refractory group, as compared with the initial treatment group (P<0.05). Furthermore, the complete remission rate and the effective rate were significantly lower in the survivin-positive group, as compared with the survivin-negative group (P<0.05). The overall survival, progression free survival and 1 and 3 year survival rates of the survivin-positive group were significantly higher, as compared with the survivin-negative group (P<0.05). The results of the present study suggested that the protein expression of survivin was upregulated in refractory MM tissues, which was indicative of a poor short- and long-term efficacy for FVADT chemotherapy. PMID:27446274

  1. Occupation and multiple myeloma: an occupation and industry analysis

    PubMed Central

    Gold, Laura S; Milliken, Kevin; Stewart, Patricia; Purdue, Mark; Severson, Richard; Seixas, Noah; Blair, Aaron; Davis, Scott; Hartge, Patricia; De Roos, Anneclaire J

    2011-01-01

    Background Multiple myeloma (MM) is an incurable plasma cell malignancy with a poorly understood etiology. The purpose of our research was to examine relationships between lifetime occupations and MM in a relatively large case-control study. Methods MM cases (n=180) were identified through cancer registries in the Seattle-Puget Sound area and Detroit. Population-based controls (n=481) were identified using random digit dialing and Medicare and Medicaid Services files. In-person interviews were conducted to ascertain occupational histories. Standard occupational classification (SOC) and standard industrial classification (SIC) codes were assigned to each job held by each participant. Unconditional logistic regression was used to generate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between MM and having ever worked in each occupation/industry and according to duration of employment in an occupation/industry. Results The risk of MM was associated with several manufacturing occupations and industries, including machine operators and tenders, not elsewhere classified (SOC 76) (OR=1.8, CI=1.0–3.3); textile, apparel, and furnishing machine operators and tenders (SOC 765) (OR=6.0, CI=1.7–21); and machinery manufacturing, except electrical (SIC 35) (OR=3.3, CI=1.7–6.7). Several service occupations and industries, such as food and beverage preparation (SOC 521) (OR=2.0, CI=1.1–3.8), were also associated with MM. One occupation that has been associated with MM in several previous studies, painters, paperhangers, and plasterers (SOC 644), was associated with a non–significantly elevated risk (OR=3.6, CI=0.7–19). Conclusions We found associations between the risk of MM and employment in several manufacturing and service-related occupations and industries. PMID:20623662

  2. Personal Financial Effects of Multiple Myeloma and its Treatment

    PubMed Central

    Goodwin, Julia A.; Coleman, Elizabeth Ann; Sullivan, Ellen; Easley, Robin; McNatt, Paula K.; Chowdhury, Nupur; Stewart, Carol Beth

    2013-01-01

    Background Improvements in some treatment programs for multiple myeloma (MM) are increasing survival. As patients live longer with MM as a chronic disease, the personal financial effects of MM treatment become a serious concern. Objective The objective of this study was to identify the personal financial effects of MM and its treatment in five areas: employment, disability, health/medical and life insurance, retirement, and out-of-pocket expenses. Methods We mailed a questionnaire about financial issues to 1015 patients who had received intensive treatment for MM at the study site. Data analysis included descriptive statistics and comparisons using independent t-tests. Results Our sample (n=762; mean age 61, SD 9.26), experienced issues with employment (66% employed at diagnosis and treatment; 33% employed at questionnaire time), disability (35% applied), health/medical and life insurance (29% lost coverage and 8% changed coverage), retirement (13% retired during treatment), and out-of-pocket expenses (36% of income in first treatment year and 28% of income during most recent 12 months). Conclusions Issues of employment, disability, health insurance, retirement, and out-of-pocket costs for treatment are major challenges for patients. Implications for Practice In the midst of assessing physical needs during clinical trials for chemotherapy and stem cell transplants, health care providers must keep sight of patients' personal financial needs so that we can intervene promptly with referrals to social work, rehabilitation therapy, and other health care professions to help patients decrease the personal financial effects of MM and its treatment. PMID:23047800

  3. Expression of GITR Enhances Multiple Myeloma Cell Sensitivity to Bortezomib.

    PubMed

    Zhao, Yinghao; Zhang, Kun; Li, Guangquan; Zhang, Xingyi; Shi, Donglei

    2015-01-01

    Recently tumor necrosis factor receptor super family member 18 (TNFRSF18, also called GITR) has been identified as a novel tumor suppressor gene in Multiple Myeloma (MM), undergoing aberrant DNA methylation-mediated gene expression silencing. Furthermore, the expression of GITR blocks canonical NF-κB activation in MM cells in response to TNFα. Bortezomib, a proteasome inhibitor, can induce NF-κB activation, which may significantly influence the drug response in MM patients. In this study, we aim to elucidate if GITR status is associated with response to Bortezomib in MM cells through regulating GITR mediated NF-κB blockade. We found that GITR was significantly downregulated in MM patients and cell lines. Overexpression of GITR inhibited non-canonical NF-κB activation induced by TNFα. Moreover, NF-κB inhibitor induced apoptosis in GITR-deficient MM cells in response to TNFα. In addition, overexpression of GITR could inhibit Bortezomib-induced NF-κB activation and enhance the cytotoxicity of Bortezomib in GITR-deficient MM cell line (MM1.S). In contrast, knockdown of GITR attenuated the cytotoxic effect of Bortezomib on GITR proficient MM (RPMI) cell line and increased NF-κB activation. Finally, overexpression of GITR enhanced the sensitivity to Bortezomib in co-culture with bone marrow stromal cells and significantly reduced the tumor growth in MM1.S xenograft mice. In conclusion, we demonstrated that GITR expression can enhance the sensitivity to Bortezomib by inhibiting Bortezomib-induced NF-κB activation.

  4. Tumor cells in multiple myeloma patients inhibit myeloma-reactive T cells through carcinoembryonic antigen-related cell adhesion molecule-6.

    PubMed

    Witzens-Harig, Mathias; Hose, Dirk; Jünger, Simone; Pfirschke, Christina; Khandelwal, Nisit; Umansky, Ludmila; Seckinger, Anja; Conrad, Heinke; Brackertz, Bettina; Rème, Thierry; Gueckel, Brigitte; Meißner, Tobias; Hundemer, Michael; Ho, Anthony D; Rossi, Jean-Francois; Neben, Kai; Bernhard, Helga; Goldschmidt, Hartmut; Klein, Bernard; Beckhove, Philipp

    2013-05-30

    Although functionally competent cytotoxic, T cells are frequently observed in malignant diseases, they possess little ability to react against tumor cells. This phenomenon is particularly apparent in multiple myeloma. We here demonstrate that cytotoxic T cells reacted against myeloma antigens when presented by autologous dendritic cells, but not by myeloma cells. We further show by gene expression profiling and flow cytometry that, similar to many other malignant tumors, freshly isolated myeloma cells expressed several carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) at varying proportions. Binding and crosslinking of CEACAM-6 by cytotoxic T cells inhibited their activation and resulted in T-cell unresponsiveness. Blocking of CEACAM-6 on the surface of myeloma cells by specific monoclonal antibodies or CEACAM-6 gene knock down by short interfering RNA restored T-cell reactivity against malignant plasma cells. These findings suggest that CEACAM-6 plays an important role in the regulation of CD8+ T-cell responses against multiple myeloma; therefore, therapeutic targeting of CEACAM-6 may be a promising strategy to improve myeloma immunotherapy.

  5. Biological aspects of altered bone remodeling in multiple myeloma and possibilities of pharmacological intervention.

    PubMed

    Kupisiewicz, Kasia

    2011-05-01

    Multiple myeloma is a fatal B cell neoplasm often resulting in focal and in some cases more diffuse destruction of bone. The bone destruction is a result of increased activity of bone resorbing cells--multinucleated osteoclasts emerging through of multiple fusions. In multiple myeloma, clonally expanding cancer cells provide a stimulatory signal for osteoclast recruitment, differentiation and excessive bone resorption. The stimulatory actions of myeloma cells are believed to be mediated via the production of cytokines and local factors or by modulating bone microenvironment in order to stimulate osteoclastic bone resorption. However, our recent study revealed potentially a novel and more intimate contribution of myeloma cells to the bone destruction. Our analysis of the bone biopsies from myeloma patients showed fully integrated malignant nuclei inside osteoclasts, which were transcriptionally active. As a result, about 30% of the osteoclasts in the bone marrow biopsies from myeloma patients were in fact osteoclast-myeloma cell hybrids. As the functional relevance of this novel cell type remained uncertain, the aim of my PhD study became to 1) strengthen the evidence of the existence of hybrid cells, 2) elucidate the functional differences between hybrid cells and non-hybrid OCs and 3) relate these findings to the pathogenesis of osteolytic disease in multiple myeloma. To this end, I developed a culture model of osteoclast-myeloma cell fusion between (pre)osteoclasts already committed to fuse and myeloma cells selected for adherence. The model was applied for testing of the bone resorptive properties of hybrid cells identified by labelling with green fluorescence. When comparing the highly fluorescent and non-fluorescent OCs on bone slices, it seemed that the frequency of highly fluorescent osteoclasts actively resorbing bone was increased as compared with non-fluorescent osteoclasts. This was assessed in two independent ways. Furthermore, these fluorescent

  6. Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma

    PubMed Central

    Cui, Grace; Senpan, Angana; Yang, Xiaoxia; Lu, Lan; Weilbaecher, Katherine N.; Prochownik, Edward V.; Lanza, Gregory M.; Tomasson, Michael H.

    2015-01-01

    Multiple myeloma pathogenesis is driven by the MYC oncoprotein, its dimerization with MAX, and the binding of this heterodimer to E-Boxes in the vicinity of target genes. The systemic utility of potent small molecule inhibitors of MYC-MAX dimerization was limited by poor bioavailability, rapid metabolism, and inadequate target site penetration. We hypothesized that new lipid-based MYC-MAX dimerization inhibitor prodrugs delivered via integrin-targeted nanoparticles (NP) would overcome prior shortcomings of MYC inhibitor approaches and prolong survival in a mouse model of cancer. An Sn 2 lipase-labile prodrug inhibitor of MYC-MAX dimerization (MI1-PD) was developed which decreased cell proliferation and induced apoptosis in cultured multiple myeloma cell lines alone (P < 0.05) and when incorporated into integrin-targeted lipid-encapsulated NPs (P < 0.05). Binding and efficacy of NPs closely correlated with integrin expression of the target multiple myeloma cells. Using a KaLwRij metastatic multiple myeloma mouse model, VLA-4–targeted NPs (20 nm and 200 nm) incorporating MI1-PD (D) NPs conferred significant survival benefits compared with respective NP controls, targeted (T) no-drug (ND), and untargeted (NT) control NPs (T/D 200: 46 days vs. NT/ND: 28 days, P < 0.05 and T/D 20: 52 days vs. NT/ND: 29 days, P = 0.001). The smaller particles performed better of the two sizes. Neither MI1 nor MI1-PD provided survival benefit when administered systemically as free compounds. These results demonstrate for the first time that a small molecule inhibitor of the MYC transcription factor can be an effective anticancer agent when delivered using a targeted nanotherapy approach. PMID:25824336

  7. Imaging Findings of Plasmacytoma of Both Breasts as a Preceding Manifestation of Multiple Myeloma

    PubMed Central

    Park, Young Mi

    2016-01-01

    Breast plasmacytoma is an extremely rare tumor. It can occur as a primary isolated tumor or as an extramedullary manifestation in multiple myeloma. This report describes the unusual case of a primary extramedullary plasmacytoma that progressed to multiple myeloma within 15 months in a 35-year-old woman. The patient had been initially diagnosed with a primary extramedullary plasmacytoma of the epidural soft tissue at the cervical 6-thoracic 1 spine level and the stomach. The patient had received chemotherapy and the disease had been in remission. One year later, the disease recurred, affecting both breasts, right clavicle, and orbit. Three months later, the disease had progressed to multiple myeloma. I report this case, focusing on the findings of mammography, ultrasonography, magnetic resonance imaging, and positron emission tomography of bilateral breast plasmacytoma, and provide a review of the literature. PMID:26925106

  8. Minimal Residual Disease Assessment in the Context of Multiple Myeloma Treatment.

    PubMed

    Nishihori, Taiga; Song, Jinming; Shain, Kenneth H

    2016-04-01

    With contemporary therapeutic strategies in multiple myeloma, heretofore unseen depth and rate of responses are being achieved. These strategies have paralleled improvements in outcome of multiple myeloma patients. The integration of the next generation of proteasome inhibitors and antibody therapeutics promise continued improvements in therapy with the expectation of consistent depth of response not quantifiable by current clinical methods. As such, there is a growing need to develop adequate tools to evaluate deeper disease response after therapy and to refine the response criteria including the minimal residual disease. Several emerging techniques are being evaluated for these purposes including multi-parameter flow cytometry, allele-specific oligonucleotide polymerase chain reaction, next-generation sequencing, and imaging modalities. In this review, we highlight the recent developments and evaluate advantages and limitations of the current technologies to assess minimal residual disease. We also discuss future applications of these methodologies in potentially guiding multiple myeloma treatment decisions.

  9. Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.

    PubMed

    Guillerey, Camille; Nakamura, Kyohei; Vuckovic, Slavica; Hill, Geoffrey R; Smyth, Mark J

    2016-04-01

    Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM. PMID:26801219

  10. Outcome after autologous stem cell transplantation for multiple myeloma in patients with preceding plasma cell disorders.

    PubMed

    Kumar, Shaji K; Dingli, David; Lacy, Martha Q; Dispenzieri, Angela; Hayman, Suzanne R; Buadi, Francis K; Rajkumar, S Vincent; Litzow, Mark R; Gertz, Morie A

    2008-04-01

    A third of patients with multiple myeloma (MM) have a preceding diagnosis of plasma cell proliferative disorder (PCPD), mostly monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM) or plasmacytoma. While autologous stem cell transplantation (SCT) improves survival in MM, it is not clear if patients with preceding PCPD have a different outcome. We identified 151 patients with preceding PCPD from among 804 patients undergoing SCT, and their outcomes were compared. The response rates, including complete responses, were similar between the groups. Patients with a preceding diagnosis of MGUS had longer time to progression (TTP; 27.5 months vs. 17.2 months, P = 0.01), and longer overall survival (OS) from transplant (80.2 months vs. 48.3 months, P = 0.03) compared to those with de novo myeloma. However no differences were seen among those with a preceding diagnosis of SMM or plasmacytoma in terms of TTP or OS from transplant when compared to those with de novo myeloma. Multivariate analysis indicated that the presence of MGUS prior to myeloma was prognostic for post-transplant relapse independent of other known risk factors. Patients with pre-existing MGUS prior to myeloma diagnosis have a better outcome following HDT, reflecting more indolent disease and a favourable biology than those presenting with de novo myeloma. PMID:18318761

  11. Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.

    PubMed

    Guillerey, Camille; Nakamura, Kyohei; Vuckovic, Slavica; Hill, Geoffrey R; Smyth, Mark J

    2016-04-01

    Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM.

  12. 11C-Methionine-PET: a novel and sensitive tool for monitoring of early response to treatment in multiple myeloma.

    PubMed

    Lückerath, Katharina; Lapa, Constantin; Albert, Christa; Herrmann, Ken; Jörg, Gerhard; Samnick, Samuel; Einsele, Herrmann; Knop, Stefan; Buck, Andreas K

    2015-04-10

    Multiple myeloma (MM) remains an essentially incurable hematologic malignancy. However, new treatment modalities and novel drugs have been introduced and thus additional tools for therapy monitoring are increasingly needed. Therefore, we evaluated the radiotracers 11C-Methionine (paraprotein-biosynthesis) and 18F-FDG (glucose-utilization) for monitoring response to anti-myeloma-therapy and outcome prediction. Influence of proteasome-inhibition on radiotracer-uptake of different MM cell-lines and patient-derived CD138+ plasma cells was analyzed and related to tumor-biology. Mice xenotransplanted with MM.1S tumors underwent MET- and FDG-μPET. Tumor-to-background ratios before and after 24 h, 8 and 15 days treatment with bortezomib were correlated to survival. Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression. In xenotransplanted mice, MET-uptake significantly decreased by 30-79% as early as 24 h after bortezomib injection. No significant differences were detected thus early with FDG. This finding was confirmed in patient-derived MM cells. Importantly, early reduction of MET- but not FDG-uptake correlated with improved survival and reduced tumor burden in mice. Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy. Early changes in MET-uptake have predictive potential regarding response and survival. MET-PET holds promise to individualize therapies in MM in future.

  13. miRNAs in multiple myeloma – a survival relevant complex regulator of gene expression

    PubMed Central

    Seckinger, Anja; MeiΔner, Tobias; Moreaux, Jérôme; Benes, Vladimir; Hillengass, Jens; Castoldi, Mirco; Zimmermann, Jürgen; Ho, Anthony D.; Jauch, Anna; Goldschmidt, Hartmut; Klein, Bernard; Hose, Dirk

    2015-01-01

    Purpose microRNAs regulate gene-expression in biological and pathophysiological processes, including multiple myeloma. Here we address i) What are the number and magnitude of changes in miRNA-expression between normal plasma cells and myeloma- or MGUS-samples, and the latter two? ii) What is the biological relevance and how does miRNA-expression impact on gene-expression? iii) Is there a prognostic significance, and what is its background? Experimental design Ninety-two purified myeloma-, MGUS-, normal plasma cell- and myeloma cell line-samples were investigated using miChip-arrays interrogating 559 human miRNAs. Impact on gene-expression was assessed by Affymetrix DNA-microarrays in two cohorts of myeloma patients (n = 677); chromosomal aberrations were assessed by iFISH, survival for 592 patients undergoing up-front high-dose chemotherapy. Results Compared to normal plasma cells, 67/559 miRNAs (12%) with fold changes of 4.6 to −3.1 are differentially expressed in myeloma-, 20 (3.6%) in MGUS-samples, and three (0.5%) between MGUS and myeloma. Expression of miRNAs is associated with proliferation, chromosomal aberrations, tumor mass, and gene expression-based risk-scores. This holds true for target-gene signatures of regulated mRNAs. miRNA-expression confers prognostic significance for event-free and overall survival, as do respective target-gene signatures. Conclusions The myeloma-miRNome confers a pattern of small changes of individual miRNAs impacting on gene-expression, biological functions, and survival. PMID:26472281

  14. Does my patient with a serum monoclonal spike have multiple myeloma?

    PubMed

    Bianchi, Giada; Ghobrial, Irene M

    2012-04-01

    A monoclonal spike on serum protein electrophoresis is a frequent finding in the general population and pathognomonic of a plasma cell dyscrasia. In otherwise healthy individuals, it is diagnostic of two asymptomatic, premalignant conditions called monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) which carry a lifelong risk of progression to multiple myeloma (MM) or related malignancy. This article discusses the criteria for diagnosis of MGUS, SMM, and MM; current recommendations for follow-up and risk factors for progression to MM of patients with MGUS and SMM; and diagnostic evaluation of suspected MM transformation. PMID:22463833

  15. Genetic variants in DNA repair pathways are not associated with disease progression among multiple myeloma patients.

    PubMed

    Thyagarajan, Bharat; Arora, Mukta; Guan, Weihua; Barcelo, Helene; Jackson, Scott; Kumar, Shaji; Gertz, Morie

    2013-11-01

    DNA damage induced by high dose melphalan and autologous transplantation is repaired by the nucleotide excision repair (NER) and base excision repair (BER) pathways. We evaluated the association between single nucleotide polymorphisms (SNPs) (n=311) in the NER and BER pathways and disease progression in 695 multiple myeloma patients who underwent autologous transplantation. None of the SNPs were associated with disease progression. Pathway based analyses showed that the NER pathway had a borderline association with disease progression (p=0.09). These findings suggest that common variation in the NER and BER pathways do not substantially influence disease progression in multiple myeloma patients.

  16. Double filtration plasmapheresis in a dog with multiple myeloma and hyperviscosity syndrome

    PubMed Central

    Lippi, I.; Perondi, F.; Ross, S.J.; Marchetti, V.; Lubas, G.; Guidi, G.

    2015-01-01

    A 12 year old, 38 kg, mix-breed, intact male dog presented with a 20 day history of clinical signs consistent with hyperviscosity syndrome secondary to multiple myeloma. The dog received three double filtration plasmapheresis treatments on day 0, 7 and 22 after presentation. A significant (p<0.05) reduction in serum total protein, alpha-2 and gamma globulins was found following each treatment. These reductions were accompanied by a complete resolution, although temporary, of the clinical signs of hyperviscosity syndrome. The present study reported for the first time the use of double filtration plasmapheresis to reduce clinical signs of hyperviscosity syndrome in a dog with multiple myeloma. PMID:26623375

  17. The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease

    PubMed Central

    Brandl, Andreas; Müller, Marc; Hofbauer, Lorenz C.; Beilhack, Andreas; Ebert, Regina; Glüer, Claus C.; Tiwari, Sanjay; Schütze, Norbert; Jakob, Franz

    2016-01-01

    Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment. PMID:27158817

  18. Exploration for the multi-effect of cardamom in's resistance to multiple myeloma.

    PubMed

    Zhihua, Zhao; Jianping, Yang; Miaomiao, Sun; Kuisheng, Chen

    2014-11-01

    This paper aimed to probe the cardamom in effect on the viability, proliferation, apoptosis and periodic function of the multiple myeloma, and explore its mechanism. We used CCK-8 method to evaluate the effect of cardamom in on the viability of PBMNCs (Persom Blood Mononuclear Normal Cells). EdU can test the influence of small cell proliferation. We used the method of PI single-staining flow cytometry, in order to test the influence of tumor cell cycle. AO (Acridine Orange), EB (Ethidium Bromide) double staining fluorescene microscope was applied to observe the influence of tumor apoptotic morphology. It can be concluded that cardamom in can inhibit the viability and proliferation of MM (Multiple Myeloma) cells and cardamom in is the anti-myeloma drug with strong viability. PMID:25410063

  19. Exploration for the multi-effect of cardamom in's resistance to multiple myeloma.

    PubMed

    Zhihua, Zhao; Jianping, Yang; Miaomiao, Sun; Kuisheng, Chen

    2014-11-01

    This paper aimed to probe the cardamom in effect on the viability, proliferation, apoptosis and periodic function of the multiple myeloma, and explore its mechanism. We used CCK-8 method to evaluate the effect of cardamom in on the viability of PBMNCs (Persom Blood Mononuclear Normal Cells). EdU can test the influence of small cell proliferation. We used the method of PI single-staining flow cytometry, in order to test the influence of tumor cell cycle. AO (Acridine Orange), EB (Ethidium Bromide) double staining fluorescene microscope was applied to observe the influence of tumor apoptotic morphology. It can be concluded that cardamom in can inhibit the viability and proliferation of MM (Multiple Myeloma) cells and cardamom in is the anti-myeloma drug with strong viability.

  20. Exposure to hair-coloring products and the risk of multiple myeloma.

    PubMed Central

    Herrinton, L J; Weiss, N S; Koepsell, T D; Daling, J R; Taylor, J W; Lyon, J L; Swanson, G M; Greenberg, R S

    1994-01-01

    An interview study of persons diagnosed with multiple myeloma between 1977 and 1981 and suitable control subjects was conducted to test the hypothesis that exposure to hair dyes increases the risk of multiple myeloma. Among women, there was little evidence that prior regular use of hair dyes (odds ratio [OR] = 1.0; 95% confidence interval [CI] = 0.70, 1.4) or prior employment as a hairdresser (OR = 1.1; 95% CI = 0.43, 2.7) increased risk; however, the former comparison was limited by the lack of detailed information concerning the exposure. Among men, there was a modest association of regular use of hair dyes (OR = 1.5; 95% CI = 0.75, 2.9) with myeloma, but this was based on a small number of exposed persons. PMID:8017540

  1. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group

    PubMed Central

    Avet-Loiseau, Hervé; Lonial, Sagar; Usmani, Saad; Siegel, David; Anderson, Kenneth C.; Chng, Wee-Joo; Moreau, Philippe; Attal, Michel; Kyle, Robert A.; Caers, Jo; Hillengass, Jens; San Miguel, Jesús; van de Donk, Niels W. C. J.; Einsele, Hermann; Bladé, Joan; Durie, Brian G. M.; Goldschmidt, Hartmut; Mateos, María-Victoria; Palumbo, Antonio; Orlowski, Robert

    2016-01-01

    The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification. PMID:27002115

  2. Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma

    PubMed Central

    Mithraprabhu, Sridurga; Kalff, Anna; Chow, Annie; Khong, Tiffany; Spencer, Andrew

    2014-01-01

    Histone deacetylases (HDAC) control gene expression through their ability to acetylate proteins, thereby influencing a diverse range of cellular functions. Class I HDAC (HDAC1–3 and 8) and HDAC6 are predominantly upregulated in malignancies and their altered expression in some cancers has a significant prognostic implication. The expression and prognostic consequence of dysregulated Class I HDAC and HDAC6, key players in multiple myeloma (MM), are unknown. This study hypothesized that HDAC are dysregulated in MM and patients with high expression have significantly poorer prognostic outcomes. Quantitative PCR for 11 HDAC (Class I, II, and IV) was performed in genetically heterogeneous human myeloma cell lines (HMCL) and primary MM and compared to normal plasma cells (PC). In HMCL, HDAC1–3 and 8 (Class I), and HDAC5 and HDAC10 (Class II) were significantly upregulated compared to normal PC. In primary MM, the median expression level of all of the HDAC, except HDAC1 and HDAC11, were elevated when compared to normal PC. Patients with higher levels of HDAC1–3, HDAC4, HDAC6, and HDAC11 transcripts demonstrated a significantly shorter progression-free survival (PFS). Immunohistochemical staining for HDAC1 and HDAC6 on bone marrow trephines from a uniformly treated cohort of transplant eligible MM patients revealed that HDAC1 protein was detectable in most patients and that higher levels of MM cell HDAC1 protein expression (≥90 % versus ≤20 % MM cell positivity) correlated with both shorter PFS (P = 0 .07) and shorter overall survival (P = 0 .003). Conversely, while the majority of patients expressed HDAC6, there was no correlation between HDAC6 levels and patient outcome. Together, these results indicate that overexpression of Class I HDAC, particularly HDAC1, is associated with poor prognosis in MM. PMID:25482492

  3. Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma.

    PubMed

    Flores-Montero, Juan; de Tute, Ruth; Paiva, Bruno; Perez, José Juan; Böttcher, Sebastian; Wind, Henk; Sanoja, Luzalba; Puig, Noemí; Lecrevisse, Quentin; Vidriales, María Belén; van Dongen, Jacques J M; Orfao, Alberto

    2016-01-01

    In recent years, several studies on large series of multiple myeloma (MM) patients have demonstrated the clinical utility of flow cytometry monitoring of minimal residual disease (flow-MRD) in bone marrow (BM), for improved assessment of response to therapy and prognostication. However, disturbing levels of variability exist regarding the specific protocols and antibody panels used in individual laboratories. Overall, consensus exists about the utility of combined assessment of CD38 and CD138 for the identification of BM plasma cells (PC); in contrast, more heterogeneous lists of markers are used to further distinguish between normal/reactive PCs and myeloma PCs in the MRD settings. Among the later markers, CD19, CD45, CD27, and CD81, together with CD56, CD117, CD200, and CD307, have emerged as particularly informative; however, no single marker provides enough specificity for clear discrimination between clonal PCs and normal PCs. Accordingly, multivariate analyses of single PCs from large series of normal/reactive vs. myeloma BM samples have shown that combined assessment of CD138 and CD38, together with CD45, CD19, CD56, CD27, CD81, and CD117 would be ideally suited for MRD monitoring in virtually every MM patient. However, the specific antibody clones, fluorochrome conjugates and sources of the individual markers determines its optimal (vs. suboptimal or poor) performance in an eight-color staining. Assessment of clonality, via additional cytoplasmic immunoglobulin (CyIg) κ vs. CyIgλ evaluation, may contribute to further establish the normal/reactive vs. clonal nature of small suspicious PC populations at high sensitivity levels, provided that enough cells are evaluated.

  4. Spinal focal lesion detection in multiple myeloma using multimodal image features

    NASA Astrophysics Data System (ADS)

    Fränzle, Andrea; Hillengass, Jens; Bendl, Rolf

    2015-03-01

    Multiple myeloma is a tumor disease in the bone marrow that affects the skeleton systemically, i.e. multiple lesions can occur in different sites in the skeleton. To quantify overall tumor mass for determining degree of disease and for analysis of therapy response, volumetry of all lesions is needed. Since the large amount of lesions in one patient impedes manual segmentation of all lesions, quantification of overall tumor volume is not possible until now. Therefore development of automatic lesion detection and segmentation methods is necessary. Since focal tumors in multiple myeloma show different characteristics in different modalities (changes in bone structure in CT images, hypointensity in T1 weighted MR images and hyperintensity in T2 weighted MR images), multimodal image analysis is necessary for the detection of focal tumors. In this paper a pattern recognition approach is presented that identifies focal lesions in lumbar vertebrae based on features from T1 and T2 weighted MR images. Image voxels within bone are classified using random forests based on plain intensities and intensity value derived features (maximum, minimum, mean, median) in a 5 x 5 neighborhood around a voxel from both T1 and T2 weighted MR images. A test data sample of lesions in 8 lumbar vertebrae from 4 multiple myeloma patients can be classified at an accuracy of 95% (using a leave-one-patient-out test). The approach provides a reasonable delineation of the example lesions. This is an important step towards automatic tumor volume quantification in multiple myeloma.

  5. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: a review of the current understanding of epidemiology, biology, risk stratification, and management of myeloma precursor disease.

    PubMed

    Agarwal, Amit; Ghobrial, Irene M

    2013-03-01

    The term monoclonal gammopathy of undetermined significance (MGUS) was coined in 1978. The recent advances in our knowledge about MGUS and smoldering multiple myeloma (SMM) have helped us better understand the pathogenesis of myeloma. It seems that myeloma evolves from a precursor state in almost all cases. We do not completely understand the multistep process from the precursor state to myeloma, but studies like whole genome sequencing continue to improve our understanding of this process. The process of transformation may not be linear acquisition of changes, but rather a branched heterogeneous process. Clinical features that are prognostic of rapid transformation have been identified, but no specific molecular markers have been identified. Even with recent advances, multiple myeloma remains an incurable disease in the vast majority, and intervening at the precursor state provides a unique opportunity to alter the natural history of the disease. A limitation is that a vast majority of patients with precursor disease, especially low-risk MGUS, will never progress to myeloma in their lifetime, and treating these patients is not only unnecessary but may be potentially harmful. The challenge is to identify a subset of patients with the precursor state that would definitely progress to myeloma and in whom interventions will have a meaningful impact. As our understanding of the molecular and genetic processes improves, these studies will guide the selection of high-risk patients more appropriately and ultimately direct a tailored management strategy to either delay progression to symptomatic myeloma or even "cure" a person at this premalignant stage. PMID:23224402

  6. The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

    PubMed Central

    Walz, Simon; Kowalewski, Daniel Johannes; Schuster, Heiko; Weisel, Katja; Backert, Linus; Kahn, Stefan; Nelde, Annika; Stroh, Tatjana; Handel, Martin; Kohlbacher, Oliver; Kanz, Lothar; Salih, Helmut Rainer; Rammensee, Hans-Georg; Stevanović, Stefan

    2015-01-01

    Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8+ T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell–based immunotherapy of MM. PMID:26138685

  7. Case report: gallium study showing a rare form of multiple myeloma

    SciTech Connect

    Meyers, E.; Kasner, J.R.

    1981-12-01

    A case study is presented in which a rare form of multiple myeloma with soft tissue involvememt was diagnosed by a gallium scan using 3 mCi of Ga-67 citrate. Subsequent resting cardiac blood pool images suggested pericardial rather than myocardial involvement. (JMT)

  8. Single Agent Lenalidomide Activity in Multiple Myeloma Relapse Evidenced Uniquely by CT/PET

    PubMed Central

    Gozzetti, Alessandro; Rossi, Vania; Cerase, Alfonso; Papini, Giulia; Defina, Marzia; Bocchia, Monica

    2012-01-01

    A 71 year old female with multiple myeloma presented with back pain seven year after autologous stem cell transplant. Skeletal bone survey and magnetic resonance imaging did not show a relapse that was evidenced by CT/PET. Lenalidomide as single agent induced a complete disappearance of the lesions 6 months later and confirmed after one year at CT/PET. PMID:22811790

  9. Discovery – Velcade®: A New Tool in the Fight against Multiple Myeloma

    Cancer.gov

    Velcade® represents a new type of anticancer drug called proteasome inhibitors. It has shown promise in the treatment of multiple myeloma, a cancer of the white blood cells. Velcade® is being studied for use in a variety of blood cancers and solid tumors.

  10. Effectiveness of percutaneous vertebroplasty in patients with multiple myeloma having vertebral pain

    PubMed Central

    Nas, Ömer Fatih; İnecikli, Mehmet Fatih; Hacıkurt, Kadir; Büyükkaya, Ramazan; Özkaya, Güven; Özkalemkaş, Fahir; Ali, Rıdvan; Erdoğan, Cüneyt; Hakyemez, Bahattin

    2016-01-01

    PURPOSE We aimed to assess the effectiveness, benefits, and reliability of percutaneous vertebroplasty (PV) in patients with vertebral involvement of multiple myeloma. METHODS PV procedures performed on 166 vertebrae of 41 patients with multiple myeloma were retrospectively evaluated. Most of our patients were using level 3 (moderate to severe pain) analgesics. Magnetic resonance imaging was performed before the procedure to assess vertebral involvement of multiple myeloma. The following variables were evaluated: affected vertebral levels, loss of vertebral body height, polymethylmethacrylate (PMMA) cement amount applied to the vertebral body during PV, PMMA cement leakages, and pain before and after PV as assessed by a visual analogue scale (VAS). RESULTS Median VAS scores of patients decreased from 9 one day before PV, to 6 one day after the procedure, to 3 one week after the procedure, and eventually to 1 three months after the procedure (P < 0.001). During the PV procedure, cement leakage was observed at 68 vertebral levels (41%). The median value of PMMA applied to the vertebral body was 6 mL. CONCLUSION Being a minimally invasive and easily performed procedure with low complication rates, PV should be preferred for serious back pain of multiple myeloma patients. PMID:26912107

  11. The simultaneous occurrence of multiple myeloma and JAK2 positive myeloproliferative neoplasms - Report on two cases

    PubMed Central

    Badelita, S; Dobrea, C; Colita, A; Dogaru, M; Dragomir, M; Jardan, C; Coriu, D

    2015-01-01

    Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis. Abbreviations:JAK2 = Janus kinase 2 gene, PMF = primary myelofibrosis, MPNs = myeloproliferative neoplasms, ET = essential thrombocythemia, PV = polycythemia vera, MM = multiple myeloma, WBC = white blood cells, Hb = haemoglobin, Ht = haematocrit, Plt = platelets, BMB = bone marrow biopsy, CBC = blood cell count, CT = computerized tomography, LAP = leukocyte alkaline phosphatase, MGUS = monoclonal gammopathy of undetermined significance. PMID:25914740

  12. Endocarditis due to Gemella haemolysans in a newly diagnosed multiple myeloma patient

    PubMed Central

    Liu, Dongyan; Bateman, Thomas; Carr, Elisabeth; Foster, Paul

    2016-01-01

    An 87-year-old Caucasian woman with hypertension, diabetes mellitus type 2, and COPD was admitted with 1-week duration of back pain and weight gain. The physical examination revealed jugular venous distention, rales in the left lower lung field, and severe pitting edema over lower extremities. As workup for leukocytosis, blood cultures grew Gemella haemolysans. Subsequently, a transthoracic echocardiogram revealed vegetation on the non-coronary aortic leaflet and mild aortic stenosis. She was treated with ampicillin and gentamicin. After further investigation, the patient was diagnosed with plasma cell myeloma, the monoclonal lambda type. This is the first reported case of G. haemolysans endocarditis in a multiple myeloma patient. PMID:27609731

  13. Endocarditis due to Gemella haemolysans in a newly diagnosed multiple myeloma patient.

    PubMed

    Liu, Dongyan; Bateman, Thomas; Carr, Elisabeth; Foster, Paul

    2016-01-01

    An 87-year-old Caucasian woman with hypertension, diabetes mellitus type 2, and COPD was admitted with 1-week duration of back pain and weight gain. The physical examination revealed jugular venous distention, rales in the left lower lung field, and severe pitting edema over lower extremities. As workup for leukocytosis, blood cultures grew Gemella haemolysans. Subsequently, a transthoracic echocardiogram revealed vegetation on the non-coronary aortic leaflet and mild aortic stenosis. She was treated with ampicillin and gentamicin. After further investigation, the patient was diagnosed with plasma cell myeloma, the monoclonal lambda type. This is the first reported case of G. haemolysans endocarditis in a multiple myeloma patient. PMID:27609731

  14. Fatigue, Sleep, Pain, Mood and Performance Status in Patients with Multiple Myeloma

    PubMed Central

    Coleman, Elizabeth Ann; Goodwin, Julia A.; Coon, Sharon K.; Richards, Kathy; Enderlin, Carol; Kennedy, Robert; Stewart, Carol B.; McNatt, Paula; Lockhart, Kim; Anaissie, Elias J.; Barlogie, Bart

    2010-01-01

    Background Cancer-related fatigue and insomnia are common distressing symptoms and may affect mood and performance status. Objective to describe fatigue, sleep, pain, mood and performance status and the relationships among these variables in 187 patients newly diagnosed with multiple myeloma (MM) and conduct an analysis using the correlates of fatigue. Interventions/Methods Data were from baseline measures from the study, using the Profile of Mood States (POMS) and the Functional Assessment of Cancer Therapy - Fatigue to assess fatigue, the Actigraph to measure sleep, the Wong/Baker Faces Pain Rating Scale to assess pain, the POMS to assess mood, and the 6-minute walk test along with a back/leg/chest dynamometer to test muscle strength to assess performance status. Data analysis consisted of descriptive statistics, Pearson and Spearman rho correlations and multiple regression using fatigue as the dependent variable. All p values were two-sided, and those with < .05 considered significant. Results Patients newly diagnosed with MM presented with fatigue, pain, sleep and mood disturbances, and diminished functional performance. The regression model, which included all of these variables along with age, gender and stage of disease, was statistically significant with a large measure of effect. Mood was a significant individual contributor to the model. Conclusions Among patients with MM, fatigue, pain, sleep, mood and functional performance are interrelated. Implications for Practice Interventions are needed to decrease fatigue and pain and to improve sleep, mood and functional performance. PMID:21522061

  15. A mathematical model of cell equilibrium and joint cell formation in multiple myeloma.

    PubMed

    Koenders, M A; Saso, R

    2016-02-01

    In Multiple Myeloma Bone Disease healthy bone remodelling is affected by tumour cells by means of paracrine cytokinetic signalling in such a way that osteoclast formation is enhanced and the growth of osteoblast cells inhibited. The participating cytokines are described in the literature. Osteoclast-induced myeloma cell growth is also reported. Based on existing mathematical models for healthy bone remodelling a three-way equilibrium model is presented for osteoclasts, osteoblasts and myeloma cell populations to describe the progress of the illness in a scenario in which there is a secular increase in the cytokinetic interactive effectiveness of paracrine processes. The equilibrium state for the system is obtained. The paracrine interactive effectiveness is explored by parameter variation and the stable region in the parameter space is identified. Then recently-discovered joint myeloma-osteoclast cells are added to the model to describe the populations inside lytic lesions. It transpires that their presence expands the available parameter space for stable equilibrium, thus permitting a detrimental, larger population of osteoclasts and myeloma cells. A possible relapse mechanism for the illness is explored by letting joint cells dissociate. The mathematics then permits the evaluation of the evolution of the cell populations as a function of time during relapse.

  16. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.

    PubMed

    Nelson, Erik A; Walker, Sarah R; Kepich, Alicia; Gashin, Laurie B; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C; Frank, David A

    2008-12-15

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  17. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3

    PubMed Central

    Nelson, Erik A.; Walker, Sarah R.; Kepich, Alicia; Gashin, Laurie B.; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C.

    2008-01-01

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  18. Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction?

    PubMed Central

    Janz, Siegfried; Zhan, Fenghuang; Tricot, Guido

    2015-01-01

    Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains – just like many other cancers – a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138−, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/β-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma “stemness”, the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease. PMID:26415231

  19. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease.

    PubMed

    Eda, Homare; Santo, Loredana; Wein, Marc N; Hu, Dorothy Z; Cirstea, Diana D; Nemani, Neeharika; Tai, Yu-Tzu; Raines, Sarah E; Kuhstoss, Stuart Allen; Munshi, Nikhil C; Kronenberg, Henry M; Raje, Noopur S

    2016-06-01

    Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease

  20. Is there still a role for allogeneic stem-cell transplantation in multiple myeloma?

    PubMed Central

    Bensinger, William I.

    2007-01-01

    Despite significant improvements in survival for multiple myeloma patients through autologous stem-cell transplantation (SCT) and the introduction of novel drugs, the disease remains incurable for all but a small fraction of patients. Only allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect. High transplant-related mortality with allogeneic SCT is currently the major limitation to wider use of this potentially curative modality. Mortality can be reduced through the use of lower-intensity conditioning regimens which allow engraftment of allogeneic stem cells, but this comes at a cost of higher rates of disease progression and relapse. Promising studies to improve outcomes of allogeneic transplants include the use of more intensive non-myeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering to improve the graft-versus-myeloma activity while reducing graft-versus-host disease (GVHD), post-transplant maintenance, and targeted conditioning therapies such as bone-seeking radioisotopes. PMID:18070719

  1. Augmented expression of urokinase plasminogen activator and extracellular matrix proteins associates with multiple myeloma progression.

    PubMed

    Khan, Rehan; Gupta, Nidhi; Kumar, Raman; Sharma, Manoj; Kumar, Lalit; Sharma, Alpana

    2014-06-01

    Multiple myeloma (MM) represents a B cell malignancy, characterized by a monoclonal proliferation of malignant plasma cells. Interactions between tumor cells and extracellular matrix (ECM) are of importance for tumor invasion and metastasis. Protein levels of urokinase plasminogen activator (uPA) and fibulin 1, nidogen and laminin in plasma and serum respectively and mRNA levels of these molecules in peripheral blood mononuclear cells were determined in 80 subjects by using ELISA and quantitative PCR and data was analyzed with severity of disease. Pearson correlation was determined to observe interrelationship between different molecules. A statistical significant increase for ECM proteins (laminin, nidogen and fibulin 1) and uPA at circulatory level as well as at mRNA level was observed compared to healthy controls. The levels of these molecules in serum might be utilized as a marker of active disease. Significant positive correlation of all ECM proteins with uPA was found and data also correlates with severity of disease. Strong association found between ECM proteins and uPA in this study supports that there might be interplay between these molecules which can be targeted. This study on these molecules may help to gain insight into processes of growth, spread, and clinical behavior of MM.

  2. Multiple myeloma and glyphosate use: a re-analysis of US Agricultural Health Study (AHS) data.

    PubMed

    Sorahan, Tom

    2015-02-01

    A previous publication of 57,311 pesticide applicators enrolled in the US Agricultural Health Study (AHS) produced disparate findings in relation to multiple myeloma risks in the period 1993-2001 and ever-use of glyphosate (32 cases of multiple myeloma in the full dataset of 54,315 applicators without adjustment for other variables: rate ratio (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.4; 22 cases of multiple myeloma in restricted dataset of 40,719 applicators with adjustment for other variables: RR 2.6, 95% CI 0.7 to 9.4). It seemed important to determine which result should be preferred. RRs for exposed and non-exposed subjects were calculated using Poisson regression; subjects with missing data were not excluded from the main analyses. Using the full dataset adjusted for age and gender the analysis produced a RR of 1.12 (95% CI 0.50 to 2.49) for ever-use of glyphosate. Additional adjustment for lifestyle factors and use of ten other pesticides had little effect (RR 1.24, 95% CI 0.52 to 2.94). There were no statistically significant trends for multiple myeloma risks in relation to reported cumulative days (or intensity weighted days) of glyphosate use. The doubling of risk reported previously arose from the use of an unrepresentative restricted dataset and analyses of the full dataset provides no convincing evidence in the AHS for a link between multiple myeloma risk and glyphosate use. PMID:25635915

  3. Identification of MAGE-C1 (CT-7) epitopes for T-cell therapy of multiple myeloma

    PubMed Central

    Anderson, Larry D.; Cook, Danielle R.; Yamamoto, Tori N.; Berger, Carolina; Maloney, David G.; Riddell, Stanley R.

    2011-01-01

    Multiple myeloma is incurable with standard therapies but is susceptible to a T-cell-mediated graft versus myeloma effect after allogeneic stem cell transplantation. We sought to identify myeloma-specific antigens that might be used for T-cell immunotherapy of myeloma. MAGE-C1 (CT-7) is a cancer-testis antigen that is expressed by tumor cells in >70% of myeloma patients and elicits a humoral response in up to 93% of patients with CT-7+ myeloma. No CD8+ T-cell epitopes have been described for CT-7, so we used a combination of reverse immunology and immunization of HLA-A2 transgenic mice with a novel cell-based vaccine to identify three immunogenic epitopes of CT-7 that are recognized by human CD8+ T-cells. CT-7-specific T-cells recognizing two of these peptides are able to recognize myeloma cells as well as CT-7 gene-transduced tumor cells, demonstrating that these epitopes are naturally processed and presented by tumor cells. This is the first report of the identification of immunogenic CD8+ T-cell epitopes of MAGE-C1 (CT-7), which is the most commonly expressed cancer-testis antigen found in myeloma, and these epitopes may be promising candidate targets for vaccination or T-cell therapy of myeloma or other CT-7+ malignancies. PMID:21461886

  4. Where we were, where we are, where we are going: progress in multiple myeloma.

    PubMed

    Bergsagel, P Leif

    2014-01-01

    The celebration of the 50th anniversary of the founding of the American Society of Clinical Oncology provides the occasion to review the progress that has been made in the biology and treatment of multiple myeloma. With the advent of melphalan and cyclophosphamide in the early 1960s the median survival of patients with multiple myeloma more than doubled from 10 months to approximately 24 months. Throughout multiple clinical trials in the 1970s and 1980s, melphalan and prednisone remained the gold standard, with a 3-year survival of 42%. The use of high-dose melphalan with autologous hematopoietic stem cell support provided an incremental advance in the 1990s. The outlook for patients was dramatically improved in the 2000s with the introduction of thalidomide analogs and proteasome inhibitors, so that the 3-year survival of patients treated in 2008 with melphalan and prednisone had increased to 66%. The 2010s are dominated by studying the optimal combination, sequence, and duration of therapies. These clinical advances have occurred along with our evolving understanding of the molecular pathogenesis of myeloma. Myeloma can be divided into two main groups: hyperdiploid, with multiple trisomies of odd-numbered chromosomes, and nonhyperdiploid, with recurrent immunoglobulin heavy chain gene translocations. Disease progression is associated with rearrangements of MYC, the most common mutation in myeloma, present in nearly half of patients. Genomic studies have highlighted marked subclonal heterogeneity that poses one of the main challenges to successful control of the disease. This problem will be addressed in future studies in the 2020s, which will include a focus on immunologic approaches such as monoclonal antibodies, checkpoint inhibitors, engineered T-cells, and novel immunomodulators.

  5. Fever of unknown origin (FUO) caused by multiple myeloma: the diagnostic value of the Naprosyn test.

    PubMed

    Cunha, Burke A; Bouyarden, Michael; Hamid, Naveed S

    2006-01-01

    Fever of unknown origin (FUO) remains a difficult diagnostic problem. The causes of FUO have changed over the years. Neoplastic disorders have now displaced infectious diseases as the most common cause of FUOs. Most neoplasms are associated with no or low-grade temperatures, with some important exceptions. Hypernephromas and lymphomas are neoplasms typically associated with high spiking fevers or may present as FUOs. Hematologic malignancies, that is, the acute and chronic leukemias, myeloproliferative disorders, and multiple myeloma, do not usually present with acute fevers or as FUOs. We present an elderly male patient who presented with an FUO, whose history is significant for multiple myeloma in remission. Differential diagnostic possibilities in this patient included plasma cell leukemia, relapse of multiple myeloma, secondary/superimposed malignancy, or opportunistic infection. The main differential diagnosis for his FUO was between neoplastic and infectious disorders. As part of the diagnostic workup, a Naprosyn test (naproxen 375 mg [by mouth] every 12 hours for 3 days) was used to differentiate neoplastic from infectious causes of FUO in this patient. The Naprosyn test was positive, which indicated a neoplastic explanation for the patient's FUO and eliminated, along with the infectious disease workup, an infectious explanation for his FUO. The patient's FUO was finally determined to be the result of a relapse of multiple myeloma and not of a secondary malignancy or malignant transformation of myeloma into plasma cell leukemia. We conclude the Naprosyn test remains a valuable diagnostic test to use to narrow differential diagnostic possibilities in patients with FUOs when a malignancy is a diagnostic consideration. PMID:16963369

  6. Acute renal failure after treatment with sunitinib in a patient with multiple myeloma.

    PubMed

    Leung, Nelson; Saucier, Nathan A; Zeldenrust, Steven R; Gunderson, Heidi D; Cornell, Lynn D

    2009-08-01

    Sunitinib is a multiple tyrosine kinase receptors inhibitor that is approved for the treatment of advanced renal cell carcinoma. Amongst its targets are fetal liver tyrosine kinase receptor 3 (FLT 3) and vascular endothelial growth factor receptor (VEGFR). Renal toxicity has not been reported from the trials, but several patients have been reported to develop a pre-eclampsia-like syndrome. We report the first case of acute tubular necrosis in a patient with multiple myeloma following treatment with sunitinib.

  7. Myeloma-specific multiple peptides able to generate cytotoxic T lymphocytes: A potential therapeutic application in multiple myeloma and other plasma cell disorders

    PubMed Central

    Bae, Jooeun; Smith, Robert; Daley, John; Mimura, Naoya; Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.

    2013-01-01

    Purpose The efficacy of peptide vaccines may be enhanced by stimulating immune cells with multiple peptides derived from distinct tumor-associated antigens. We have evaluated the heteroclitic XBP1 US184–192 (YISPWILAV), heteroclitic XBP1 SP367–375 (YLFPQLISV), native CD138260–268 (GLVGLIFAV), and native CS1239–247 (SLFVLGLFL) peptides, which have strong HLA-A2 affinity and immunogenicity in combination, for their ability to elicit multiple myeloma antigen-specific responses. Experimental Design Multipeptide-specific cytotoxic T lymphocytes (MP-CTL) were generated by the stimulation of CD3+ T lymphocytes from HLA-A2+ individuals with either autologous mature dendritic cells or T2 cells pulsed with a cocktail of these four peptides. Results The peptide cocktail did not compromise tumor antigen-specific activity of CTL. MP-CTL displayed increased total, effector memory (CCR7−CD45RO+), and activated (CD69+) CD3+CD8+ T lymphocytes. In addition, MP-CTL demonstrated IFN-γ production, cell proliferation, and cytotoxicity against HLA-A2+ multiple myeloma cells, including HLA-A2+ MM patients’ cells. Importantly, MP-CTL showed specific responses in functional assays to each relevant peptide, but not to an irrelevant HLA-A2 specific CMV pp65 (NLVPMVATV) peptide. Conclusions These results highlight the potential therapeutic application of vaccination with a cocktail of HLA-A2 specific peptides to induce CTL with a broad spectrum of immune responses against multiple myeloma antigens. PMID:22753586

  8. Multiple myeloma and exposure to pesticides: a Canadian case-control study.

    PubMed

    Pahwa, Punam; Karunanayake, Chandima P; Dosman, James A; Spinelli, John J; McDuffie, Helen H; McLaughlin, John R

    2012-01-01

    The objective of this study was to investigate the putative associations of specific pesticides with multiple myeloma. A matched, population-based, case-control study was conducted among men residing in six Canadian provinces (Quebec, Ontario, Manitoba, Saskatchewan, Alberta, and British Columbia). Data were collected on 342 multiple myelome cases and 1506 age and province of residence matched controls. Data were collected by mailed questionnaires to capture demographic characteristics, antecedent medical history, detailed lifetime occupational history, smoking history, family history of cancer, and exposure to broadly characterized pesticides at home, work, and practicing hobbies. Details of pesticide exposures were collected by telephone interview for those who reported 10 hours or more per year of exposure. Exposure to pesticides grouped into major chemical classes resulted in increased risk being detected only for carbamate insecticides [odds ratio (OR) and 95% confidence interval (CI) 1.90 (1.11, 3.27) adjusted for potential confounders]. An exposure to fungicide captan [2.35 (1.03, 5.35)] was positively associated with the incidence of multiple myeloma. While an exposure to carbaryl [1.89 (0.98, 3.67)] was associated with the incidence of multiple myelome with borderline significance. The authors further suggest that certain pesticide exposures may have a role in multiple myeloma etiology, and identify specific factors warranting investigation in other populations.

  9. TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms

    PubMed Central

    Rauert, H; Stühmer, T; Bargou, R; Wajant, H; Siegmund, D

    2011-01-01

    The huge majority of myeloma cell lines express TNFR2 while a substantial subset of them failed to show TNFR1 expression. Stimulation of TNFR1 in the TNFR1-expressing subset of MM cell lines had no or only a very mild effect on cellular viability. Surprisingly, however, TNF stimulation enhanced cell death induction by CD95L and attenuated the apoptotic effect of TRAIL. The contrasting regulation of TRAIL- and CD95L-induced cell death by TNF could be traced back to the concomitant NFκB-mediated upregulation of CD95 and the antiapoptotic FLIP protein. It appeared that CD95 induction, due to its strength, overcompensated a rather moderate upregulation of FLIP so that the net effect of TNF-induced NFκB activation in the context of CD95 signaling is pro-apoptotic. TRAIL-induced cell death, however, was antagonized in response to TNF because in this context only the induction of FLIP is relevant. Stimulation of TNFR2 in myeloma cells leads to TRAF2 depletion. In line with this, we observed cell death induction in TNFR1-TNFR2-costimulated JJN3 cells. Our studies revealed that the TNF-TNF receptor system adjusts the responsiveness of the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms that generate a highly context-dependent net effect on myeloma cell survival. PMID:21850048

  10. Pulmonary Nocardiosis in a Multiple Myeloma Patient Treated with Proteasome Inhibitors

    PubMed Central

    Mendonca, Nikolai P.; Kadayakkara, Deepak K.; Forde, Inga C.; Rudkovaskaia, Anastasiia; Saul, Zane K.; Lobo, David J.

    2016-01-01

    Patient: Male, 71 Final Diagnosis: Pulmonary nocardiosis Symptoms: Cough • dyspnea • fever Medication: Carfillzomib Clinical Procedure: Bronchoscopy Specialty: Infectious Diseases Objective: Rare co-existance of disease or pathology Background: The use of proteasome inhibitors like Bortezomib to treat multiple myeloma has been associated with increased rates of opportunistic infections, including Nocardia, especially when lymphopenia is present. The prevalence or association of such infections with newer agents like Carfilzomib is not known. Case Report: A 71-year-old man with multiple myeloma presented with a 6-week history of respiratory symptoms and cyclic fevers. He was undergoing chemotherapy with Carfilzomib. Work-up revealed severe lymphopenia and a CT chest showed multiple lung nodules and a mass-like consolidation. He underwent a bronchoscopy, and respiratory cultures grew Nocardia species. He responded well to intravenous antibiotics with resolution of symptoms and CT findings. Conclusions: With the introduction of newer agents like Carfilzomib for the treatment of multiple myeloma, clinicians must maintain a high degree of suspicion for opportunistic infections to achieve early diagnosis and treatment. PMID:26861506

  11. [Diagnosis of multiple myeloma in primary care. Suspicion with an appropriate clinical history].

    PubMed

    Alvarez-Cordovés, M M; Mirpuri-Mirpuri, P G; Pérez-Monje, A

    2013-09-01

    Monoclonal gammopathies are a group of disorders characterized by stable or progressive clonal proliferation of plasma cells producing similar immunoglobulins. Multiple myeloma is characteristic of the presence of bone marrow infiltration by plasma cells, osteolytic lesions, and M component in serum or urine. As cancer cells multiply, they can cause pain and destruction of bone, and if affecting the spine, they can press on nerves causing pain and paresthesias. In patients of advanced age (average 69 years) with bone pain not associated with trauma, and which does not improve with treatment, a differential diagnosis should be performed with multiple myeloma. This should include, at least, a full blood count, biochemistry, total protein, protein electrophoresis, immunofixation, and radiographs of painful areas.

  12. [Diagnosis of multiple myeloma in primary care. Suspicion with an appropriate clinical history].

    PubMed

    Alvarez-Cordovés, M M; Mirpuri-Mirpuri, P G; Pérez-Monje, A

    2013-09-01

    Monoclonal gammopathies are a group of disorders characterized by stable or progressive clonal proliferation of plasma cells producing similar immunoglobulins. Multiple myeloma is characteristic of the presence of bone marrow infiltration by plasma cells, osteolytic lesions, and M component in serum or urine. As cancer cells multiply, they can cause pain and destruction of bone, and if affecting the spine, they can press on nerves causing pain and paresthesias. In patients of advanced age (average 69 years) with bone pain not associated with trauma, and which does not improve with treatment, a differential diagnosis should be performed with multiple myeloma. This should include, at least, a full blood count, biochemistry, total protein, protein electrophoresis, immunofixation, and radiographs of painful areas. PMID:24034763

  13. Multiple Myeloma Relapse Following Autologous Stem Cell Transplant Presenting With Diffuse Pulmonary Nodules

    PubMed Central

    Sumrall, Bradley; Diethelm, Lisa; Brown, Archie

    2013-01-01

    Background Multiple myeloma is a common disease, accounting for about 10% of hematologic malignancies in the United States. For eligible patients, the treatment of choice includes induction therapy (usually involving newer biologic agents) followed by autologous stem cell transplant; however, this treatment is generally not considered curative, and relapses usually occur. However, extramedullary relapse is an uncommon presentation, and relapses that involve the lungs have only rarely been described. Case Report We report the case of a patient who underwent an autologous stem cell transplant for multiple myeloma and subsequently relapsed with diffuse pulmonary nodules. She then had a rapid clinical and serologic response following initiation of salvage therapy. Conclusion This case is remarkable for both the radiographic appearance of the pulmonary involvement, as well as the rapid resolution of these findings after 2 cycles of treatment with bortezomib, dexamethasone, and lenalidomide. PMID:24358007

  14. [Advances Research on C-MYC Proto-oncogene in Multiple Myeloma -Review].

    PubMed

    Huang, He; Guo, Wen-Jian; Yao, Ron-Xin

    2016-08-01

    Multiple myeloma(MM) as one of the most common tumors of hmatologic system, is characterized by malignant proliferation of plasma cells, and the chemotherapy is the main therapeutic method. MM is an incurable disease because of drug-resistance of MM cells. Although the pathogenesis of MM remains unknown, the chromosome abnormalities exit in half of the patients, particularly the highly expressed gene C-MYC. Furthermore, plenty of clinical researches indicated a high expression level of C-MYC implied worse progression and/or poor prognosis of MM. Recently, the work exploiting the compounds targeting MYC has made substantial progress, even in the MM therapy. In this article, briefly the recent advances of the research on C-MYC proto-oncogene in multiple myeloma are reviewed. PMID:27531809

  15. Flail chest stabilization with Nuss operation in presence of multiple myeloma.

    PubMed

    Lee, Song Am; Hwang, Jae Joon; Chee, Hyun Keun; Kim, Yo Han; Lee, Woo Surng

    2014-05-01

    Nowadays the Nuss operation has been widely adopted as a minimally invasive procedure and standard surgical choice in pectus excavatum. However, much debate and concern have been raised regarding its applicability in adults with pectus excavatum flail chest and other thoratic wall deformities, as compared with younger patients, in terms of complications after surgery. To stabilize the segment of paradoxical chest wall movement we performed the Nuss operation on a patient with multiple myeloma who sustained blunt thoracic trauma. The patient presented with paradoxical movement of the thoracic wall and sternum instability due to multiple myeloma, which led to severe dyspnea, hypoxemia, hypercapnea, and bedridden state. His condition progressed to acute respiratory distress syndrome and did not respond to conservative treatment. We performed the Nuss operation on the patient, and his clinical symptoms were relieved after surgery. The patient regained the ability to walk unassisted and was discharged from the hospital without any specific events.

  16. Bleeding and thrombosis in multiple myeloma and related plasma cell disorders.

    PubMed

    Coppola, Antonio; Tufano, Antonella; Di Capua, Mirko; Franchini, Massimo

    2011-11-01

    A variety of disease- and treatment-related factors affect the coagulation system and the risk of bleeding and thrombotic complications in patients with multiple myeloma (MM) and related plasma cell disorders (PCD). As commonly observed in other cancer settings, the malignant clone induces a cytokine environment responsible for a hypercoagulable state. The increase of blood viscosity and impairment of platelet and coagulation function due to circulating monoclonal proteins are considered key mechanisms in the hemostatic abnormalities frequently detected in patients with PCD. However, clinically significant bleeding is relatively rare and poorly correlated with these abnormalities. Management is often challenging because of the multifactorial pathogenesis and underestimation or misdiagnosis of acquired bleeding disorders, particularly acquired von Willebrand syndrome. In recent years, growing interest in thromboembolic risk has emerged after the introduction of novel and more effective antimyeloma agents (thalidomide and lenalidomide), which was associated with increased risk of venous thromboembolism, particularly when associated with dexamethasone and multiagent chemotherapy in newly diagnosed patients. The clinical impact of bleeding and thrombotic complications in patients with PCD, with emphasis on MM, will be discussed in this review, reporting the current knowledge about pathophysiologic mechanisms and implications for management.

  17. Serum Parathyroid Hormone Is a New Potential Risk Factor in Multiple Myeloma

    PubMed Central

    Won, Eun-Jeong; Kim, Hye-Ran; Choi, Hyun-Jung; Park, Hye-Ri; Shin, Jong-Hee; Suh, Soon-Pal; Ryang, Dong-Wook; Shin, Myung-Geun

    2014-01-01

    We hypothesized that serum PTH might be associated with various clinicopathological parameters in multiple myeloma (MM). So we investigated the implications of serum PTH in MM patients and the relationship with other risk factors of MM. A total of 115 patients who were newly diagnosed with MM were enrolled. Serum PTH level was 24.7 ± 34.9 (ranged 0.0–284.1) pg/mL. Serum levels of IgG, IgM, FLC-lambda, albumin, and LDH were in positive correlation with serum PTH. Compared to non-high PTH (<68.3 pg/mL) group, the hazard ratio (HR) for overall survival was higher for group with high PTH level (≥68.3 pg/mL) (HR, 1.710). Furthermore, the patient group with high PTH level showed inferior progression-free survival than non-high PTH group (P = 0.056). Interestingly, subgroup analysis showed that serum PTH level at diagnosis was associated with risk factors and clinical outcome in MM patients, especially in complete remission group, transplantation cases, ISS stage II cases, and cases without chromosome abnormality. In conclusion, this study showed that blood PTH level in MM at diagnosis was associated with risk factors and clinical outcome in MM patients. PMID:24967406

  18. CD4+CD25+ cells in multiple myeloma related renal impairment

    PubMed Central

    Huang, Hongdong; Luo, Yang; Liang, Yumei; Long, Xi-Dai; Peng, Youming; Liu, Zhihua; Wen, Xiaojun; Jia, Meng; Tian, Ru; Bai, Chengli; Li, Cui; Dong, Xiaoqun

    2015-01-01

    CD4+CD25+ cells are critical regulators in almost all of the animal models of human organ-specific autoimmune diseases, transplant rejection and allergic diseases. We aimed to explore the role of CD4+CD25+ cells in the pathogenesis of multiple myeloma (MM) related renal impairment (RI). Thirty patients with MM related RI and 30 healthy volunteers were studied. The number of CD4+CD25+ cells was examined by flow cytometry. Clinical and laboratory data were collected from each subject. Glomerular injury was assessed by histopathology. Serum IL-2, IL-4 and IL-6 were analyzed by ELISA. CD4+CD25+ cells significantly decreased in MM related RI patients compared to the controls (P<0.05). CD4+CD25+ cell number was negatively associated with blood urea nitrogen (BUN), supernatant IL-4, serum IL-6, monoclonal immunoglobulin and β2-microglobulin, as well as bone marrow plasma cell percentage and proteinuria; whereas positively associated with estimated glomerular filtration rate (eGFR) (all P < 0.05). CD4+CD25+ cells gradually decreased as the Clinic Stage increased. The number of CD4+CD25+ cells reduced in MM related RI patients, and was correlated with disease severity. CD4+CD25+ cells may play an important role in the pathogenesis of MM related RI. PMID:26564056

  19. Clinicopathological significance of p15 promoter hypermethylation in multiple myeloma: a meta-analysis.

    PubMed

    Wei, Bing; Yang, Shuhua; Zhang, Bo; Feng, Yong

    2016-01-01

    Published studies reported that loss of function of the p15(INK4B) gene is caused by hypermethylation; however, whether or not the inactivation is associated with the incidence and clinical significance of multiple myeloma (MM) remains unclear. In this study, we performed a meta-analysis to quantitatively determine the effects of p15 hypermethylation on the incidence of MM. The related research articles in English and Chinese languages were evaluated. The data were extracted and assessed independently. The pooled data were analyzed and odds ratios were calculated and summarized. Sixteen eligible studies were selected for final analysis. We demonstrated that p15 hypermethylation is significantly higher in MM than that in normal bone marrow, as well as monoclonal gammopathy of undetermined significance. However, aberrant p15 hypermethylation was not significantly higher in advanced MM than that in early-stage MM. The results of this study reveal that p15 hypermethylation is correlated with an increased risk in the progression of monoclonal gammopathy of undetermined significance to MM. p15 hypermethylation, which induces the loss of function of the p15 gene, plays a critical role in the early tumorigenesis of MM and serves as a reputable diagnostic marker and potential drug target. PMID:27445492

  20. Abnormal IGF-Binding Protein Profile in the Bone Marrow of Multiple Myeloma Patients.

    PubMed

    Bieghs, Liesbeth; Brohus, Malene; Kristensen, Ida B; Abildgaard, Niels; Bøgsted, Martin; Johnsen, Hans E; Conover, Cheryl A; De Bruyne, Elke; Vanderkerken, Karin; Overgaard, Michael T; Nyegaard, Mette

    2016-01-01

    Insulin-like growth factor (IGF) signalling plays a key role in homing, progression, and treatment resistance in multiple myeloma (MM). In the extracellular environment, the majority of IGF molecules are bound to one of six IGF-binding proteins (IGFBP1-6), leaving a minor fraction of total IGF free and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM (n = 17), monoclonal gammopathy of undetermined significance (MGUS) (n = 37), and control individuals (n = 15), using ELISA (IGFs) and 125I-IGF1 Western Ligand Blotting (IGFBPs). MGUS and MM patients displayed a significant increase in intact IGFBP-2 (2.5-3.8 fold) and decrease in intact IGFBP-3 (0.6-0.5 fold) in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration. PMID:27111220

  1. Expression and significance of miR-21 in multiple myeloma patients.

    PubMed

    Wang, J H; Zhou, W W; Liu, B X; Man, D L; Yang, Z D; Liu, F R; Shang, H

    2016-01-01

    The aim of the present study is to examine the expression level of peripheral mir-21 in multiple myeloma (MM) patients and to determine its clinical significance. MM patients (30), monoclonal gammopathy of undetermined significance (MGUS) patients (14), and normal controls (20) were recruited to determine the serum level of β2-MG, IgA and IgM, IgG, λ, κ, TP, ALB, Hb, LDH, and Ca(2+). Gene expression of mir-21 was quantified by SYBR green real-time fluorescent quantitative PCR. We found that the expression level of serum mir-21 in the MM group was significantly higher than the MGUS group and the NC group (P < 0.01). According to the ISS installment, the level of mir-21, lgG, κ, and ALB in the MM group in stage I differed from that in stages II and III. The level of IgA, β2-MG in stage III was higher as compared with stage I and II (P < 0.05 and P < 0.01).The levels of mir-21, κ, (κ+λ), IgG, (IgG + IgA + IgM), and β2-MG in MM patients were positively correlated with ALB (P < 0.01). Based on the results, miR-21 plays an important role as an oncogene. Mir-21 may be important in the occurrence, development, and disease prognosis of MM. PMID:26909911

  2. Abnormal IGF-Binding Protein Profile in the Bone Marrow of Multiple Myeloma Patients

    PubMed Central

    Bieghs, Liesbeth; Brohus, Malene; Kristensen, Ida B.; Abildgaard, Niels; Bøgsted, Martin; Johnsen, Hans E.; Conover, Cheryl A.; De Bruyne, Elke; Vanderkerken, Karin

    2016-01-01

    Insulin-like growth factor (IGF) signalling plays a key role in homing, progression, and treatment resistance in multiple myeloma (MM). In the extracellular environment, the majority of IGF molecules are bound to one of six IGF-binding proteins (IGFBP1-6), leaving a minor fraction of total IGF free and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM (n = 17), monoclonal gammopathy of undetermined significance (MGUS) (n = 37), and control individuals (n = 15), using ELISA (IGFs) and 125I-IGF1 Western Ligand Blotting (IGFBPs). MGUS and MM patients displayed a significant increase in intact IGFBP-2 (2.5–3.8 fold) and decrease in intact IGFBP-3 (0.6–0.5 fold) in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration. PMID:27111220

  3. Clinicopathological significance of p15 promoter hypermethylation in multiple myeloma: a meta-analysis

    PubMed Central

    Wei, Bing; Yang, Shuhua; Zhang, Bo; Feng, Yong

    2016-01-01

    Published studies reported that loss of function of the p15INK4B gene is caused by hypermethylation; however, whether or not the inactivation is associated with the incidence and clinical significance of multiple myeloma (MM) remains unclear. In this study, we performed a meta-analysis to quantitatively determine the effects of p15 hypermethylation on the incidence of MM. The related research articles in English and Chinese languages were evaluated. The data were extracted and assessed independently. The pooled data were analyzed and odds ratios were calculated and summarized. Sixteen eligible studies were selected for final analysis. We demonstrated that p15 hypermethylation is significantly higher in MM than that in normal bone marrow, as well as monoclonal gammopathy of undetermined significance. However, aberrant p15 hypermethylation was not significantly higher in advanced MM than that in early-stage MM. The results of this study reveal that p15 hypermethylation is correlated with an increased risk in the progression of monoclonal gammopathy of undetermined significance to MM. p15 hypermethylation, which induces the loss of function of the p15 gene, plays a critical role in the early tumorigenesis of MM and serves as a reputable diagnostic marker and potential drug target. PMID:27445492

  4. Copper-zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma.

    PubMed

    Salem, Kelley; McCormick, Michael L; Wendlandt, Erik; Zhan, Fenghuang; Goel, Apollina

    2015-01-01

    Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper-zinc superoxide dismutase (CuZnSOD or SOD1) correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266) and the BTZ-resistant (BR) lines (MM.1SBR, 8226BR) were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1), and glutathione (GSH) were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF) augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity. PMID:25485927

  5. Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma

    PubMed Central

    Salem, Kelley; McCormick, Michael L.; Wendlandt, Erik; Zhan, Fenghuang; Goel, Apollina

    2014-01-01

    Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper–zinc superoxide dismutase (CuZnSOD or SOD1) correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266) and the BTZ-resistant (BR) lines (MM.1SBR, 8226BR) were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1), and glutathione (GSH) were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF) augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity. PMID:25485927

  6. Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma

    PubMed Central

    Xu, Yinyin; Chen, Bingda; George, Suraj K; Liu, Beizhong

    2015-01-01

    Multiple myeloma (MM) induced bone lesion is one of the most crippling characteristics, and the MM secreted Dickkopf-1 (DKK1) has been reported to play important role in this pathologic process. However, the underlying regulation mechanisms involved in DKK1 expression are still unclear. In this study, we validated the expression patterns of microRNA (miR) 15a, 34a, 152, and 223 in MM cells and identified that miR-152 was significantly downregulated in the MM group compared with the non-MM group, and that miR-152 level was negatively correlated with the expression of DKK1 in the MM cells. Mechanistic studies showed that manipulating miR-152 artificially in MM cells led to changes in DKK-1 expression, and miR-152 blocked DKK1 transcriptional activity by binding to the 3′UTR of DKK1 mRNA. Importantly, we revealed that MM cells stably expressing miR-152 improved the chemotherapy sensitivity, and counteracted the bone disruption in an intrabone-MM mouse model. Our study contributes better understanding of the regulation mechanism of DKK-1 in MM, and opens up the potential for developing newer therapeutic strategies in the MM treatment. PMID:26400224

  7. The Arkansas approach to therapy of patients with multiple myeloma.

    PubMed

    Barlogie, Bart; Anaissie, Elias; van Rhee, Frits; Pineda-Roman, Mauricio; Zangari, Maurizio; Shaughnessy, John; Epstein, Joshua; Crowley, John

    2007-12-01

    This chapter gives an account of the experience of the Arkansas myeloma program since 1989 with transplant-supported high-dose melphalan, novel agents, and prognostic factors as they relate to standard laboratory features, gene expression profiling, and magnetic resonance imaging (MRI). Incorporation of novel agents and new concepts, such as post-tandem transplant consolidation therapy, has improved the rate and duration of complete response and prolonged event-free and overall survival rates. With Total Therapy 2, median survival exceeds 8 years, while Total Therapy 3 with added bortezomib has sustained complete remissions in more than 90% of patients at 2 years which, when used as a survival surrogate in Total Therapy 2, assured a high 6-year survival rate of 75%. Gene expression profiling identified 15% of patients with very short survival. MRI-defined focal lesions are associated with poor outcome, while their resolution - although slower than the time course of attaining clinical complete remission - conferred superior survival. Representing a frequent source of recurrence, with genetic profiles (in both plasma and stromal cells) distinct from those in random bone-marrow samples, therapeutic efforts are directed at hastening onset and increasing frequency of focal lesion resolution. PMID:18070718

  8. MGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and management.

    PubMed

    Rajkumar, S Vincent

    2005-01-01

    Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic, pre-malignant disorders characterized by monoclonal plasma cell proliferation in the bone marrow and absence of end-organ damage. Recent advances in the pathogenesis, natural history, and prognosis of MGUS and SMM are reviewed. A new risk stratification system to determine the prognosis of MGUS using the size and type of M protein, and the serum free light chain assay is discussed. PMID:16304401

  9. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma.

    PubMed

    Ribatti, D; Nico, B; Vacca, A

    2006-07-20

    Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in multiple myeloma (MM). The encouraging results of preclinical and clinical trials in which MM has been treated by targeting the tumor microenvironment are also discussed.

  10. Management of Multiple Myeloma Complicated by Hepatitis C Virus Reactivation: The Role of New Antiviral Therapy.

    PubMed

    Mahale, Parag; Thomas, Sheeba K; Kyvernitakis, Andreas; Torres, Harrys A

    2016-01-01

    Reactivation of chronic hepatitis C virus (HCV) infection has been reported in cancer patients receiving chemotherapy. In this study, we report the first case, to our knowledge, of thalidomide-induced acute exacerbation and reactivation of chronic HCV infection complicating management of multiple myeloma. Sofosbuvir-based antiviral therapy helped achieve viral clearance and normalization of liver enzymes, thus allowing access to future potentially life-saving chemotherapy agents. PMID:26885541

  11. Under-ascertainment of multiple myeloma among participants in UK atmospheric atomic and nuclear weapons tests.

    PubMed

    Roff, S R

    2003-12-01

    An inter-comparison of cases of multiple myeloma among UK participants in the UK's atmospheric atomic and nuclear weapons tests ascertained by direct follow up methods detected at least a third more cases than a strategy relying solely on data linkage between the Office of National Statistics and the Service Records Offices. These finding have implications for the conduct and robustness of follow up studies of long term health effects among participants in nuclear weapons tests.

  12. Clinical Use of Proteasome Inhibitors in the Treatment of Multiple Myeloma

    PubMed Central

    Merin, Noah M.; Kelly, Kevin R.

    2014-01-01

    Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of neoplastic plasma cells. The use of proteasome inhibitors in the treatment of MM has led to significant improvements in outcomes. This article reviews data on the use of the two approved proteasome inhibitors (bortezomib and carlfilzomib), as well as newer agents under development. Emphasis is placed on the clinical use of proteasome inhibitors, including management of side effects and combination with other agents. PMID:25545164

  13. Diagnostic x-ray procedures and risk of leukemia, lymphoma, and multiple myeloma

    SciTech Connect

    Boice, J.D. Jr.; Morin, M.M.; Glass, A.G.; Friedman, G.D.; Stovall, M.; Hoover, R.N.; Fraumeni, J.F. Jr. )

    1991-03-13

    Exposure to diagnostic x-rays and the risk of leukemia, non-Hodgkin's lymphoma (NHL), and multiple myeloma were studied within two prepaid health plans. Adult patients with leukemia (n = 565), NHL (n = 318), and multiple myeloma (n = 208) were matched to controls (n = 1390), and over 25,000 x-ray procedures were abstracted from medical records. Dose response was evaluated by assigning each x-ray procedure a score based on estimated bone marrow dose. X-ray exposure was not associated with chronic lymphocytic leukemia, one of the few malignant conditions never linked to radiation (relative risk (RR), 0.66). For all other forms of leukemia combined (n = 358), there was a slight elevation in risk (RR, 1.17) but no evidence of a dose-response relationship when x-ray procedures near the time of diagnosis were excluded. Similarly, patients with NHL were exposed to diagnostic x-ray procedures more often than controls (RR, 1.32), but the RR fell to 0.99 when the exposure to diagnostic x-ray procedures within 2 years of diagnosis was ignored. For multiple myeloma, overall risk was not significantly high (RR, 1.14), but there was consistent evidence of increasing risk with increasing numbers of diagnostic x-ray procedures. These data suggest that persons with leukemia and NHL undergo x-ray procedures frequently just prior to diagnosis for conditions related to the development or natural history of their disease. There was little evidence that diagnostic x-ray procedures were causally associated with leukemia or NHL. The risk for multiple myeloma, however, was increased among those patients who were frequently exposed to x-rays.

  14. Expected long-term survival of patients diagnosed with multiple myeloma in 2006-2010.

    PubMed

    Brenner, Hermann; Gondos, Adam; Pulte, Dianne

    2009-02-01

    New therapeutic options have led to substantial increases in survival expectations of younger patients with multiple myeloma in recent years. In the past, the impact of these innovations on long-term survival has been disclosed only with substantial delay. We aimed to derive up-to-date estimates of long-term survival expectations of concurrently diagnosed multiple myeloma patients. Using data from the 1973-2005 database of the Surveillance, Epidemiology, and End Results (SEER) Program, we employed a novel model-based projection method to project 5-and 10-year relative survival expectations of multiple myeloma patients in the United States diagnosed in 2006-2010. Preliminary empirical evaluation of the method using historical data indicated good performance. Projected 5-year relative survival for patients diagnosed in 2006-2010 below 45 years of age is 68.0%, which exceeds the most up-to-date estimates obtained from traditional cohort and period analysis by 15.5 and 7.0 percent units respectively. Ten-year relative survival projection for patients in this age group is 55.3%, exceeding the most up-to-date estimates from traditional cohort and period analysis by 19.7 and 7.4 percent units respectively. By contrast, survival projections remain much lower and hardly exceed estimates from traditional survival analysis for older patients. Patients diagnosed with multiple myeloma in 2006-2010, especially those diagnosed at younger ages, are expected to have much higher long-term survival perspectives than suggested by previously available survival statistics. PMID:19144659

  15. Management of Multiple Myeloma Complicated by Hepatitis C Virus Reactivation: The Role of New Antiviral Therapy

    PubMed Central

    Mahale, Parag; Thomas, Sheeba K.; Kyvernitakis, Andreas; Torres, Harrys A.

    2016-01-01

    Reactivation of chronic hepatitis C virus (HCV) infection has been reported in cancer patients receiving chemotherapy. In this study, we report the first case, to our knowledge, of thalidomide-induced acute exacerbation and reactivation of chronic HCV infection complicating management of multiple myeloma. Sofosbuvir-based antiviral therapy helped achieve viral clearance and normalization of liver enzymes, thus allowing access to future potentially life-saving chemotherapy agents. PMID:26885541

  16. Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells.

    PubMed

    Kiraz, Yağmur; Neergheen-Bhujun, Vidushi S; Rummun, Nawraj; Baran, Yusuf

    2016-02-01

    Multiple myeloma is of great concern since existing therapies are unable to cure this clinical condition. Alternative therapeutic approaches are mandatory, and the use of plant extracts is considered interesting. Punica granatum and its derived products were suggested as potential anticancer agents due to the presence of bioactive compounds. Thus, polypenolic-rich extracts of the non-edible parts of P. granatum were investigated for their antiproliferative and apoptotic effects on U266 multiple myeloma cells. We demonstrated that there were dose-dependent decreases in the proliferation of U266 cells in response to P. granatum extracts. Also, exposure to the extracts triggered apoptosis with significant increases in loss of mitochondrial membrane potential in U266 cells exposed to the leaves and stem extracts, while the flower extract resulted in slight increases in loss of MMP. These results were confirmed by Annexin-V analysis. These results documented the cytotoxic and apoptotic effects of P. granatum extracts on human U266 multiple myeloma cells via disruption of mitochondrial membrane potential and increasing cell cycle arrest. The data suggest that the extracts can be envisaged in cancer chemoprevention and call for further exploration into the potential application of these plant parts.

  17. Oleocanthal inhibits proliferation and MIP-1α expression in human multiple myeloma cells.

    PubMed

    Scotece, M; Gómez, R; Conde, J; Lopez, V; Gómez-Reino, J J; Lago, F; Smith, A B; Gualillo, O

    2013-01-01

    Multiple myeloma (MM) is a plasma cell malignancy that causes devastating bone destruction by activating osteoclasts in the bone marrow milieu. MM is the second of all hematological malignancies. Thus, the search for new pharmacological weapons is under intensive investigation being MM a critically important public health goal. Recently, it has been demonstrated that macrophage inflammatory protein 1- alpha (MIP-1 α) is crucially involved in the development of osteolytic bone lesions in MM. Phenolic components of extra virgin olive oil are reported to have anti tumor activity. However, the underlying mechanisms and specific targets of extra virgin olive oil remain to be elucidated. In the present study, we investigated the effects of a recently isolated novel extra virgin olive oil polyphenol, oleocanthal, on the human multiple myeloma cell line ARH-77. Here we report that this natural compound has a remarkable in vitro activity by inhibiting MIP-1 α expression and secretion in MM cells. In addition, we also demonstrated that oleocanthal inhibits MM cells proliferation by inducing the activation of apoptosis mechanisms and by down-regulating ERK1/2 and AKT signal transduction pathways. This in vitro study suggests a therapeutic potential of oleocanthal in treating multiple myeloma. PMID:23521677

  18. Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies

    PubMed Central

    Caltagirone, Simona; Ruggeri, Marina; Aschero, Simona; Gilestro, Milena; Oddolo, Daniela; Gay, Francesca; Bringhen, Sara; Musolino, Caterina; Baldini, Luca; Musto, Pellegrino; Petrucci, Maria T.; Gaidano, Gianluca; Passera, Roberto; Bruno, Benedetto; Palumbo, Antonio; Boccadoro, Mario; Omedè, Paola

    2014-01-01

    Multiple myeloma is a plasma cell disorder characterized by malignant plasma cell infiltration in the bone marrow, serum and/or urine monoclonal protein and organ damage. The aim of this study was to investigate the impact of chromosome 1 abnormalities in a group of elderly patients (>65 years) with newly diagnosed multiple myeloma enrolled in the GIMEMA-MM-03-05 trial and treated with bortezomib, melphalan and prednisone or bortezomib, melphalan, prednisone and thalidomide followed by bortezomib and thalidomide maintenance. We also evaluated the link between chromosome 1 abnormalities and other clinical, genetic and immunophenotypic features by a multivariate logistic regression model. Interphase fluorescence in situ hybridization on immunomagnetically purified plasma cells and bone marrow multiparameter flow cytometry were employed. A multivariate Cox model showed that chromosome 1 abnormalities, age >75 years and a CD19+/CD117− immunophenotype of bone marrow plasma cells were independent risk factors for overall survival in elderly patients with newly diagnosed multiple myeloma. Moreover, a detrimental effect of thalidomide, even when administered in association with bortezomib, was observed in patients with abnormal chromosome 1 as well as in those with 17p deletion, while the benefit of adding thalidomide to the bortezomib-melphalan-prednisone regimen was noted in patients carrying an aggressive CD19+/CD117− bone marrow plasma cell immunophenotype. This trial was registered at www.clinicaltri-als.gov as #NCT01063179. PMID:25015938

  19. Small interfering RNA silencing of interleukin-6 in mesenchymal stromal cells inhibits multiple myeloma cell growth.

    PubMed

    Teoh, Hoon Koon; Chong, Pei Pei; Abdullah, Maha; Sekawi, Zamberi; Tan, Geok Chin; Leong, Chooi Fun; Cheong, Soon Keng

    2016-01-01

    Studies demonstrated that mesenchymal stromal cells (MSC) from bone marrow stroma produced high concentration of interleukin-6 (IL-6) that promoted multiple myeloma cell growth. In view of the failure of IL-6 monoclonal antibody therapy to demonstrate substantial clinical responses in early clinical trials, more effective methods are needed in order to disrupt the favourable microenvironment provided by the bone marrow stroma. In this study, we evaluated the short interfering RNA (siRNA)-mediated silencing of IL-6 in MSC and the efficacy of these genetically modified MSC, with IL-6 suppression, on inhibition of U266 multiple myeloma cell growth. IL-6 mRNA and protein were significantly suppressed by 72h post IL-6 siRNA transfection without affecting the biological properties of MSC. Here we show significant inhibition of cell growth and IL-6 production in U266 cells co-cultured with MSC transfected with IL-6 siRNA when compared to U266 cells co-cultured with control MSC. We also show that the tumour volume and mitotic index of tumours in nude mice co-injected with U266 and MSC transfected with IL-6 siRNA were significantly reduced compared to tumours of mice co-injected with control MSC. Our results suggest potential use of RNA interference mediated therapy for multiple myeloma.

  20. [CAR Technology and Its Application in Treatment of Multiple Myeloma--Review].

    PubMed

    Li, Tong; Wang, Hong-Tao; Liu, Zhuo-Gang

    2016-02-01

    Multiple myeloma (MM) is a hematologic malignancy resulted from genetic mutations in the process of B lymphocyte differentiating into plasma cells, the chemotherapy is the main treatment method, especially with the development of proteasome inhibitors and other drugs, the overall survival rate of MM patients has improved greatly, but the chemoresistance is still an important reason for treatment failure. Chimeric antigen receptor (CAR)-modified T lymphocyte therapy is a new method for tumor adoptive immunotherapy. By means of genetic modification, T cells are able to identify the target antigen specifically, and to kill target cells without major histocompatibility complex (MHC) restriction, therefore the specific killing activity is conspicuous, which has got considerable attention by the public, and has made remarkable achievements particularly in the treatment of B-lineage leukemia and lymphoma, but no systematic literatures were reported in the field of multiple myeloma using CAR therapy. Therefore, this review summarizes the research results of different CAR target in vivo and in vitro experiments for multiple myeloma. PMID:26913437

  1. Toxic substance exposure and multiple myeloma: a case-control study.

    PubMed

    Morris, P D; Koepsell, T D; Daling, J R; Taylor, J W; Lyon, J L; Swanson, G M; Child, M; Weiss, N S

    1986-06-01

    By means of a population-based, multicenter case-control investigation, certain toxic substances were evaluated as risk factors for multiple myeloma. Interviews were completed on 698 subjects with newly diagnosed multiple myeloma, and 1,683 controls were selected from the same geographic areas as those of the cases. Respondents were asked if they had ever been "highly" exposed" to one or more of a list of toxic substances or to other substances not on the list. With the aid of a toxicologist, responses were then categorized into 20 exposure groups. Those who reported past exposure to pesticides had an estimated relative risk of 2.6 for multiple myeloma [95% confidence interval (CI) = 1.5-4.6]. Subjects exposed to a variety of compounds commonly used by painters had an estimated relative risk of 1.6 (95% CI = 1.1-2.4). An increased risk also was found for those who were exposed to sources of carbon monoxide (relative risk = 1.8, 95% CI = 1.0-3.2). Associations of borderline statistical significance were found for metals and organically high polymers (plastics and elastomers). No statistically significant associations were seen for exposure to fertilizers; dyes and inks; alkalies; acids; other caustic substances; chemical asphyxiants; aliphatic, chlorinated, or aromatic hydrocarbons; aldehydes and ketones; ethers; esters; oils; dusts; or asbestos.

  2. Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma

    PubMed Central

    2014-01-01

    Background Multiple myeloma is characterized by clonal expansion of B cells producing monoclonal immunoglobulins or fragments thereof, which can be detected in the serum and/or urine and are ideal target antigens for patient-specific immunotherapies. Methods Using phage particles as immunological carriers, we employed a novel chemically linked idiotype vaccine in a clinical phase I/II trial including 15 patients with advanced multiple myeloma. Vaccines composed of purified paraproteins linked to phage were manufactured successfully for each patient. Patients received six intradermal immunizations with phage idiotype vaccines in three different dose groups. Results Phage idiotype was well tolerated by all study participants. A subset of patients (80% in the middle dose group) displayed a clinical response indicated by decrease or stabilization of paraprotein levels. Patients exhibiting a clinical response to phage vaccines also raised idiotype-specific immunoglobulins. Induction of a cellular immune response was demonstrated by a cytotoxicity assay and delayed type hypersensitivity tests. Conclusion We present a simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible patient-specific therapy for patients with advanced multiple myeloma and produced promising anti-tumor activity in a subset of patients. PMID:24885819

  3. Micromolecular multiple myeloma with chronic kidney failure in a young female patient on continuous hemodialysis.

    PubMed

    Rotaru, Ionela; Badea, M; Tănase, Alina Daniela; Foarfă, Camelia

    2013-01-01

    The maximum incidence of multiple myeloma appears in the 6th-7th decade of life and although the number of patients aged les than 60 years is increasing in recent years, the diagnosis of a monoclonal gammopathy in a young patient, under the age of 40 years remains a rarity. Literature data cite an incidence of approximately 2.2% in patients less than 40-year-old and an incidence of 0.3% in patients less than 30-year-old of all cases diagnosed with multiple myeloma. We present the case of a 32-year-old patient, being on continuous hemodialysis for chronic kidney failure for about a year, at the Hematology Clinic of Craiova, Romania. We investigate the origin of a serum monoclonal component revealed when performing serum protein electrophoresis. Bone marrow examination revealed the presence of a plasma cell infiltrate of 18%, which associated with the presence of a serum monoclonal component and in the conditions of renal failure as a complication of the disease, has allowed the diagnosis of multiple myeloma.

  4. 'Like a sieve': an exploratory study on cognitive impairments in patients with multiple myeloma.

    PubMed

    Potrata, B; Cavet, J; Blair, S; Howe, T; Molassiotis, A

    2010-11-01

    The aim of this study was to obtain a more in-depth understanding of cognitive impairments and concerns as described by patients with multiple myeloma and the strategies used to cope with them. Semi-structured qualitative interviews were undertaken with 15 multiple myeloma patients of differing age ranges and at various stages of their disease. Various cognitive impairments, such as problems with short-term memory, poor recall and lack of concentration were observed and/or expressed in at least 10 out of 15 patients, all of them long(er)-term survivors. In some patients cognitive impairments significantly interfered with their personal and professional lives, and for some patients these were described as permanent. The patients used various coping strategies, from denial, taking notes, writing diaries, reading simpler texts, using talking books and videos, to using systems for counting medication to cope with the results of their cognitive impairment. Our findings differ from much of the contemporary literature which states that if cognitive impairments in cancer patients occur, they are mostly mild and transient. More proactive supportive care is needed to help patients with multiple myeloma to cope with poorer cognitive functioning.

  5. Renal complications in multiple myeloma and related disorders: Survivorship care plan of the IMF Nurse Leadership Board

    PubMed Central

    Faiman, Beth; Tariman, Joseph D.; Mangan, Patricia A.; Spong, Jacy

    2012-01-01

    Kidney dysfunction is a common clinical feature of symptomatic multiple myeloma. Some degree of renal insufficiency or renal failure is present at diagnosis or will occur during the course of the disease, and which, if not reversed, will adversely effect overall survival and quality of life. Chronic insults to the kidneys from other illnesses, treatment, or multiple myeloma itself can further damage renal function and increase the risk for additional complications, such as anemia. Patients with multiple myeloma who have light chain (Bence Jones protein) proteinuria may experience renal failure or progress to end-stage renal disease (ESRD) and require dialysis due to light chain cast nephropathy. Kidney failure in patients with presumed multiple myeloma may also result from amyloidosis, light chain deposition disease, or acute tubular necrosis caused by nephrotoxic agents; therefore identification of patients at risk for kidney damage is essential. The International Myeloma Foundation’s Nurse Leadership Board have developed these practice recommendations for screening for renal function, identifying positive and negative contributing risk and environmental factors, selecting appropriate therapies and supportive care measures to decrease progression to ESRD and dialysis, and reducing and managing renal complications in patients with multiple myeloma. PMID:21816711

  6. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

    PubMed Central

    Mitchell, Jonathan S.; Li, Ni; Weinhold, Niels; Försti, Asta; Ali, Mina; van Duin, Mark; Thorleifsson, Gudmar; Johnson, David C.; Chen, Bowang; Halvarsson, Britt-Marie; Gudbjartsson, Daniel F.; Kuiper, Rowan; Stephens, Owen W.; Bertsch, Uta; Broderick, Peter; Campo, Chiara; Einsele, Hermann; Gregory, Walter A.; Gullberg, Urban; Henrion, Marc; Hillengass, Jens; Hoffmann, Per; Jackson, Graham H.; Johnsson, Ellinor; Jöud, Magnus; Kristinsson, Sigurður Y.; Lenhoff, Stig; Lenive, Oleg; Mellqvist, Ulf-Henrik; Migliorini, Gabriele; Nahi, Hareth; Nelander, Sven; Nickel, Jolanta; Nöthen, Markus M.; Rafnar, Thorunn; Ross, Fiona M.; da Silva Filho, Miguel Inacio; Swaminathan, Bhairavi; Thomsen, Hauke; Turesson, Ingemar; Vangsted, Annette; Vogel, Ulla; Waage, Anders; Walker, Brian A.; Wihlborg, Anna-Karin; Broyl, Annemiek; Davies, Faith E.; Thorsteinsdottir, Unnur; Langer, Christian; Hansson, Markus; Kaiser, Martin; Sonneveld, Pieter; Stefansson, Kari; Morgan, Gareth J.; Goldschmidt, Hartmut; Hemminki, Kari; Nilsson, Björn; Houlston, Richard S.

    2016-01-01

    Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10−8), 6q21 (rs9372120, P=9.09 × 10−15), 7q36.1 (rs7781265, P=9.71 × 10−9), 8q24.21 (rs1948915, P=4.20 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development. PMID:27363682

  7. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma.

    PubMed

    Mitchell, Jonathan S; Li, Ni; Weinhold, Niels; Försti, Asta; Ali, Mina; van Duin, Mark; Thorleifsson, Gudmar; Johnson, David C; Chen, Bowang; Halvarsson, Britt-Marie; Gudbjartsson, Daniel F; Kuiper, Rowan; Stephens, Owen W; Bertsch, Uta; Broderick, Peter; Campo, Chiara; Einsele, Hermann; Gregory, Walter A; Gullberg, Urban; Henrion, Marc; Hillengass, Jens; Hoffmann, Per; Jackson, Graham H; Johnsson, Ellinor; Jöud, Magnus; Kristinsson, Sigurður Y; Lenhoff, Stig; Lenive, Oleg; Mellqvist, Ulf-Henrik; Migliorini, Gabriele; Nahi, Hareth; Nelander, Sven; Nickel, Jolanta; Nöthen, Markus M; Rafnar, Thorunn; Ross, Fiona M; da Silva Filho, Miguel Inacio; Swaminathan, Bhairavi; Thomsen, Hauke; Turesson, Ingemar; Vangsted, Annette; Vogel, Ulla; Waage, Anders; Walker, Brian A; Wihlborg, Anna-Karin; Broyl, Annemiek; Davies, Faith E; Thorsteinsdottir, Unnur; Langer, Christian; Hansson, Markus; Kaiser, Martin; Sonneveld, Pieter; Stefansson, Kari; Morgan, Gareth J; Goldschmidt, Hartmut; Hemminki, Kari; Nilsson, Björn; Houlston, Richard S

    2016-07-01

    Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10(-8)), 6q21 (rs9372120, P=9.09 × 10(-15)), 7q36.1 (rs7781265, P=9.71 × 10(-9)), 8q24.21 (rs1948915, P=4.20 × 10(-11)), 9p21.3 (rs2811710, P=1.72 × 10(-13)), 10p12.1 (rs2790457, P=1.77 × 10(-8)), 16q23.1 (rs7193541, P=5.00 × 10(-12)) and 20q13.13 (rs6066835, P=1.36 × 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.

  8. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma.

    PubMed

    Kikuchi, Jiro; Koyama, Daisuke; Wada, Taeko; Izumi, Tohru; Hofgaard, Peter O; Bogen, Bjarne; Furukawa, Yusuke

    2015-12-01

    Alterations in chromatin modifications, such as histone methylation, have been suggested as mediating chemotherapy resistance in several cancer types; therefore, elucidation of the epigenetic mechanisms that underlie drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified histone H3-lysine 27 (H3K27) as a critical residue for epigenetic modification in multiple myeloma. We determined that abrogation of drug-induced H3K27 hypermethylation is associated with cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance, using a coculture system to evaluate stroma cell adhesion-dependent alterations in multiple myeloma cells. Cell adhesion counteracted anticancer drug-induced hypermethylation of H3K27 via inactivating phosphorylation of the transcription regulator EZH2 at serine 21, leading to the sustained expression of antiapoptotic genes, including IGF1, B cell CLL/lymphoma 2 (BCL2), and hypoxia inducible factor 1, α subunit (HIF1A). Pharmacological and genetic inhibition of the IGF-1R/PI3K/AKT pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. Together, our findings identify and characterize an epigenetic mechanism that underlies CAM-DR and suggest that kinase inhibitors to counteract EZH2 phosphorylation should be included in combination chemotherapy to increase therapeutic index. PMID:26517694

  9. Comparative Effectiveness on Survival of Zoledronic Acid versus Pamidronate in Multiple Myeloma

    PubMed Central

    Sanfilippo, KM; Gage, B; Luo, S; Weilbaecher, K; Tomasson, M; Vij, R; Colditz, G; Carson, K

    2015-01-01

    Zoledronic acid and pamidronate are the two bisphosphonates approved to reduce multiple myeloma skeletal complications in the United States. Little prior evidence exists comparing survival outcomes between the two. We evaluated the incidence of skeletal related events and overall survival in myeloma patients treated with zoledronic acid versus pamidronate using a cohort of 1,018 United States Veterans. At median follow-up of 26.9 months, patients receiving zoledronic acid had a 22% reduction in risk of death compared to pamidronate (hazard ratio (HR) 0.78; 95% CI, 0.67–0.92). The benefit persisted after controlling for potential confounders. Adjusted Cox modeling with inverse probability weighting and propensity score matching supported these findings. Zoledronic acid was also associated with a 25% decrease in skeletal-related events. Zoledronic acid is associated with increased overall survival and decreased skeletal related events compared to pamidronate in patients with multiple myeloma and should become the preferred bisphosphonate. PMID:24844358

  10. The road to cure in multiple myeloma starts with smoldering disease

    PubMed Central

    Salem, Karma Z; Ghobrial, Irene M

    2015-01-01

    Introduction Smoldering multiple myeloma (SMM) is a heterogeneous clinical entity that defines patients in the spectrum of disease progression from monoclonal gammopathy of undetermined significance to multiple myeloma (MM). Current standard of care is observation until end organ damage occurs. In spite of this, the scientific community has begun to question whether the strategy of watchful waiting should be replaced with earlier therapeutic intervention with the ultimate goal of preventing clonal heterogeneity and end organ damage. Areas covered In this review, we challenge the concept of observation as the best option of therapy in SMM. We present current data on diagnosis, prognostic factors of disease progression and studies that have been conducted to date to determine whether earlier therapeutic interventions will lead to an improvement in overall survival of patients with MM. Expert opinion If the recommendations of treatment of SMM were to change, the scientific body of evidence would have to overcome four major hurdles: to demonstrate that early intervention leads to prolonged survival and delay in development of end organ damage, that it does not have long-term toxicities, that it is implemented in patients with a high-likelihood of developing myeloma and that it does not lead to the outgrowth of more resistant clones. Only well-designed clinical trials will determine whether cure can be achieved with earlier interventions. PMID:25995973

  11. Understanding biology to tackle the disease: Multiple myeloma from bench to bedside, and back.

    PubMed

    Bianchi, Giada; Anderson, Kenneth C

    2014-01-01

    Multiple myeloma (MM) is a cancer of antibody-producing plasma cells. The pathognomonic laboratory finding is a monoclonal immunoglobulin or free light chain in the serum and/or urine in association with bone marrow infiltration by malignant plasma cells. MM develops from a premalignant condition, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage termed smoldering multiple myeloma (SMM), which differs from active myeloma by the absence of disease-related end-organ damage. Unlike MGUS and SMM, active MM requires therapy. Over the past 6 decades, major advancements in the care of MM patients have occurred, in particular, the introduction of novel agents (ie, proteasome inhibitors, immunomodulatory agents) and the implementation of hematopoietic stem cell transplantation in suitable candidates. The effectiveness and good tolerability of novel agents allowed for their combined use in induction, consolidation, and maintenance therapy, resulting in deeper and more sustained clinical response and extended progression-free and overall survival. Previously a rapidly lethal cancer with few therapeutic options, MM is the hematologic cancer with the most novel US Food and Drug Administration-approved drugs in the past 15 years. These advances have resulted in more frequent long-term remissions, transforming MM into a chronic illness for many patients. PMID:25266555

  12. The natural products parthenolide and andrographolide exhibit anti-cancer stem cell activity in multiple myeloma.

    PubMed

    Gunn, Ellen J; Williams, John T; Huynh, Daniel T; Iannotti, Michael J; Han, Changho; Barrios, Francis J; Kendall, Stephen; Glackin, Carlotta A; Colby, David A; Kirshner, Julia

    2011-06-01

    Multiple myeloma (MM) is an incurable plasma cell malignancy where nearly all patients succumb to a relapse. The current preclinical models of MM target the plasma cells, constituting the bulk of the tumor, leaving the cancer stem cells to trigger a relapse. Utilizing a three-dimensional tissue culture system where cells were grown in extracellular matrix designed to reconstruct human bone marrow, we tested the anti-multiple myeloma cancer stem cell (MM-CSC) potential of two natural product inhibitors of nuclear factor κB (NFκB). Here we show that parthenolide and andrographolide are potent anti-MM-CSC agents. Both natural products demonstrated preferential toxicity toward MM-CSCs over non-tumorigenic MM cells. Addition of the bone marrow stromal compartment abrogated andrographolide activity while having no effect on parthenolide cytoxicity. This is the first report of a natural product with anti-CSC activity in myeloma, suggesting that it has the potential to improve the survival of patients with MM by eliminating the relapse-causing MM-CSCs. PMID:21417826

  13. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

    PubMed Central

    Kikuchi, Jiro; Koyama, Daisuke; Wada, Taeko; Izumi, Tohru; Hofgaard, Peter O.; Bogen, Bjarne; Furukawa, Yusuke

    2015-01-01

    Alterations in chromatin modifications, such as histone methylation, have been suggested as mediating chemotherapy resistance in several cancer types; therefore, elucidation of the epigenetic mechanisms that underlie drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified histone H3–lysine 27 (H3K27) as a critical residue for epigenetic modification in multiple myeloma. We determined that abrogation of drug-induced H3K27 hypermethylation is associated with cell adhesion–mediated drug resistance (CAM-DR), which is the most important form of drug resistance, using a coculture system to evaluate stroma cell adhesion–dependent alterations in multiple myeloma cells. Cell adhesion counteracted anticancer drug–induced hypermethylation of H3K27 via inactivating phosphorylation of the transcription regulator EZH2 at serine 21, leading to the sustained expression of antiapoptotic genes, including IGF1, B cell CLL/lymphoma 2 (BCL2), and hypoxia inducible factor 1, α subunit (HIF1A). Pharmacological and genetic inhibition of the IGF-1R/PI3K/AKT pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. Together, our findings identify and characterize an epigenetic mechanism that underlies CAM-DR and suggest that kinase inhibitors to counteract EZH2 phosphorylation should be included in combination chemotherapy to increase therapeutic index. PMID:26517694

  14. Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics

    PubMed Central

    Greenberg, Alexandra J.; Rajkumar, S. Vincent

    2012-01-01

    Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), is one of the most common premalignant conditions in the general population. The cause of MGUS is largely unknown. Recent studies show that there is an increased prevalence of MGUS in blood relatives of persons with lymphoproliferative and plasma cell proliferative disorders, suggesting presence of shared underlying genetic influences. In the past few years, additional studies have examined risk factors and biologic characteristics that may contribute to the increased prevalence of MGUS among relatives of probands with MGUS, MM, and other blood malignancies. This article reviews the known epidemiology and risk factors for familial MGUS and myeloma, the risk of lymphoproliferative disorders and other malignancies among blood-relatives of patients with MGUS and MM, and discusses future directions for research. PMID:22354002

  15. Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway.

    PubMed

    Chen, Yan; Huang, Ruibin; Ding, Jianghua; Ji, Dexiang; Song, Bing; Yuan, Liya; Chang, Hong; Chen, Guoan

    2015-04-20

    Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors. We here report that EGFR inhibition solely exhibited moderate inhibition in KRAS/NRAS/BRAF wildtype (triple-WT) MM cells, whilst had no effect in myeloma cells with any of the mutated genes. The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor. Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells. The inhibition could be restored by addition of NADPH. Dual EGFR/ERBB2 inhibitor Afatinib also exhibited similar effects. Further genetic silencing of EGFR, ERBB2 and mTOR indicated that major effect conferred by ERBB2 was via convergence to EGFR pathway in MM. Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

  16. Altered cytokine and chemokine profiles in multiple myeloma and precursor disease

    PubMed Central

    Zingone, Adriana; Wang, Weixin; Corrigan-Cummins, Meghan; Wu, Shengyang P.; Plyler, Ryan; Korde, Neha; Kwok, Mary; Manasanch, Elisabet E.; Tageja, Nishant; Bhutani, Manisha; Mulquin, Marcia; Zuchlinski, Diamond; Yancey, Mary Ann; Roschewski, Mark; Zhang, Yong; Roccaro, Aldo M.; Ghobrial, Irene M.; Calvo, Katherine R.; Landgren, Ola

    2014-01-01

    Currently, no reliable biomarkers are available to predict transformation from smoldering myeloma (SMM) to multiple myeloma (MM). Using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) we assessed the levels of a broad range of cytokines and chemokines in the peripheral blood (PB) and bone marrow (BM) supernatant collected from 14 SMM and 38 MM patients and compared to healthy donors. We found significantly increased levels of key cytokines, in particular CXCL8 (IL-8), associated with progressive disease state (controls→SMM→MM). Cytokine profiles were found similar in PB and BM. Five of fourteen SMM patients (36%) progressed to MM. Our findings, although based on a limited number of patients, suggest that serum-based cytokines may have a future role as biomarkers for disease progression and could potentially be assessed as novel targets for treatment. PMID:25043675

  17. The effect of 1-phenylalanine mustard on anti-globulin antibodies in multiple myeloma

    PubMed Central

    Waller, Marion; Moon, J. H.; Irby, R.; Toone, E. C.

    1971-01-01

    An immunochemical and serological study of a patient with rheumatoid arthritis who developed multiple myeloma and was treated with 1-phenylalanine mustard showed a striking difference in the effect of this drug on the rapidly dividing cells, as opposed to the resting plasma cells. The titres of anti-globulin antibodies such as the IgG serum agglutinators and the IgM rheumatoid factors were little altered although the IgG myeloma spike has disappeared following therapy. Fractionation of two different serum samples from 1966 and 1970 showed the IgG paraprotein to be serologically inactive for anti-globulin activity. This paraprotein was also characterized by producing only a single IgG precipitin line with horse anti-human whole serum antibody while the normal IgG globulins always showed a double line. ImagesFIG. 1FIG. 2FIG. 3FIG. 5 PMID:4993198

  18. Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma

    PubMed Central

    Chang, Xiubao; Zhu, Yuanxiao; Shi, Changxin; Stewart, A. Keith

    2014-01-01

    Although immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, are widely used in the treatment of multiple myeloma (MM), the molecular mechanism of IMiDs' action is largely unknown. In this review, we will summarize recent advances in the application of IMiDs in MM cancer treatment as well as their effects on immunomodulatory activities, anti-angiogenic activities, intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells, anti-inflammatory activities, anti-proliferation, pro-apoptotic effects, cell cycle arrest, and inhibition of cell migration and metastasis. In addition, the potential IMiDs' target protein, IMiDs' target protein's functional role, and the potential molecular mechanisms of IMiDs resistance will be discussed. We wish, by presentation of our naive discussion, that this review article will facilitate further investigation in these fields. PMID:24374776

  19. Infused vincristine and adriamycin with high dose methylprednisolone (VAMP) in advanced previously treated multiple myeloma patients.

    PubMed Central

    Forgeson, G. V.; Selby, P.; Lakhani, S.; Zulian, G.; Viner, C.; Maitland, J.; McElwain, T. J.

    1988-01-01

    Forty-five patients with relapsed or refractory multiple myeloma received continuous infusions of vincristine (0.4 mg total dose daily for 4 days) and adriamycin (9 mg m-2 daily for 4 days) with a high dose of methylprednisolone (1 g m-2 i.v. or p.o. daily by 1 h infusion), the VAMP regimen. Sixteen (36%) responded, with a median duration of remission of 11 months and median survival of 20 months. Major toxicities encountered were infective and cardiovascular. Two smaller groups of myeloma patients were treated with high dose methylprednisolone (HDMP) alone, or VAMP plus weekly low dose cyclophosphamide (Cyclo-VAMP). HDMP produced short responses in 25% of patients with less toxicity than VAMP. Cyclo-VAMP was used in a highly selected group of patients who had previously responded to high dose melphalan. It was well tolerated and produced responses in 61% of this group. PMID:3207601

  20. A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells

    PubMed Central

    Milan, Enrico; Perini, Tommaso; Resnati, Massimo; Orfanelli, Ugo; Oliva, Laura; Raimondi, Andrea; Cascio, Paolo; Bachi, Angela; Marcatti, Magda; Ciceri, Fabio; Cenci, Simone

    2015-01-01

    Multiple myeloma (MM) is the paradigmatic proteasome inhibitor (PI) responsive cancer, but many patients fail to respond. An attractive target to enhance sensitivity is (macro)autophagy, recently found essential to bone marrow plasma cells, the normal counterpart of MM. Here, integrating proteomics with hypothesis-driven strategies, we identified the autophagic cargo receptor and adapter protein, SQSTM1/p62 as an essential component of an autophagic reserve that not only synergizes with the proteasome to maintain proteostasis, but also mediates a plastic adaptive response to PIs, and faithfully reports on inherent PI sensitivity. Lentiviral engineering revealed that SQSTM1 is essential for MM cell survival and affords specific PI protection. Under basal conditions, SQSTM1-dependent autophagy alleviates the degradative burden on the proteasome by constitutively disposing of substantial amounts of ubiquitinated proteins. Indeed, its inhibition or stimulation greatly sensitized to, or protected from, PI-induced protein aggregation and cell death. Moreover, under proteasome stress, myeloma cells selectively enhanced SQSTM1 de novo expression and reset its vast endogenous interactome, diverting SQSTM1 from signaling partners to maximize its association with ubiquitinated proteins. Saturation of such autophagic reserve, as indicated by intracellular accumulation of undigested SQSTM1-positive aggregates, specifically discriminated patient-derived myelomas inherently susceptible to PIs from primarily resistant ones. These aggregates correlated with accumulation of the endoplasmic reticulum, which comparative proteomics identified as the main cell compartment targeted by autophagy in MM. Altogether, the data integrate autophagy into our previously established proteasome load-versus-capacity model, and reveal SQSTM1 aggregation as a faithful marker of defective proteostasis, defining a novel prognostic and therapeutic framework for MM. PMID:26043024

  1. Cytogenetic Alterations in Multiple Myeloma: Prognostic Significance and the Choice of Frontline Therapy.

    PubMed

    Stella, Flavia; Pedrazzini, Estela; Agazzoni, Mara; Ballester, Oscar; Slavutsky, Irma

    2015-01-01

    Multiple myeloma tumor cells demonstrate multiple and often complex genetic lesions as evaluated by standard cytogenetic/FISH studies. Over the past decade, specific abnormalities have been associated with standard or high-risk clinical behavior and they have become strong prognostic indicators. Further, as evidenced by recent randomized clinical trials, the choice of front-line therapy (transplant vs. no transplant, inclusion of novel drugs such as bortezomib, thalidomide, and lenalidomide) may be able to overcome the adverse effect of high-risk genetic lesions. PMID:26506456

  2. Overcoming inherent resistance to histone deacetylase inhibitors in multiple myeloma cells by targeting pathways integral to the actin cytoskeleton

    PubMed Central

    Mithraprabhu, S; Khong, T; Spencer, A

    2014-01-01

    Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with multiple myeloma (MM). Although HDACi have demonstrable synergy when combined with proteasome inhibitors (PIs), recent evidence indicates that combination of HDACi and PI is beneficial only in a subset of patients with advanced MM, clearly indicating that other rational combinations should be explored. In this context we hypothesized that understanding the molecular signature associated with inherent resistance to HDACi would provide a basis for the identification of therapeutic combinations with improved clinical efficacy. Using human myeloma cell lines (HMCL) categorized as sensitive, intermediate or resistant to HDACi, gene expression profiling (GEP) and gene ontology enrichment analyses were performed to determine if a genetic signature associated with inherent resistance to HDACi-resistance could be identified. Correlation of GEP to increasing or decreasing sensitivity to HDACi indicated a unique 35-gene signature that was significantly enriched for two pathways – regulation of actin cytoskeleton and protein processing in endoplasmic reticulum. When HMCL and primary MM samples were treated with a combination of HDACi and agents targeting the signaling pathways integral to the actin cytoskeleton, synergistic cell death was observed in all instances, thus providing a rationale for combining these agents with HDACi for the treatment of MM to overcome resistance. This report validates a molecular approach for the identification of HDACi partner drugs and provides an experimental framework for the identification of novel therapeutic combinations for anti-MM treatment. PMID:24651437

  3. Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells

    PubMed Central

    Lub, Susanne; Maes, Anke; Maes, Ken; De Veirman, Kim; De Bruyne, Elke; Menu, Eline; Fostier, Karel; Kassambara, Alboukadel; Moreaux, Jérôme; Hose, Dirk; Leleu, Xavier; King, Randall W.

    2016-01-01

    The anaphase promoting complex/cyclosome (APC/C) is an ubiquitin ligase involved in cell cycle. During the metaphase-anaphase transition the APC/C is activated by Cdc20. The aim of this study is to elucidate the importance and therapeutic potential of APC/C and its co-activator Cdc20 in multiple myeloma (MM). Gene expression analysis revealed that Cdc20 was expressed at higher levels in gene expression-based high-risk MM patients. Moreover, high Cdc20 expression correlated with poor prognosis. Treatment of human myeloma cell lines with proTAME, an APC/C inhibitor, resulted in an accumulation of APC/CCdc20 substrate cyclin B1 and an accumulation of cells in metaphase. Moreover we observed a significant dose-dependent decrease in viability and increase in apoptosis in MM cells upon proTAME treatment. The induction of apoptosis was accompanied with caspase 3, 8, 9 and PARP cleavage. A similar metaphase arrest and induction of apoptosis were obtained with specific knockdown of Cdc20. In addition, we demonstrated the accumulation of Bim was partially responsible for the observed cell death. Combining proTAME with another APC/C inhibitor apcin or the alkylating agent melphalan resulted in enhanced anti-MM activity. This study suggests that the APC/C and its co-activator Cdc20 could be a new and promising target especially in high-risk MM patients. PMID:26716651

  4. Clinical significance of CD81 expression by clonal plasma cells in high-risk smoldering and symptomatic multiple myeloma patients.

    PubMed

    Paiva, B; Gutiérrez, N-C; Chen, X; Vídriales, M-B; Montalbán, M-Á; Rosiñol, L; Oriol, A; Martínez-López, J; Mateos, M-V; López-Corral, L; Díaz-Rodríguez, E; Pérez, J-J; Fernández-Redondo, E; de Arriba, F; Palomera, L; Bengoechea, E; Terol, M-J; de Paz, R; Martin, A; Hernández, J; Orfao, A; Lahuerta, J-J; Bladé, J; Pandiella, A; Miguel, J-F San

    2012-08-01

    The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81(+) SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma. PMID:22333880

  5. S-phase induction by interleukin-6 followed by chemotherapy in patients with refractory multiple myeloma.

    PubMed

    de Nully Brown, P; Jensen, P O; Diamant, M; Mortensen, B T; Hovgaard, D; Gimsing, P; Nissen, N I

    1998-11-01

    The plasma cell labeling index (PCLI) in patients with multiple myeloma (MM) is relatively low and this has been associated with the low rate of remission following chemotherapy. Interleukin-6 (IL-6) has been demonstrated to be a major growth factor of myeloma cells. In order to increase the S-phase proportion of myeloma cells, which might increase the sensitivity to chemotherapy, we gave rhIL-6 followed by chemotherapy to 15 myeloma patients with refractory disease. A total of 25 treatment cycles were administered since ten patients had two cycles. The rhIL-6 dose was 2.5 (n = 3), 5.0 (n = 6) and 10.0 microg/kg (n = 6) by subcutaneous injection once daily for 5 days and chemotherapy was administered on the last day of rhIL-6 injection. The effect of rhIL-6 treatment on labeling index (LI) was heterogeneous, but no statistically significant change was noted for this particular group as a whole. In two patients an increase (mean 7.7%) in LI of mononuclear bone marrow cells during the rhIL-6 treatment was demonstrated and in one patient a decrease of 2.8% was seen. Assessment of PCLI demonstrated an increase of 2.9% in one out of six patients and a decrease of 1.9% in one out of six patients. None of the 15 patients achieved remission according to standard criteria. During the rhIL-6 treatment, 14 of the 15 patients developed mild constitutional adverse events (AE) well known in patients treated with IL-6, and none of the AE in the subsequent chemotherapy phase were related to IL-6. In conclusion, our study demonstrated that rhIL-6 can be administered safely to patients with refractory MM, but the cell cycle recruitment approach was not sufficiently effective to be of clinical value.

  6. Molecular pathogenesis of multiple myeloma: chromosomal aberrations, changes in gene expression, cytokine networks, and the bone marrow microenvironment.

    PubMed

    Klein, Bernard; Seckinger, Anja; Moehler, Thomas; Hose, Dirk

    2011-01-01

    This chapter focuses on two aspects of myeloma pathogenesis: (1) chromosomal aberrations and resulting changes in gene and protein expression with a special focus on growth and survival factors of malignant (and normal) plasma cells and (2) the remodeling of the bone marrow microenvironment induced by accumulating myeloma cells. We begin this chapter with a discussion of normal plasma cell generation, their survival, and a novel class of inhibitory factors. This is crucial for the understanding of multiple myeloma, as several abilities attributed to malignant plasma cells are already present in their normal counterpart, especially the production of survival factors and interaction with the bone marrow microenvironment (niche). The chapter closes with a new model of pathogenesis of myeloma.

  7. Th22 cells increase in poor prognosis multiple myeloma and promote tumor cell growth and survival

    PubMed Central

    Di Lullo, Giulia; Marcatti, Magda; Heltai, Silvia; Brunetto, Emanuela; Tresoldi, Cristina; Bondanza, Attilio; Bonini, Chiara; Ponzoni, Maurilio; Tonon, Giovanni; Ciceri, Fabio; Bordignon, Claudio; Protti, Maria Pia

    2015-01-01

    There is increased production of plasmacytoid dendritic cells (pDCs) in the bone marrow (BM) of multiple myeloma (MM) patients and these favor Th22 cell differentiation. Here, we found that the frequency of interleukin (IL)-22+IL-17−IL-13+ T cells is significantly increased in peripheral blood (PB) and BM of stage III and relapsed/refractory MM patients compared with healthy donors and patients with asymptomatic or stage I/II disease. Th22 cells cloned from the BM of MM patients were CCR6+CXCR4+CCR4+CCR10− and produced IL-22 and IL-13 but not IL-17. Furthermore, polyfunctional Th22-Th2 and Th22-Th1 clones were identified based on the co-expression of additional chemokine receptors and cytokines (CRTh2 or CXCR3 and IL-5 or interferon gamma [IFNγ], respectively). A fraction of MM cell lines and primary tumors aberrantly expressed the IL-22RA1 and IL-22 induced STAT-3 phosphorylation, cell growth, and resistance to drug-induced cell death in MM cells. IL-13 treatment of normal BM mesenchymal stromal cells (MSCs) induced STAT-6 phosphorylation, adhesion molecule upregulation, and increased IL-6 production and significantly favored MM cell growth compared with untreated BM MSCs. Collectively, our data show that increased frequency of IL-22+IL-17−IL-13+ T cells correlates with poor prognosis in MM through IL-22 and IL-13 protumor activity and suggest that interference with IL-22 and IL-13 signaling pathways could be exploited for therapeutic intervention. PMID:26155400

  8. HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment

    SciTech Connect

    Borsi, Enrica; Perrone, Giulia; Terragna, Carolina; Martello, Marina; Zamagni, Elena; Tacchetti, Paola; Pantani, Lucia; Brioli, Annamaria; Dico, Angela Flores; Zannetti, Beatrice Anna; Rocchi, Serena; Cavo, Michele

    2014-11-01

    Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma. - Highlights: • HIF-1α inhibition induces a mild apoptotic cell death. • Down-modulation of cytokine-induced signaling cascades upon HIF-1α inhibition. • Reduced interaction between MM cells and BMSCs upon HIF-1α down-modulation. • Reduced PCs adhesion to the extracellular matrix protein induced by EZN-2968. • HIF-1α inhibition may be an attractive therapeutic strategy for Multiple Myeloma.

  9. Risk of acute myeloid leukaemia and multiple myeloma in workers exposed to benzene.

    PubMed Central

    Wong, O

    1995-01-01

    OBJECTIVE--To determine the risk of developing acute myeloid leukaemia (AML) and multiple myeloma in a cohort of workers exposed to benzene. The results were used to show the importance of taking specificity of disease into consideration in causation analysis. METHODS--Data were derived from a cohort of workers employed at two Goodyear plants in Ohio in the manufacture of Pliofilm. Based on data in the Pliofilm study, several papers that examined the relation between exposure to benzene and leukaemia (all cell types combined) have been published. In the current analyses based on updated data in the study, standardised mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated for AML and multiple myeloma by cumulative exposure to benzene. The results based on AML were compared with those for leukaemia (all cell types combined) published previously. RESULTS--An exposure response relation was shown between cumulative exposure to benzene and AML. No increased risk of AML was detected for cumulative exposure to benzene below 200 ppm-years (SMR 0.91). Above 200 ppm-years, risk of AML rose drastically; reaching a significant SMR of 98.37 for > 400 ppm-years. For multiple myeloma, no relation with exposure to benzene was detected. CONCLUSION--Analysis specific to AML shows the importance of taking specificity of disease into consideration in causation analysis. This investigation shows that previous analyses based on all leukaemia cell types combined have incorrectly set the estimated threshold too low, and have underestimated risk above the threshold. Current regulatory policies that rely on previous analyses based on all leukaemia cell types combined should be re-examined. PMID:7627314

  10. Effect of CYP2C19 and CYP3A4 gene polymorphisms on the efficacy of bortezomib-based regimens in patients with multiple myeloma

    PubMed Central

    ZHOU, WEIWEI; AN, GUANGYU; JIAN, YUAN; GUO, HUAN; CHEN, WENMING

    2015-01-01

    Bortezomib is used to treat patients with multiple myeloma. It is primarily metabolized by the enzyme cytochrome P450 (CYP). Variations in the capacity of bortezomib metabolism affect the treatment outcomes and the side-effects experienced by patients. In the present study, polymorphisms in the CYP3A4 and CYP2C19 genes were analyzed by polymerase chain reaction in 56 newly-diagnosed patients with multiple myeloma. The polymorphisms analyzed included the c.681G>A, c.636G>A and c.-806C>T polymorphisms of CYP2C19. The CYP3A4 gene was sequenced after amplification and was classified into normal and mutant types. Associations between the metabolizer genotypes of CYP3A4 and CYP2C19, the therapeutic efficacy of bortezomib-based regimens, and the occurrence of peripheral neuropathy were studied. The results identified no significant differences in gender, serum β2 microglobulin, creatinine, blood albumin, isotypes, and the Durie-Salmon and International Staging System stages between the CYP2C19 poor + intermediate metabolizer types and the extensive + ultrarapid metabolizer types. In addition, it was revealed that the CYP2C19 and CYP3A4 phenotypes did not affect the efficacy of bortezomib-based regimens, nor were they correlated with peripheral neuropathy. Additional large-scale studies are required in order to evaluate the role of CYP enzymes in bortezomib treatments for patients with multiple myeloma. PMID:26622646

  11. Multiple myeloma and engine exhausts, fresh wood, and creosote: a case-referent study

    SciTech Connect

    Flodin, U.; Fredriksson, M.; Persson, B.

    1987-01-01

    The effect of potential risk factors for multiple myeloma was evaluated in a case-referent study encompassing 131 cases and 431 randomized referents, all alive. Information on exposure was obtained with questionnaires mailed to the subjects. An analysis of the material by means of the Miettinen confounder score technique resulted in a few rate ratios significantly exceeding unity--namely, occupational exposure to engine exhausts, creosote, and fresh wood. In view of other studies that suggest ionizing radiation as a risk factor, it was somewhat surprising that low-level gamma radiation from background exposure was less common among the cases than the referents.

  12. Prognostic value of unrelated atypical serum immunofixation patterns during multiple myeloma therapy.

    PubMed

    Guimarães, Cristina; Bergantim, Rui; Ramalho, Renata; Couto, Nuno; Guimarães, João T; Trigo, Fernanda

    2012-06-26

    Autologous stem cell transplantation (ASCT) is the gold standard therapy for suitable multiple myeloma (MM) patients after induction with high dose therapy. To date, the evidence of a reliable marker of prognosis in these cases remains scarce. Our aim was to evaluate appearance of unrelated atypical serum immunofixation patterns (ASIPs) as a marker of prognosis in MM patients submitted to ASCT. We retrospectively analysed data from 65 patients. Interestingly, we observed that presence of ASIPs was associated with longer progression-free survival and longer overall survival. Our results suggested that presence of ASIPs could be a novel marker of good prognosis in MM patients submitted to ASCT.

  13. Multiple Myeloma Treatment Strategies with Novel Agents in 2011: A European Perspective

    PubMed Central

    Beksac, Meral; Bladé, Joan; Cavenagh, Jamie; Cavo, Michele; Delforge, Michel; Dimopoulos, Meletios; Drach, Johannes; Einsele, Hermann; Facon, Thierry; Goldschmidt, Hartmut; Harousseau, Jean-Luc; Hess, Urs; Kropff, Martin; Leal da Costa, Fernando; Louw, Vernon; Magen-Nativ, Hila; Mendeleeva, Larisa; Nahi, Hareth; Plesner, Torben; San-Miguel, Jesús; Sonneveld, Pieter; Udvardy, Miklos; Sondergeld, Pia; Palumbo, Antonio

    2011-01-01

    The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices. PMID:21441574

  14. Quadruple Cancers of Non-producing Multiple Myeloma, Cholangiocellular Carcinoma, and Two Different Thyroid Cancers.

    PubMed

    Mizutani, Shinsuke; Kuroda, Junya; Sasaki, Nana; Kiyota, Miki; Tatekawa, Shotaro; Tsukamoto, Taku; Maegawa, Saori; Chinen, Yoshiaki; Shimura, Yuji; Nagoshi, Hisao; Kobayashi, Tsutomu; Horiike, Shigeo; Tando, So; Fushiki, Shinji; Taniwaki, Masafumi

    2016-01-01

    We report the case of a 72-year-old man who presented with non-producing multiple myeloma (MM) with three additional concomitant solid tumors that were identified by postmortem autopsy. The disease was refractory to anti-MM therapy including bortezomib and lenalidomide, and he finally died of bacterial pneumonia with diffuse alveolar damage 8 months after the diagnosis. An autopsy revealed that he was also affected by three other solid cancers, cholangiocellular carcinoma, medullary thyroid cancer and papillary thyroid cancer that were clinically asymptomatic and remained undiagnosed before death. A review of the literature suggests that primary quadruple cancers including MM are extremely rare. PMID:27150876

  15. Multiple myeloma treatment strategies with novel agents in 2011: a European perspective.

    PubMed

    Ludwig, Heinz; Beksac, Meral; Bladé, Joan; Cavenagh, Jamie; Cavo, Michele; Delforge, Michel; Dimopoulos, Meletios; Drach, Johannes; Einsele, Hermann; Facon, Thierry; Goldschmidt, Hartmut; Harousseau, Jean-Luc; Hess, Urs; Kropff, Martin; Leal da Costa, Fernando; Louw, Vernon; Magen-Nativ, Hila; Mendeleeva, Larisa; Nahi, Hareth; Plesner, Torben; San-Miguel, Jesús; Sonneveld, Pieter; Udvardy, Miklos; Sondergeld, Pia; Palumbo, Antonio

    2011-01-01

    The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices.

  16. European perspective on multiple myeloma treatment strategies: update following recent congresses.

    PubMed

    Ludwig, Heinz; Avet-Loiseau, Hervé; Bladé, Joan; Boccadoro, Mario; Cavenagh, Jamie; Cavo, Michele; Davies, Faith; de la Rubia, Javier; Delimpasi, Sosana; Dimopoulos, Meletios; Drach, Johannes; Einsele, Hermann; Facon, Thierry; Goldschmidt, Hartmut; Hess, Urs; Mellqvist, Ulf-Henrik; Moreau, Philippe; San-Miguel, Jesús; Sondergeld, Pia; Sonneveld, Pieter; Udvardy, Miklos; Palumbo, Antonio

    2012-01-01

    The management of multiple myeloma has undergone profound changes over the recent past as a result of advances in our understanding of the disease biology as well as improvements in treatment and supportive care strategies. Notably, recent years have seen a surge in studies incorporating the novel agents thalidomide, bortezomib, and lenalidomide into treatment for different disease stages and across different patient groups. This article presents an update to a previous review of European treatment practices and is based on discussions during an expert meeting that was convened to review novel agent data published or presented at medical meetings until the end of 2011 and to assess their impact on treatment strategies.

  17. Renal Thrombotic Microangiopathy Associated with the Use of Bortezomib in a Patient with Multiple Myeloma

    PubMed Central

    Van Keer, Jan; Delforge, Michel; Dierickx, Daan; Peerlinck, Kathelijne; Lerut, Evelyne; Sprangers, Ben

    2016-01-01

    Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-proven case. In addition, reexposure to bortezomib 18 months later was associated with recurrence of TMA. This supports a possible causal role of bortezomib. The exact mechanisms remain to be elucidated. PMID:27293920

  18. Hyporeninemic hypoaldosteronism associated with multiple myeloma: 11 years of follow-up.

    PubMed

    Shaked, Y; Blau, A; Shpilberg, O; Samra, Y

    1993-08-01

    Hyporeninemic hypoaldosteronism is an important underlying condition, causing hyperkalemia with hyperchloremic metabolic acidosis, disproportionate to the degree of renal insufficiency present. The principal defect in this syndrome is a reduced level of plasma renin activity, which results in secondary hypoaldosteronism. Diabetes mellitus is usually the primary underlying renal disease, though other causes of renal diseases associated with this syndrome have been described. This case report describes for the first time an elderly patient with multiple myeloma, in remission for more than 11 years, associated with the syndrome of hyporeninemic hypoaldosteronism at the time of diagnosis. The complete resolution of the syndrome after vigorous chemotherapy is an intriguing possibility.

  19. Risk of Early Mortality in Patients With Newly Diagnosed Multiple Myeloma

    PubMed Central

    Hsu, Pei; Lin, Ting-Wei; Gau, Jyh-Pyng; Yu, Yuan-Bin; Hsiao, Liang-Tsai; Tzeng, Cheng-Hwai; Chen, Po-Min; Chiou, Tzeon-Jye; Liu, Jin-Hwang; Liu, Yao-Chung; Liu, Chia-Jen

    2015-01-01

    Abstract The overall survival of patients with multiple myeloma (MM) has been improved greatly over the last 2 decades with the broader use of novel drugs and autologous tandem transplantation. However, more than one tenth of myeloma patients still die shortly after diagnosis. We therefore aim to investigate the risk factors of early mortality (death within 60 days after diagnosis) in patients with MM. We included in this study 451 consecutive patients with MM, newly diagnosed at an Asian tertiary medical center between January 1, 2002 and April 30, 2015. A total of 57 subjects who experienced early mortality were identified. Risk factors for early mortality in myeloma patients were collected and analyzed. Early mortality occurred in 57 (12.6%) of the myeloma patients. In the multivariate analysis, being male (adjusted OR 2.93, 95% CI 1.17–7.31), serum albumin < 3.5 g/dL (adjusted OR 2.71, 95% CI 1.09–6.74), primary plasma cell leukemia (adjusted OR 17.61, 95% CI 1.01–306.05), serum albumin (adjusted OR 2.70, 95% CI 1.15–6.38), corrected serum calcium ≥ 12 mg/dL (adjusted OR 2.94, 95% CI 1.21–7.14), and LDH ≥ 250 U/L (adjusted OR 3.07, 95% CI 1.50–6.27) were identified as independent risk factors of early mortality. Pneumonia with other infections contributed most to early mortality (n = 36, 65%), followed by renal failure and cardiac failure. The early mortality rate is high (12.6%) in patients with MM. Patients who are male and those with primary plasma cell leukemia, low serum albumin, high-corrected serum calcium, or LDH are at risk of early mortality. Nearly two thirds of the myeloma patients who experienced early mortality in our study (37 of 57, 65%) died of infection. Once a high-risk group is identified, much effort is required to target new approaches for prevention, early detection, and treatment of infections. PMID:26683968

  20. Analysis of Signal Transducer and Activator of Transcription 3 (Stat 3) Pathway in Multiple Myeloma

    PubMed Central

    Quintanilla-Martinez, Leticia; Kremer, Marcus; Specht, Katja; Calzada-Wack, Julia; Nathrath, Michaela; Schaich, Robert; Höfler, Heinz; Fend, Falko

    2003-01-01

    The signal transducer and activator of transcription molecules (Stats) play key roles in cytokine-induced signal transduction. Recently, it was proposed that constitutively activated Stat 3 (Stat 3 phosphorylated) contributes to the pathogenesis of multiple myeloma (MM) by preventing apoptosis and inducing proliferation. The study aim was to investigate Stat 3 activation in a series of multiple myeloma (MM) cases and its effect on downstream targets such as the anti-apoptotic proteins Bcl-xL, Mcl-1, and Bcl-2, and the cell-cycle protein cyclin D1. Forty-eight cases of MM were analyzed. Immunohistochemistry was performed on paraffin sections using antibodies against cyclin D1, Bcl-2, Bcl-xL, Mcl-1, p21, Stat 3, and Stat 3 phosphorylated (P). Their specificity was corroborated by Western blot analysis using eight human MM cell lines as control. The proliferation rate was assessed with the antibody MiB1. In addition, the mRNA levels of cyclin D1 and Stat 3 were determined by quantitative real-time reverse transcriptase-polymerase chain reaction of paraffin-embedded microdissected tissue. Three different groups determined by the expression of Stat 3P and cyclin D1 (protein and mRNA) were identified: group 1, Stat 3-activated (23 cases, 48%). All cases revealed nuclear expression of Stat 3P. No elevation of Stat 3 mRNA was identified in any of the cases. Three cases in this group showed intermediate to low cyclin D1 protein and mRNA expression. Group 2 included 15 (31%) cases with cyclin D1 staining and lack of Stat 3P. All cases showed intermediate to high levels of cyclin D1 mRNA expression. Group 3 included 10 (21%) cases with no expression of either cyclin D1 or Stat 3P. High levels of anti-apoptotic proteins Bcl-xL and Mcl-1 were identified in 89% and 100% of all cases, respectively. In contrast to Bcl-xL and Mcl-1, the expression of Bcl-2 showed an inverse correlation with proliferation rate (P: 0.0003). No significant differences were found between the three

  1. Cyclic oscillation of blood neutrophils in a patient with multiple myeloma

    SciTech Connect

    Chikkappa, G.; Chanana, A.D.; Chandra, P.; Cronkite, E.P.; Thompson, K.H.

    1980-01-01

    A patient with multiple myeloma developed periodic blood neutropenia (periodicity of 15 to 25 days) after 3 yr of intermittent treatment with cytotoxic agents. Peaks of serum colony-stimulating activity (CSA) level coincided with valleys of blood neutrophils. Fraction of marrow neutrophils in the multiplicative pool was high during blood neutrophil valleys and low during neutrophil peaks. In contrast, the maturation storage pool exhibited the reverse pattern. An increased fraction of marrow neutrophilic cells in the multiplicative pool was in active proliferation during a blood neutrophil valley and a decreased fraction during a blood neutrophil peak. These findings suggest that the marrow granulopoiesis was regulated through CSA. The defect causing the periodicity was probably related to the reduced number of neutrophils in the marrow maturation storge pool, which in turn may be related to a reduced and/or defective granulocytic stem cell pool size consiquent to the long-term administration of cytotoxic drugs and/or infiltration of the marrow by myeloma cells.

  2. Oligodendroglioma metastasis to the bone marrow mimicking multiple myeloma: A case report

    PubMed Central

    JIAN, YUAN; GAO, WEN; WU, YIN; LI, YANCHEN; ZHANG, YONG; YANG, GUANGZHONG; CHEN, WENMING

    2016-01-01

    The present study reports a case of a 59-year-old male suffering from oligodendroglioma that metastasized to the bone marrow (BM). The metastasis was detected 5 years after craniotomy was performed for the resection of the primary tumor; however, it manifested as multiple myeloma (MM)-like bone lesions, a small M component and myeloma cell-like morphology in the BM. A brain magnetic resonance imaging scan was performed; evidence from the previously performed oligodendroglioma resection was observed on the scan, but there were no significant findings, which made the diagnosis particularly challenging. The patient exhibited no response to the multiple combination therapies administered targeting MM and oligodendroglioma, and subsequently developed epilepsy and pneumonia, prior to succumbing to multiple organ failure. Among the various tumor types involving the central nervous system, oligodendroglioma is the least likely to metastasize; thus, distant metastases from brain oligodendrogliomas are extremely rare. To the best of our knowledge, this is the first case of metastatic oligodendroglioma presenting with typical MM-like symptoms and without any recurrence in the brain. PMID:27347150

  3. Oculomotor Nerve Palsy as a Rare Presentation and First Sign of Multiple Myeloma.

    PubMed

    Panda, Bijnya Birajita; Parija, Sucheta; Mallick, Jyotiranjan; Pujahari, Susanta

    2016-05-01

    Acquired oculomotor nerve palsy has varied aetiologies like vascular (diabetes, heart disease, atherosclerosis and posterior communicating artery aneurysm), space occupying lesions or tumours, inflammation, infection, trauma, demyelinating disease like Multiple sclerosis, autoimmune disorders such as Myasthenia gravis, postoperatively as a complication of neurosurgery, cavernous sinus thrombosis etc. Cranial Nerve palsies as one of the first symptoms of multiple myeloma have been reported sparsely in literature. We report a case of a 60-year-old woman who developed sudden onset right-sided pupil sparing oculomotor nerve palsy along with a tender swelling at right sternoclavicular joint. Cranial and orbital magnetic resonance imaging and cerebrospinal fluid examination demonstrated no abnormalities. Immunological investigations and histopathological analysis of sternoclavicular joint swelling confirmed the diagnosis of IgG type multiple myeloma. After confirmation of diagnosis we started her with appropriate chemotherapy, after which the palsy resolved within one month. The cause of the palsy was probably due to nerve ischemia due to hyper viscosity of the serum. PMID:27437257

  4. Oculomotor Nerve Palsy as a Rare Presentation and First Sign of Multiple Myeloma

    PubMed Central

    Parija, Sucheta; Mallick, Jyotiranjan; Pujahari, Susanta

    2016-01-01

    Acquired oculomotor nerve palsy has varied aetiologies like vascular (diabetes, heart disease, atherosclerosis and posterior communicating artery aneurysm), space occupying lesions or tumours, inflammation, infection, trauma, demyelinating disease like Multiple sclerosis, autoimmune disorders such as Myasthenia gravis, postoperatively as a complication of neurosurgery, cavernous sinus thrombosis etc. Cranial Nerve palsies as one of the first symptoms of multiple myeloma have been reported sparsely in literature. We report a case of a 60-year-old woman who developed sudden onset right-sided pupil sparing oculomotor nerve palsy along with a tender swelling at right sternoclavicular joint. Cranial and orbital magnetic resonance imaging and cerebrospinal fluid examination demonstrated no abnormalities. Immunological investigations and histopathological analysis of sternoclavicular joint swelling confirmed the diagnosis of IgG type multiple myeloma. After confirmation of diagnosis we started her with appropriate chemotherapy, after which the palsy resolved within one month. The cause of the palsy was probably due to nerve ischemia due to hyper viscosity of the serum. PMID:27437257

  5. Upper Gastrointestinal Bleeding from Gastric Amyloidosis in a Patient with Smoldering Multiple Myeloma

    PubMed Central

    Gjeorgjievski, Mihajlo; Purohit, Treta; Amin, Mitual B.; Kurtin, Paul J.; Cappell, Mitchell S.

    2015-01-01

    Amyloidosis is a common complication of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM). This proteinaceous material can be deposited intercellularly in any organ system, including the gastrointestinal (GI) tract. In the GI tract, amyloidosis affects the duodenum most commonly, followed by the stomach and colorectum. Gastric amyloidosis causes symptoms of nausea, vomiting, early satiety, abdominal pain, and GI bleeding. A case of upper GI bleeding from gastric amyloidosis is presented in a patient with SMM. Esophagogastroduodenoscopy (EGD) revealed a gastric mass. Endoscopic biopsies revealed amyloid deposition in the lamina propria, consistent with gastric amyloidosis. Liquid chromatography tandem mass spectrometry performed on peptides extracted from Congo red-positive microdissected areas of paraffin-embedded stomach specimens revealed a peptide profile consistent with AL- (lambda-) type amyloidosis. Based on this and multiple other case reports, we recommend that patients with GI bleeding and MGUS, SMM, or MM undergo EGD and pathologic examination of endoscopic biopsies of identified lesions using Congo red stains for amyloidosis for early diagnosis and treatment. PMID:26366309

  6. Upper Gastrointestinal Bleeding from Gastric Amyloidosis in a Patient with Smoldering Multiple Myeloma.

    PubMed

    Gjeorgjievski, Mihajlo; Purohit, Treta; Amin, Mitual B; Kurtin, Paul J; Cappell, Mitchell S

    2015-01-01

    Amyloidosis is a common complication of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM). This proteinaceous material can be deposited intercellularly in any organ system, including the gastrointestinal (GI) tract. In the GI tract, amyloidosis affects the duodenum most commonly, followed by the stomach and colorectum. Gastric amyloidosis causes symptoms of nausea, vomiting, early satiety, abdominal pain, and GI bleeding. A case of upper GI bleeding from gastric amyloidosis is presented in a patient with SMM. Esophagogastroduodenoscopy (EGD) revealed a gastric mass. Endoscopic biopsies revealed amyloid deposition in the lamina propria, consistent with gastric amyloidosis. Liquid chromatography tandem mass spectrometry performed on peptides extracted from Congo red-positive microdissected areas of paraffin-embedded stomach specimens revealed a peptide profile consistent with AL- (lambda-) type amyloidosis. Based on this and multiple other case reports, we recommend that patients with GI bleeding and MGUS, SMM, or MM undergo EGD and pathologic examination of endoscopic biopsies of identified lesions using Congo red stains for amyloidosis for early diagnosis and treatment. PMID:26366309

  7. Immunoglobulin heavy/light chain analysis enhances the detection of residual disease and monitoring of multiple myeloma patients

    PubMed Central

    Batinić, Josip; Perić, Zinaida; Šegulja, Dragana; Last, James; Prijić, Sanja; Dubravčić, Klara; Volarić, Lidija; Sertić, Dubravka; Radman, Ivo; Bašić-Kinda, Sandra; Matišić, Danica; Batinić, Drago; Labar, Boris; Nemet, Damir

    2015-01-01

    Aim To evaluate the clinical utility of incorporating a novel heavy/light chain immunoassay (HLC) into the existing methods for the assessment of multiple myeloma (MM) patients. Methods Convenience sera samples from 90 previously treated IgG and IgA MM patients in different disease stages were analyzed. The study was conducted in Clinical Hospital Center Zagreb between 2011 and 2013. The collected sera were analyzed by standard laboratory techniques (serum protein electrophoresis, quantification of total immunoglobulins, serum immunofixation, serum free light chain [FLC] assay) and HLC assay. Results HLC ratios outside the normal range were found in 58 of 90 patients, including 28 out of 61 patients with total immunoglobulin measurements within the normal range and 5 out of 23 patients in complete response. Both elevated HLC isotype level and abnormal HLC ratio correlated with the parameters of tumor burden, including percentage of plasma cells in the bone marrow (P < 0.001 and P = 0.002, respectively) and an abnormal serum FLC ratio (for both P < 0.001). In addition, abnormal HLC isotype level correlated with serum beta-2-microglobulin level (P = 0.038). In terms of prognosis, abnormal HLC isotype level and abnormal HLC ratio were significantly associated with shorter overall survival (P < 0.001 and P = 0.002, respectively). Interestingly, suppression of the uninvolved (polyclonal) isotype pair, but not other non-myeloma immunoglobulin isotypes, was also associated with a shorter overall survival (P = 0.021). In a multivariate analysis, an abnormal HLC ratio and β2-microglobulin level >3.5mg/L were independent risk factors for survival. Conclusion The new HLC assay has greater sensitivity in detecting monoclonal protein, correlates with tumor burden markers, and affects patients' outcome. PMID:26088851

  8. Comparison of 18F-FDG PET/CT and PET/MRI in patients with multiple myeloma

    PubMed Central

    Sachpekidis, Christos; Hillengass, Jens; Goldschmidt, Hartmut; Mosebach, Jennifer; Pan, Leyun; Schlemmer, Heinz-Peter; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

    2015-01-01

    PET/MRI represents a promising hybrid imaging modality with several potential clinical applications. Although PET/MRI seems highly attractive in the diagnostic approach of multiple myeloma (MM), its role has not yet been evaluated. The aims of this prospective study are to evaluate the feasibility of 18F-FDG PET/MRI in detection of MM lesions, and to investigate the reproducibility of bone marrow lesions detection and quantitative data of 18F-FDG uptake between the functional (PET) component of PET/CT and PET/MRI in MM patients. The study includes 30 MM patients. All patients initially underwent 18F-FDG PET/CT (60 min p.i.), followed by PET/MRI (120 min p.i.). PET/CT and PET/MRI data were assessed and compared based on qualitative (lesion detection) and quantitative (SUV) evaluation. The hybrid PET/MRI system provided good image quality in all cases without artefacts. PET/MRI identified 65 of the 69 lesions, which were detectable with PET/CT (94.2%). Quantitative PET evaluations showed the following mean values in MM lesions: SUVaverage=5.5 and SUVmax=7.9 for PET/CT; SUVaverage=3.9 and SUVmax=5.8 for PET/MRI. Both SUVaverage and SUVmax were significantly higher on PET/CT than on PET/MRI. Spearman correlation analysis demonstrated a strong correlation between both lesional SUVaverage (r=0.744) and lesional SUVmax (r=0.855) values derived from PET/CT and PET/MRI. Regarding detection of myeloma skeletal lesions, PET/MRI exhibited equivalent performance to PET/CT. In terms of tracer uptake quantitation, a significant correlation between the two techniques was demonstrated, despite the statistically significant differences in lesional SUVs between PET/CT and PET/MRI. PMID:26550538

  9. Management of Side Effects of Novel Therapies for Multiple Myeloma: Consensus Statements Developed by the International Myeloma Foundation’s Nurse Leadership Board

    PubMed Central

    Bertolotti, Page; Bilotti, Elizabeth; Colson, Kathleen; Curran, Kathleen; Doss, Deborah; Faiman, Beth; Gavino, Maria; Jenkins, Bonnie; Lilleby, Kathy; Love, Ginger; Mangan, Patricia A.; McCullagh, Emily; Miceli, Teresa; Miller, Kena; Rogers, Kathryn; Rome, Sandra; Sandifer, Stacey; Smith, Lisa C.; Tariman, Joseph D.; Westphal, Jeanne

    2014-01-01

    Nurses play an essential role in managing the care of patients with multiple myeloma, who require education and support to receive and adhere to optimal therapy. The International Myeloma Foundation created a Nurse Leadership Board comprised of oncology nurses from leading cancer centers and community practices. An assessment survey identified the need for specific recommendations for managing key side effects of novel antimyeloma agents. Myelosuppression, thromboembolic events, peripheral neuropathy, steroid toxicities, and gastrointestinal side effects were selected for the first consensus statements. The board developed recommendations for healthcare providers in any medical setting, including grading of side-effect toxicity and strategies for managing the side effects in general, with specific recommendations pertaining to the novel agents. PMID:18490252

  10. Kinetics of tumor growth and regression in IgG multiple myeloma

    PubMed Central

    Sullivan, Peter W.; Salmon, Sydney E.

    1972-01-01

    Studies of immunoglobulin synthesis, total body tumor cell number, and tumor kinetics were carried out in a series of patients with IgG multiple myeloma. The changes in tumor size associated with tumor growth or with regression were underestimated when the concentration of serum M-component was used as the sole index of tumor mass. Calculation of the total body M-component synthetic rate (corrected for concentration-dependent changes in IgG metabolism) and tumor cell number gave a more accurate and predictable estimate of changes in tumor size. Tumor growth and drug-induced tumor regression were found to follow Gompertzian kinetics, with progressive retardation of the rate of change of tumor size in both of these circumstances. This retardation effect, describable with a constant α, may be caused by a shift in the proportion of tumor cells in the proliferative cycle. Drug sensitivity of the tumor could be described quantitatively with a calculation of BO, the tumor's initial sensitivity to a given drug regimen. Of particular clinical significance, the magnitude of a given patient's tumor regression could be predicted from the ratio of BO to α. Mathematical proof was obtained that the retardation constant determined during tumor regression also applied to the earlier period of tumor growth, and this constant was used to reconstruct the preclinical history of disease. In the average patient, fewer than 5 yr elapse from the initial tumor cell doubling to its clinical presentation with from 1011 to more than 1012 myeloma cells in the body. The reduction in total body tumor mass in most patients responding to therapy ranges from less than one to almost two orders of magnitude. Application of predictive kinetic analysis to the design of sequential drug regimens may lead to further improvement in the treatment of multiple myeloma and other tumors with similar growth characteristics. PMID:5040867

  11. Interleukin-6-related genotypes, body mass index, and risk of multiple myeloma and plasmacytoma.

    PubMed

    Cozen, Wendy; Gebregziabher, Mulugeta; Conti, David V; Van Den Berg, David J; Coetzee, Gerhard A; Wang, Sophia S; Rothman, Nathaniel; Bernstein, Leslie; Hartge, Patricia; Morhbacher, Ann; Coetzee, Simon G; Salam, Muhammad T; Wang, Wei; Zadnick, John; Ingles, Sue A

    2006-11-01

    Interleukin-6 (IL-6) promotes normal plasma cell development and proliferation of myeloma cells in culture. We evaluated IL-6 genotypes and body mass index (BMI) in a case-control study of multiple myeloma and plasmacytoma. DNA samples and questionnaires were obtained from incident cases of multiple myeloma (n = 134) and plasmacytoma (n = 16; plasma cell neoplasms) ascertained from the Los Angeles County population-based cancer registry and from siblings or cousins of cases (family controls, n = 112) and population controls (n = 126). Genotypes evaluated included IL-6 promoter gene single nucleotide polymorphisms (SNP) at positions -174, -572, and -597; one variable number of tandem repeats (-373 A(n)T(n)); and one SNP in the IL-6 receptor (IL-6ralpha) gene at position -358. The variant allele of the IL-6 promoter SNP -572 was associated with a roughly 2-fold increased risk of plasma cell neoplasms when cases were compared with family [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 0.7-4.7] or population controls (OR, 2.4; 95% CI, 1.2-4.7). The -373 9A/9A genotype was associated with a decreased risk compared with the most common genotype (OR for cases versus family controls, 0.4; 95% CI, 0.1-1.7; OR for cases versus population controls, 0.3; 95% CI, 0.1-0.9). No other SNPs were associated with risk. Obesity (BMI >or= 30 kg/m(2)) increased risk nonsignificantly by 40% and 80% when cases were compared with family controls or population controls, respectively, relative to persons with a BMI of <25 kg/m(2). These results suggest that IL-6 promoter genotypes may be associated with increased risk of plasma cell neoplasms.

  12. Decreased Ferroportin Promotes Myeloma Cell Growth and Osteoclast Differentiation

    PubMed Central

    Gu, Zhimin; Wang, He; Xia, Jiliang; Yang, Ye; Jin, Zhendong; Xu, Hongwei; Shi, Jumei; De Domenico, Ivana; Tricot, Guido; Zhan, Fenghuang

    2016-01-01

    Iron homeostasis is disrupted in multiple myeloma, a difficult-to-cure plasma cell malignancy with lytic bone lesions. Here, we systematically analyzed iron gene expression signature and demonstrated that mRNA expression of iron exporter ferroportin (FPN1) is significantly downregulated in myeloma cells and correlates negatively with clinic outcome. Restoring expression of FPN1 reduces intracellular liable iron pool, inhibits STAT3-MCL-1 signaling, and suppresses myeloma cells growth. Furthermore, we demonstrated that mRNA of FPN1 is also downregulated at the initial stages of osteoclast differentiation and suppresses myeloma cell–induced osteoclast differentiation through regulating iron regulator TFRC, NF-κB, and JNK pathways. Altogether, we demonstrated that downregulation of FPN1 plays critical roles in promoting myeloma cell growth and bone resorption in multiple myeloma. PMID:25855377

  13. Bone marrow megakaryocytes, soluble P-selectin and thrombopoietic cytokines in multiple myeloma patients.

    PubMed

    Lemancewicz, Dorota; Bolkun, Lukasz; Mantur, Maria; Semeniuk, Janusz; Kloczko, Janusz; Dzieciol, Janusz

    2014-01-01

    The expression of adhesion molecules and other cell-surface molecules is substantial in the communication between plasma cells and bone marrow microenvironment, and may lead to increased proliferation of myeloma cells. Many of the cytokines involved in multiple myeloma (MM) pathogenesis, e.g. thrombopoietin (TPO) and interleukin-6 (IL-6), play a pivotal role in different developmental stages of megakaryocytopoiesis and thrombopoiesis. The principal aim of our study was to explore the relationship between thrombopoietic cytokines, megakaryocytes (MKs) and soluble P-selectin (sP-selectin) levels in MM patients before and after anti-angiogenic treatment. Forty-four patients (20 female and 24 male) with a newly diagnosed MM were examined in three groups, following a division based on the International Staging System, ISS. Plasma levels of TPO, IL-6 and soluble P-selectin (human sP-selectin) were measured by means of ELISA. Bone marrow specimens were studied to determine the number of MKs and the so-called "naked nuclei" (NN), as well as the expression of platelet-derived growth factor (PDGF). The comparison revealed a significantly higher concentration of cytokines and sP-selectin in newly diagnosed MM patients compared to healthy volunteers: for TPO, p=0.01, IL-6, p=0.0005 and sP-selectin, p=0.00008, respectively. Marked differences were observed in the concentration of sP-selectin, expression of PDGF and MKs counts between patients with MM stage I and MM stage III. Statistically meaningful correspondences were also found between MKs versus TPO, NN versus TPO, as well as MKs versus MPV, p=0.009, p=0.004 and p=0.0005, respectively. Furthermore, the analysis exhibited some statistically meaningful divergences between initial concentrations of sP-selectin in subgroups with different response after chemotherapy. The initial concentration of sP-selectin in the group of MM patients with complete or partial remission stood at 31.86 ± 6.13 ng/ml. In the remaining patients

  14. Hemibody irradiation. An effective second-line therapy in drug-resistance multiple myeloma

    SciTech Connect

    Singer, C.R.; Tobias, J.S.; Giles, F.; Rudd, G.N.; Blackman, G.M.; Richards, J.D.

    1989-06-15

    The authors report the results of treatment of 41 patients with melphalan-resistant multiple myeloma using single half-body irradiation (HBI) or double half-body irradiation (DHBI). Patients were grouped using prognostic classification reported by the Medical Research Council. Patients in group I and II showed the best response to therapy with reduction in serum of urinary paraprotein and improvement in symptoms, most notably a marked reduction in bone pain. In these groups five patients have survived over 2 years after therapy. The therapeutic response appeared better in those patients who received DHBI as opposed to those whom treated with single HBI. Patients in group III did not achieve prolonged survival but effective relief of bone pain was a consistent finding in these patients also. Thus HBI represents an alternative to combination chemotherapy as second-line treatment of patients with melphalan-resistant multiple myeloma. A comparative study of HBI versus combination chemotherapy is now indicated to establish which therapeutic approach is most effective.

  15. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma

    PubMed Central

    Spencer, Andrew; Yoon, Sung-Soo; Harrison, Simon J.; Morris, Shannon R.; Smith, Deborah A.; Brigandi, Richard A.; Gauvin, Jennifer; Kumar, Rakesh; Opalinska, Joanna B.

    2014-01-01

    The PI3K/AKT pathway is constitutively active in hematologic malignancies, providing proliferative and antiapoptotic signals and possibly contributing to drug resistance. We conducted an open-label phase 1 study to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of afuresertib—an oral AKT inhibitor—in patients with advanced hematologic malignancies. Seventy-three patients were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day because of 2 dose-limiting toxicities in the 150-mg cohort (liver function test abnormalities). The most frequent adverse events were nausea (35.6%), diarrhea (32.9%), and dyspepsia (24.7%). Maximum plasma concentrations and area under the plasma concentration-time curves from time 0 to 24 hours were generally dose proportional at >75-mg doses; the median time to peak plasma concentrations was 1.5 to 2.5 hours post dose, with a half-life of approximately 1.7 days. Three multiple myeloma patients attained partial responses; an additional 3 attained minimal responses. Clinical activity was also observed in non-Hodgkin lymphoma, Langerhan's cell histiocytosis, and Hodgkin disease. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against hematologic malignancies, including multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00881946. PMID:25075128

  16. Recurrent hypoglycaemia in multiple myeloma: a case of Munchausen syndrome by proxy in an elderly patient.

    PubMed

    Ben-Chetrit, E; Melmed, R N

    1998-08-01

    A 73-year-old woman with multiple myeloma experienced four episodes of loss of consciousness, convulsions and profuse sweating whilst she was in the hospital. A thorough investigation in the department of medicine disclosed that with each attack, she had a serum glucose < 1.6 mM L-1, insulin level > 1400 pMol L-1 (N- < 150) and a normal level of serum C-peptide. Since she had no anti-insulin antibodies (which may rarely exist in multiple myeloma), a diagnosis of exogenous injection of insulin was made. A search for a possible perpetrator discovered that the patient had a daughter who was a surgical nurse and who was genuinely concerned whenever she was told that her mother was about to be discharged from the hospital. If she was the perpetrator in the present case, then it is possible that the motive for such an action was to postpone the mother's discharge from hospital. This case is an example of a 'factitious disease by proxy' in an elderly patient. The aim of the present report is to alert the medical personnel to the possibility that Munchausen's syndrome by proxy may also occur in the elderly.

  17. Multiple myeloma, leukemia, and breast cancer among the US radium dial workers

    SciTech Connect

    Stebbings, J.H.; Lucas, H.F.; Stehney, A.F.

    1983-01-01

    The relationships of radium exposure to mortality from multiple myeloma, leukemia, and breast cancer were studied in three cohorts of female dial workers defined by year of first employment. Mortality was compared with that expected from US white female rates, with and without adjustment for local mortality rates. Dose-response relationships of these cancers to systemic intake of radium were determined in workers whose body burdens had been measured in vivo since 1955. Incident cases of multiple myeloma occurred in the pre-1930 cohort; however, analyses of body burdens and durations of employment suggest that external radiation was more likely to have been responsible than was internal radium. Leukemia incidence and mortality have not been elevated overall among the female dial workers, either in the pre-1930 or the post-1930 cohorts, but cases have tended to occur early and in subjects with higher body burdens. Extensive analyses of breast cancer data have uncovered several observations weighing against a causal interpretation of the association between radium and breast cancer.

  18. Is this the time to introduce minimal residual disease in multiple myeloma clinical practice?

    PubMed

    Paiva, Bruno; Puig, Noemi; García-Sanz, Ramón; San Miguel, Jesús F

    2015-05-01

    Increasing therapeutic options and prolonged survival in multiple myeloma have raised interest in the concept of depth of response and its importance to predict patients' outcomes. Although the efficacy of current treatment approaches has greatly improved in the past decade, the definition of complete response (CR) remains unaltered and continues to use conventional serological and morphologic techniques. That notwithstanding, there is growing interest in minimal residual disease (MRD) monitoring, which has emerged in recent years as one of the most relevant prognostic factors in multiple myeloma. MRD can be assessed both inside (e.g., immunophenotypic and molecular techniques) and outside the bone marrow (e.g., PET/CT). Here, we focus on flow- and molecular-based assays by which different cooperative groups have demonstrated the efficacy of MRD assessment to predict outcomes even among patients in CR, and irrespectively of disease risk. Although further standardization is still required, the time has come to implement MRD monitoring in prospective clinical trials as a sensitive tool to evaluate treatment efficacy and for risk-adapted treatment, particularly in the consolidation and maintenance settings. Here, we present a comprehensive and critical review on the methodologic aspects, specific characteristics, and clinical significance of MRD monitoring by flow cytometry, PCR, and next-generation sequencing. PMID:25754350

  19. Front line treatment of elderly multiple myeloma in the era of novel agents

    PubMed Central

    Venon, Marie-Dominique; Roccaro, Aldo M; Gay, Julie; Moreau, Anne-Sophie; Dulery, Remy; Facon, Thierry; Ghobrial, Irene M; Leleu, Xavier

    2009-01-01

    Melphalan combined with prednisone (MP) has long been the historical treatment of reference for a large proportion of elderly myeloma (MM) patients ineligible for autologous stem cell transplantation, and is still the backbone of new regimens that include the new era of novel agents. Melphalan–prednisone–thalidomide (MPT) and melphalan–prednisone–bortezomib (Velcade®, MPV), proved superior to MP, currently appear to be the treatments of choice for this population. In the near future melphalan–prednisone–lenalidomide (Revlimid®, MPR) will also provide a third therapeutic option (MPT, MPV, and MPR), in elderly multiple myeloma, eventually. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel agents have somewhat different toxicity profiles. Dexamethasone-based regimen is another option and questions regarding the relative efficacy of melphalan-based versus low-dose dexamethasone-based regimens will require randomized phase III trials. More intensive approaches with new drug combinations or with the incorporation of polyethylene glycolated (PEGylated) liposomal doxorubicin will also require additional studies. Additionally, the important issue of maintenance treatment needs to be further investigated. These new and emerging therapies offer multiple effective treatment options for MM patients and greatly enhanced treatment strategies for clinicians. PMID:19707399

  20. Dexamethasone, all trans retinoic acid and interferon alpha 2a in patients with refractory multiple myeloma.

    PubMed

    Avilés, A; Rosas, A; Huerta-Guzmán, J; Talavera, A; Cleto, S

    1999-02-01

    Few effective regimen are available for patients with refractory multiple myeloma (RMM). Generally, responses are scarce and disease free survival is very short. We developed a new therapeutic option in these patients using dexamethasone (40 mg/m2, i.v., daily, days 1 to 4), all-trans retinoic acid (45 mg/m2, po, daily, days 5 to 14) and interferon alpha 2a (9.0 MU, daily, subcutaneously, days 5 to 14). The treatment was administered every 21 days for 6 cycles. In a pilot study, 12 patients, heavily treated with chemotherapy and radiotherapy and in some cases with interferon, were allocated to receive the afore mentioned treatment. Response was observed in 10 patients (83%). With a median follow-up of 36.1 months (range 27 to 41), seven patients remain alive and disease-free without any treatment. Two patients were failures and have died due to tumor progression. Toxicity was mild and all patients received treatment according to the planned doses of drugs. The use of biological modifiers in combination with dexamethasone offer a safe and effective therapeutic option in patients with refractory multiple myeloma. More studies are warranted to define the role of this type of treatment.

  1. Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series.

    PubMed

    Wolf, Jeffrey; Richardson, Paul G; Schuster, Michael; LeBlanc, Annette; Walters, Ian B; Battleman, David S

    2008-10-01

    Bortezomib therapy has become an important part of the standard of care for patients with relapsed multiple myeloma, and preliminary clinical evidence suggests that bortezomib retreatment in patients previously treated with the drug may prolong disease control. This retrospective study was designed to clarify the utility of bortezomib as a repeat therapy. We reviewed records from 3 major cancer centers that had participated in the phase II (SUMMIT or CREST) or phase III (APEX) registration studies to identify patients who were subsequently retreated off protocol with bortezomib-based therapy. We found 22 patients who received bortezomib retreatment following a 60 or more day gap between bortezomib treatments. Twelve patients had intervening therapy between initial bortezomib treatment and bortezomib retreatment. During retreatment, 14 of 22 patients received bortezomib in combination with another antineoplastic agent. The overall response rate for bortezomib retreatment was 50% (9% complete responses). The median length of retreatment was 5.1 months in responding patients and 2.4 months in nonresponding patients. Therapy was terminated due to unmanageable toxicity in 2 patients during retreatment, compared with 6 patients during initial treatment. During retreatment, no patients required dose reduction due to peripheral neuropathy, compared to 4 patients during their initial treatment. Thus, bortezomib retreatment appears to be safe and effective. Favorable observed response rates with bortezomib retreatment suggest that it may be a viable option for relapsed or refractory multiple myeloma, even in patients previously exposed to bortezomib.

  2. Occurrence and prognostic significance of cytogenetic evolution in patients with multiple myeloma

    PubMed Central

    Binder, M; Rajkumar, S V; Ketterling, R P; Dispenzieri, A; Lacy, M Q; Gertz, M A; Buadi, F K; Hayman, S R; Hwa, Y L; Zeldenrust, S R; Lust, J A; Russell, S J; Leung, N; Kapoor, P; Go, R S; Gonsalves, W I; Kyle, R A; Kumar, S K

    2016-01-01

    Cytogenetic evaluation at the time of diagnosis is essential for risk stratification in multiple myeloma, however little is known about the occurrence and prognostic significance of cytogenetic evolution during follow-up. We studied 989 patients with multiple myeloma, including 304 patients with at least two cytogenetic evaluations. Multivariable-adjusted regression models were used to assess the associations between the parameters of interest and cytogenetic evolution as well as overall survival. The prognostic significance of baseline cytogenetic abnormalities was most pronounced at the time of diagnosis and attenuated over time. In the patients with serial cytogenetic evaluations, the presence of t(11;14) at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow-up (odds ratio (OR)=0.22, 95% confidence interval (CI)=0.09–0.56, P=0.001), while the presence of at least one trisomy or tetrasomy was associated with increased odds (OR=2.96, 95% CI=1.37–6.42, P=0.006). The development of additional abnormalities during the 3 years following diagnosis was associated with increased subsequent mortality (hazard ratio=3.31, 95% CI=1.73–6.30, P<0.001). These findings emphasize the importance of the underlying clonal disease process for risk assessment and suggest that selected patients may benefit from repeated risk stratification. PMID:26967818

  3. Smoldering multiple myeloma: natural history and recognition of an evolving type.

    PubMed

    Rosiñol, L; Bladé, J; Esteve, J; Aymerich, M; Rozman, M; Montoto, S; Giné, E; Nadal, E; Filella, X; Queralt, R; Carrió, A; Montserrat, E

    2003-11-01

    Patients with smoldering multiple myeloma (SMM) meet the diagnostic criteria of multiple myeloma (MM) but are asymptomatic. Between January 1978 and July 2001, 53 patients (median age 63 years) were diagnosed with SMM. The median serum M-protein and proportion of bone marrow plasma cells were 36 g/l and 27% respectively. Two subsets of SMM were identified: (i) evolving SMM (n = 22), characterized by a progressive increase in serum M-protein, a previously recognized monoclonal gammopathy of undetermined significance (MGUS) and a significant higher proportion of IgA type and (ii) non-evolving SMM (n = 26) with stable M-protein that abruptly increases when symptomatic MM develops. Thirty-four patients developed symptomatic MM. The median time to progression in the overall series was 3.2 years and the only feature associated with a shorter time to progression was the evolving versus non-evolving type (1.3 vs. 3.9 years respectively, P = 0.007). The pattern of progression consisted of anaemia, lytic bone lesions or both, without renal failure, hypercalcaemia or extramedullary plasmacytomas. Fifty-seven per cent of patients that required chemotherapy showed no or minimal response. The median survival from diagnosis and from progression was 8.2 and 3.5 years respectively. PMID:14616966

  4. Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications.

    PubMed

    Gonzalez-Paz, Natalia; Chng, Wee J; McClure, Rebecca F; Blood, Emily; Oken, Martin M; Van Ness, Brian; James, C David; Kurtin, Paul J; Henderson, Kimberly; Ahmann, Gregory J; Gertz, Morie; Lacy, Martha; Dispenzieri, Angela; Greipp, Philip R; Fonseca, Rafael

    2007-02-01

    The biological and clinical implications of p16 gene methylation in multiple myeloma (MM) are still unclear despite previous studies. In this comprehensive study, using methylation-specific PCR (MS-PCR), we show that p16 methylation is relatively common and occurs in monoclonal gammopathy of undetermined significance (MGUS; n=17), smoldering multiple myeloma (SMM; n=40), and MM (n=522) at a prevalence of 24%, 28%, and 34%, respectively. However, p16 methylation does not appear to affect gene expression level. In a large cohort of patients with long-term follow-up information (n=439), there was no difference in overall survival between patients with or without p16 methylation. We also found no association between p16 methylation and the main cytogenetic categories, although it was more common among patients with 17p13.1 deletions (p53 locus), a genetic progression event in MM. In addition, p16 methylation has no apparent effect on the cycle because there was also no difference in the plasma cell labeling index (a direct measurement of proliferation) between patients with and without p16 methylation. Our results question a major role for p16 methylation in the oncogenesis of the PC neoplasm, and we now believe p16 methylation may be a marker for overall epigenetic changes associated with disease progression, with no obvious direct biological or clinical consequences. PMID:16840723

  5. Management of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM).

    PubMed

    Kyle, Robert A; Buadi, Francis; Rajkumar, S Vincent

    2011-06-01

    Monoclonal gammopathy of undetermined significance (MGUS) is defined as a serum M protein level of less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of end-organ damage. The prevalence of MGUS is 3.2% in the white population but is approximately twice that high in the black population. MGUS may progress to multiple myeloma, AL amyloidosis, Waldenström macroglobulinemia, or lymphoma. The risk of progression is approximately 1% per year, but the risk continues even after more than 25 years of observation. Risk factors for progression include the size of the serum M protein, the type of serum M protein, the number of plasma cells in the bone marrow, and the serum free light chain ratio. Smoldering (asymptomatic) multiple myeloma (SMM) is characterized by the presence of an M protein level of 3 g/dL or higher and/or 10% or more monoclonal plasma cells in the bone marrow but no evidence of end-organ damage. The overall risk of progression to a malignant condition is 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% to 2% per year for the following 10 years. Patients with both MGUS and SMM must be followed up for their lifetime. PMID:21888255

  6. Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma.

    PubMed

    Ma, Cynthia X; Lacy, Martha Q; Rompala, John F; Dispenzieri, Angela; Rajkumar, S Vincent; Greipp, Philip R; Fonseca, Rafael; Kyle, Robert A; Gertz, Morie A

    2004-07-01

    Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. We retrospectively reviewed 32 patients diagnosed with adult-acquired FS between April 1968 and June 2002 at Mayo Clinic (Rochester, MN). At diagnosis, most patients had monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), with a median creatinine level of 176.8 microM (2.0 mg/dL; range, 79.56-327.08 microM [0.9-3.7 mg/dL]) and evidence of osteomalacia. During the average 65 months (range, 2-238 months) of follow-up, 5 patients developed end-stage renal disease (ESRD) and only 1 of 14 patients with MGUS transformed to multiple myeloma (MM). Also, 14 deaths occurred, with only 1 from ESRD but 4 from alkylator-related leukemia or myelodysplastic syndrome. Chemotherapy offered little benefit on renal functions of MGUS or SMM patients. In conclusion, FS associated with monoclonal gammopathy does not appear to confer an additional risk of subsequent evolution to MM. ESRD occurs late in the disease process. PMID:15010372

  7. Case Report on Renal Failure Reversal in Lambda Chain Multiple Myeloma with Bortezomib and Dexamethasone

    PubMed Central

    Patibandla, Bhanu K.; Alwassia, Ahmad A.; Bartley, Anthony; Sandhu, Gurprataap S.; Rooney, James; Black, Robert M.

    2014-01-01

    Renal failure (RF) reversal in multiple myeloma (MM) is associated with an improved prognosis. Light chain myeloma, serum creatinine (SCr) > 4 mg/dL, extensive proteinuria, early infections, and certain renal biopsy findings are associated with lower rates of RF reversal. Our patient is a 67-year-old female with multiple poor prognostic factors for RF reversal who demonstrated a rapid renal response with bortezomib and dexamethasone (BD) regimen. She presented initially with altered mental status. On exam, she appeared lethargic and dehydrated and had generalized tenderness. She had been taking ibuprofen as needed for pain for a few weeks. Labs showed a white cell count—18,900/μL with no bandemia, hemoglobin 10.8 gm/dL, potassium—6.7 mEq/L, bicarbonate—15 mEq/L, blood urea nitrogen—62 mg/dL, SCr—5.6 mg/dL (baseline: 1.10), and corrected calcium—11.8 mg/dL. A rapid flu test was positive. Imaging studies were unremarkable. Her EKG showed sinus tachycardia and her urinalysis was unremarkable. The unexplained RF in an elderly individual in conjunction with hypercalcemia and anemia prompted a MM work-up; eventually, lambda variant MM was diagnosed. An immediate (4 days) renal response defined as 50% reduction in SCr was noticed after initiation of the BD regimen. PMID:25045553

  8. Nordihydroguaiaretic Acid Inhibits an Activated FGFR3 Mutant, and Blocks Downstream Signaling in Multiple Myeloma Cells

    PubMed Central

    Meyer, April N.; McAndrew, Christopher W.; Donoghue, Daniel J.

    2008-01-01

    Activating mutations within Fibroblast Growth Factor Receptor 3 (FGFR3), a receptor tyrosine kinase, are responsible for human skeletal dysplasias including achondroplasia and the neonatal lethal syndromes, Thanatophoric Dysplasia (TD) type I and II. Several of these same FGFR3 mutations have also been identified somatically in human cancers, including multiple myeloma, bladder carcinoma and cervical cancer. Based on reports that strongly activated mutants of FGFR3 such as the TDII (K650E) mutant signal preferentially from within the secretory pathway, the inhibitory properties of nordihydroguaiaretic acid (NDGA), which blocks protein transport through the Golgi, were investigated. NDGA was able to inhibit FGFR3 autophosphorylation both in vitro and in vivo. In addition, signaling molecules downstream of FGFR3 activation such as STAT1, STAT3 and MAPK were inhibited by NDGA treatment. Using HEK293 cells expressing activated FGFR3-TDII, together with several multiple myeloma cell lines expressing activated forms of FGFR3, NDGA generally resulted in a decrease in MAPK activation by 1 hour, and resulted in increased apoptosis over 24 hours. The effects of NDGA on activated FGFR3 derivatives targeted either to the plasma membrane or the cytoplasm were also examined. These results suggest that inhibitory small molecules such as NDGA that target a specific subcellular compartment may be beneficial in the inhibition of activated receptors such as FGFR3 that signal from the same compartment. PMID:18794123

  9. Neutralising antibodies in patients with multiple myeloma receiving maintenance therapy with interferon alpha 2b.

    PubMed Central

    Bell, J. B.; Barfoot, R.; Iveson, T.; Powles, R. L.; Millar, B. C.

    1994-01-01

    In a study of 29 patients who were receiving or had received interferon alpha 2b (IFN-alpha 2b) as maintenance therapy for multiple myeloma, antibodies were detected in 58% (17/29) of patients measured by a solid-phase enzyme-linked immunosorbent assay (ELISA). Only 7/17 patients who were positive for antibody in the ELISA had neutralising antibody to IFN-alpha 2b, measured by virus growth inhibition. These patients comprised six who were receiving IFN-alpha 2b at the time of assessment and one who had finished treatment. Among patients who were receiving the cytokine, four had progressive disease, one was in complete remission and one in partial remission. Neutralising activity was also detected to natural human leucocyte IFN-alpha in the same patients. Two patients who were positive for neutralising antibody remain in remission and are continuing to receive IFN-alpha 2b. These two patients have since lost their neutralising titre. No neutralising antibody to IFN-alpha 2b or natural human leucocyte IFN-alpha was detected in serum from six normal donors. The data suggest that neutralising antibody formation in patients with multiple myeloma is not responsible for relapse in patients receiving IFN-alpha 2b. The transient nature of neutralising antibody production in patients who remain in remission suggests that this response to IFN-alpha 2b is not associated with memory B cells. PMID:7917911

  10. Simultaneous occurrence of Hodgkin's lymphoma and multiple myeloma: A case report and review of the literature

    PubMed Central

    HUANG, CHEN; ZHAO, GUIMIN; WANG, LIANJING; ZHANG, HUICHAO; WU, XIAOLIN; ZHANG, MINGZENG; MA, RUIJUAN; WANG, LING; LIU, YUEPING; LIU, LIHONG

    2016-01-01

    Hodgkin's lymphoma (HL) is a type of hematological neoplasm that generally appears alone, with a low incidence. The majority of cases histopathologically present as B-cell lymphoma. Multiple myeloma (MM) is defined as the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin (Ig). The coexistence of HL and MM is rare, however, the present study reports such a case. On May 31, 2012, a 45-year-old man was diagnosed with HL, stage III, 31 months ago. At the same time, computed tomography and magnetic resonance imaging showed osteolytic lesions, a significant increase in IgA λ chains, and multiple myeloma cells on bone marrow aspiration. Following 8 cycles of chemotherapy, the patient received maintenance treatment with thalidomide and dexamethasone. During 2 years of follow-up, the patient has maintained a complete response for HL and a stable disease state for MM. The coexistence of HL and MM is rare. Further study of such cases may explain the associations between these two tumors and aid the production of effective treatment options. PMID:27313755

  11. Dexamethasone, all trans retinoic acid and interferon alpha 2a in patients with refractory multiple myeloma.

    PubMed

    Avilés, A; Rosas, A; Huerta-Guzmán, J; Talavera, A; Cleto, S

    1999-02-01

    Few effective regimen are available for patients with refractory multiple myeloma (RMM). Generally, responses are scarce and disease free survival is very short. We developed a new therapeutic option in these patients using dexamethasone (40 mg/m2, i.v., daily, days 1 to 4), all-trans retinoic acid (45 mg/m2, po, daily, days 5 to 14) and interferon alpha 2a (9.0 MU, daily, subcutaneously, days 5 to 14). The treatment was administered every 21 days for 6 cycles. In a pilot study, 12 patients, heavily treated with chemotherapy and radiotherapy and in some cases with interferon, were allocated to receive the afore mentioned treatment. Response was observed in 10 patients (83%). With a median follow-up of 36.1 months (range 27 to 41), seven patients remain alive and disease-free without any treatment. Two patients were failures and have died due to tumor progression. Toxicity was mild and all patients received treatment according to the planned doses of drugs. The use of biological modifiers in combination with dexamethasone offer a safe and effective therapeutic option in patients with refractory multiple myeloma. More studies are warranted to define the role of this type of treatment. PMID:10850283

  12. Combination therapy with thalidomide, incadronate, and dexamethasone for relapsed or refractory multiple myeloma.

    PubMed

    Ochiai, Naoya; Yamada, Noriko; Uchida, Ryo; Fuchida, Shin-ichi; Okano, Akira; Hatsuse, Mayumi; Okamoto, Masashi; Ashihara, Eishi; Shimazaki, Chihiro

    2005-10-01

    The feasibility and efficacy of a combination of thalidomide, incadronate, and dexamethasone (TID) were studied in 12 patients with relapsed or refractory multiple myeloma. The protocol, consisting of 300 mg/day of thalidomide administered orally, intravenous incadronate (10 mg/day) administered weekly, and 12 mg/day dexamethasone for 4 days, was repeated every 3 weeks. Evaluations of efficacy and toxicity were carried out every 3 weeks and were continued for 3 cycles. Three patients were excluded during the study because of apnea, severe somnolence, and pancytopenia. Of 9 evaluated patients, the partial responses achieved in 3 patients and the minor responses achieved in 4 patients corresponded to a response rate of 78% according to the criteria of the European Group for Blood and Marrow Transplantation. In addition, painful osteolytic symptoms improved rapidly after 1 cycle of TID therapy in the 10 patients evaluated. These data suggest that TID is a feasible and promising therapeutic approach for refractory and relapsed multiple myeloma.

  13. Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting

    PubMed Central

    Rotta, Marcello; Storer, Barry E.; Sahebi, Firoozeh; Shizuru, Judith A.; Bruno, Benedetto; Lange, Thoralf; Agura, Edward D.; McSweeney, Peter A.; Pulsipher, Michael A.; Hari, Parameswaran; Maziarz, Richard T.; Chauncey, Thomas R.; Appelbaum, Frederick R.; Sorror, Mohamed L.; Bensinger, William; Sandmaier, Brenda M.; Storb, Rainer F.

    2009-01-01

    Autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT (auto/alloHCT) provides cytoreduction and graft-versus-myeloma effects. We report on long-term outcomes of 102 patients with multiple myeloma who received auto/alloHCT with a median follow-up of 6.3 years. Treatment consisted of high-dose melphalan and autograft followed by 2-Gy total body irradiation, with or without fludarabine, and alloHCT from human leukocyte antigen-identical siblings. Postgrafting immunosuppressive agent was cyclosporine or tacrolimus and mycophenolate mofetil. Forty-two percent of patients developed grade 2 to 4 acute graft-versus-host disease (GVHD) and 74% extensive chronic GVHD. Five-year nonrelapse mortality after allografting was 18%, 95% related to GVHD or infections. Among 95 patients with detectable disease, 59 achieved complete remissions. Median time to progression was 5 years. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 3 years. Five-year OS and PFS were 64% and 36%, respectively. Seventy-three patients receiving autoHCT within 10 months from treatment initiation had 5-year OS of 69% and PFS of 37%. In multivariate analysis, β-2-microglobulin of more than 3.5 μg/mL at diagnosis and auto/alloHCT more than 10 months after treatment initiation correlated with shorter OS (P = .03 and P = .02) and PFS (P = .04 and P = .03), whereas Karnofsky scores less than 90% at allotransplantation correlated with shorter PFS only (P = .005). Long-term disease control and GVHD remain key issues. PMID:19015394

  14. International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease

    PubMed Central

    Terpos, Evangelos; Morgan, Gareth; Dimopoulos, Meletios A.; Drake, Matthew T.; Lentzsch, Suzanne; Raje, Noopur; Sezer, Orhan; García-Sanz, Ramón; Shimizu, Kazuyuki; Turesson, Ingemar; Reiman, Tony; Jurczyszyn, Artur; Merlini, Giampaolo; Spencer, Andrew; Leleu, Xavier; Cavo, Michele; Munshi, Nikhil; Rajkumar, S. Vincent; Durie, Brian G.M.; Roodman, G. David

    2013-01-01

    Purpose The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) –related bone disease. Methodology An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. Recommendations Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability. PMID:23690408

  15. Outcome of patients with multiple myeloma and renal failure on novel regimens.

    PubMed

    Soleymanian, Tayebeh; Soleimani, Adel; Musavi, Asadollah; Mojtahedi, Kourosh; Hamid, Gholamreza

    2016-03-01

    Renal involvement occurs in 20-40% of newly diagnosed multiple myeloma (MM) patients, and diagnosis of myeloma is frequently made after investigation for unexplained renal disease. This is a retrospective study between 2006 and 2013 in which 57 consecutive patients seen at the Nephrology Unit with diagnosis of MM were enrolled. MM was diagnosed for the first time because of renal dysfunction and/or proteinuria in these patients. The mean age of the patients (65% male) was 58.3 ± 12.7 years. The median baseline serum creatinine was 3.5 mg/dL (1.4-14.5). Anemia (hemoglobin <12 g/dL) was noted in 88% and hypercalcemia (calcium >10.5 mg/dL) in 35% of patients. Early hemodialysis was started in 28 patients (49%). Thalidomide plus dexamethasone (16% on bortezomib) were the main therapeutic regimens. Three patients (5%) underwent autologous stem cell transplantation. Twenty-six patients (45.6%) died during a median follow-up of 25 months (1-90). The mean age of patients who died was significantly higher than the age in patients who were alive (62.2 ± 12.7 vs. 55.2 ± 11.9 years, respectively; P = 0.037). Early hemodialysis had no significant effect on mortality rate. The one-, three and five year patient survival was 71%, 54%, and 41%, respectively. The median overall survival of patients was 50 months. Prolonged patient survival can be expected in myeloma patients with renal failure or on dialysis by applying novel therapeutic agents. PMID:26997388

  16. Is retention of zoledronic acid onto bone different in multiple myeloma and breast cancer patients with bone metastasis?

    PubMed

    Søe, Kent; Plesner, Torben; Jakobsen, Erik H; Hansen, Charlotte T; Jørgensen, Henrik B; Delaissé, Jean-Marie

    2013-08-01

    Zoledronic acid (Zol) is used to treat bone disease in both multiple myeloma (MM) and breast cancer patients with bone metastasis (BC). However, bones of MM and BC patients show a difference in retention of the bisphosphonate used for bone scintigraphy. Therefore, we hypothesized that disease-specific factors may differently influence Zol retention in MM and BC patients. We tested this hypothesis in an investigator initiated phase II clinical trial in which we compared the whole-body retention (WBrt) of Zol in a cohort of 30 multiple myeloma (MM) and 30 breast cancer (BC) (20 Zol naive and 40 with six or more previous administrations). On average, 62% of the administered Zol was retained in the skeleton of both MM and BC patients and independently of the number of treatments. WBrt of Zol did not correlate with cross-linked C-telopeptide (CTX) levels, but linear regression analyses showed that WBrt of Zol correlated with bone-specific alkaline phosphatase (bALP) levels in BC (p = 0.001), and with CTX/bALP in Zol naive MM patients (p = 0.012). Especially in BC patients, WBrt correlated with age (p = 0.014) independently of kidney function. In MM patients WBrt was found to primarily correlate with the extent of bone disease (p = 0.028). Multivariate linear regression analyses of the entire cohort pointed out that WBrt of Zol was best predicted by age (p < 0.000), osseous lesions (p < 0.001), and the preceding Zol dosing (p < 0.005) (r(2)  = 0.97). Comparing bone scintigrams with CT/X-ray images showed a poor correlation between sites of active bone disease and binding of scintigraphy bisphosphonate in 36% of MM patients and in 13% of BC patients. We conclude that WBrt of Zol is primarily determined by two non-disease related factors and only one disease related, but that there may be differences in retention or drug delivery at individual sites of bone disease between MM and BC patients. In order to find the optimal dosing of Zol, these

  17. [Monomorphic post-transplant T-lymphoproliferative disorder after autologous stem cell transplantation for multiple myeloma].

    PubMed

    Ishikawa, Tetsuya; Shimizu, Hiroaki; Takei, Toshifumi; Koya, Hiroko; Iriuchishima, Hirono; Hosiho, Takumi; Hirato, Junko; Kojima, Masaru; Handa, Hiroshi; Nojima, Yoshihisa; Murakami, Hirokazu

    2016-01-01

    We report a rare case of T cell type monomorphic post-transplant lymphoproliferative disorders (PTLD) after autologous stem cell transplantation. A 53-year-old man with multiple myeloma received autologous stem cell transplantation and achieved a very good partial response. Nine months later, he developed a high fever and consciousness disturbance, and had multiple swollen lymph nodes and a high titer of Epstein-Barr (EB) virus DNA in his peripheral blood. Neither CT nor MRI of the brain revealed any abnormalities. Cerebrospinal fluid contained no malignant cells, but the EB virus DNA titer was high. Lymph node biopsy revealed T cell type monomorphic PTLD. Soon after high-dose treatment with methotrexate and cytosine arabinoside, the high fever and consciousness disturbance subsided, and the lymph node swelling and EB virus DNA disappeared. Given the efficacy of chemotherapy in this case, we concluded that the consciousness disturbance had been induced by central nervous system involvement of monomorphic PTLD. PMID:26861102

  18. Secondary lymphoblastic leukemia occurring 38 months after the primary diagnosis of multiple myeloma: A case report

    PubMed Central

    Li, Junxun; Zhan, Jieyu; Zhang, Fan; Ye, Zhuangjian; Ouyang, Juan

    2016-01-01

    Multiple myeloma (MM) is a malignant plasma cell neoplasm characterized by the accumulation of plasma cells in the bone marrow, the subsequent destruction of bone and organ dysfunction. The present study describes the case of a 66-year-old male patient who presented with the typical clinical manifestations of MM. The patient was administered a bortezomib and dexamethasone regimen for 2 cycles and achieved complete remission. Lenalidomide, vincristine, pirarubicin, dexamethasone, melphalan and thalidomide was used successively in consolidation therapy and maintenance therapy. The patient developed secondary B-cell lymphoblastic leukemia 38 months after the primary MM diagnosis was made. Owing to the exposure of the patient to a variety of therapeutic agents, it could be inferred that multiple immune defects may have played an important role in the secondary lymphoblastic leukemia of the patient. Microscopic examination and flow cytometry detection were important in identifying the secondary malignancy in this MM case. PMID:27446359

  19. Synchronous presentation of Gaucher disease and solitary plasmacytoma with progression to multiple myeloma.

    PubMed

    Hawkesford, M P H; Bowey, A J; Rao, J; Meara, N J

    2011-11-01

    A 37-year-old Polish immigrant presented with unilateral hip pain and difficulty weight-bearing. Plain radiography and magnetic resonance imaging (MRI) revealed a lytic lesion in the acetabulum, with abnormal serum electrophoresis and bone marrow biopsy. The patient was diagnosed with two rare conditions presenting synchronously - Gaucher disease and plasmacytoma. He was treated with enzyme therapy and radiotherapy, but subsequently developed a recurrence of plasmacytoma in the right femur, confirmed with bone marrow biopsy. This was also treated with radiotherapy, followed by a retrograde femoral nail to reduce the risk of pathological fracture. The patient went on to develop multiple lytic lesions in the ribs and vertebra, seen on MRI. Further bone marrow biopsy confirmed dissemination of the plasmacytoma into multiple myeloma, for which he was treated with systemic chemotherapy. In patients presenting with refractory bone or joint pain, haematological and histological investigations should be considered to exclude less common diagnoses. PMID:22089053

  20. [Monomorphic post-transplant T-lymphoproliferative disorder after autologous stem cell transplantation for multiple myeloma].

    PubMed

    Ishikawa, Tetsuya; Shimizu, Hiroaki; Takei, Toshifumi; Koya, Hiroko; Iriuchishima, Hirono; Hosiho, Takumi; Hirato, Junko; Kojima, Masaru; Handa, Hiroshi; Nojima, Yoshihisa; Murakami, Hirokazu

    2016-01-01

    We report a rare case of T cell type monomorphic post-transplant lymphoproliferative disorders (PTLD) after autologous stem cell transplantation. A 53-year-old man with multiple myeloma received autologous stem cell transplantation and achieved a very good partial response. Nine months later, he developed a high fever and consciousness disturbance, and had multiple swollen lymph nodes and a high titer of Epstein-Barr (EB) virus DNA in his peripheral blood. Neither CT nor MRI of the brain revealed any abnormalities. Cerebrospinal fluid contained no malignant cells, but the EB virus DNA titer was high. Lymph node biopsy revealed T cell type monomorphic PTLD. Soon after high-dose treatment with methotrexate and cytosine arabinoside, the high fever and consciousness disturbance subsided, and the lymph node swelling and EB virus DNA disappeared. Given the efficacy of chemotherapy in this case, we concluded that the consciousness disturbance had been induced by central nervous system involvement of monomorphic PTLD.

  1. Cytogenetic abnormality in patients with multiple myeloma analyzed by fluorescent in situ hybridization

    PubMed Central

    Hu, Ying; Chen, Wenming; Chen, Shilun; Huang, Zhongxia

    2016-01-01

    Objective To analyze the fluorescent in situ hybridization (FISH) data and the association with clinical characteristics, therapy response, and survival time in patients with multiple myeloma. Method We performed a retrospective review of patients with multiple myeloma from November 2010 to April 2014. Results Cytogenetic abnormalities by FISH were detectable in 66% of patients. One cytogenetic abnormality, two cytogenetic abnormalities, and complex abnormalities were detectable in 21.2%, 51.5%, and 27.3% of cases, respectively. 1q21 amplification, t(4p16.3/14q32), and 17p deletion were observed in 69.7%, 30.3%, and 21.2% of cases, respectively. Total response rates (complete response [CR] + near CR + partial response) were 93.8% and 82.1%, respectively, in cytogenetic normality group and abnormality group. CR rates were 50% and 32.1%, respectively. Median overall survival (OS) time was 51 months and 24 months, respectively, in cytogenetic normality group and abnormality group (P<0.05). Median OS time was not significantly different between 1q21 amplification group and no 1q21 amplification group in patients with FISH abnormalities (P>0.05). Median OS time was not significantly different between t(4;14) group and no t(4;14) group in patients with FISH abnormalities (P>0.05). Seven patients of 17p deletion died in 2 years. Conclusion Multiple myeloma is characterized by a high occurrence of chromosomal aberrations. 1q21 amplification and t(4;14) are the most common abnormalities. Multiple cytogenetic abnormalities are frequently observed in the same one patient. The total response rate, CR rate, and OS time are worse in cytogenetic abnormal patients compared with cytogenetic normal patients. Patients with 17p deletion have a very poor prognosis. Future goals of therapy will be to achieve minimal residual disease, biomarkers, and genomic data, which might provide a better estimate of the depth of response to therapy and OS. PMID:27042105

  2. The impact of intra-clonal heterogeneity on the treatment of multiple myeloma.

    PubMed

    Brioli, Annamaria; Melchor, Lorenzo; Cavo, Michele; Morgan, Gareth J

    2014-05-01

    It is clear that cancers comprise a mixture of clones, a feature termed intra-clonal heterogeneity, that compete for spatial and nutritional resources in a fashion that leads to disease progression and therapy resistance. This process of competition resembles the schema proposed by Darwin to explain the origin of the species, and applying these evolutionary biology concepts to cancer has the potential to improve our treatment strategies. Multiple myeloma (MM) has a unique set of characteristics that makes it a perfect model in which to study the presence of intra-clonal heterogeneity and its impact on therapy. Novel therapies have improved the outcome of MM patients, increasing both progression-free and overall survival. Current therapy comprises an induction, consolidation and maintenance phases and it is important to consider how these components of MM therapy are affected by the presence of intra-clonal heterogeneity. In this evolutionary context therapy can be considered as a selective pressure differentially acting on the myeloma clones and impacting on their chances of survival. In this review current knowledge of intra-clonal heterogeneity, as well as its impact on the different components of MM treatment is discussed. PMID:24580032

  3. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma

    PubMed Central

    Lahuerta, Juan J.; Pepin, François; González, Marcos; Barrio, Santiago; Ayala, Rosa; Puig, Noemí; Montalban, María A.; Paiva, Bruno; Weng, Li; Jiménez, Cristina; Sopena, María; Moorhead, Martin; Cedena, Teresa; Rapado, Immaculada; Mateos, María Victoria; Rosiñol, Laura; Oriol, Albert; Blanchard, María J.; Martínez, Rafael; Bladé, Joan; San Miguel, Jesús; Faham, Malek; García-Sanz, Ramón

    2014-01-01

    We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma (MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD– by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P < .0001) and overall survival (median not reached vs 81 months; P = .02), compared with patients who were MRD+. When stratifying patients by different levels of MRD, the respective TTP medians were: MRD ≥10−3 27 months, MRD 10−3 to 10−5 48 months, and MRD <10−5 80 months (P = .003 to .0001). Ninety-two percent of VGPR patients were MRD+. In complete response patients, the TTP remained significantly longer for MRD– compared with MRD+ patients (131 vs 35 months; P = .0009). PMID:24646471

  4. Lenalidomide Maintenance for High Risk Multiple Myeloma after Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Alsina, Melissa; Becker, Pamela S.; Zhong, Xiaobo; Adams, Alexia; Hari, Parameswaran; Rowley, Scott; Stadtmauer, Edward A.; Vesole, David H.; Logan, Brent; Weisdorf, Daniel; Qazilbash, Muzaffar; Popplewell, Leslie L.; McClune, Brian; Bensinger, William; Riches, Marcie; Giralt, Sergio A.; Pasquini, Marcelo C.

    2016-01-01

    Allogeneic hematopoietic cell transplantation (alloHCT) with reduced intensity conditioning is an appealing option for patients with high risk multiple myeloma (MM). However, progression after alloHCT remains a challenge. Maintenance therapy after alloHCT may offer additional disease control and allow time for a graft-versus-myeloma effect. The primary objective of this clinical trial was to determine the tolerability and safety profile of maintenance lenalidomide (LEN) given on days 1–21 of 28 days cycles, with intra-patient dose escalation during 12 months/cycles after alloHCT. Thirty alloHCT recipients (median age 54 years) with high risk MM were enrolled at 8 centers between 2009–2012. The median time from alloHCT to LEN initiation was 96 days (66–171 days). Eleven patients (37%) completed maintenance and 10 mg daily was the most commonly delivered dose (44%).Most common reasons for discontinuation were aGVHD (37%) and disease progression (37%). Cumulative incidence of grades III–IV acute GVHD from time of initiation of Len was 17%. Outcomes at 18 months after initiation of maintenance were MM progression, 28%; transplant related mortality, 11%; and progression-free and overall survival, 63% and 78%, respectively. The use of LEN post alloHCT is feasible at lower doses, although associated with a 38% incidence of aGVHD. Survival outcomes observed in this high risk MM population warrant further study of this approach. PMID:24769014

  5. Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma.

    PubMed

    Raninga, Prahlad V; Di Trapani, Giovanna; Vuckovic, Slavica; Bhatia, Maneet; Tonissen, Kathryn F

    2015-06-20

    Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-κβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-κβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-κβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM. PMID:25945832

  6. Modeling progression risk for smoldering multiple myeloma: results from a prospective clinical study.

    PubMed

    Cherry, Benjamin M; Korde, Neha; Kwok, Mary; Manasanch, Elisabet E; Bhutani, Manisha; Mulquin, Marcia; Zuchlinski, Diamond; Yancey, Mary Ann; Maric, Irina; Calvo, Katherine R; Braylan, Raul; Stetler-Stevenson, Maryalice; Yuan, Constance; Tembhare, Prashant; Zingone, Adriana; Costello, Rene; Roschewski, Mark J; Landgren, Ola

    2013-10-01

    The risk of progression to multiple myeloma (MM) from the precursor condition smoldering MM (SMM) varies considerably among individual patients. Reliable markers for progression to MM are vital to advance the understanding of myeloma precursor disease and for the development of intervention trials designed to delay/prevent MM. The Mayo Clinic and Spanish PETHEMA have proposed models to stratify patient risk based on clinical parameters. The aim of our study was to define the degree of concordance between these two models by comparing the distribution of patients with SMM classified as low, medium and high risk for progression. A total of 77 patients with SMM were enrolled in our prospective natural history study. Per study protocol, each patient was assigned risk scores based on both the Mayo and the Spanish models. The Mayo Clinic model identified 38, 35 and four patients as low, medium and high risk, respectively. The Spanish PETHEMA model classified 17, 22 and 38 patients as low, medium and high risk, respectively. There was significant discordance in overall patient risk classification (28.6% concordance) and in classifying patients as low versus high (p < 0.0001), low versus non-low (p = 0.0007) and high versus non-high (p < 0.0001) risk. There is a need for prospectively validated models to characterize individual patient risk of transformation to MM. PMID:23311294

  7. Rapid evolution of drug resistance of multiple myeloma in the microenvironment with drug gradients

    NASA Astrophysics Data System (ADS)

    Wu, Amy; Zhang, Qiucen; Lambert, Guillaume; Khin, Zayar; Silva, Ariosto; Gatenby, Robert; Kim, John; Pourmand, Nader; Austin, Robert; Sturm, James

    2013-03-01

    Drug resistance in cancer is usually caused by the spatial drug gradients in tumor environment. Here, we culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region for 12 days. The myeloma cells grew rapidly and formed 3D colonies in the regions with less drug concentration. However, we have seen emergent colonies forming in regions with drug concentration above the minimal inhibitory concentration in less than one week. Once the cells have occupied the regions with less drug concentration, they tend to migrate toward the regions with higher drug concentration in a collective behavior. To characterize their resistance, we collect them from this microfluidic system, for further analysis of the dose response. We find that the IC50 (drug concentration that inhibits 50% of controlled population) of the cells, undergone a drug gradient, increase 16-fold of the wildtype cells. We further discover that these resistant cells express more Multidrug Resistance (mdr) protein, which pumps out the drugs and causes drug resistance, than the wildtype. Our current works on RNA-sequencing analysis may discover other biomolecular mechanisms that may confer the drug resistance.

  8. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma.

    PubMed

    Martinez-Lopez, Joaquin; Lahuerta, Juan J; Pepin, François; González, Marcos; Barrio, Santiago; Ayala, Rosa; Puig, Noemí; Montalban, María A; Paiva, Bruno; Weng, Li; Jiménez, Cristina; Sopena, María; Moorhead, Martin; Cedena, Teresa; Rapado, Immaculada; Mateos, María Victoria; Rosiñol, Laura; Oriol, Albert; Blanchard, María J; Martínez, Rafael; Bladé, Joan; San Miguel, Jesús; Faham, Malek; García-Sanz, Ramón

    2014-05-15

    We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma (MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD(-) by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P < .0001) and overall survival (median not reached vs 81 months; P = .02), compared with patients who were MRD(+). When stratifying patients by different levels of MRD, the respective TTP medians were: MRD ≥10(-3) 27 months, MRD 10(-3) to 10(-5) 48 months, and MRD <10(-5) 80 months (P = .003 to .0001). Ninety-two percent of VGPR patients were MRD(+). In complete response patients, the TTP remained significantly longer for MRD(-) compared with MRD(+) patients (131 vs 35 months; P = .0009).

  9. Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma

    PubMed Central

    Raninga, Prahlad V.; Di Trapani, Giovanna; Vuckovic, Slavica; Bhatia, Maneet; Tonissen, Kathryn F.

    2015-01-01

    Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-кβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-кβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-кβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM. PMID:25945832

  10. Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma.

    PubMed

    Raninga, Prahlad V; Di Trapani, Giovanna; Vuckovic, Slavica; Bhatia, Maneet; Tonissen, Kathryn F

    2015-06-20

    Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-κβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-κβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-κβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM.

  11. Mechanisms for autophagy modulation by isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells

    PubMed Central

    Dykstra, Kaitlyn M.; Allen, Cheryl; Born, Ella J.; Tong, Huaxiang; Holstein, Sarah A.

    2015-01-01

    Multiple myeloma (MM) is characterized by the production of monoclonal protein (MP). We have shown previously that disruption of the isoprenoid biosynthetic pathway (IBP) causes a block in MP secretion through a disruption of Rab GTPase activity, leading to an enhanced unfolded protein response and subsequent apoptosis in MM cells. Autophagy is induced by cellular stressors including nutrient deprivation and ER stress. IBP inhibitors have been shown to have disparate effects on autophagy. Here we define the mechanisms underlying the differential effects of IBP inhibitors on autophagic flux in MM cells utilizing specific pharmacological inhibitors. We demonstrate that IBP inhibition induces a net increase in autophagy as a consequence of disruption of isoprenoid biosynthesis which is not recapitulated by direct geranylgeranyl transferase inhibition. IBP inhibitor-induced autophagy is a cellular defense mechanism as treatment with the autophagy inhibitor bafilomycin A1 enhances the cytotoxic effects of GGPP depletion, but not geranylgeranyl transferase inhibition. Immunofluorescence microscopy studies revealed that IBP inhibitors disrupt ER to Golgi trafficking of monoclonal light chain protein and that this protein is not a substrate for alternative degradative pathways such as aggresomes and autophagosomes. These studies support further development of specific GGTase II inhibitors as anti-myeloma agents. PMID:26595805

  12. Extramedullary Cardiac Multiple Myeloma-A Case Report and Contemporary Review of the Literature.

    PubMed

    Coakley, Maria; Yeneneh, Beeletsega; Rosenthal, Allison; Fonseca, Rafael; Mookadam, Farouk

    2016-05-01

    Multiple myeloma (MM) is characterized by a clonal proliferation of plasma cells. Although the bone marrow is the usual site of involvement, extramedullary plasmacytomas (EMPs) also occur, affecting any tissue. Cardiac and pericardial involvement, although described, have been rare occurrences. We present the case of a 61-year-old female patient 47 days after autologous stem cell transplant for MM who developed cardiac tamponade owing to extramedullary recurrence of myeloma, pulmonary embolism, and takotsubo cardiomyopathy. We performed a review of the published studies of all cases of MM presenting at diagnosis or relapse with cardiac or pericardial involvement in the past 25 years. Including our patient, 34 patients with plasmacytoma involving cardiac or pericardial structures were identified from the literature search. Approximately equal numbers of patients were male and female (42% and 57%, respectively). The mean age was 62 years. Primary plasmacytomas accounted for 12% of the cases. A history of MM, EMP, or monoclonal gammopathy of uncertain significance was noted in two thirds of the cases (66.6%). Treatment included chemotherapy and/or high-dose corticosteroids in 81.1% of cases and 27% underwent radiation therapy. The reporting of all cases to date has focused on unusual findings, rather than treatment approaches or new therapeutic strategies that might benefit patients. We suggest the formation of a database of all cases of cardiac and pericardial EMPs, with a focus on predictive disease variables, standardized staging, outcomes, and survival, to ensure that patients are optimally treated in the modern era. PMID:27009538

  13. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.

    PubMed

    Zangari, M; Anaissie, E; Barlogie, B; Badros, A; Desikan, R; Gopal, A V; Morris, C; Toor, A; Siegel, E; Fink, L; Tricot, G

    2001-09-01

    The occurrence of deep-vein thrombosis (DVT) in patients with newly diagnosed multiple myeloma, who were randomly assigned to receive identical induction chemotherapy with or without thalidomide, are reported in this study. The 2 study arms were comparable with respect to key myeloma prognostic factors and known risk factors for DVT. One hundred patients received induction chemotherapy including 4 cycles of continuous infusion of combinations of dexamethasone, vincristine, doxorubicin, cyclophosphamide, etoposide, and cisplatin, and each patient completed at least one induction cycle. DVT developed in 14 of 50 patients (28%) randomly assigned to receive thalidomide but in only 2 of 50 patients (4%) not given the agent (P =.002). All episodes of DVT occurred during the first 3 cycles of induction. Administration of thalidomide was resumed safely in 75% of patients receiving anticoagulation therapy. Thus, thalidomide given in combination with multiagent chemotherapy and dexamethasone is associated with a significantly increased risk of DVT, which appears to be safely treated with anticoagulation and does not necessarily warrant discontinuation of thalidomide.

  14. FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells

    PubMed Central

    Suvannasankha, Attaya; Tompkins, Douglas R.; Edwards, Daniel F.; Petyaykina, Katarina V.; Crean, Colin D.; Fournier, Pierrick G.; Parker, Jamie M.; Sandusky, George E.; Ichikawa, Shoji; Imel, Erik A.; Chirgwin, John M.

    2015-01-01

    Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone. PMID:25944690

  15. [Subcutaneous bortezomib as a new promising way to successful maintenance therapy in multiple myeloma].

    PubMed

    Grosicki, Sebastian

    2012-01-01

    Multiple myeloma (MM) despite the introduction to clinical practice of a new drugs in the last years, and still searching of new points of the handle for targeting treatment, remaining incurable disease. Even most intensive and most modern induction-consolidation regimens is not in the state to eradicate of the clone of myeloma, and even complete remission in immunofixation the most often after some time ends progression. Optimal way of maintenance treatment is still searching, which would be maximally effective near acceptable toxicity. Now hypothesis about possible successful maintenance therapy, which may prolong survival of MM patients became more actual in the face of the introduction to the studies with maintenance of a new drugs as: thalidomide, lenalidomide and bortesomib. The expectations on the essential progress to establish the optimal bortesomib-based regimen of the maintenance treatment in MM cause the results of the studies with its subcutaneous administration, which proved comparable efficacy with advantage in toxicity profile, especially neurological in comparison to classic intravenous way.

  16. Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone for heavily pretreated relapsed or refractory multiple myeloma.

    PubMed

    Jimenez-Zepeda, Victor H; Reece, Donna E; Trudel, Suzanne; Chen, Christine; Tiedemann, Rodger; Kukreti, Vishal

    2013-03-01

    The combination of lenalidomide, bortezomib and dexamethasone (RVD) has shown excellent efficacy in patients with relapsed or refractory multiple myeloma (RRMM). The aim of our study was to assess the efficacy and toxicity profile of RVD for patients with advanced RRMM. We retrospectively reviewed the records of all patients with RRMM treated with RVD between March 2009 and December 2011. Thirty patients received ≥ 1 full cycle of RVD. Primary endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). After a median of 5 cycles (1-16), a very good partial response (VGPR) was seen in 10%, partial response (PR) in 36.7% and stable disease (SD) in 13.3% (ORR of 46.7%). Disease progression occurred in 21 patients at a median of 3 months (range 1.41-4.59). Eight patients (26%) experienced grade 3/4 adverse events, including anemia, neutropenia, muscle weakness and pneumonia. No patient experienced worsening peripheral neuropathy. Although RVD has been previously shown to be effective in RRMM, the ORR and PFS we observed were affected by very advanced disease status and heavy prior exposure to novel agents. Nevertheless, six of these patients with RRMM experienced a benefit of ≥ 6 months, suggesting synergism of this immunomodulatory derivative/proteasome inhibitor combination and/or re-establishment of drug sensitivity by an emergent myeloma clone.

  17. In vitro growth of hematopoietic progenitors and stromal bone marrow cells from patients with multiple myeloma.

    PubMed

    Martínez-Jaramillo, Guadalupe; Vela-Ojeda, Jorge; Flores-Guzmán, Patricia; Mayani, Hector

    2011-02-01

    In the present study we have determined the content of hematopoietic and stromal progenitors in multiple myeloma (MM) bone marrow, and assessed their in vitro growth. Marrow cells were obtained from 17 MM patients at the time of diagnosis, and from 6 hematologically normal subjects. When mononuclear cells (MNC) from MM marrow were cultured, reduced numbers of hematopoietic progenitors were detected and their growth in long-term cultures was deficient, as compared to cultures of normal cells. When cell fractions enriched for CD34(+) Lin(-) cells were obtained, the levels of hematopoietic progenitors from MM marrow were within the normal range, and so was their growth kinetics in liquid suspension cultures. The levels of fibroblast progenitors in MM were not statistically different from those in normal marrow; however, their proliferation potential was significantly reduced. Conditioned media from MM-derived MNC and stroma cells contained factors that inhibited normal progenitor cell growth. Our observations suggest that hematopoietic progenitors in MM marrow are intrinsically normal; however, their growth in LTMC may be hampered by the presence of abnormal accessory and stroma cells. These results suggest that besides its role in the generation of osteolytic lesions and the expansion of the myeloma clone, the marrow microenvironment in MM may have a negative effect on hematopoiesis. PMID:20621354

  18. IgM multiple myeloma with an extremely rare non-aggressive presentation: A case report

    PubMed Central

    Greuter, Thomas; Browne, Martin; Dommann-Scherrer, Corina; Binder, Daniel; Renner, Christoph; Kapp, Ursula

    2016-01-01

    In the present study, the case of a 41-year-old man with immunoglobulin (Ig)M multiple myeloma (MM) that presented with an unusually non-aggressive clinical course who has survived for >9 years to date, is presented. Initial diagnosis of symptomatic MM was established according to the International Myeloma Working Group consensus statement and guidelines. Due to the mild symptoms, no therapy was administered and the patient was closely followed up. Eight years after initial diagnosis, clinical, morphological and genetic progression occurred with the development of hypercalcemia, progressively deteriorating polyneuropathy, clonal expansion of plasma cells up to 50% of hematopoietic cells and demonstration of the typical t(11;14) translocation (Ig heavy chain locus rearrangement). Subsequently, 4 cycles of induction chemotherapy with velcade, cyclophosphamide and dexamethasone, were administered. At the time of writing, the patient remained alive in generally good health. To the best of our knowledge, with a survival time of >9 years, this case reports the longest survival time of an IgM MM patient to date, which contradicts previous evidence that suggests IgM MM exhibits an aggressive clinical course.

  19. Overview of recent trends in diag