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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

    MedlinePlus

    Multiple myeloma Overview Multiple myeloma is a cancer that forms in a type of white blood cell called a plasma cell. Plasma cells help ... by making antibodies that recognize and attack germs. Multiple myeloma causes cancer cells to accumulate in the bone ...

  3. Multiple myeloma.

    PubMed

    Peller, Patrick J

    2015-04-01

    This article presents a review of multiple myeloma, precursor states, and related plasma cell disorders. The clinical roles of fluorodeoxyglucose PET/computed tomography (CT) and the potential to improve the management of patients with multiple myeloma are discussed. The clinical and research data supporting the utility of PET/CT use in evaluating myeloma and other plasma cell dyscrasias continues to grow.

  4. Multiple myeloma

    PubMed Central

    2010-01-01

    Abstract Advances in the imaging and treatment of multiple myeloma have occurred over the past decade. This article summarises the current status and highlights how an understanding of both is necessary for optimum management. PMID:20159661

  5. [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.

  6. Multiple Myeloma Symptoms

    MedlinePlus

    ... Treatment Center Finder Home » About Multiple Myeloma » Symptoms Multiple Myeloma Symptoms Multiple myeloma symptoms may vary by patient, ... to be managed or prevented. The most common multiple myeloma symptoms may include: Bone pain or bone fractures ...

  7. Multiple myeloma.

    PubMed

    Kumar, Shaji K; Rajkumar, Vincent; Kyle, Robert A; van Duin, Mark; Sonneveld, Pieter; Mateos, María-Victoria; Gay, Francesca; Anderson, Kenneth C

    2017-07-20

    Multiple myeloma is a malignancy of terminally differentiated plasma cells, and patients typically present with bone marrow infiltration of clonal plasma cells and monoclonal protein in the serum and/or urine. The diagnosis of multiple myeloma is made when clear end-organ damage attributable to the plasma cell proliferative disorder or when findings that suggest a high likelihood of their development are present. Distinguishing symptomatic multiple myeloma that requires treatment from the precursor stages of monoclonal gammopathy of undetermined significance and smouldering multiple myeloma is important, as observation is the standard for those conditions. Much progress has been made over the past decade in the understanding of disease biology and individualized treatment approaches. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have joined the traditional armamentarium (corticosteroids, alkylating agents and anthracyclines) and, along with high-dose therapy and autologous haemopoietic stem cell transplantation, have led to deeper and durable clinical responses. Indeed, an increasing proportion of patients are achieving lasting remissions, raising the possibility of cure for this disease. Success will probably depend on using combinations of effective agents and treating patients in the early stages of disease, such as patients with smouldering multiple myeloma.

  8. 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

  9. Non-redundant roles for Th17 and Th22 cells in multiple myeloma clinical correlates

    PubMed Central

    Di Lullo, Giulia; Marcatti, Magda; Protti, Maria Pia

    2016-01-01

    ABSTRACT We recently reported that in multiple myeloma increased Th22 cell frequencies correlate with poor prognosis. Here we show that within the same patients' cohort Th17 cells associate with bone disease and not with prognosis. Thus, we propose that Th22 and Th17 cells play non-redundant roles in multiple myeloma and constitute independent therapeutic targets. PMID:27141378

  10. Non-redundant roles for Th17 and Th22 cells in multiple myeloma clinical correlates.

    PubMed

    Di Lullo, Giulia; Marcatti, Magda; Protti, Maria Pia

    2016-04-01

    We recently reported that in multiple myeloma increased Th22 cell frequencies correlate with poor prognosis. Here we show that within the same patients' cohort Th17 cells associate with bone disease and not with prognosis. Thus, we propose that Th22 and Th17 cells play non-redundant roles in multiple myeloma and constitute independent therapeutic targets.

  11. 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 ...

  12. Complications of multiple myeloma.

    PubMed

    Bladé, Joan; Rosiñol, Laura

    2007-12-01

    Multiple myeloma, also known as myeloma or plasma cell myeloma, is a progressive hematologic disease. Complications of multiple myeloma include renal insufficiency, hematologic complications (anemia, bone marrow failure, bleeding disorders), infections, bone complications (pathologic fractures, spinal cord compression, hyercalcemia), and neurologic complications (spinal cord and nerve root compression, intracranial plasmacytomas, leptomeningeal involvement, among others). This article reviews these various complications connected to multiple myeloma, examining their various causes and possible treatment.

  13. Hyperamylasaemia in multiple myeloma.

    PubMed

    Bloemendal, H J; Lobatto, S

    1996-07-01

    A 71-year-old woman, known to have multiple myeloma, was admitted because of fever, abdominal pain and hyperamylasaemia and hyperamylasuria. She was diagnosed as having acute pancreatitis. Because the diagnosis could not be confirmed, and serum lipase was normal, it appeared that this patient had developed an amylase-producing myeloma lesion in the pelvis.

  14. Multiple Myeloma and Diabetes

    PubMed Central

    Issa, Zeinab A.; Zantout, Mira S.; Azar, Sami T.

    2011-01-01

    Multiple myeloma is a malignant plasma cell disorder that accounts for approximately 10% of all hematologic cancers. It is characterized by accumulation of clonal plasma cells, predominantly in the bone marrow. The prevalence of type 2 diabetes is increasing; therefore, it is expected that there will be an increase in the diagnosis of multiple myeloma with concomitant diabetes mellitus. The treatment of multiple myeloma and diabetes mellitus is multifaceted. The coexistence of the two conditions in a patient forms a major challenge for physicians. PMID:22363889

  15. 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.

  16. Multiple Myeloma: Patient Handbook

    MedlinePlus

    ... most commonly used clinical staging system, the Durie-Salmon Stag- ing System, demonstrates the correlation between the ... The “measured myeloma cell mass” for the Durie- Salmon Staging System was calculated from stud- ies in ...

  17. Can Multiple Myeloma Be Found Early?

    MedlinePlus

    ... Phone Search Search En Español Category Cancer A-Z Early Detection, Diagnosis, and Staging Can Multiple Myeloma Be Found Early? Signs and Symptoms of Multiple Myeloma Tests to Find Multiple Myeloma Diagnosing Multiple Myeloma from ...

  18. 11C-Methionine-PET in Multiple Myeloma: Correlation with Clinical Parameters and Bone Marrow Involvement.

    PubMed

    Lapa, Constantin; Knop, Stefan; Schreder, Martin; Rudelius, Martina; Knott, Markus; Jörg, Gerhard; Samnick, Samuel; Herrmann, Ken; Buck, Andreas K; Einsele, Hermann; Lückerath, Katharina

    2016-01-01

    Multiple myeloma (MM) remains an essentially incurable hematologic malignancy originating from clonal plasma cells. This study evaluated the usefulness of the radiotracers (11)C-methionine (MET) and (18)F-2`-deoxy-2`-fluorodeoxyglucose (FDG) for staging and re-staging in MM. 43 patients with MM underwent both MET- and FDG-PET/CT for staging or re-staging within 3±2 days. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with the degree of bone marrow (BM) involvement and standard clinical parameters of disease activity. Additionally, BM samples were stained for L-type amino acid transporter 1 (LAT1) expression in 15 patients. MET-PET detected focal lesions (FL) in 39/43 subjects (90.7%), whereas 10 patients were missed in FDG-PET/CT (detection rate, 33/43; 76.7%; p<0.05). MET depicted more FL in 28/43 patients (65.1%; p<0.001), whereas in the remainder (34.9%, n=15) both tracers yielded comparable results. LAT1 was highly expressed on the cell surface of myeloma cells. Both FDG and MET uptake correlated significantly with biopsy-proven BM involvement (p<0.001), with MET demonstrating a stronger correlation (SUVmean, r=0.9 vs r=0.6; SUVmax, r=0.88 vs r=0.58). Abnormal beta-2-microglobulin and free light chain levels correlated with the presence of focal intramedullary lesions detected in MET- or FDG-PET/CT (MET, p=0.006 and p=0.01, respectively; FDG, p=0.02 and p=0.01). MET appears to be superior to FDG for staging and re-staging of both intra- and extramedullary MM lesions. Tracer uptake correlates with BM involvement, β2m and FLC levels and appears to be a more accurate marker of tumor burden and disease activity.

  19. 11C-Methionine-PET in Multiple Myeloma: Correlation with Clinical Parameters and Bone Marrow Involvement

    PubMed Central

    Lapa, Constantin; Knop, Stefan; Schreder, Martin; Rudelius, Martina; Knott, Markus; Jörg, Gerhard; Samnick, Samuel; Herrmann, Ken; Buck, Andreas K.; Einsele, Hermann; Lückerath, Katharina

    2016-01-01

    Multiple myeloma (MM) remains an essentially incurable hematologic malignancy originating from clonal plasma cells. This study evaluated the usefulness of the radiotracers 11C-methionine (MET) and 18F-2`-deoxy-2`-fluorodeoxyglucose (FDG) for staging and re-staging in MM. 43 patients with MM underwent both MET- and FDG-PET/CT for staging or re-staging within 3±2 days. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with the degree of bone marrow (BM) involvement and standard clinical parameters of disease activity. Additionally, BM samples were stained for L-type amino acid transporter 1 (LAT1) expression in 15 patients. MET-PET detected focal lesions (FL) in 39/43 subjects (90.7%), whereas 10 patients were missed in FDG-PET/CT (detection rate, 33/43; 76.7%; p<0.05). MET depicted more FL in 28/43 patients (65.1%; p<0.001), whereas in the remainder (34.9%, n=15) both tracers yielded comparable results. LAT1 was highly expressed on the cell surface of myeloma cells. Both FDG and MET uptake correlated significantly with biopsy-proven BM involvement (p<0.001), with MET demonstrating a stronger correlation (SUVmean, r=0.9 vs r=0.6; SUVmax, r=0.88 vs r=0.58). Abnormal beta-2-microglobulin and free light chain levels correlated with the presence of focal intramedullary lesions detected in MET- or FDG-PET/CT (MET, p=0.006 and p=0.01, respectively; FDG, p=0.02 and p=0.01). MET appears to be superior to FDG for staging and re-staging of both intra- and extramedullary MM lesions. Tracer uptake correlates with BM involvement, β2m and FLC levels and appears to be a more accurate marker of tumor burden and disease activity. PMID:26877783

  20. Treatment of multiple myeloma

    PubMed Central

    Rajkumar, S. Vincent

    2013-01-01

    The treatment of multiple myeloma has changed dramatically in the past decade. The increase in the number of active agents has generated numerous possible drug combinations that can be used in the first-line and relapsed settings. As a result, there is considerable confusion about the choice of regimens for initial therapy, role of transplantation in the era of new drugs, end points for therapy, and the role of maintenance therapy. A hotly debated area is whether treatment approaches should achieve cure or disease control, which impacts greatly on the treatment strategy employed. This article provides an update on the treatment of multiple myeloma, with a focus on recent advances, newly diagnosed disease, role of transplantation and maintenance therapy. A synthesized approach to the treatment of myeloma is presented, along with a discussion of key paradigms that need to be challenged. PMID:21522124

  1. [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. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  2. 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.

  3. Multiple myeloma: current perspectives.

    PubMed

    Slovak, Marilyn L

    2011-12-01

    Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells characterized by complex genetic aberrations and heterogeneous outcomes. Over the past 25 years, cytogenetic analysis has played a key role in the diagnosis and management of MM. This article reviews the conventional cytogenetics, molecular cytogenetics, and genomic diagnostics of MM and highlights a few recent clinical trials that demonstrate the impact of genetic risk stratification on the treatment of this plasma cell malignancy.

  4. Clinicopathological correlates of plasma cell CD56 (NCAM) expression in multiple myeloma.

    PubMed

    Kraj, Maria; Sokołowska, Urszula; Kopeć-Szlezak, Joanna; Pogłód, Ryszard; Kruk, Barbara; Woźniak, Jolanta; Szpila, Tomasz

    2008-02-01

    The aim of this prospective, long-term study was to define the flow cytometric characteristics of plasma cell CD56 expression as well as determine the clinical characteristics of 204 multiple myeloma (MM) patients and 26 plasma cell leukemia (PCL) patients with regard to CD56 expression. CD56 expression intensity was determined by measurement of antigen molecules on the cell defined as Antibodies Bound per Cell (ABC) and calculation of Relative Fluorescence Intensity (RFI). CD56 expression was found in 66% of MM and 54% of PCL cases. The RFI values for individual MM patients ranged from 7.6 to 27.4 while ABC values on MM plasma cells from 2255 to 58469. There was a correlation between the proportion of all bone marrow CD38(++)/CD138(+) cells with CD56 expression and ABC and RFI indices. With regard to CD56 expression positive patients, the CD56(-) MM patients presented lower frequency of osteolysis (p = 0.01). The median survival was 48 months in CD56(+) patients and 43 months (p = 0.84) in CD56(-) cases. In conclusion, CD56 expression carries no distinct adverse prognosis and the lack of CD56 expression does not define a unique clinicopathological or prognostic entity in MM. A remarkable heterogeneity of CD56 expression intensity in CD56(+) patients imposes the necessity of determining CD56 expression intensity in candidates to antibody-based therapy.

  5. Multiple Myeloma: An Update

    PubMed Central

    Al-Farsi, Khalil

    2013-01-01

    Multiple myeloma is a rare, largely incurable malignant disease of plasma cells. Patients usually present with hypercalcemia, renal insufficiency, anemia and/or lytic bony lesions along with a monoclonal protein in the serum and/or urine in addition to an increase in the number of clonal plasma cells in the bone marrow. Patients with myeloma live on an average for five to seven years, with their survival dependent on the presence or absence of different prognostic markers. Treatment of younger fit patients is with induction therapy consisting of steroids with one or more novel anti-myeloma agents followed by high dose melphalan and autologous stem cell transplantation, while older and less fit patients are treated with melphalan-based combination chemotherapy. Supportive care is of paramount importance and includes the use of bisphosphonates, prophylactic antibiotics, thrombosis prophylaxis and the use of hematopoietic growth factors along with the treatment of complications of disease and its therapy. As more progress is being made and deeper responses are being attained, the disease might turn into a potentially curable one in the near future. PMID:23386937

  6. What Happens After Treatment for Multiple Myeloma?

    MedlinePlus

    ... Myeloma Stops Working Multiple Myeloma After Treatment What Happens After Treatment for Multiple Myeloma? For most people, ... is likely to come back again. When that happens, the last thing you want is to have ...

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. [Pomalidomide for multiple myeloma].

    PubMed

    Fouquet, G; Macro, M; Decaux, O; Fohrer, C; Guidez, S; Demarquette, H; Le Grand, C; Prodhomme, C; Renaud, L; Bories, C; Herbaux, C; Karlin, L; Roussel, M; Benboubker, L; Hulin, C; Arnulf, B; Leleu, X

    2015-09-01

    Once characterized by a very poor outcome, multiple myeloma (MM) now has a significantly prolonged survival, with major improvements allowed by the use of "novel agents": proteasome inhibitors (first-in-class bortezomib) and immunomodulatory compounds (IMiDs; first-in-class thalidomide and lenalidomide). However, the vast majority - if not all - of patients with MM ultimately end up being refractory to all existing drugs, including these efficient novel agents. There is a clear unmet medical need in this situation, which warrants the development of the next generation of proteasome inhibitors and IMiDs, as well as new drug classes. This review focuses on pomalidomide, the next generation IMiD, recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy.

  12. [Close correlations between CD20 expression, a small mature plasma cell morphology and t(11 ; 14) in multiple myeloma].

    PubMed

    Matsuda, Isao; Mori, Yuki; Nakagawa, Yasunori; Sawanobori, Masakazu; Uemura, Naoki; Suzuki, Kenshi

    2005-12-01

    Stratification of patients with multiple myeloma (MM) may be important. We investigated 138 MM patients, focusing on correlations between CD20 expression, 11 ; 14 translocation, morphology of MM cells, cyclin D1 immunostaining, and the prognosis. About 15% of patients (7/47cases) were CD20-positive, small mature MM cells, with positive cyclin D1 in the nucleus and 11; 14 translocation. Two color analysis of CD38 x CD20 antigens may be necessary to investigate CD20 expression on MM cells. Rituximab may be effective for the treatment of CD20-positive MM.

  13. Impact of genes highly correlated with MMSET myeloma on survival of Non-MMSET myeloma patients

    PubMed Central

    Wu, S. Peter; Pfeiffer, Ruth M.; Ahn, Inhye E.; Mailankody, Sham; Sonneveld, Pieter; van Duin, Mark; Munshi, Nikhil; Walker, Brian; Morgan, Gareth; Landgren, Ola

    2017-01-01

    Purpose The poor prognosis of multiple myeloma with t(4;14) is driven by the fusion of genes encoding MMSET and immunoglobulin heavy chain. Specific genes affected by MMSET and their clinical implications in Non-MMSET myeloma remain undetermined. Experimental design We obtained gene-expression profiles of 1,032 newly diagnosed myeloma patients enrolled in Total Therapy 2, Total Therapy 3, Myeloma IX, and HOVON65-GMMGHD4 trials, and 156 patients from Multiple Myeloma Resource Collection. Probes most correlated with MMSET myeloma were selected based on a multivariable linear regression and Bonferroni correction, and refined based on the strength of association with survival in Non-MMSET patients. Results Ten MMSET-like probes were associated with poor survival in Non-MMSET myeloma. Non-MMSET myeloma patients in the highest quartile of the 10-gene signature (MMSET-like myeloma) had 5-year overall survival similar to that of MMSET myeloma (highest quartile vs. lowest quartile hazard ratio [HR]=2.0, 95% confidence interval [CI] 1.5-2.8 in MMSET-like myeloma; HR=2.3, 95% CI: 1.6-3.3 in MMSET myeloma). Analyses of MMSET-like gene signature suggested the involvement of p53 and MYC pathways. Conclusion MMSET-like gene signature captures a subset of high-risk myeloma patients under-represented by conventional risk stratification platforms, and defines a distinct biological subtype. PMID:26847058

  14. Multiple Myeloma: Diagnosis and Treatment.

    PubMed

    Michels, Thomas C; Petersen, Keith E

    2017-03-15

    Multiple myeloma accounts for 1.6% of all cancer cases and approximately 10% of hematologic malignancies in the United States. In 2015, an estimated 28,850 new cases of multiple myeloma were diagnosed in the United States, and the disease caused more than 11,000 deaths. Patients older than 65 years account for 85% of those diagnosed with multiple myeloma, and there is a twofold increased incidence in blacks compared with whites. Patients may present with bone pain or with symptoms that are often nonspecific, such as nausea, vomiting, malaise, weakness, recurrent infections, and weight loss. Many patients present with only laboratory abnormalities, such as anemia, renal disease, and elevated protein levels. The diagnosis of multiple myeloma requires increased numbers of immature, abnormal, or atypical plasma cells in the bone marrow; a monoclonal protein in the serum or urine; or characteristic bone lesions. The diagnostic workup in a patient with suspected multiple myeloma should include a complete blood count with differential; serum chemistries; creatinine, lactate dehydrogenase, and beta2-microglobulin tests; immunoglobulin studies; skeletal survey; and bone marrow evaluation. Initiation of chemotherapy and assessment of eligibility for autologous stem cell transplantation require referral to an oncologist. Most patients with multiple myeloma will receive thromboprophylaxis, bisphosphonate therapy, and prophylaxis against infection at some point in their treatment. Family physicians play a role in assessing these patients for infection, adverse treatment effects, and renal and thrombotic complications, and in managing issues related to pain, nutrition, and psychosocial support.

  15. Multiple myeloma: diagnosis and treatment.

    PubMed

    Nau, Konrad C; Lewis, William D

    2008-10-01

    Multiple myeloma, the most common bone malignancy, is occurring with increasing frequency in older persons. Typical symptoms are bone pain, malaise, anemia, renal insufficiency, and hypercalcemia. Incidental discovery on comprehensive laboratory panels is common. The disease is diagnosed with serum or urine protein electrophoresis or immunofixation and bone marrow aspirate analysis. Skeletal radiographs are important in staging multiple myeloma and revealing lytic lesions, vertebral compression fractures, and osteoporosis. Magnetic resonance imaging and positron emission tomography or computed tomography are emerging as useful tools in the evaluation of patients with myeloma; magnetic resonance imaging is preferred for evaluating acute spinal compression. Nuclear bone scans and dual energy x-ray absorptiometry have no role in the diagnosis and staging of myeloma. The differential diagnosis of monoclonal gammopathies includes monoclonal gammopathy of uncertain significance, smoldering (asymptomatic) and symptomatic multiple myeloma, amyloidosis, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, and rare plasma cell leukemia and heavy chain diseases. Patients with monoclonal gammopathy of uncertain significance or smoldering multiple myeloma should be followed closely, but not treated. Symptomatic multiple myeloma is treated with chemotherapy followed by autologous stem cell transplantation, if possible. Melphalan, prednisolone, dexamethasone, vincristine, doxorubicin, bortezomib, and thalidomide and its analogue lenalidomide have been used successfully. It is important that family physicians recognize and appropriately treat multiple myeloma complications. Bone pain is treated with opiates, bisphosphonates, radiotherapy, vertebroplasty, or kyphoplasty; nephrotoxic nonsteroidal anti-inflammatory drugs should be avoided. Hypercalcemia is treated with isotonic saline infusions, steroids, furosemide, or bisphosphonates. Because of susceptibility to infections

  16. Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma.

    PubMed

    Heider, Ulrike; Langelotz, Corinna; Jakob, Christian; Zavrski, Ivana; Fleissner, Claudia; Eucker, Jan; Possinger, Kurt; Hofbauer, Lorenz C; Sezer, Orhan

    2003-04-01

    Increased bone resorption is a hallmark of multiple myeloma and is attributable to osteoclast activation. Recent studies showed that the receptor activator of nuclear factor kappaB ligand (RANKL) is the key mediator of osteoclastogenesis and plays a crucial role in bone destruction in malignant bone disease. We found that human myeloma cells express RANKL and analyzed the association of the RANKL expression with the presence of osteolytic bone disease in patients with multiple myeloma. Flow cytometry was performed on bone marrow samples derived from controls and multiple myeloma patients with or without osteolytic bone lesions on conventional radiography. Plasma cells were identified as CD38++/CD138+ cells. The level of RANKL expression on the surface of bone marrow plasma cells was correlated with the bone status of the patients. The bone marrow plasma cells from controls showed no or only a weak surface expression of RANKL, and the median mean fluorescence index (MFI) was 6. In contrast, expression of RANKL could be detected on bone marrow plasma cells from all of the patients with multiple myeloma, and median MFI was 47. The difference in MFI for RANKL expression of bone marrow plasma cells from controls and myeloma patients was highly significant (P < 0.0005). Myeloma patients with osteolytic bone lesions showed a significantly higher expression of RANKL (median MFI = 60; range, 16-2494) compared with patients without osteolysis (median MFI = 16; range, 6-229; P < 0.0005). These results show for the first time that the level of RANKL expression by myeloma cells correlates significantly with osteolytic bone disease.

  17. 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

  18. Correlations among different markers determined by immunochemical methods used for the diagnosis and monitoring of intact immunoglobulin multiple myeloma cases.

    PubMed

    Dogaru, Monica; Lazăr, Veronica; Coriu, Daniel

    2012-01-01

    The purpose of this study was to determine the correlations between the concentration of free light chains (kappa, lambda and ratio kappa/lambda) and two other markers, M- protein and pathological total intact immunoglobulin in four groups of patients with intact immunoglobulin multiple myeloma (IIMM) at the diagnosis and during the treatment. In this study 354 samples coming from 46 patients with IIMM were assayed, out of which: 19, IgGkappa; 13, IgGlambda; 7, IgAkappa; 7, IgAlambda. At the diagnosis, immunofixation was positive in all samples and serum protein electrophoresis quantified M- protein for all patients. Free light chains concentrations were abnormal in 92.25% of patients with concentrations above the reference ranges in all patients with IgGkappa and IgAkappa MM. The intact immunoglobulins were elevated in 83.12% of cases. Pearson correlation coefficient showed correlations among the free light chains serum levels (kappa, lambda and ratio kappa/lambda), M- protein and intact immunoglobulins in two groups with IIMM (IgGlambda, IgAlambda). Spearman correlation coefficient values analysis showed that there is a good correlation between M-protein and FLCs (kappa, lambda and ratio kappa/lambda) in three patient groups (IgGkappa, IgGlambda and IgAlambda), excepting IgAkappa myeloma group where the correlation was insignificant. Regarding the intact immunoglobulin, Spearman coefficient showed significant correlations with FLCs concentrations in two groups (IgGlambda and IgAlambda) and an insignificant correlation in the group with IgGkappa MM. For the group of patients with IgAkappa myeloma, the Spearman coefficient showed that IgA concentrations did not correlate with the concentrations of FLCs. The individual correlation (for each patient) among FLCs, M- protein and intact immunoglobulins in 8 patients with IgGkappa IIMM proved to be more significant as compared with the degree of correlation established for the entire group of patients among these markers

  19. Bisphosphonates in multiple myeloma.

    PubMed

    Mhaskar, Rahul; Redzepovic, Jasmina; Wheatley, Keith; Clark, Otavio Augusto Camara; Miladinovic, Branko; Glasmacher, Axel; Kumar, Ambuj; Djulbegovic, Benjamin

    2010-03-17

    Bisphosphonates are specific inhibitors of osteoclastic activity and are currently used as supportive therapy for multiple myeloma (MM). However, the exact clinical role of bisphosphonates in MM remains unclear. This update of the first review published in 2002. We have also analyzed observational studies targeting osteonecrosis of jaw (ONJ). We searched the literature using the methods outlined in the previous review. We also searched observational studies or case reports examining ONJ. We selected RCTs with a parallel design related to the use of bisphosphonate in myeloma. We also selected observational studies or case reports examining bisphosphonates related to ONJ. We have reported pooled data using either hazard ratio or risk ratio and, when appropriate, as absolute risk reduction and the number needed to treat to prevent or to cause a pathological event. We have assessed statistical heterogeneity and reported I(2) statistic. This review includes 17 trials with 1520 patients analyzed in bisphosphonates groups, and 1490 analyzed in control groups. In comparison with placebo/no treatment, the pooled analysis demonstrated the beneficial effect of bisphosphonates on prevention of pathological vertebral fractures (RR= 0.74 (95% CI: 0.62 to 0.89), P = 0.001), total skeletal related events (SREs) (RR= 0.80 (95% CI: 0.72 to 0.89), P < 0.0001) and on amelioration of pain (RR = 0.75 (95% CI: 0.60 to 0.95), P = 0.01). We found no significant effect of bisphosphonates on overall survival (OS), progression-free survival (PFS), hypercalcemia or on the reduction of non-vertebral fractures. The indirect meta-analyses did not find the superiority of any particular type of bisphosphonate over others. Only two RCTs reported ONJ. The identified observational studies suggested that ONJ may be a common event (range: 0% to 51%). Adding bisphosphonates to the treatment of MM reduces pathological vertebral fractures, SREs and pain but not mortality. Assuming the baseline risk of 20

  20. Oligosecretory biclonal multiple myeloma.

    PubMed

    Koshy, Nebu; Ong, Menchu G; Nordberg, Mary Lowery; Turturro, Francesco; Cotelingam, James D

    2013-01-01

    Among the plasma cell dyscrasias, non-secretory myeloma is one of the rarest. This diagnosis is based on the absence of monoclonal proteins in the serum and urine. When serum free light chains are trace and the kappa: lambda ratio normal, clonality may however be established by PCR. We present a case of an oligosecretory myeloma confirmed by PCR, which would have hitherto been classified as non-secretory.

  1. What Should You Ask Your Doctor about Multiple Myeloma?

    MedlinePlus

    ... Phone Search Search En Español Category Cancer A-Z Early Detection, Diagnosis, and Staging Can Multiple Myeloma Be Found Early? Signs and Symptoms of Multiple Myeloma Tests to Find Multiple Myeloma Diagnosing Multiple Myeloma from ...

  2. [Radiological diagnostics of multiple myeloma].

    PubMed

    D'Anastasi, M; Grandl, S; Reiser, M F; Baur-Melnyk, A

    2014-06-01

    Robust and reliable imaging methods are required to estimate the skeletal tumor load in multiple myeloma, as well as for the diagnosis of extraskeletal manifestations. Imaging also plays an essential role in the assessment of fracture risk and of vertebral fractures. The conventional skeletal survey has been the gold standard in the imaging of multiple myeloma for many years. Other modalities which have been investigated and are in use are whole-body computed tomography (WBCT), 18F-fluorodeoxyglucose positron emission tomography computed tomography (FDG PET-CT) and whole-body magnetic resonance imaging (WBMRI). These techniques are able to depict both mineralized bone and the bone marrow with a high sensitivity for myeloma lesions. Several studies have shown that cross-sectional imaging is superior to the skeletal survey in the detection of myeloma lesions and WBMRI has been shown to be significantly more sensitive than WBCT for the detection of focal myeloma lesions as well as for diffuse infiltration. The FDG PET-CT technique has a sensitivity comparable to WBMRI. Due to the higher sensitivity in the detection of myeloma lesions WBCT and WBMRI should replace the skeletal survey. A WBCT should be performed if there is suspicion of multiple myeloma. If no focal lesions are found WBMRI or at least MRI of the spine and pelvis should be additionally performed if available. If WBMRI has been initially performed and focal lesions are present, an additional WBCT may be performed to assess the extent of bone destruction and fracture risk. In cases of monoclonal gammopathy of undetermined significance (MGUS), solitary and smoldering myeloma, a WBMRI, if available, should be performed in addition to WBCT.

  3. Positive correlation between bone marrow mast cell density and ISS prognostic index in patients with multiple myeloma.

    PubMed

    Pappa, Constantina A; Tsirakis, George; Roussou, Parascevi; Xekalou, Athina; Goulidaki, Nectaria; Konsolas, Ioannis; Alexandrakis, Michael G; Stathopoulos, Efstathios N

    2013-12-01

    We evaluated mast cell density (MCD) in myeloma bone marrow biopsies and correlated it with stage of disease and markers of angiogenesis. Fifty-three untreated myeloma patients and 28 of them responded to therapy were studied. Mast cells were highlighted using immunohistochemical stain for tryptase. Angiogenesis was evaluated measuring microvascular density and serum levels of basic-fibroblast growth factor and tumor necrosis factor-alpha. MCD was higher in untreated patients, compared to healthy population and responders. Significant association was found between MCD with angiogenesis and clinical stage of disease, suggesting that mast cells could be used as target for myeloma treatment. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Maintenance therapy in multiple myeloma

    PubMed Central

    Mewawalla, Prerna; Chilkulwar, Abhishek

    2016-01-01

    Despite recent advances, multiple myeloma remains an incurable disease. Induction therapy followed by autologous transplantation has become the standard of care. The idea of maintenance therapy in multiple myeloma is not new. Starting with chemotherapy in 1975, to interferon in 1998, to novel agents recently, a multitude of agents have been explored in patients with multiple myeloma. In spite of the novel agents, multiple myeloma continues to be an incurable disease with the progression-free survival after autologous transplant rarely exceeding 3 years. The goal of using maintenance therapy has been to improve the outcomes following autologous transplantation by increasing the progression-free survival, deepening remissions and perhaps increasing overall survival. It has been shown that patients with a stringent complete response (CR) have a better outcome [Kapoor et al. 2013]. It is becoming increasingly common to check minimal residual disease (MRD) as a means of assessing depth of response. It has also been shown that patients with no MRD have not only a better progression-free survival but also a better overall survival compared with patients who are MRD positive. This makes it even more important to find agents for maintenance therapy, which can further deepen and maintain responses. Here, we present a comprehensive review of the agents studied as maintenance for multiple myeloma and their efficacy, both in terms of overall survival, progression-free survival and toxicity. PMID:28203343

  5. What Are the Key Statistics about Multiple Myeloma?

    MedlinePlus

    ... Myeloma About Multiple Myeloma What Are the Key Statistics About Multiple Myeloma? Multiple myeloma is a relatively ... in women). Visit the American Cancer Society’s Cancer Statistics Center for more key statistics. Written by References ...

  6. Targeting autophagy in multiple myeloma.

    PubMed

    Yun, Zhuang; Zhichao, Jin; Hao, Yao; Ou, Ji; Ran, Yang; Wen, Dong; Qun, Shen

    2017-08-01

    Autophagy plays an important role in plasma cell ontogeny and in the pathophysiology of multiple myeloma. Autophagy is usually considered a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in maintaining the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death in myeloma cells, and could synergize with proteasome inhibitors. However, the excessive activation of autophagy could also lead to the extreme degradation of the organelles that induce autophagic cell death. Hence, the activation of autophagic cell death might also represent a promising approach for treating myeloma. Recent studies have demonstrated that autophagy also mediates drug resistance in myeloma cells and the complications of myeloma, while the inhibition of autophagy may reverse the response to drugs. In this study, we have mainly reviewed recent research on autophagy in relationship to the therapeutic effect, the reversal of drug resistance, and the mediation of complications. Copyright © 2017. Published by Elsevier Ltd.

  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. [Pneumococcal septic arthritis revealing a multiple myeloma].

    PubMed

    Renou, F; Gerber, A; Moiton, M-P; Ferrandiz, D; Yvin, J-L

    2007-03-01

    The most common presenting features of multiple myeloma are bone pain, anemia, renal failure or hypercalcemia. Bacterial infection as the initial presentation of this desease is rare. We report the case of a 62-year-old man with pneumococcal septic arthritis of the knee revealing a multiple myeloma. Pneumococcal infection should lead to a suspicion of underlying illness and especially the multiple myeloma.

  9. Preclinical animal models of multiple myeloma

    PubMed Central

    Lwin, Seint T; Edwards, Claire M; Silbermann, Rebecca

    2016-01-01

    Multiple myeloma is an incurable plasma-cell malignancy characterized by osteolytic bone disease and immunosuppression. Murine models of multiple myeloma and myeloma bone disease are critical tools for an improved understanding of the pathogenesis of the disease and the development of novel therapeutic strategies. This review will cover commonly used immunocompetent and xenograft models of myeloma, describing the advantages and disadvantages of each model system. In addition, this review provides detailed protocols for establishing systemic and local models of myeloma using both murine and human myeloma cell lines. PMID:26909147

  10. Multiple myeloma with extramedullary disease.

    PubMed

    Oriol, Albert

    2011-11-01

    Plasmacytoma is a tumor mass consisting of atypical plasma cells. Incidence of plasmacytomas associated with multiple myeloma range from 7% to 17% at diagnosis and from 6% to 20% during the course of the disease. In both situations, occurrence of extramedullary disease has been consistently associated with a poorer prognosis of myeloma. Extramedullary relapse or progression occurs in a variety of clinical circumstances and settings, and therefore requires individualization of treatment. Alkylating agents, bortezomib, and immunomodulatory drugs, along with corticoids, have been used to treat extramedullary relapse but, because of the relatively low frequency or detection rate of extramedullary relapse, no efficacy data are available from controlled studies in this setting.

  11. [Mandibular lesions in multiple myeloma].

    PubMed

    Scutellari, P N; Orzincolo, C

    1992-03-01

    A review was made of 237 cases of multiple myeloma seen at the Institute of Radiology and Hematology of the Ferrara University from 1984 through 1990. The results showed skeletal involvement of the mandible to be present in 25 patients (10.54%). The diagnosis of multiple myeloma was based on the following criteria: 1) increased number of abnormal, atypical or immature plasma cells in the bone marrow; 2) the presence of a monoclonal protein in the serum or urine; 3) bone lesions consistent with those of myeloma. Symptoms include pain and swelling of the oral cavity, tooth mobility and loss, numbness along the inferior dental nerve, and paresthesia of the lower lip. The typical radiographic appearance is a well-defined "punched-out" lytic defect, solitary or multiple; sometimes, the defect enlarges and appears "bubbly" or septated. Permeative lytic areas, with blurred outlines, are a rare pattern, which is radiologically indistinguishable from skeletal metastases. The involvement of the oral cavity and jaw in multiple myeloma has been often reported in literature: nevertheless, if radiographs of the jaws had been systematically taken in all the cases, its incidence would probably have been much higher than previously suspected.

  12. Novel therapies for multiple myeloma.

    PubMed

    Ryoo, Joan J; Cole, Craig Emmitt; Anderson, Kenneth C

    2002-09-01

    Multiple myeloma (MM) continues to evade cure by conventional therapies, increasing the urgency for new, biologically based treatments. Reviewed in this discussion are novel chemotherapies under clinical trial that capitalize upon greater comprehension of tumor pathophysiology. In targeting tumor biology, these therapies serve as a model of treatment with great potential for improving outcomes in patients with MM.

  13. 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.

  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 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

  15. 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

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

    MedlinePlus

    ... and Treatment? Multiple Myeloma About 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 ...

  17. The role of Capon in multiple myeloma.

    PubMed

    Shen, Yaodong; Liu, Haiyan; Gu, Siyu; Wei, Ziwei; Liu, Hong

    2017-07-01

    Capon is a ligand protein of nitric oxide synthase 1. Recently, studies have shown that Capon is involved in the development of tumors. It is independent of the regulation of nitric oxide synthase 1 in this process. At the same time, studies have found that nitric oxide synthase 1 is expressed in multiple myeloma, but its role in the development and progression of myeloma remains unclear. In this study, we found that there was a different expression of Capon between the normal multiple myeloma cells and the adherent multiple myeloma cells. In the process of myeloma cell proliferation, the reduced expression of Capon reduces the arrest of the cell cycle in the G1 phase and promotes the proliferation of myeloma cells. Cell adhesion-mediated drug resistance is one of the most important factors, which affect the chemotherapy effect of multiple myeloma. If the expression of Capon is decreased, myeloma cells are adhered to fibronectin or bone marrow stromal cells (bone marrow mesenchymal stem cells). In addition, the sensitivity of the cell line to chemotherapeutic agents was reduced after silencing Capon in the myeloma cell line which was adhered to bone marrow mesenchymal stem cells. We also found that reduced expression of Capon resulted in the activation of the AKT signaling pathway. In conclusion, these results may be helpful in studying the role of Capon in multiple myeloma.

  18. Oral ixazomib maintenance therapy in multiple myeloma.

    PubMed

    Offidani, Massimo; Corvatta, Laura; Gentili, Silvia; Maracci, Laura; Leoni, Pietro

    2016-01-01

    Continuous therapy has proven to be an effective therapeutic strategy to improve the outcome of both young and elderly multiple myeloma patients. Remarkably, lenalidomide and bortezomib showed to play a crucial role in this setting due to their safety profile allowing long-term exposure. Ixazomib, the first oral proteasome inhibitor to be evaluated in multiple myeloma, exerts substantial anti-myeloma activity as a single agent and particularly in combination with immunomodulatory drugs and it may be an attractive option for maintenance therapy. Here we address the issue of maintenance therapy as part of a therapeutic approach of multiple myeloma patients focusing on the potential role of ixazomib.

  19. Cutaneous Manifestations of Multiple Myeloma

    PubMed Central

    Behera, Binodini; Pattnaik, Monali; Sahu, Bharti; Mohanty, Prasenjeet; Jena, Swapna; Mohapatra, Liza

    2016-01-01

    Multiple myeloma (MM) is a proliferative disorder of plasma cells which produce abnormal immunoglobulin proteins. Skin involvement is rarely found in this disorder. They are either specific or nonspecific lesions. We report four such interesting patients who presented to us initially with common dermatoses such as leukocytoclastic vasculitis, pyoderma gangrenosum, and vesiculobullous disorders and were subsequently diagnosed to have MM. There were no skeletal involvements or renal function abnormality at the time of presentation. Unusual presentation, nonresponsiveness to conventional therapy, and abnormal blood parameters prompted us to suspect some underlying systemic conditions which were later confirmed to be MM after serum immunoelectrophoresis for M-band and bone marrow biopsy. PMID:27904188

  20. Multiple Myeloma: Diagnosis and Treatment

    PubMed Central

    Rajkumar, S. Vincent; Kumar, Shaji

    2016-01-01

    The diagnosis and treatment of multiple myeloma (MM) has changed dramatically in the last decade. The disease definition has been updated to allow highly specific biomarkers in addition to established markers of end-organ damage. The staging system has been revised to combine both measures of tumor burden and disease biology. Advances in therapy have resulted in a significant improvement of overall survival. New drugs introduced in the last few years include carfilzomib, pomalidomide, and panobinostat. In addition, monoclonal antibodies such as elotuzumab and daratumumab have shown promising clinical activity. In this review, we outline the current approach to diagnosis, prognosis, and management of MM. PMID:26763514

  1. [Thalidomide, cereblon and multiple myeloma].

    PubMed

    Ogura, Toshihiko

    2015-01-01

    Cereblon was identified as a direct target of thalidomide by Prof. H. Handa, and this pioneering work triggered active research on IMiDs (immunomodulatory drugs), which include thalidomide-derivatives, such as lenalidomide and pomalidomide. These small molecules have been shown to bind to cereblon (CRBN) to modulate its activity as a substrate receptor. In addition, structural analyses on CRBN have revealed unique actions of these small agents, by which degradation of transcription factors is controlled in a specific and unique way. I summarize recent progress on CRBN-CRLA ubiquitin ligase and IMiDs, focusing on the therapeutic application of these drugs for treatment of multiple myeloma.

  2. Cutaneous Manifestations of Multiple Myeloma.

    PubMed

    Behera, Binodini; Pattnaik, Monali; Sahu, Bharti; Mohanty, Prasenjeet; Jena, Swapna; Mohapatra, Liza

    2016-01-01

    Multiple myeloma (MM) is a proliferative disorder of plasma cells which produce abnormal immunoglobulin proteins. Skin involvement is rarely found in this disorder. They are either specific or nonspecific lesions. We report four such interesting patients who presented to us initially with common dermatoses such as leukocytoclastic vasculitis, pyoderma gangrenosum, and vesiculobullous disorders and were subsequently diagnosed to have MM. There were no skeletal involvements or renal function abnormality at the time of presentation. Unusual presentation, nonresponsiveness to conventional therapy, and abnormal blood parameters prompted us to suspect some underlying systemic conditions which were later confirmed to be MM after serum immunoelectrophoresis for M-band and bone marrow biopsy.

  3. Paraneoplastic hyperamylasaemia in association with multiple myeloma.

    PubMed

    Calvo-Villas, Jose M; Alvarez, Iván; Carretera, Elena; Espinosa, Juan; Sicilia, Francisco

    2007-01-01

    Marked hyperamylasaemia associated with an amylase-producing multiple myeloma appears to be a fairly unusual phenomenon. The present report describes a fatal case of multiple myeloma associated with paraneoplastic hyperamylasaemia without evidence of pancreatic or salivary gland involvement. Serum and urine amylase levels paralleled the myeloma response to chemotherapy and disease progression. The importance of paraneoplastic hyperamylasaemia as a useful myeloma marker to monitor disease progression and treatment response is emphasized. Conventional chemotherapy at diagnosis and salvage treatment with bortezomib at relapse failed to achieve a long-term response and to decrease the serum amylase to a normal level.

  4. 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.

  5. Multiple myeloma presenting as acute pancreatitis.

    PubMed

    Mishra, Shakti Bedanta; Azim, Afzal; Mukherjee, Arindam

    2017-09-01

    A 36 year old male presented to the emergency department with severe epigastric pain, nausea, vomiting without hematemesis, diarrhea and anorexia. He presented with respiratory distress, shock and fever at the emergency. He was intubated and shifted to the intensive care unit with the diagnosis of acute pancreatitis with hypercalcemia and an elevated amylase and lipase's well as thrombocytopenia and elevated creatinine. CT scan of abdomen was done which showed lytic bone lesions in the spine and necrosis of the pancrease. He was evaluated for multiple myeloma and it was confirmed in a bone marrow biopsy. Multiple myeloma usually is seen in patients aged more than 60 yrs. The typical presentation of multiple myeloma is anemia, back pain, and an elevated sedimentation rate. Patients with multiple myeloma have hypercalcemia but it's rarely manifested as acute pancreatitis. This case shows a rare presentation of multiple myeloma as acute pancreatitis in a younger adult. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Innovative Agents in Multiple Myeloma

    PubMed Central

    Faiman, Beth; Richards, Tiffany

    2014-01-01

    Multiple myeloma (MM) remains an incurable cancer of the bone marrow plasma cells. However, the overall survival of patients with MM has increased dramatically within the past decade. This is due, in part, to newer agents such as immunomodulatory drugs (lenalidomide, thalidomide, and pomalidomide) and proteasome inhibitors (bortezomib, carfilzomib, MLN9708). These and several other new classes of drugs have arisen from an improved understanding of the complex environment in which genetic changes occur. Improved understanding of genetic events will enable clinicians to better stratify risk before and during therapy, tailor treatment, and test the value of personalized interventions. The ultimate goal in this incurable disease setting is to reduce the impact of cancer- or chemotherapy-related side effects. Nurses and advanced practitioners are integral to the treatment team. Thus, each should be aware of changes to the current drug landscape. Targeted drugs with sophisticated mechanisms of action are currently under investigation. Patients gain access to newer drugs within the context of clinical trials. Awareness of such trials will help accrual and determine if therapeutic benefit exists. In this article, we will describe new agents with unique and targeted mechanisms of action that have activity in patients with relapsed and/or refractory multiple myeloma. PMID:25089218

  7. [Correlation between Expression of CD200 and Regulatory T Cells in Multiple Myeloma and Its Significance in Prognostic Stratification].

    PubMed

    Zhu, Ming-Xia; Wan, Wen-Li; Li, Hai-Shen; Wang, Yan-Fang; Wang, Jing; Ling, Hui-Sen; Yan, Xin-Xing; Ke, Xiao-Yan

    2016-10-01

    To study the correlation between expression of CD200 and regulatory T cells (Tregs) in multiple myeloma(MM) patients and to explore its significance in prognostic stratification. CD200 and other immunophenotypes, including CD38, CD138, CD56, CD19, CD20, CD117, cytoplasm light chain Kappa and Lambda in bone marrow samples, and Tregs in peripheral blood were detected by flow cytometry from 78 newly diagnosed MM patients. Serum concentrations of hemoglobin(Hb), β2 microglobulin (β2-MG) and lactate dehydrogenase (LDH) were detected, respectively. The new risk stratification of patients was carried out according to international stage system (ISS) and cytogenetic characteristics. The correlation between expression of CD200 and Tregs in MM patients was analyzed and their differences in prognosis were compared. The positive rate of CD200 expression was 71.79% in 78 patients (56/78). The expression of CD200 in sex and age of patients was no significant different. The expression of CD117 in CD200(+) group was significantly higher than that of in CD200(-) group (P=0.032). There was no significant difference in the expression of CD20, CD56 and CD19 between 2 groups. The level of Hb in CD200(+) group was significantly lower than that in CD200(-) group (P=0.035). The level of β2-MG in CD200(+) group was significantly higher than that in CD200(-) group (P=0.013). There was no significant difference in the level of LDH between 2 groups. In CD200(+) group, 17 patients were in stageⅠ, accounting for 58.62% (17/29), 30 patients were in stageⅡ, accounting for 75% (30/40), 9 patients were in stage Ⅲ, accounting for 100% (9/9). With the increase of CD200 expression intensity, the risk of prognostic stratification went up (P=0). The brighter CD200 expressed, the worse the prognosis was. The percentage of Trges in CD200(+) group was significantly higher than that of in CD200(-) group (P=0.043). The content of Tregs was positively correlated with the expression of CD200 (r=0

  8. [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.

  9. Hypodiploid multiple myeloma is characterized by more aggressive molecular markers than non-hyperdiploid multiple myeloma

    PubMed Central

    Van Wier, Scott; Braggio, Esteban; Baker, Angela; Ahmann, Gregory; Levy, Joan; Carpten, John D.; Fonseca, Rafael

    2013-01-01

    Multiple myeloma can be categorized into hyperdiploid or non-hyperdiploid myeloma based on the number of chromosomes found in the tumor clone. Among the non-hyperdiploid myelomas, the hypodiploid subtype has the most aggressive clinical phenotype, but the genetic differences between groups are not completely defined. In order to understand the genetic background of hypodiploid multiple myeloma better, we compared the genomic (array-based comparative genomic hybridization) and transcriptomic (gene expression profiling) background of 49 patients with hypodiploid myeloma with 50 other non-hyperdiploid and 125 hyperdiploid myeloma patients. There were significant chromosomal and gene expression differences between hyperdiploid patients and non-hyperdiploid and hypodiploid patients. Non-hyperdiploid and hypodiploid patients shared most of the chromosomal abnormalities; nevertheless a subset of these abnormalities, such as monosomies 13, 14 and 22, was markedly increased in hypodiploid patients. Furthermore, deletions of 1p, 12p, 16q and 17p, all associated with poor outcome or progression in multiple myeloma, were significantly enriched in hypodiploid patients. Molecular risk-stratification indices reinforce the worse prognosis associated with hypodiploid multiple myeloma compared with non-hyperdiploid multiple myeloma. Gene expression profiling clustered hypodiploid and non-hyperdiploid subgroups closer than hyperdiploid myeloma but also highlighted the up-regulation of CCND2, WHSC1/MMSET and FGFR3 in the hypodiploid subtype. In summary, hypodiploid multiple myeloma is genetically similar to non-hyperdiploid multiple myeloma but characterized by a higher prevalence of genetic alterations associated with poor outcome and disease progression. It is provocative to hypothesize that hypodiploid multiple myeloma is an advanced stage of non-hyperdiploid multiple myeloma. PMID:23716545

  10. Inherited predisposition to multiple myeloma

    PubMed Central

    Koura, Divya T.

    2013-01-01

    Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, after non-Hodgkin lymphoma. Family pedigree analyses of high-risk families, case-control studies and racial disparities in disease incidence all point to a potential inherited predisposition to MM. Genome-wide association studies (GWASs) have identified susceptibility loci in a number of cancers and such studies are currently underway in MM. To date, GWASs in MM have identified several potential regions of interest for further study on chromosomes 3p22, 7p15.3, 8q24 and 2p23.3. In addition, several targets of paraproteins (so called ‘paratargs’) in MM have been identified. Hyperphosphorylation of the paratarg protein, which is inherited in an autosomal dominant manner, appears a common mechanism underlying the antigenicity of these proteins. One particular protein, hyperphosphorylated paratarg-7 (pP-7) is a common target in persons with myeloma and has also been identified in affected members of several high-risk MM families. It appears that the frequency of pP-7 as an antigenic target may be particularly high in African American patients with MM, which could be part of the explanation for observed racial disparities in the incidence of MM. In this review we focus on available data in the area of inherited predisposition to MM, and highlight future research directions. PMID:23926460

  11. High levels of periostin correlate with increased fracture rate, diffuse MRI pattern, abnormal bone remodeling and advanced disease stage in patients with newly diagnosed symptomatic multiple myeloma

    PubMed Central

    Terpos, E; Christoulas, D; Kastritis, E; Bagratuni, T; Gavriatopoulou, M; Roussou, M; Papatheodorou, A; Eleutherakis-Papaiakovou, E; Kanellias, N; Liakou, C; Panagiotidis, I; Migkou, M; Kokkoris, P; Moulopoulos, L A; Dimopoulos, M A

    2016-01-01

    Periostin is an extracellular matrix protein that is implicated in the biology of normal bone remodeling and in different cancer cell growth and metastasis. However, there is no information on the role of periostin in multiple myeloma (MM). Thus, we evaluated periostin in six myeloma cell lines in vitro; in the bone marrow plasma and serum of 105 newly diagnosed symptomatic MM (NDMM) patients and in the serum of 23 monoclonal gammopathy of undetermined significance (MGUS), 33 smoldering MM (SMM) patients, 30 patients at the plateau phase post-first-line therapy, 30 patients at first relapse and 30 healthy controls. We found high levels of periostin in the supernatants of myeloma cell lines compared with ovarian cancer cell lines that were not influenced by the incubation with the stromal cell line HS5. In NDMM patients the bone marrow plasma periostin was almost fourfold higher compared with the serum levels of periostin and correlated with the presence of fractures and of diffuse magnetic resonance imaging pattern of marrow infiltration. Serum periostin was elevated in NDMM patients compared with healthy controls, MGUS and SMM patients and correlated with advanced disease stage, high lactate dehydrogenase, increased activin-A, increased bone resorption and reduced bone formation. Patients at first relapse had also elevated periostin compared with healthy controls, MGUS and SMM patients, while even patients at the plateau phase had elevated serum periostin compared with healthy controls. These results support an important role of periostin in the biology of myeloma and reveal periostin as a possible target for the development of antimyeloma drugs. PMID:27716740

  12. [Bone lesion in multiple myeloma].

    PubMed

    Ise, Mikiko; Takagi, Toshiyuki

    2007-12-01

    Bone destruction is a hallmark of multiple myeloma(MM). Almost all MM patients develop osteolytic bone lesions that can cause pathologic fractures and severe bone pain. Osteolytic lesions result from increased bone resorption due to osteoclast stimulation and decreased bone formation due to osteoblast inhibition. Plain radiography, CT, and MRI are established imaging techniques in MM. FDG-PET imaging is promising newer scanning technique under current evaluation. The aggressive features of MM bone lesions have significantly contributed to poor prognosis. Therefore, a systemic approach to analgesia, which includes radiotherapy and orthopedic intervention, must be applied as a part of the comprehensive care plan of MM patient. Bisphosphonates have been shown to reduce vertebral fractures and bone pain.

  13. 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.

  14. Autologous Stem Cell Transplant Followed By Maintenance Therapy in Treating Elderly Patients With Multiple Myeloma

    ClinicalTrials.gov

    2017-02-20

    Extramedullary Plasmacytoma; Isolated Plasmacytoma of Bone; Light Chain Deposition Disease; Primary Systemic Amyloidosis; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma

  15. 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

  16. Carfilzomib for the treatment of multiple myeloma.

    PubMed

    Lue, J; Goel, S; Mazumder, A

    2013-03-01

    Carfilzomib is a second-generation selective proteasome inhibitor that has been recently approved in the use for refractory multiple myeloma. It has been shown to be beneficial in both bortezomib-resistant and bortezomib-naive patients, with a tolerable side effect profile. Peripheral neuropathy is less common in patients receiving carfilzomib compared to bortezomib. Recent and ongoing clinical trials are establishing the role of carfilzomib in the treatment of refractory multiple myeloma.

  17. Novel Induction Regimens in Multiple Myeloma.

    PubMed

    Runcie, Karie D; Mark, Tomer M

    2015-12-01

    Multiple myeloma is the second most common hematologic malignancy and predominantly affects the elderly. The introduction of novel agents such as thalidomide, lenalidomide, and bortezomib has improved progression-free survival, overall survival, and quality of life in myeloma patients. Next generation agents such as carfilzomib hold further promise for increased depth and length of remission. Autologous stem cell transplant remains a useful tool in the treatment of multiple myeloma, but not all patients are eligible for this procedure. As therapy becomes more effective, determination of the right therapy in the right patient becomes paramount. The focus of this review is a critical analysis of combinations of the novel agents in the treatment of newly diagnosed multiple myeloma in both transplant eligible and ineligible patients.

  18. Smoldering Multiple Myeloma: Emerging Concepts and Therapeutics.

    PubMed

    Sundararajan, Srinath; Kumar, Abhijeet; Korde, Neha; Agarwal, Amit

    2016-04-01

    Smoldering multiple myeloma (SMM) is a pre-malignant condition with an inherent risk for progression to multiple myeloma (MM). The 2014 IMWG guidelines define smoldering multiple myeloma as a monoclonal gammopathy disorder with serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10-60 % without any myeloma-defining events or amyloidosis. The risk for progression of SMM to MM vary based on clinical, laboratory, imaging, and molecular characteristics. Observation, with periodic monitoring is the current standard of care for SMM. Over last few years, research advances in SMM have led to the delineation of newer risk factors for progression and identification of a "high-risk" group that would potentially benefit from early treatment. This review focuses on advances in the SMM risk-stratification model and recent clinical trials in this patient population.

  19. Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients.

    PubMed

    Blimark, Cecilie; Holmberg, Erik; Mellqvist, Ulf-Henrik; Landgren, Ola; Björkholm, Magnus; Hultcrantz, Malin; Kjellander, Christian; Turesson, Ingemar; Kristinsson, Sigurdur Y

    2015-01-01

    Infections are a major cause of morbidity and mortality in patients with multiple myeloma. To estimate the risk of bacterial and viral infections in multiple myeloma patients, we used population-based data from Sweden to identify all multiple myeloma patients (n=9253) diagnosed from 1988 to 2004 with follow up to 2007 and 34,931 matched controls. Cox proportional hazard models were used to estimate the risk of infections. Overall, multiple myeloma patients had a 7-fold (hazard ratio =7.1; 95% confidence interval = 6.8-7.4) risk of developing any infection compared to matched controls. The increased risk of developing a bacterial infection was 7-fold (7.1; 6.8-7.4), and for viral infections 10-fold (10.0; 8.9-11.4). Multiple myeloma patients diagnosed in the more recent calendar periods had significantly higher risk of infections compared to controls (P<0.001). At one year of follow up, infection was the underlying cause in 22% of deaths in multiple myeloma patients. Mortality due to infections remained constant during the study period. Our findings confirm that infections represent a major threat to multiple myeloma patients. The effect on infectious complications due to novel drugs introduced in the treatment of multiple myeloma needs to be established and trials on prophylactic measures are needed.

  20. CARs in the Lead Against Multiple Myeloma.

    PubMed

    Ormhøj, Maria; Bedoya, Felipe; Frigault, Matthew J; Maus, Marcela V

    2017-04-01

    The recent clinical success of CD19-directed chimeric antigen receptor (CAR) T cell therapy in chronic and acute leukemia has led to increased interest in broadening this technology to other hematological malignancies and solid tumors. Now, advances are being made using CAR T cell technology to target myeloma antigens such as B cell maturation antigen (BCMA), CD138, and kappa-light chain as well as CD19 on putative myeloma stem cells. To date, only a limited number of multiple myeloma patients have received CAR T cell therapy but preliminary results have been encouraging. In this review, we summarize the recently reported results of clinical trials conducted utilizing CAR T cell therapy in multiple myeloma (MM).

  1. 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

  2. Bone Disease in Multiple Myeloma.

    PubMed

    Eda, Homare; Santo, Loredana; David Roodman, G; Raje, Noopur

    2016-01-01

    Bone involvement represented by osteolytic bone disease (OBD) or osteopenia is one of the pathognomonic and defining characteristics of multiple myeloma (MM). Nearly 90 % of patients with MM develop osteolytic bone lesions, frequently complicated by skeletal-related events (SRE) such as severe bone pain, pathological fractures, vertebral collapse, hypercalcemia, and spinal cord compression. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. OBD is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Inhibition of osteolysis and stimulation of OB differentiation leads to reduced tumor growth in vivo. Therefore, novel agents targeting OBD are promising therapeutic strategies not only for the treatment of MM OBD but also for the treatment of MM. Several novel agents in addition to bisphosphonates are currently under investigation for their positive effect on bone remodeling via OC inhibition or OB stimulation. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from MM OBD but also capitalizing on the resultant antitumor activity.

  3. 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

  4. Abnormalities in Chromosomes 1q and 13 Independently Correlate With Factors of Poor Prognosis in Multiple Myeloma.

    PubMed

    Kim, Miyoung; Ju, Young Su; Lee, Eun Jin; Kang, Hee Jung; Kim, Han Sung; Cho, Hyoun Chan; Kim, Hyo Jung; Kim, Jung Ah; Lee, Dong Soon; Lee, Young Kyung

    2016-11-01

    We comprehensively profiled cytogenetic abnormalities in multiple myeloma (MM) and analyzed the relationship between cytogenetic abnormalities of undetermined prognostic significance and established prognostic factors. The karyotype of 333 newly diagnosed MM cases was analyzed in association with established prognostic factors. Survival analysis was also performed. MM with abnormal karyotypes (41.1%) exhibited high international scoring system (ISS) stage, frequent IgA type, elevated IgG or IgA levels, elevated calcium levels, elevated creatine (Cr) levels, elevated β2-microglobulin levels, and decreased Hb levels. Structural abnormalities in chromosomes 1q, 4, and 13 were independently associated with elevated levels of IgG or IgA, calcium, and Cr, respectively. Chromosome 13 abnormalities were associated with poor prognosis and decreased overall survival. This is the first study to demonstrate that abnormalities in chromosomes 1q, 4, and 13 are associated with established factors for poor prognosis, irrespective of the presence of other concurrent chromosomal abnormalities. Chromosome 13 abnormalities have a prognostic impact on overall survival in association with elevated Cr levels. Frequent centromeric breakpoints appear to be related to MM pathogenesis.

  5. Abnormalities in Chromosomes 1q and 13 Independently Correlate With Factors of Poor Prognosis in Multiple Myeloma

    PubMed Central

    Kim, Miyoung; Ju, Young-Su; Lee, Eun Jin; Kang, Hee Jung; Kim, Han-Sung; Cho, Hyoun Chan; Kim, Hyo Jung; Kim, Jung-Ah; Lee, Dong Soon

    2016-01-01

    Background We comprehensively profiled cytogenetic abnormalities in multiple myeloma (MM) and analyzed the relationship between cytogenetic abnormalities of undetermined prognostic significance and established prognostic factors. Methods The karyotype of 333 newly diagnosed MM cases was analyzed in association with established prognostic factors. Survival analysis was also performed. Results MM with abnormal karyotypes (41.1%) exhibited high international scoring system (ISS) stage, frequent IgA type, elevated IgG or IgA levels, elevated calcium levels, elevated creatine (Cr) levels, elevated β2-microglobulin levels, and decreased Hb levels. Structural abnormalities in chromosomes 1q, 4, and 13 were independently associated with elevated levels of IgG or IgA, calcium, and Cr, respectively. Chromosome 13 abnormalities were associated with poor prognosis and decreased overall survival. Conclusions This is the first study to demonstrate that abnormalities in chromosomes 1q, 4, and 13 are associated with established factors for poor prognosis, irrespective of the presence of other concurrent chromosomal abnormalities. Chromosome 13 abnormalities have a prognostic impact on overall survival in association with elevated Cr levels. Frequent centromeric breakpoints appear to be related to MM pathogenesis. PMID:27578511

  6. 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

  7. 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

  8. Update of thrombosis in multiple myeloma.

    PubMed

    Leebeek, Frank W G

    2016-04-01

    With the introduction of thalidomide and multi-agent chemotherapy in the treatment of multiple myeloma around 15years ago a strongly increased risk of venous thrombosis was observed. The occurrence of venous thrombosis in multiple myeloma is not only determined by the kind of treatment, but also by several other factors, including disease specific factors, patient-specific factors, changes in pro-and anticoagulant factors and fibrinolysis. Studies showed a prevalence of up to 25% in patients with newly diagnosed multiple myeloma. Therefore these patients nowadays receive prophylaxis with aspirin, low molecular weight heparin or warfarin in order to reduce the risk of venous thrombosis. It is however still debatable which patients should receive prophylaxis and what the best kind of prophylaxis is, considering both the risk of thrombosis and the risk of bleeding. In recent years several new anti-myeloma agents have been developed and investigated in large clinical studies. The risk of thrombosis using these new drugs seems less than with thalidomide and lenalidomide-based regimens. In this article an update on prevention and management of thrombotic events in patients with multiple myeloma is given. © 2016 Elsevier Ltd. All rights reserved.

  9. Panobinostat for the Treatment of Multiple Myeloma.

    PubMed

    Laubach, Jacob P; Moreau, Philippe; San-Miguel, Jesús F; Richardson, Paul G

    2015-11-01

    Panobinostat is a potent oral deacetylase inhibitor that alters gene expression through epigenetic mechanisms and inhibits protein degradation. It was recently approved by the FDA and EMA for use in combination with bortezomib and dexamethasone in patients with multiple myeloma who have received ≥2 prior regimens, including bortezomib and an immunomodulatory drug. Panobinostat was approved based on results from the phase III PANORAMA 1 trial in patients with relapsed or relapsed and refractory multiple myeloma, which showed that panobinostat plus bortezomib and dexamethasone significantly extended progression-free survival (median, 12.0 months) compared with placebo plus bortezomib and dexamethasone (median, 8.1 months; P < 0.0001). Additional ongoing trials are evaluating panobinostat in combination with other partners in the relapsed/refractory and newly diagnosed treatment settings. This review focuses on panobinostat and its mechanism of action, pharmacokinetics, and clinical data in the treatment of relapsed or relapsed and refractory multiple myeloma.

  10. 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

  11. 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.

  12. [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.

  13. Cancer stem cells: controversies in multiple myeloma.

    PubMed

    Brennan, Sarah K; Matsui, William

    2009-11-01

    Increasing data suggest that the initiation, relapse, and progression of human cancers are driven by specific cell populations within an individual tumor. However, inconsistencies have emerged in precisely defining phenotypic markers that can reliably identify these "cancer stem cells" in nearly every human malignancy studied to date. Multiple myeloma, one of the first tumors postulated to be driven by a rare population of cancer stem cells, is no exception. Similar to other diseases, controversy surrounds the exact phenotype and biology of multiple myeloma cells with the capacity for clonogenic growth. Here, we review the studies that have led to these controversies and discuss potential reasons for these disparate findings. Moreover, we speculate how these inconsistencies may be resolved through studies by integrating advancements in both myeloma and stem cell biology.

  14. 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

  15. Management and prognosis of multiple myeloma.

    PubMed

    Kyle, R A; Elveback, L R

    1976-12-01

    Patients with asymptomatic or smoldering multiple myeloma should not be treated but should be observed closely for progression. For symptomatic myeloma, chemotherapy is indicated. Melphalan, the agent of choice, should be given with prednisone for 1 week of every 6 weeks, If melphalan brings no response, or response and then relapse, cyclophosphamide (Cytoxan) should be give intravenously every 4 weeks or orally every day. BCNU, CCNU, and doxorubicin (Adriamycin) have also shown activity in myeloma. Hypercalcemia occurs in one-third of patients and should be countered with hydration, corticosteroids, Neutra-Phos, or mithramycin. Long-term hemodialysis has achieved some success. The combination of sodium flouride and calcium carbonate produces new bone formation; it seems a useful adjunct in treatment for myelomatous bone disease. Radiation should be utilized only for severe, localized pain or for solitary lesions. Survival with multiple myeloma varies, mean durations being 2 to 3 years. Multivariate analysis indicates that serum creatinine and calcium levels are the most significant indicators regarding 2-year survival. We have found monoclonal proteinuria not significantly more frequent with renal insufficiency than with normal renal function, renal insufficiency not significantly more frequent with lambda than with kappa chains, and survival not significantly greater with IgG myeloma than with IgA.

  16. Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment.

    PubMed

    Ponzetta, Andrea; Benigni, Giorgia; Antonangeli, Fabrizio; Sciumè, Giuseppe; Sanseviero, Emilio; Zingoni, Alessandra; Ricciardi, Maria Rosaria; Petrucci, Maria Teresa; Santoni, Angela; Bernardini, Giovanni

    2015-11-15

    Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice. Herein we report that the number of KLRG1(-) NK cells endowed with potent effector function rapidly and selectively decreases in bone marrow during multiple myeloma growth, this correlating with decreased bone marrow NK cell degranulation in vivo. Altered NK cell subset distribution was dependent on skewed chemokine/chemokine receptor axes in the multiple myeloma microenvironment, with rapid downmodulation of the chemokine receptor CXCR3 on NK cells, increased CXCL9 and CXCL10, and decreased CXCL12 expression in bone marrow. Similar alterations in chemokine receptor/chemokine axes were observed in patients with multiple myeloma. Adoptive transfer experiments demonstrated that KLRG1(-) NK cell migration to the bone marrow was more efficient in healthy than multiple myeloma-bearing mice. Furthermore, bone marrow localization of transferred CXCR3-deficient NK cells with respect to wild type was enhanced in healthy and multiple myeloma-bearing mice, suggesting that CXCR3 restrains bone marrow NK cell trafficking. Our results indicate that multiple myeloma-promoted CXCR3 ligand upregulation together with CXCL12 downmodulation act as exit signals driving effector NK cells outside the bone marrow, thus weakening the antitumor immune response at the primary site of tumor growth.

  17. 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.

  18. Expression of CD66a in multiple myeloma.

    PubMed

    Satoh, Yukihiko; Hayashi, Toshiaki; Takahashi, Tohru; Itoh, Fumio; Adachi, Masaaki; Fukui, Mikiko; Kuroki, Motomu; Kuroki, Masahide; Imai, Kohzoh; Hinoda, Yuji

    2002-01-01

    CD66a is a member of the carcinoembryonic antigen family and has been suggested to function as an intercellular adhesion molecule and cell growth regulator. Expression of CD66a in myeloma cells was examined with mAb TS135 against CD66a transfectants of murine-transformed fibroblasts. The reactivity of mAb TS135 with CD66a, CD66c, and CD66e was revealed. CD66a in myeloma cells was considered to be detectable with this mAb, since CD66c and CD66e are not expressed in them. CD66a was detected in three myeloma cell lines and an IgM-producing B-cell line. In clinical bone marrow specimens, including 18 multiple myeloma, two primary macroglobulinemia, and a case of CLL-like chronic lymphoproliferation with monoclonal IgG production, CD66a and three conventional myeloma cell markers (PCA-1, CD38, and CD56) were examined by indirect immunofluorescence assay. The results showed that 18 out of 21 cases (86%) were CD66a+, and PCA-1 showed the highest correlation with CD66a among conventional markers. Primary macroglobulinemia and chronic lymphoproliferation were also CD66a+. Two-dimensional flow cytometry with mAbs TS135 and CD38 confirmed the reactivity of TS135 with myeloma cells in those bone marrow specimens. The findings suggest that CD66a is expressed in multiple myeloma with high frequency. Copyright 2002 Wiley-Liss, Inc.

  19. Cellular immunotherapy in multiple myeloma: lessons from preclinical models.

    PubMed

    Binsfeld, M; Fostier, K; Muller, J; Baron, F; Schots, R; Beguin, Y; Heusschen, R; Caers, J

    2014-12-01

    The majority of multiple myeloma patients relapse with the current treatment strategies, raising the need for alternative therapeutic approaches. Cellular immunotherapy is a rapidly evolving field and currently being translated into clinical trials with encouraging results in several cancer types, including multiple myeloma. Murine multiple myeloma models are of critical importance for the development and refinement of cellular immunotherapy. In this review, we summarize the immune cell changes that occur in multiple myeloma patients and we discuss the cell-based immunotherapies that have been tested in multiple myeloma, with a focus on murine models.

  20. 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

  1. Hyponatraemia in patients with multiple myeloma.

    PubMed

    Mirvis, Eitan; De-Silva, Dunnya; Mehta, Atul

    2015-12-11

    Hyponatraemia is the most common electrolyte disturbance encountered in clinical practice. Several causes of hyponatraemia are recognised and in many patients the aetiology may be multifactorial. An important cause is water intoxication and this is often iatrogenic. We present three patients, all of whom suffered from multiple myeloma, who illustrate different aspects of hyponatraemia, its causes and management.

  2. Zoom Zoom: racing CARs for multiple myeloma.

    PubMed

    Maus, Marcela V; June, Carl H

    2013-04-15

    Chimeric antigen receptors redirect T cells to surface antigens. Discovery and validation of appropriate target antigens expand the possible indications for chimeric-antigen receptor (CAR)-T cells. B-cell maturation antigen (BCMA) is expressed only on mature B cells and plasma cells and promotes their survival. BCMA is a promising target for CAR-T cells in multiple myeloma.

  3. 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

  4. How I treat smoldering multiple myeloma.

    PubMed

    Ghobrial, Irene M; Landgren, Ola

    2014-11-27

    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. © 2014 by The American Society of Hematology.

  5. 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

  6. 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

  7. 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

  8. Fundamentals in the management of multiple myeloma.

    PubMed

    Fadilah, S A W

    2010-09-01

    Progress in our understanding of multiple myeloma and its treatment has resulted in a more tailored approach to patient management, with different therapeutics regimens for different patient populations. The decision to initiate therapy depends primarily on the presence of symptoms which has to balance the chance of tumor clearance and against the risks of treatment related mortality. Selection of appropriate initial treatment should be based primarily on patient's characteristics (biologic age, co-morbidities), the disease characteristics (tumor burden and genetic risk profile) and the expected toxicity profile of the different regimens. When treatment begins, in younger transplant eligible patients the goal is to achieve high quality responses with intensive therapies as the quality of response appears to be important surrogates for long-term outcome. In the majority of myeloma patients in whom intensive treatment is not an option due to advanced age and co-morbidities, treatment should emphasize on optimal disease control to obtain symptomatic relief and to maintain a satisfactory quality of life. The introduction of novel agents has substantially changed the treatment paradigm of this otherwise incurable disease. The utilization of these drugs has moved from relapse setting to the front line setting and has benefited all patient groups. Because of these rapid developments and many treatment options we need good quality clinical studies to guide clinical practice in the management of patients with multiple myeloma. This review presents an update on current concepts of diagnosis and treatment of patients with multiple myeloma and provides recommendations on tailored therapies with particular reference to the local practice. The information presented herein may be used by the health care providers caring for myeloma patients as a guideline to counsel patients to understand their disease and the treatment better.

  9. 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.

  10. [Amyloidosis in the course of multiple myeloma].

    PubMed

    Mazur, Grzegorz; Usnarska-Zubkiewicz, Lidia; Wróbel, Tomasz; Biedroń, Monika; Nowicka, Jadwiga; Ganczarski, Grzegorz; Kuliczkowski, Kazimierz

    2005-04-01

    The amyloidoses are group of heterogeneous disorders, in which synthesized and secreted proteins, as a soluble molecules, are formed into insoluble, fibrillar tissue deposits, leading to organ dysfunction. Classification now is based on the chemical nature of the fibrillar component of the deposits. One of these is light-chain amyloidosis (AL). The aim of the study was to describe of multiple myeloma patients and amyloidosis. The study group consisted of 45 patients (16 men and 29 women). The diagnosis was made by fine-needle aspiration of subcutaneous fat and then staining the tissue with Congo red. We also analyse the concentration of the serum SAA. We analyse the most characteristic features of AL as hearth failure, proteinuria, renal failure, carpal tunnel syndrome, hepatosplenomegaly, macroglossia and orthostatic hypotension. Among the multiple myeloma patients we found 17 with AL amyloid and 35 persons with elevated concentration of the serum SAA. The most frequent symptoms were related with renal failure and heart failure.

  11. Multiple myeloma associated with an Evan's syndrome.

    PubMed

    Bechir, Achour; Haifa, Regaieg; Nesrine, Ben Sayed; Emna, Bouslema; Senda, Mejdoub; Asma, Achour; Amina, Bouatay Bouzouita; Mrabet, Senda; Yosra, Ben Youssef; Mondher, Kortas; Abderrahim, Khelif

    2016-01-01

    Auto-immun events are rare in multiple myeloma (MM). Here, we report one MM case complicated by Evans syndrome (Autoimmun hemolytic anemia (AIHA) associated with thrombocytopenia). A 52-year-old man was admitted in nephrology department with severe anemia, renal insufficiency and hypergamma globulinemia. Laboratory exams showed acute hemolysis due to an IgG warm autoantibody. Serum electrophoresis revealed the presence of a monoclonal IgG protein and urinary M protein was 2g/day. A whole body CT-Scan showed osteolytic lesions of vertebral body of C5, D4, L3, L4 and the left iliac wing. The diagnosis of multiple myeloma and Evan's syndrome was made, we underwent chemotherapy by BTD (bortezomib-thalidomide-dexamethasone) and continuous corticosteroid therapy but unfortunately the patient died secondary of a Lactic acidosis. The relationship between MM and hemolysis remain unclear.

  12. 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.

  13. New Developments in Diagnosis, Prognosis, and Assessment of Response in Multiple Myeloma.

    PubMed

    Landgren, Ola; Rajkumar, S Vincent

    2016-11-15

    Over the past few years, the management of multiple myeloma has changed. We have new guidelines regarding how to set the diagnosis, when to initiate therapy, and how to monitor treatment response. In 2014, the updated International Myeloma Working Group (IMWG) diagnostic criteria changed the definition of multiple myeloma from being a disease defined by symptoms to a disease defined by biomarkers. Today, modern combination therapies have reported up to 60% to 80% of patients reaching a complete response. As a logical and necessary step forward, investigators have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. Recent meta-analysis data show that MRD negativity is associated with longer progression-free survival and overall survival. In 2016, the updated IMWG response criteria include MRD as the deepest level of treatment response in multiple myeloma. Simultaneously, we are still quite behind in our understanding of the heterogeneous biology of multiple myeloma and its implications for therapy. Emerging DNA sequencing data show that newly diagnosed multiple myeloma patients have a broad range of mutations, which are distributed unevenly in multiple parallel subclones already present at diagnosis. To move beyond the ill-defined category of "high-risk multiple myeloma," which confers to approximately 25% of all newly diagnosed patients, prospective studies are needed to dissect tumor biology and define multiple myeloma subtypes, and, based on biology, seek to define rational therapies for individual subtypes. This article discusses novel insights and gives perspectives on diagnosis and MRD monitoring and future directions for prognosis and clinical management of multiple myeloma. Clin Cancer Res; 22(22); 5428-33. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "MULTIPLE MYELOMA MULTIPLYING THERAPIES".

  14. [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.

  15. 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

    2015-08-14

    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.

  16. Dynamic contrast-enhanced magnetic resonance imaging parameters correlate with advanced revised-ISS and angiopoietin-1/angiopoietin-2 ratio in patients with multiple myeloma.

    PubMed

    Terpos, Evangelos; Matsaridis, Dimitris; Koutoulidis, Vassilis; Zagouri, Flora; Christoulas, Dimitrios; Fontara, Sophia; Panourgias, Evangelia; Gavriatopoulou, Maria; Kastritis, Efstathios; Dimopoulos, Meletios A; Moulopoulos, Lia A

    2017-08-01

    The aim of the study was to assess the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with newly diagnosed multiple myeloma (MM) who were treated with novel anti-myeloma agents. We studied 60 previously untreated MM patients at diagnosis, 14 with smoldering MM (SMM) and 5 with MGUS. All patients underwent MRI of the thoracolumbar spine and pelvis before the administration of any kind of therapy, and DCE-MRI was performed. The MRI perfusion parameters evaluated were wash-in (WIN), washout (WOUT), time-to-peak (TTPK), time-to-maximum slope (TMSP), and the WIN/TMSP ratio. The following serum levels of angiogenic cytokines were measured on the day of MRI: VEGF, angiogenin (Ang), angiopoietin-1 (Angp-1), and -2 (Angp-2). Symptomatic MM patients had increased WIN compared to SMM (p < 0.05) and MGUS patients (p = 0.001). TTPK was decreased, and WIN/TMSP was increased in both symptomatic and SMM patients compared to MGUS patients (p < 0.05). Symptomatic MM patients had decreased TMSP compared to MGUS patients. The Angp-1/Angp-2 ratio was reduced in symptomatic MM compared to SMM (p = 0.017) and MGUS patients (p < 0.001). TTPK correlated with Angp-1/Angp-2 ratio and importantly with R-ISS. Patients with R-ISS-3 had lower TTPK median value (23 s, range 18-29 s) compared to patients with R-ISS-2 (48 s, range 27-68 s) and patients with R-ISS-1 MM (54 s, range 42-76 s; p ANOVA = 0.01). A subset of patients with low TTPK (lower quartile) had shorter time to progression compared to all other patients. These data suggest that certain DCE-MRI parameters correlate with R-ISS and adverse prognostic features of angiogenesis, such as the ratio of Angp-1/Angp-2.

  17. The evaluation of minimal residual disease in multiple myeloma by fluorescent molecular beacons in real time PCR of IgH gene rearrangements and correlation with flow cytometry.

    PubMed

    Kara, I O; Duman, B B; Afsar, C U

    2013-01-01

    Multiple myeloma (MM) patients relapse after a period of time despite longer disease-free survival due to novel treatment options. In this study we aimed to assess the value of real-time polymerase chain reaction (RT-PCR) for detecting the immunoglobulin heavy chain (IgH) gene rearrangement using allele-specific molecular beacons as fluorescence probes to quantify minimal residual disease (MRD) and also to correlate post-treatment flow cytometric detection of plasma cells' (PCs) expression of CD19, CD38, CD45, CD56 and CD138 in MM. After diagnosis of 17 MM patients, the CDR1, CDR2 and CDR3 regions of the IgH gene were analysed and sequenced to identify IgH's clonal nature. Unique sequences of the clonal IgH rearrangement were used to design specific molecular beacon probes for each MM patient. Examined were also the co-expression of CD19, CD38, CD45, CD56, and CD138 molecules in bone marrow aspirates of patients with MM by flow cytometry. Detection of MRD was positive in 13 (76%) of 17 patients by RT-PCR. The infiltration ratio was significantly correlated with CD138 expression (p=0.009). Significant correlation was also found between RT-PCR detection of MRD and CD138 expression (p=0.006). Nevertheless, no correlation was observed among other surface antigens (CD38, CD45, CD56). Our results indicated that RT-PCR with specific molecular beacons provide a feasible, accurate and reproducible method for the determination of MRD in MM. Flow cytometry detection of CD138 expression may be used as a disease marker in addition to RT-PCR.

  18. Lymphocyte profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: flow-cytometric characterization and analysis in a two-dimensional correlation biplot.

    PubMed

    Van den Hove, L E; Meeus, P; Derom, A; Demuynck, H; Verhoef, G E; Vandenberghe, P; Boogaerts, M A

    1998-06-01

    The distribution of 27 T-, B-, and natural killer-cell subsets in the peripheral blood of 40 patients with multiple myeloma (MM), ten patients with monoclonal gammopathy of undetermined significance (MGUS), and 40 healthy donors was investigated by means of classical univariate statistics and advanced multivariate data-analytical techniques. The latter approach was used to describe, represent, and analyze lymphocyte subset distribution in a two-dimensional correlation biplot, allowing comparison of complex lymphocyte profiles (i.e., compound lymphocyte subset distributions) of individual subjects rather than isolated subset values of selected patient and/or donor groups. The correlation biplot revealed that, in accordance with the univariate statistics, the MM patients were characterized by marked shifts towards CD8+, CD57+, CD62L-, CD(16+56)+, and HLA-DR+ T cells, suggesting in vivo immune activation. The activation profile was most markedly observed in treated MM patients in the advanced disease stage category. The lymphocyte profiles of MGUS patients were heterogeneous, with approximately half of them located in the swarm of MM patients and the other half in the swarm of healthy donors. Although the univariate statistics revealed significant differences between MGUS patients and healthy donors only within the B-cell compartment, the correlation biplot revealed that two MGUS patients clearly had a typical T-cell activation profile similar to that of the MM patients. One MGUS patient with a T-cell activation profile progressed 13 months later to a stage IA MM and required chemotherapy. A marked lymphocyte profile shift in one MM patient was associated with terminal and aggressive disease transformation. Our study illustrates further the practical use of correlation biplots for the detection of aberrant lymphocyte profiles and/or profile shifts in individual patients.

  19. [Multiple myeloma and other plasma cell dyscrasias].

    PubMed

    Nagy, Zsolt

    2016-06-06

    Multiple myeloma is the most common primary malignant disease of bone marrow. It mainly occurs among elderly people and, according to international databases, it is twice as frequent in men, however in our country this fact cannot be observed because of the high male mortality rate. The presence of this disease increased by more than one and the half times during the last 60 years. The five year survival for multiple myeloma has increased from 25% to 40% since the seventies due to high-dose chemotherapy followed by autologous stem cell transplantation and the new anti-myeloma drugs which were introduced in the last decade, such as immunomodulators (IMiD) like thalidomide, lenalidomide, pomalidomide and proteasome inhibitors (PI) like bortezomib, carfilzomib, ixazomib. The number of treatment options are growing fast, and not only because of using new combinations of medications, but also due to the development of investigational products which are available for the patients by participating in a clinical trial.

  20. Bortezomib for previously untreated multiple myeloma.

    PubMed

    de la Rubia, Javier; Roig, Mónica

    2011-08-01

    The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as bortezomib, in the last decade have resulted in a new scenario expected to impact favorably on the outcome of MM patients. In the transplant and nontransplant setting, several randomized trials have shown that front-line treatment with bortezomib-based combinations are superior to conventional treatment and have allowed for a significant increase of complete response rate, with a positive impact on progression-free survival. Furthermore, this drug appears to be active in patients with high-risk disease and comorbidities. Thus, bortezomib-containing regimens are now considered as a new standard of care for newly diagnosed myeloma patients. In this article, we will attempt to overview the results of bortezomib when administered as a standard component of front-line therapy for MM patients.

  1. 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.

  2. The Danish National Multiple Myeloma Registry

    PubMed Central

    Gimsing, Peter; Holmström, Morten O; Klausen, Tobias Wirenfelt; Andersen, Niels Frost; Gregersen, Henrik; Pedersen, Robert Schou; Plesner, Torben; Pedersen, Per Trøllund; Frederiksen, Mikael; Frølund, Ulf; Helleberg, Carsten; Vangsted, Annette; de Nully Brown, Peter; Abildgaard, Niels

    2016-01-01

    Aim The Danish National Multiple Myeloma Registry (DMMR) is a population-based clinical quality database established in January 2005. The primary aim of the database is to ensure that diagnosis and treatment of plasma cell dyscrasia are of uniform quality throughout the country. Another aim is to support research. Patients are registered with their unique Danish personal identification number, and the combined use of DMMR, other Danish National registries, and the Danish National Cancer Biobank offers a unique platform for population-based translational research. Study population All newly diagnosed patients with multiple myeloma (MM), smoldering MM, solitary plasmacytomas, and plasma cell leukemia in Denmark are registered annually; ~350 patients. Amyloid light-chain amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), monoclonal gammopathy of undetermined significance and monoclonal gammopathy of undetermined significance with polyneuropathy have been registered since 2014. Main variables The main registered variables at diagnosis are patient demographics, baseline disease characteristics, myeloma-defining events, clinical complications, prognostics, first- and second-line treatments, treatment responses, progression free, and overall survival. Descriptive data Up to June 2015, 2,907 newly diagnosed patients with MM, 485 patients with smoldering MM, 64 patients with plasma cell leukemia, and 191 patients with solitary plasmacytomas were registered. Registration completeness of new patients is ~100%. A data validation study performed in 2013–2014 by the Danish Myeloma Study Group showed >95% data correctness. Conclusion The DMMR is a population-based data validated database eligible for clinical, epidemiological, and translational research. PMID:27822103

  3. Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells.

    PubMed

    Shi, Yijiang; Daniels-Wells, Tracy R; Frost, Patrick; Lee, Jihye; Finn, Richard S; Bardeleben, Carolyne; Penichet, Manuel L; Jung, Michael E; Gera, Joseph; Lichtenstein, Alan

    2016-10-01

    DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Overexpression of DEPTOR specifically occurs in a model of multiple myeloma. Its silencing in multiple myeloma cells is sufficient to induce cytotoxicity, suggesting that DEPTOR is a potential therapeutic target. mTORC1 paralysis protects multiple myeloma cells against DEPTOR silencing, implicating mTORC1 in the critical role of DEPTOR in multiple myeloma cell viability. Building on this foundation, we interrogated a small-molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay. One compound was identified that also prevented DEPTOR-mTOR binding in human myeloma cells, with subsequent activation of mTORC1 and mTORC2. In a surface plasmon resonance (SPR) assay, the compound bound to recombinant DEPTOR but not to mTOR. The drug also prevented binding of recombinant DEPTOR to mTOR in the SPR assay. Remarkably, although activating TORC1 and TORC2, the compound induced apoptosis and cell-cycle arrest in multiple myeloma cell lines and prevented outgrowth of human multiple myeloma cells in immunodeficient mice. In vitro cytotoxicity against multiple myeloma cell lines was directly correlated with DEPTOR protein expression and was mediated, in part, by the activation of TORC1 and induction of p21 expression. Additional cytotoxicity was seen against primary multiple myeloma cells, whereas normal hematopoietic colony formation was unaffected. These results further support DEPTOR as a viable therapeutic target in multiple myeloma and suggest an effective strategy of preventing binding of DEPTOR to mTOR. Cancer Res; 76(19); 5822-31. ©2016 AACR. ©2016 American Association for Cancer Research.

  4. 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. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Iron increases the susceptibility of multiple myeloma cells to bortezomib

    PubMed Central

    Campanella, Alessandro; Santambrogio, Paolo; Fontana, Francesca; Frenquelli, Michela; Cenci, Simone; Marcatti, Magda; Sitia, Roberto; Tonon, Giovanni; Camaschella, Clara

    2013-01-01

    Multiple myeloma is a malignant still incurable plasma cell disorder. Pharmacological treatment based on proteasome inhibition has improved patient outcome; however, bortezomib-resistance remains a major clinical problem. Inhibition of proteasome functionality affects cellular iron homeostasis and iron is a potent inducer of reactive oxygen species and cell death, unless safely stored in ferritin. We explored the potential role of iron in bortezomib-resistance. We analyzed iron proteins, oxidative status and cell viability in 7 multiple myeloma cell lines and in plasma cells from 5 patients. Cells were treated with increasing bortezomib concentrations with or without iron supplementation. We reduced ferritin levels by both shRNA technology and by drug-induced iron starvation. Multiple myeloma cell lines are characterized by distinct ferritin levels, which directly correlate with bortezomib resistance. We observed that iron supplementation upon bortezomib promotes protein oxidation and cell death, and that iron toxicity inversely correlates with basal ferritin levels. Bortezomib prevents ferritin upregulation in response to iron, thus limiting the ability to buffer reactive oxygen species. Consequently, reduction of basal ferritin levels increases both bortezomib sensitivity and iron toxicity. In patients’ cells, we confirmed that bortezomib prevents ferritin increase, that iron supplementation upon bortezomib increases cell death and that ferritin reduction overcomes bortezomib resistance. Bortezomib affects iron homeostasis, sensitizing cells to oxidative damage. Modulation of iron status is a strategy worth exploring to improve the efficacy of proteasome inhibition therapies. PMID:23242599

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

    PubMed

    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.

  7. 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

  8. Bortezomib Combination Therapy in Multiple Myeloma

    PubMed Central

    Kapoor, Prashant; Ramakrishnan, Vijay; Rajkumar, S. Vincent

    2012-01-01

    Bortezomib was approved for the treatment of multiple myeloma in 2003. Since then several bortezomib-based combination therapies have emerged. Although some combinations have been preceded by preclinical investigations, most have followed the inevitable process in which active (or potentially active) drugs are combined with each other to create new treatment regimens. Regimens that have combined bortezomib with corticosteroids, alkylating agents, thalidomide, and/or lenalidomide have resulted in high response rates. Despite the higher and often deeper response rates and prolongation of progression-free survival with bortezomib-based multiagent regimens, an overall survival (OS) advantage has not been demonstrated with most combinations compared to the sequential approach of utilizing anti-myeloma agents, particularly in patients less than 65 with newly diagnosed myeloma. The unique properties of some of these regimens can be taken into account when choosing a particular regimen based on the clinical scenario. For example, bortezomib, thalidomide, dexamethasone (VTD) has particular value in renal failure since none of the drugs need dose modification. Similarly, the combination chemotherapy regimen VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) is of particular value in patients presenting with aggressive disease such as extramedullary plasmacytomas or plasma cell leukemia. Ongoing clinical trials are testing combinations of bortezomib with several other classes of agents, including monoclonal antibodies, and inhibitors of deacetylases, heat shock proteins, phosphatidyl inositol 3-kinase/Akt/mammalian target of rapamycin pathway and farnesyl transferase. PMID:22726546

  9. Future directions in multiple myeloma treatment.

    PubMed

    Child, J Anthony; Russell, Nigel; Sonneveld, Pieter; Schey, Steve

    2005-01-01

    Future therapy options for multiple myeloma may be directed at asymptomatic disease, as only symptomatic myeloma is treated currently. Additional genetic information from gene array analysis will mean that the identification of cases with poor prognosis will become more sophisticated. New markers are being discovered constantly, and these continuously change the picture regarding prognostic factors. More intensive treatment options increase the depth of remissions, thereby improving outcomes. In pilot studies, cyclophosphamide, thalidomide and dexamethasone (CTD) was a highly effective, well-tolerated regimen for patients refractory to initial therapy with VAD or with relapsed disease. It is being further evaluated as induction therapy in the current MRC Myeloma IX trial. Also under investigation is a small molecule derivative of thalidomide, CC-4047 (Actimid). It has between 1,000 and 10,000 times more potent antitumour necrosis factor alpha activity, with an additional immunomodulatory effect. It has been shown to be between 50 and 2,000 times more potent in the stimulation of T-cell proliferation and 50-100 times more potent in augmenting interleukin-2 and interferon-gamma production. With many possible approaches to study and work through, future strategies will revolve around exploration of the effectiveness of combinations that incorporate new agents in various disease and treatment settings. The use of genetic profiles to further delineate groups for different treatment approaches should enable the introduction of patient-specific treatment programmes in the future.

  10. Heat shock proteins in multiple myeloma

    PubMed Central

    Zhang, Lei; Fok, Jacqueline H.L.; Davies, Faith E.

    2014-01-01

    Heat shock proteins are molecular chaperones with a central role in protein folding and cellular protein homeostasis. They also play major roles in the development of cancer and in recent years have emerged as promising therapeutic targets. In this review, we discuss the known molecular mechanisms of various heat shock protein families and their involvement in cancer and in particular, multiple myeloma. In addition, we address the current progress and challenges in pharmacologically targeting these proteins as anti-cancer therapeutic strategies PMID:24675290

  11. Long-term survival in multiple myeloma

    PubMed Central

    João, Cristina; Costa, Carlos; Coelho, Inês; Vergueiro, Maria João; Ferreira, Mafalda; da Silva, Maria Gomes

    2014-01-01

    Key Clinical Message The survival of multiple myeloma patients has improved very significantly over the last decade. Still median overall survival is inferior to 5 years. A small proportion of patients survive longer than 10 years. In this paper we discuss four cases illustrating the nonhomogeneous clinical presentation and evolution of this subset of patients. Surprisingly, these long survivors do not always have deep responses and some require frequent treatments, which include autologous stem cell transplantation and novel drugs. The authors discuss several aspects of these clinical histories, including treatment options, raising hypothesis on their relation with long survivorship which may be important to have in consideration when studying this subject. PMID:25614805

  12. NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016.

    PubMed

    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; Reu, Frederic J; Singhal, Seema; Somlo, George; Stockerl-Goldstein, Keith; Treon, Steven P; Weber, Donna; Yahalom, Joachim; Shead, Dorothy A; Kumar, Rashmi

    2016-04-01

    These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

  13. Therapeutic strategies for the treatment of multiple myeloma.

    PubMed

    Saini, Neeraj; Mahindra, Anuj

    2013-04-01

    The outcome of patients with myeloma has improved significantly in the past decade with the incorporation of the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor, bortezomib. Considering nearly all patients relapse, myeloma remains an active area of investigation. There are several promising classes of agents including next generation immunomodulatory agents, proteasome inhibitors, antibody and antitumor immunotherapy approaches that are being evaluated. This article provides an overview on the therapeutic strategies in the treatment of multiple myeloma.

  14. [Multiple Myeloma - Current Status in Diagnostic Testing and Therapy].

    PubMed

    Kehrer, Michael; Koob, Sebastian; Strauss, Andreas; Wirtz, Dieter Christian; Schmolders, Jan

    2017-08-14

    Background Multiple myeloma is a haematological blood cancer of the bone marrow and is classified by the World Health Organisation (WHO) as a plasma cell neoplasm. In multiple myeloma, normal plasma cells transform into malignant myeloma cells and produce large quantities of an abnormal immunoglobulin called monoclonal protein or M protein. This ultimately causes multiple myeloma symptoms such as bone damage or kidney problems. The annual worldwide incidence of multiple myeloma is estimated to be 6 - 7/100,000 and accounts for 1% of all cancer. In Germany, there are about 6,000 cases of newly diagnosed multiple myeloma per annum. In the current era of new agents, such as immunomodulatory drugs and proteasome inhibitors and antibodies, enormous progress has been achieved in the therapy of multiple myeloma. In orthopaedics, it is essential to be able to recognise the of alarming symptoms of multiple myeloma in clinical routine and to be aware of basic diagnostic features to confirm this disease. Surgical treatment of myeloma-related bone lesions - such as stabilisation of pathological fractures - is an important domain of tumour orthopaedic surgery. Methods A comprehensive literature search was performed in PubMed using the keywords "multiple myeloma" and "diagnostic" or "therapy". This served to evaluate the available primary and secondary literature on the current status of the diagnostic testing and therapy of multiple myeloma. Systematic reviews, meta-analyses and clinical studies as well as international recommendations in therapy were included until the spring of 2016. Results There are now very sensitive screening methods for the diagnosis of multiple myeloma. Accurate diagnosis is generally based on several factors, including physical evaluation, patient history, symptoms, and diagnostic testing results. The standards for initial diagnostic tests are determined by blood and urine tests as well as a bone marrow biopsy and skeletal imaging, such as X

  15. [Inadequate erythropoietin production (epo) in patients with multiple myeloma].

    PubMed

    Kostova, Gabriela; Siljanovski, Nikola

    2004-01-01

    Anaemia is the most common haematological complication in patients with malignant diseases. It is found in 60%-90% of cases with multiple myeloma. The pathogenesis of this hypoproliferative, normochromic, normocytic anaemia is complex. Results from clinical studies which evaluate the efficacy of recombinant human erythropoietin (rHuEpo) refer to the possibility that patients with multiple myeloma independently of renal function could have Epo deficiency. Based on this finding, the aim of the study was to evaluate the erythropoietin production in patients with multiple myeloma in order to define clinical conditions of Epo deficiency and thereby enable rational use of this expensive drug. 42 patients with multiple myeloma were examined. The control group consisted of 25 patients with iron deficiency anaemia. 14 healthy volunteers represented the so-called "normal" control. The adequacy of Epo production was estimated from the graphic representation of the linear regression between Epo and haemoglobin (Hb) in the control group, as well as from O/PEpo ratio as a measure of the degree of adequacy of Epo production (O -- observed Epo value, P -- predicted Epo value from the regression equation of the control group). The erythropoietic activity was estimated from the graphic representation of the linear regression between soluble transferin receptors (sTfR) and Hb in the control group, as well as from O/PsTfR ratio, as a measure of the degree of adequacy of erythropoietic activity (O -- observed sTfR value, P -- predicted sTfR value from the regression equation of the control group). Significant inverse correlation between Epo and Hb was found in patients with multiple myeloma but preserved renal function, which was not the case in patients with renal insufficiency. 43% of patients without renal insufficiency and 85% of patients with renal insufficiency had inadequate Epo response to anaemia. In both patient groups (with and without renal insufficiency) instead of the

  16. Sellar Solitary Plasmacytoma Progressing to Multiple Myeloma

    PubMed Central

    Jiang, Chang-Zhen; Lin, Qing-Song; Wu, Xi-Yue; Wang, Chen-Yang; Kang, De-Zhi

    2014-01-01

    Abstract Sellar plasmacytoma is a rare cause of sellar lesions. Preoperative diagnosis remains a challenge. We present a 34-year-old Chinese woman with a 25-day history of headache and diplopia. A physical examination revealed incomplete left abducens nerve palsy. The initial diagnosis was invasive pituitary adenoma. The patient’s condition deteriorated suddenly the day before the arranged operating date, with the hemoglobin level declining from 113 to 70 g/L. The operation was cancelled and further studies confirmed the diagnosis of sellar solitary plasmacytoma that progressed to multiple myeloma. After undergoing radiotherapy, high-dose chemotherapy, and autologous peripheral blood stem cell transplantation, complete remission was achieved on 4 years follow-up. We reviewed the pertinent literature and reached the following conclusions: sellar plasmacytomas with development of multiple myeloma on follow-up more likely happened in men than in women; and if the sellar plasmacytoma does not compress the cranial nerve, transsphenoidal resection should be cautious because the systemic treatment with radiotherapy, chemotherapy, and autologous peripheral blood stem cell transplantation may be more effective with little invasion. PMID:25192483

  17. [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.

  18. 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.

  19. Molecularly Targeted Therapies in Multiple Myeloma

    PubMed Central

    Azab, Feda

    2014-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted. PMID:24829804

  20. Molecularly targeted therapies in multiple myeloma.

    PubMed

    de la Puente, Pilar; Muz, Barbara; Azab, Feda; Luderer, Micah; Azab, Abdel Kareem

    2014-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.

  1. Emerging drugs and combinations to treat multiple myeloma

    PubMed Central

    Larocca, Alessandra; Mina, Roberto; Gay, Francesca; Bringhen, Sara; Boccadoro, Mario

    2017-01-01

    In the past few years, multiple targeted therapies and immunotherapies including second generation immunomodulatory drugs (pomalidomide) and proteasome inhibitors (carfilzomib, ixazomib), monoclonal antibodies and checkpoint inhibitors were approved for the treatment of myeloma or entered advanced phases of clinical testing. These agents showed significant activity in advanced myeloma and increased the available treatment strategies. Pomalidomide is well-tolerated and effective in patients with relapsed/refractory multiple myeloma who have exhausted any possible treatment with lenalidomide and bortezomib. Carfilzomib, a second-generation proteasome inhibitor, is active as a single agent and in combination with other anti-myeloma agents. Ixazomib is the first oral proteasome inhibitor to be evaluated in myeloma and is associated with a good safety profile and anti-myeloma activity in relapsed/refractory patients, even in those refractory to bortezomib. Monoclonal antibodies and immune checkpoint inhibitors are likely to play a major role in the treatment of myeloma over the next decade. In phase 3 studies, triplet regimens based on these agents combined with a backbone therapy (including lenalidomide, pomalidomide or bortezomib) were more efficacious than doublet regimens in patients with relapsed/refractory multiple myeloma, with limited additional toxic effects. This paper aims to provide an overview of the recent use of these agents for the treatment of myeloma, in particular focusing on the role of multi-agent combinations. PMID:28948001

  2. Monitoring multiple myeloma by next-generation sequencing of V(D)J rearrangements from circulating myeloma cells and cell-free myeloma DNA

    PubMed Central

    Oberle, Anna; Brandt, Anna; Voigtlaender, Minna; Thiele, Benjamin; Radloff, Janina; Schulenkorf, Anita; Alawi, Malik; Akyüz, Nuray; März, Manuela; Ford, Christopher T.; Krohn-Grimberghe, Artus; Binder, Mascha

    2017-01-01

    Recent studies suggest that circulating tumor cells and cell-free DNA may represent powerful non-invasive tools for monitoring disease in patients with solid and hematologic malignancies. Here, we conducted a pilot study in 27 myeloma patients to explore the clonotypic V(D)J rearrangement for monitoring circulating myeloma cells and cell-free myeloma DNA. Next-generation sequencing was used to define the myeloma V(D)J rearrangement and for subsequent peripheral blood tracking after treatment initiation. Positivity for circulating myeloma cells/cell-free myeloma was associated with conventional remission status (P<0.001) and 91% of non-responders/progressors versus 41% of responders had evidence of persistent circulating myeloma cells/cell-free myeloma DNA (P<0.001). About half of the partial responders showed complete clearance of circulating myeloma cells/cell-free myeloma DNA despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover and, therefore, decline more rapidly after initiation of effective treatment. Positivity for circulating myeloma cells and for cell-free myeloma DNA were associated with each other (P=0.042), but discordant in 30% of cases. This indicates that cell-free myeloma DNA may not be generated entirely by circulating myeloma cells and may reflect overall tumor burden. Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma. PMID:28183851

  3. Ki-67 Immunostaining and its Correlation with Microvessel Density in Patients with Mutiple Myeloma.

    PubMed

    Himani, Bhankar; Meera, Sikka; Abhimanyu, Sharma; Usha, Rusia

    2016-01-01

    To compare Ki-67 index and microvessel density MVD) in multiple myeloma and non-myeloma patients and their correlation with each other and other prognostic markers. Forty patients were enrolled in this study between 2011-2013, 30 with multiple myelomas and 10 with non-malignant disease as controls. Proliferative activity was analyzed by Ki-67 and microvessel density (MVC) was assessed by CD34 and compared between two groups. In myeloma patients, correlation between Ki-67, MVD and other prognostic factors was assessed by Pearson correlation coefficient. According to Durie Salmon staging criteria, 13 patients were of stage 1, 5 of stage II and 12 of stage III. Ki-67 expression showed a positive correlation with MVD (r=0.729, <0.001) and was significantly higher (<0.0001) in myeloma patients (range 35-80%, mean 60.1 %) as compared to controls (range 8-25%, mean 18.1%). MVD/mm2 was also significantly (<0.0001) higher in myeloma patients (range 62-237/mm2, mean 178.0/mm2) than controls (range 5.2-50/mm2, mean 18.3/mm2). Ki-67 and MVD, both increased progressively with increasing stage of myeloma. Ki-67 showed significant positive correlation with blood urea and lactate dehydrogenase and a significant negative correlation with serum albumin. MVD showed a significant positive correlation with blood urea, lactate dehydrogenase, serum creatinine, β2 microglobulin and skeletal lesions. Ki-67 and MVD are indicators of aggressiveness and poor prognosis having significant correlation with each other and other prognostic markers of multiple myeloma. Routine assessment of these markers may help to identify high risk patients, who may benefit from with more aggressive therapy.

  4. [Immunophenotype characteristics in multiple myeloma cells and their significance].

    PubMed

    Sun, Ying; Fang, Mei-Yun; Liu, Yue-Jian

    2010-04-01

    This study was purposed to investigate the immunophenotype characteristics in multiple myeloma (MM) cells and their significance. The expressions of CD138, CD38, CD56, CD117, HLA-DR, CD3, CD7, CD13, CD33, CD19, CD20, CD22, CD34 in myeloma cells from 31 MM patients were detected by using CD45/SSC immunofluorescent flow cytometry and were confirmed with morphologic observation of myeloma cells. The results indicated that the proportion of myeloma cells detected by morphologic examination was 10%-68%, the proportion of myeloma cells detected by CD45/SSC gating was 9.72%-67.77%. The antigen positive expression rate in myeloma cells was as follows: CD138 61.29%, CD38 100%, CD56 46.15%, CD13 70.00%, CD33 29.03%, HLA-DR 74.19%, CD117 33.33%; the other antigen expressions were negative. It is concluded that the use of CD45/SSC gating technique can identify multiple myeloma cells. The proportion of myeloma cells gated was close to the result of morphological examination. The myeloma cells mainly express the antigens CD138, CD88, CD56, while the expressions of CD117, CD13, CD33 were seen in some MM patients. Myeloma cells don't express antigens of B- and T-lymphocytes, which suggest the heterogenicity of multiple antigens expressed by myeloma cells. However, the biological significance of antigen expression in myeloma cells is worthy to be further investigated.

  5. Remission maintenance therapy for multiple myeloma.

    PubMed

    1975-01-01

    The effects of various regimens of melphalan combination chemotherapy were evaluated in 508 patients with multiple myeloma. No value was confirmed from the addition of procarbazine or vincristine sulfate to melphalan-prednisone combinations. Ninety-six patients who responded to treatment were allocated at random to one of three maintenance regimens, namely intermittent courses of carmustine with prednisone, continued courses of melphalan with prednisone, or no chemotherapy. There were no differences in the frequency of relapse, the remission duration, or the survival time among these maintenace groups. The frequencies of pneumonia and herpes zoster were higher in patients receiving continued chemotherapy. Continued melphalan-prednisone chemotherapy after the first year is of no major value to responding patients with multiple cyeloma. Attempts to reduce tumor mass maximally with a change in therapy are justified.

  6. Novel therapeutic strategies for multiple myeloma

    PubMed Central

    Mimura, Naoya; Hideshima, Teru; Anderson, Kenneth C.

    2015-01-01

    Multiple Myeloma (MM) is a plasma cell malignancy which remains incurable despite of the recent emergence of multiple novel agents. Importantly, recent genetic and molecular analyses have revealed the complexity and heterogeneity of this disease, highlighting the need for therapeutic strategies to eliminate all the clones. Moreover, the bone marrow microenvironment, including stromal cells and immune cells, plays a central role in MM pathogenesis, promoting tumor cell growth, survival, and drug resistance. New classes of agents including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors have shown remarkable efficacy; however, novel therapeutic approaches are still urgently needed to further improve patient outcome. In this review, we discuss the recent advances and future strategies to ultimately develop MM therapies with curative potential. PMID:26118499

  7. Improving induction therapy in multiple myeloma.

    PubMed

    Nooka, Ajay; Gleason, Charise; Lonial, Sagar

    2010-07-01

    Significant improvements in induction therapy for multiple myeloma have been seen over the past decade for both transplant-eligible patients and transplant-ineligible patients. The emergence of novel agents in managing myeloma has revealed new directions for clinicians to approach the disease. The first determinant is transplant eligibility. With the recognition of the prognostic impact of postinduction response on overall outcomes, the importance of the choice of optimal regimen has become more important than ever. The preference of induction therapy for transplant-eligible patients has progressively changed from the alkylator-based therapies to doublet therapies to triplet therapies incorporating immunomodulatory drugs (IMiDs) and proteasome inhibitors. The role of quadruplet therapies remains unclear, but with appropriate dosage modifications, these regimens were efficacious and had an acceptable toxicity profile. Similar treatment approaches for transplant-ineligible patients resulted in superior outcomes with the triplet therapies. Many challenges remain however, such as achieving greater depth of responses with molecular remissions and more effective use of risk stratification in induction therapy. These are still to be explored.

  8. Immunotherapies targeting CD38 in Multiple Myeloma

    PubMed Central

    Atanackovic, Djordje; Steinbach, Mary; Radhakrishnan, Sabarinath Venniyil; Luetkens, Tim

    2016-01-01

    ABSTRACT Recently, the monoclonal antibody daratumumab was approved as a single agent for the treatment of patients with relapsed/refractory Multiple Myeloma (MM). Daratumumab is an antibody targeting surface molecule CD38 on myeloma cells and the agent is already widely being used based on its good tolerability and proven efficacy. We believe, however, that the efficacy of this drug and other anti-CD38 monoclonal antibodies can be further improved by combining it with other types of immunotherapies. Furthermore, surface molecule CD38 can be used as a target for immunotherapies other than just naked monoclonal antibodies. In this report, we review the expression pattern of CD38 among normal tissues and in different types of plasma cell dyscrasias including their progenitor cells, minimal residual disease, and circulating tumor cells. We summarize the physiological role of CD38 as well as its role in the pathophysiology of MM and we present the most recent clinical trials using CD38 as a target. In addition, we highlight possible combination immunotherapies incorporating anti-CD38 monoclonal antibodies and we demonstrate alternative immunotherapeutic approaches targeting the same antigen such as CD38-specific chimeric antigen receptor (CAR) T cells. PMID:27999737

  9. Immunotherapies targeting CD38 in Multiple Myeloma.

    PubMed

    Atanackovic, Djordje; Steinbach, Mary; Radhakrishnan, Sabarinath Venniyil; Luetkens, Tim

    2016-01-01

    Recently, the monoclonal antibody daratumumab was approved as a single agent for the treatment of patients with relapsed/refractory Multiple Myeloma (MM). Daratumumab is an antibody targeting surface molecule CD38 on myeloma cells and the agent is already widely being used based on its good tolerability and proven efficacy. We believe, however, that the efficacy of this drug and other anti-CD38 monoclonal antibodies can be further improved by combining it with other types of immunotherapies. Furthermore, surface molecule CD38 can be used as a target for immunotherapies other than just naked monoclonal antibodies. In this report, we review the expression pattern of CD38 among normal tissues and in different types of plasma cell dyscrasias including their progenitor cells, minimal residual disease, and circulating tumor cells. We summarize the physiological role of CD38 as well as its role in the pathophysiology of MM and we present the most recent clinical trials using CD38 as a target. In addition, we highlight possible combination immunotherapies incorporating anti-CD38 monoclonal antibodies and we demonstrate alternative immunotherapeutic approaches targeting the same antigen such as CD38-specific chimeric antigen receptor (CAR) T cells.

  10. Evolving diagnostic criteria for multiple myeloma.

    PubMed

    Rajkumar, S Vincent

    2015-01-01

    Multiple myeloma (MM) is a plasma cell malignancy historically defined by the presence of end-organ damage, specifically, hypercalcemia, renal failure, anemia, and bone lesions (CRAB features) that can be attributed to the neoplastic process. In 2014, the International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM to add specific biomarkers that can be used to make the diagnosis of the disease in patients who did not have CRAB features. In addition, the update allows modern imaging methods including computed tomography (CT) and positron emission tomography-CT to diagnose MM bone disease. These changes enable early diagnosis, and allow the initiation of effective therapy to prevent the development of end-organ damage in patients who are at the highest risk. This article reviews these and several other clarifications and revisions that were made to the diagnostic criteria for MM and related disorders. The updated disease definition for MM also automatically resulted in a revision to the diagnostic criteria for the asymptomatic phase of the disease termed smoldering MM (SMM). Thus the current diagnosis and risk-stratification of SMM is also reviewed in this article. Using specific prognostic factors, it is possible to identify a subset of patients with SMM who have a risk of progression to MM of 25% per year (high-risk SMM). An approach to the management of patients with low- and high-risk SMM is discussed. © 2015 by The American Society of Hematology. All rights reserved.

  11. Sorafenib for the treatment of multiple myeloma.

    PubMed

    Gentile, Massimo; Martino, Massimo; Recchia, Anna Grazia; Vigna, Ernesto; Morabito, Lucio; Morabito, Fortunato

    2016-06-01

    Sorafenib is an orally available compound that acts predominantly by targeting the Ras/Raf/MEK/ERK pathway and by inhibiting the vascular endothelial growth factor (VEGF). Since the Ras/Raf/MEK/ERK pathway is implicated in the proliferation of multiple myeloma (MM) cells and VEGF in bone marrow neovascularization, sorafenib is a drug offering the potential for targeting two important pathogenetic mechanisms involved in MM. Thus, sorafenib is being proposed for use in MM. In this review, the authors discuss the rationale for the use of sorafenib in MM. They then summarize the clinical development of sorafenib in MM, from initial Phase I to Phase II studies. A systematic literature review of the trials was performed using PubMed. Preliminary data from phase I/II trials showed that sorafenib had a good safety profile but minimal anti-myeloma activity as a single agent in relapsed/refractory patients. Results of phase II trials, evaluating sorafenib combined with new drugs, such as bortezomib and lenalidomide are eagerly awaited.

  12. 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.

  13. The use of biochemical markers of bone remodeling in multiple myeloma: a report of the International Myeloma Working Group.

    PubMed

    Terpos, E; Dimopoulos, M A; Sezer, O; Roodman, D; Abildgaard, N; Vescio, R; Tosi, P; Garcia-Sanz, R; Davies, F; Chanan-Khan, A; Palumbo, A; Sonneveld, P; Drake, M T; Harousseau, J-L; Anderson, K C; Durie, B G M

    2010-10-01

    Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future.

  14. Hyperglobulinemic purpura in the course of multiple myeloma.

    PubMed

    Shalit, M; Bar-Sela, S; Leviatan, A; Naparstek, Y

    1980-01-01

    Secondary hyperglobulinemic purpura of Waldenström is characterized by polyclonal gammopathy associated mainly with autoimmune diseases. Its occurrence with multiple myeloma is very rare. We described a patient who developed characteristic lesions of hyperglobulinemic purpura in the course of IgA myeloma. Skin biopsy revealed deposition of IgA in the blood vessels.

  15. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.

    PubMed

    Dimopoulos, Meletios A; Oriol, Albert; Nahi, Hareth; San-Miguel, Jesus; Bahlis, Nizar J; Usmani, Saad Z; Rabin, Neil; Orlowski, Robert Z; Komarnicki, Mieczyslaw; Suzuki, Kenshi; Plesner, Torben; Yoon, Sung-Soo; Ben Yehuda, Dina; Richardson, Paul G; Goldschmidt, Hartmut; Reece, Donna; Lisby, Steen; Khokhar, Nushmia Z; O'Rourke, Lisa; Chiu, Christopher; Qin, Xiang; Guckert, Mary; Ahmadi, Tahamtan; Moreau, Philippe

    2016-10-06

    Background Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. Methods In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. Results At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10(5) white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. Conclusions The addition of daratumumab to lenalidomide and

  16. Human Multiple Myeloma Cells Are Sensitized to Topoisomerase II Inhibitors by CRM1 Inhibition

    PubMed Central

    Turner, Joel G.; Marchion, Douglas C.; Dawson, Jana L.; Emmons, Michael F.; Hazlehurst, Lori A.; Washausen, Peter; Sullivan, Daniel M.

    2009-01-01

    Topoisomerase IIα (topo IIα) is exported from the nucleus of human myeloma cells by a CRM1-dependent mechanism at cellular densities similar to those found in patient bone marrow. When topo IIα is trafficked to the cytoplasm, it is not in contact with the DNA; thus topo IIα inhibitors are unable to induce DNA-cleavable complexes and cell death. Using a CRM1 inhibitor or a CRM1-specific small interfering RNA (siRNA), we were able to block nuclear export of topo IIα as shown by immunofluorescence microscopy. Human myeloma cell lines and patient myeloma cells isolated from bone marrow were treated with a CRM1 inhibitor or CRM1-specific siRNA and exposed to doxorubicin or etoposide (VP-16) at high cell densities. CRM1-treated cell lines or myeloma patient cells were fourfold more sensitive to topo II poisons, as determined by activated caspase assay. Normal cells were not significantly affected by CRM1-topo II combination treatment. Cell death was correlated with increased DNA double-strand breaks as shown by the comet assay. Band depletion assays of CRM1 inhibitor-exposed myeloma cells demonstrated increased topo IIα covalently bound to DNA. Topo IIα knockdown by a topo IIα-specific siRNA abrogated the CRM1-topo II therapy synergistic effect. These results suggest that blocking topo IIα nuclear export sensitizes myeloma cells to topo II inhibitors. This method of sensitizing myeloma cells suggests a new therapeutic approach to multiple myeloma. PMID:19690141

  17. Immunogenic Targets for Specific Immunotherapy in Multiple Myeloma

    PubMed Central

    Zhang, Lu; Götz, Marlies; Hofmann, Susanne; Greiner, Jochen

    2012-01-01

    Multiple myeloma remains an incurable disease although the prognosis has been improved by novel therapeutics and agents recently. Relapse occurs in the majority of patients and becomes fatal finally. Immunotherapy might be a powerful intervention to maintain a long-lasting control of minimal residual disease or to even eradicate disseminated tumor cells. Several tumor-associated antigens have been identified in patients with multiple myeloma. These antigens are expressed in a tumor-specific or tumor-restricted pattern, are able to elicit immune response, and thus could serve as targets for immunotherapy. This review discusses immunogenic antigens with therapeutic potential for multiple myeloma. PMID:22611422

  18. [Three cases of de novo multiple myeloma after kidney transplantation].

    PubMed

    Nieto-Ríos, John Fredy; Zuluaga, Mónica; Serna, Lina María; Aristizábal, Arbey; Ocampo-Kohn, Catalina; Gálvez, Kenny Mauricio; Flórez, Adriana Alejandra; Zuluaga, Gustavo

    2016-12-01

    Light chain-associated kidney compromise is frequent in patients with monoclonal gammopathies; it affects the glomeruli or the tubules, and its most common cause is multiple myeloma. It may develop after a kidney transplant due to recurrence of a preexisting multiple myeloma or it can be a de novo disease manifesting as graft dysfunction and proteinuria. A kidney biopsy is always necessary to confirm the diagnosis.We describe three cases of kidney graft dysfunction due to multiple myeloma in patients without presence of the disease before the transplant.

  19. Thalidomide and its analogues in the treatment of Multiple Myeloma

    PubMed Central

    2012-01-01

    Multiple myeloma is an incurable malignant disorder of mature B-cells that predominantly affects the elderly. The immunomodulatory drug (IMiD) thalidomide and its newer analogs demonstrate increased antitumor activity, and have had a positive impact on the natural history of multiple myeloma. Recent advances in the clinical application of these agents and in our understanding of their mechanism of action, and toxicity have made safer and smarter use of these drugs possible. This review discusses the available information regarding mechanisms of action, toxicity and clinical results on thalidomide, lenalidomide and pomalidomide in the therapy of multiple myeloma. PMID:23210501

  20. The role of maintenance therapy in multiple myeloma

    PubMed Central

    Lipe, B; Vukas, R; Mikhael, J

    2016-01-01

    Multiple myeloma is the second most common type of blood cancer and remains incurable despite advances in therapy. Current therapy for multiple myeloma includes a phased-approach, often consisting of initial induction therapy, consolidation and maintenance therapy. With an ever-growing landscape of treatment options, the approach to optimal therapy has become increasingly complex. Specifically, controversy surrounds the optimal use and duration of maintenance therapy. We conducted a comprehensive literature search to analyze the most current literature and to provide recommendations for maintenance therapy in multiple myeloma. PMID:27768093

  1. A patient with Multiple myeloma and Renal cell carcinoma.

    PubMed

    Shahi, Farhad; Ghalamkari, Marziye; Mirzania, Mehrzad; Khatuni, Mahdi

    2016-01-01

    The coexistence of two malignancies is rarely seen. A little association between hematologic malignancies especially multiple myeloma and renal cell carcinoma has been reported in the recent past. Several case series revealed a bidirectional association between these two malignancies which may be due to the common risk factors, similar cytokine growth requirements and clinical presentation. Here, we aim to describe a patient who had multiple myeloma and in his work up renal cell carcinoma was found out incidentally. We would like to create awareness among clinicians for the coincidence of Renal cell carcinoma and Multiple myeloma.

  2. A patient with Multiple myeloma and Renal cell carcinoma

    PubMed Central

    Shahi, Farhad; Ghalamkari, Marziye; Mirzania, Mehrzad; Khatuni, Mahdi

    2016-01-01

    The coexistence of two malignancies is rarely seen. A little association between hematologic malignancies especially multiple myeloma and renal cell carcinoma has been reported in the recent past. Several case series revealed a bidirectional association between these two malignancies which may be due to the common risk factors, similar cytokine growth requirements and clinical presentation. Here, we aim to describe a patient who had multiple myeloma and in his work up renal cell carcinoma was found out incidentally. We would like to create awareness among clinicians for the coincidence of Renal cell carcinoma and Multiple myeloma. PMID:27047652

  3. 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.

  4. Panobinostat for the management of multiple myeloma.

    PubMed

    Sivaraj, Dharshan; Green, Michael M; Gasparetto, Cristina

    2017-03-01

    Multiple myeloma (MM) is the second most common blood cancer following non-Hodgkin's lymphoma. While the treatments for MM have improved over the past decade, for the most part, it remains an incurable disease. For this reason newer therapeutic agents are needed to combat this malignancy. Panobinostat is a pan-deacetylase inhibitor that impedes protein destruction by disturbing the enzymatic activity of deacetylases. It was US FDA approved in February 2015 for the management of relapsed/refractory MM in combination with bortezomib and dexamethasone. Several trials are ongoing, exploring the utility of panobinostat in various other settings for the management of MM. This review will detail the biology, clinical efficacy and potential future applications of panobinostat in the treatment of MM.

  5. 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

  6. Impact of nestin analysis in multiple myeloma.

    PubMed

    Sváchová, H; Kovárová, L; Stossová, J; Potácová, A; Pour, L; Hájek, R

    2011-01-01

    Nestin, a marker of multipotent precursor cells, is an important dynamic structure; its polymerization/depolymerization influences intracellular signaling and participates in key cell processes such as proliferation, migration and cell survival. It is presumed that nestin plays a central role in carcinogenesis. It is suggested that nestin might be a suitable diagnostic and prognostic indicator of malignancy and a potential marker of cancer stem cells. Unexpectedly, nestin has been identified in mature CD138+CD38+ plasma cells (PC) of multiple myeloma patients (MM). Expression of nestin, a marker of stem/progenitor cells, in malignant PC, that are considered to be terminally differentiated, indicates that nestin might play a unique role in pathology of MM.

  7. 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

  8. Dilemmas in treating smoldering multiple myeloma.

    PubMed

    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. © 2014 by American Society of Clinical Oncology.

  9. DNA repair pathways in human multiple myeloma

    PubMed Central

    Gourzones-Dmitriev, Claire; Kassambara, Alboukadel; Sahota, Surinder; Rème, Thierry; Moreaux, Jérôme; Bourquard, Pascal; Hose, Dirk; Pasero, Philippe; Constantinou, Angelos; Klein, Bernard

    2013-01-01

    Every day, cells are faced with thousands of DNA lesions, which have to be repaired to preserve cell survival and function. DNA repair is more or less accurate and could result in genomic instability and cancer. We review here the current knowledge of the links between molecular features, treatment, and DNA repair in multiple myeloma (MM), a disease characterized by the accumulation of malignant plasma cells producing a monoclonal immunoglobulin. Genetic instability and abnormalities are two hallmarks of MM cells and aberrant DNA repair pathways are involved in disease onset, primary translocations in MM cells, and MM progression. Two major drugs currently used to treat MM, the alkylating agent Melphalan and the proteasome inhibitor Bortezomib act directly on DNA repair pathways, which are involved in response to treatment and resistance. A better knowledge of DNA repair pathways in MM could help to target them, thus improving disease treatment. PMID:23966156

  10. 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

  11. 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. © 2016 Wiley Periodicals, Inc.

  12. 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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma.

    PubMed

    Feng, Xiaoyan; Zhang, Li; Acharya, Chirag; An, Gang; Wen, Kenneth; Qiu, Lugui; Munshi, Nikhil C; Tai, Yu-Tzu; Anderson, Kenneth C

    2017-08-01

    Purpose: We study CD38 levels in immunosuppressive CD4(+)CD25(high)Foxp3(+) regulatory T cells (Treg) and further define immunomodulating effects of a therapeutic CD38 mAb isatuximab/SAR650984 in multiple myeloma.Experimental Design: We evaluated percentages of CD38-expressing subsets in Tregs from normal donors and multiple myeloma patients. Peripheral blood mononuclear cells (PBMC) were then treated with isatuximab with or without lenalidomide or pomalidomide to identify their impact on the percentage and immunosuppressive activity of Tregs on CD4(+)CD25(-) T cells (Tcons). We investigated the mechanism of increased Tregs in multiple myeloma patients in ex vivo cocultures of multiple myeloma cells with PBMCs or Tcons.Results: CD38 expression is higher on Tregs than Tcons from multiple myeloma patients versus normal donors. CD38 levels and the percentages of CD38(high) Tregs are increased by lenalidomide and pomalidomide. Isatuximab preferentially decreases Treg and increases Tcon frequencies, which is enhanced by pomalidomide/lenalidomide. Isatuximab reduces Foxp3 and IL10 in Tregs and restores proliferation and function of Tcons. It augments multiple myeloma cell lysis by CD8(+) T and natural killer cells. Coculture of multiple myeloma cells with Tcons significantly induces Tregs (iTregs), which express even higher CD38, CD25, and FoxP3 than natural Tregs. This is associated with elevated circulating CD38(+) Tregs in multiple myeloma patients versus normal donors. Conversely, isatuximab decreases multiple myeloma cell- and bone marrow stromal cell-induced iTreg by inhibiting both cell-cell contact and TGFβ/IL10. Finally, CD38 levels correlate with differential inhibition by isatuximab of Tregs from multiple myeloma versus normal donors.Conclusions: Targeting CD38 by isatuximab can preferentially block immunosuppressive Tregs and thereby restore immune effector function against multiple myeloma. Clin Cancer Res; 23(15); 4290-300. ©2017 AACR. ©2017 American

  14. 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

  15. Adipocytes secreted leptin is a pro-tumor factor for survival of multiple myeloma under chemotherapy

    PubMed Central

    Li, Qiu-bai; Mei, Hui-ling; Hu, Yu; Guo, Tao

    2016-01-01

    Accumulating evidences have shown that adipokines secreted from adipocytes contributes to tumor development, especially leptin. However, underlying mechanisms remain unclear. This study aims to explore the effect of leptin on development and chemoresistance in multiple myeloma cells and the potential mechanism. Analysis of levels of adipokines including leptin and adiponectin in 28 multiple myeloma patients identified significantly higher leptin compared with 28 normal controls(P < 0.05), and leptin level was positively correlated with clinical stage, IgG, ER, and ß2MG. Next, by using co-culture system of myeloma and adipocytes, and pharmacologic enhancement of leptin, we found that increased growth of myeloma cells and reduced toxicity of bortezomib were best observed at 50 ng/ml of leptin, along with increased expression of cyclinD1, Bcl-2 and decreased caspase-3 expression. We also found that phosphorylated AKT and STAT3 but not the proteins expression reached peak after 1h and 6h treatment of leptin, respectively. By using AG490, an agent blocking the phosphorylation of AKT and ERK, the proliferation of myeloma cells was inhibited, as well as the phosphorylation of AKT and STAT3, even adding leptin. Taken together, our study demonstrated that up-regulated leptin could stimulate proliferation of myeloma and reduce the anti-tumor effect of chemotherapy possibly via activating AKT and STAT3 pathways, and leptin might be one of the potential therapeutic targets for treating myeloma. PMID:27863383

  16. 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.

  17. Treatment of Newly Diagnosed Elderly Multiple Myeloma.

    PubMed

    Fouquet, Guillemette; Gay, Francesca; Boyle, Eileen; Bringhen, Sara; Larocca, Alessandra; Facon, Thierry; Leleu, Xavier; Palumbo, Antonio

    Multiple myeloma (MM) is a disease of the elderly, with a median age at diagnosis of approximately 70 years old, and more than 30 % of patients aged >75 years. This latter and very elderly population is going to significantly rise in the near future given the increase in life expectancy in Western countries, and, most importantly, global health status of elderly patients is improving, justifying appropriate treatments. Changes in treatment paradigm from the old melphalan-prednisone regimen used since the 1970s to its use as a backbone in a nontransplant setting since the late 1990s have highlighted different subgroups in elderly MM. Some "elderly" patients could be treated like transplant eligible patients, more likely those aged between 65 and the early 70; while a second group would rather be referred to current approved treatment regimens for the non-transplant setting. A dose-intensity approach seems reasonable for this group, aiming for the best response, eventually the complete response (CR) or even minimal residual disease (MRD). The advent of novel agents such as thalidomide, bortezomib, and most recently lenalidomide have allowed a major improvement in outcome as compared to historical combinations, and soon the novel class of monoclonal antibodies should help to further improve these patients' survival. Nonetheless, elderly patients are more susceptible to side effects and are often unable to tolerate full drug doses, and thus require lower dose intensity regimens, or novel drugs or combinations with more favourable safety profile. Recent developments in MM have focused on identifying these vulnerable patients through geriatric assessment and novel myeloma scoring system, including the notions of frailty, disability and comorbidities. Eventually, we have reached an era in which we should be able to provide individualized treatment strategies and drug doses-"tailored therapy"-to improve tolerability and optimize efficacy and ultimately survival for most

  18. 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.

  19. 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

  20. An Ex Vivo Platform for the Prediction of Clinical Response in Multiple Myeloma.

    PubMed

    Silva, Ariosto; Silva, Maria C; Sudalagunta, Praneeth; Distler, Allison; Jacobson, Timothy; Collins, Aunshka; Nguyen, Tuan; Song, Jinming; Chen, Dung-Tsa; Chen, Lu; Cubitt, Christopher; Baz, Rachid; Perez, Lia; Rebatchouk, Dmitri; Dalton, William; Greene, James; Gatenby, Robert; Gillies, Robert; Sontag, Eduardo; Meads, Mark B; Shain, Kenneth H

    2017-06-15

    Multiple myeloma remains treatable but incurable. Despite a growing armamentarium of effective agents, choice of therapy, especially in relapse, still relies almost exclusively on clinical acumen. We have developed a system, Ex vivo Mathematical Myeloma Advisor (EMMA), consisting of patient-specific mathematical models parameterized by an ex vivo assay that reverse engineers the intensity and heterogeneity of chemosensitivity of primary cells from multiple myeloma patients, allowing us to predict clinical response to up to 31 drugs within 5 days after bone marrow biopsy. From a cohort of 52 multiple myeloma patients, EMMA correctly classified 96% as responders/nonresponders and correctly classified 79% according to International Myeloma Working Group stratification of level of response. We also observed a significant correlation between predicted and actual tumor burden measurements (Pearson r = 0.5658, P < 0.0001). Preliminary estimates indicate that, among the patients enrolled in this study, 60% were treated with at least one ineffective agent from their therapy combination regimen, whereas 30% would have responded better if treated with another available drug or combination. Two in silico clinical trials with experimental agents ricolinostat and venetoclax, in a cohort of 19 multiple myeloma patient samples, yielded consistent results with recent phase I/II trials, suggesting that EMMA is a feasible platform for estimating clinical efficacy of drugs and inclusion criteria screening. This unique platform, specifically designed to predict therapeutic response in multiple myeloma patients within a clinically actionable time frame, has shown high predictive accuracy in patients treated with combinations of different classes of drugs. The accuracy, reproducibility, short turnaround time, and high-throughput potential of this platform demonstrate EMMA's promise as a decision support system for therapeutic management of multiple myeloma. Cancer Res; 77(12); 3336-51.

  1. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.

    PubMed

    Rajkumar, S Vincent; Dimopoulos, Meletios A; Palumbo, Antonio; Blade, Joan; Merlini, Giampaolo; Mateos, María-Victoria; Kumar, Shaji; Hillengass, Jens; Kastritis, Efstathios; Richardson, Paul; Landgren, Ola; Paiva, Bruno; Dispenzieri, Angela; Weiss, Brendan; LeLeu, Xavier; Zweegman, Sonja; Lonial, Sagar; Rosinol, Laura; Zamagni, Elena; Jagannath, Sundar; Sezer, Orhan; Kristinsson, Sigurdur Y; Caers, Jo; Usmani, Saad Z; Lahuerta, Juan José; Johnsen, Hans Erik; Beksac, Meral; Cavo, Michele; Goldschmidt, Hartmut; Terpos, Evangelos; Kyle, Robert A; Anderson, Kenneth C; Durie, Brian G M; Miguel, Jesus F San

    2014-11-01

    This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.

  2. Adhesion molecules--The lifelines of multiple myeloma cells.

    PubMed

    Katz, Ben-Zion

    2010-06-01

    Multiple myeloma is an incurable hematological malignancy of terminally differentiated immunoglobulin-producing plasma cells. As a common presentation of the disease, the malignant plasma cells accumulate and proliferate in the bone marrow, where they disrupt normal hematopoiesis and bone physiology. Multiple myeloma cells and the bone marrow microenvironment are linked by a composite network of interactions mediated by soluble factors and adhesion molecules. Integrins and syndecan-1/CD138 are the principal multiple myeloma receptor systems of extracellular matrix components, as well as of surface molecules of stromal cells. CD44 and RHAMM are the major hyaluronan receptors of multiple myeloma cells. The SDF-1/CXCR4 axis is a key factor in the homing of multiple myeloma cells to the bone marrow. The levels of expression and activity of these adhesion molecules are controlled by cytoplasmic operating mechanisms, as well as by extracellular factors including enzymes, growth factors and microenvironmental conditions. Several signaling responses are activated by adhesive interactions of multiple myeloma cells, and their outcomes affect the survival, proliferation and migration of these cells, and in many cases generate a drug-resistant phenotype. Hence, the adhesion systems of multiple myeloma cells are attractive potential therapeutic targets. Several approaches are being developed to disrupt the activities of adhesion molecules in multiple myeloma cells, including small antagonist molecules, direct targeting by immunoconjugates, stimulation of immune responses against these molecules, and signal transduction inhibitors. These potential novel therapeutics may be incorporated into current treatment schemes, or directed against minimal residual malignant cells during remission. Copyright © 2010. Published by Elsevier Ltd.

  3. Bone marrow myeloid cells in regulation of multiple myeloma progression.

    PubMed

    Herlihy, Sarah E; Lin, Cindy; Nefedova, Yulia

    2017-08-01

    Survival, growth, and response to chemotherapy of cancer cells depends strongly on the interaction of cancer cells with the tumor microenvironment. In multiple myeloma, a cancer of plasma cells that localizes preferentially in the bone marrow, the microenvironment is highly enriched with myeloid cells. The majority of myeloid cells are represented by mature and immature neutrophils. The contribution of the different myeloid cell populations to tumor progression and chemoresistance in multiple myeloma is discussed.

  4. [Significance of CD138/syndecan-1 for multiple myeloma immunophenotypes].

    PubMed

    Zhuang, Jun-Ling; Wang, Xuan; Wu, Yong-Ji

    2005-12-01

    To establish the method of immunophenotyping testing for patients with multiple myeloma (MM), to analyze the characteristics of antigen expression on myeloma cells, and to purify primary myeloma cells, CD45/side scatter (SSC) gating tri-color immunofluorescence (IF) flow cytometry (FCM) was used to test immunophenotype of 18 patients with MM, 20 patients with acute leukemia (AL) and 7 normal controls. Purified primary myeloma cells were obtained by means of anti-CD138 monoclonal antibody and immunomagnetic microbeads. The results showed that myeloma cells displayed a CD45 negative/low positive expression, and SSC was located between nucleated red blood cells and neutrophils. Both CD138 and CD38 were positive while most antigens of T cell, B cell and myeloid cell were negative. Positive rate of CD56 was 83.3% and HLA-DR was 44.4% positive. Compared with MM patients, CD138 was negative and CD38 was 100% positive in AL patients. CD56 was 25% positive. In normal controls, neither CD138 nor CD56 was positive. The positive rate of primary myeloma cells after purification was 73%-95% with a mean of 86%. It is concluded that CD45/SSC gating procedure is a stable and reliable method to detect immunophenotype of MM. CD138 is a correspondingly special antigen for myeloma cells. Highly enriched primary myeloma cells can be obtained by anti-CD138 antibody and immunomagnetic microbeads.

  5. Multiple myeloma and pregnancy: a case report and literature review.

    PubMed

    Borja de Mozota, Daphné; Kadhel, Philippe; Dermeche, Slimane; Multigner, Luc; Janky, Eustase

    2011-10-01

    Multiple myeloma, a hematological malignancy generally affecting elderly people, was diagnosed at the beginning of the pregnancy of a 33-year-old woman. We carried out a literature review in order to evaluate the consequences of this cancer on pregnancy and of pregnancy on multiple myeloma, as to determine the specific follow-up required. A systematic search for articles of interest published between 1949 and 16 November 2010 was performed in MEDLINE, SCOPUS and EMBASE, using the words "multiple myeloma" and "pregnancy". We identified 398 publications of potential interest, 20 of which were selected and included in the analysis. The selected articles included 26 cases. No specific risk factors were identified in pregnant women. The most common presentations were bone pain and/or anemia, as in the general population. Pregnancy seemed to have no effect on multiple myeloma progression. Most pregnancies went to term, with only two medical terminations and six cesareans performed before term, due to the severity of the cancer. No effect of the cancer or its treatment by chemotherapy during pregnancy was found in the children. Pregnancy does not seem to be contraindicated in women with multiple myeloma. Nevertheless, the management of pregnant patients with multiple myeloma is a diagnostic, therapeutic and social challenge, requiring a multidisciplinary approach and regular follow-up. Decisions should be taken based on the severity of the disease, its prognosis and maternal choice.

  6. 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

  7. 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.

  8. Cloudy corneas as an initial presentation of multiple myeloma

    PubMed Central

    Sharma, Priyanka; Madi, Haifa A; Bonshek, Richard; Morgan, Stephen J

    2014-01-01

    Summary We report a case of previously unsuspected myeloma, presenting with cornea verticillata due to intracorneal paraprotein deposition. History An 85-year-old female presented via her optician with a 4-month history of cloudy vision. She had undergone an uneventful bilateral phacoemulsification surgery 7 years earlier. Extensive spiraling corneal epithelial opacification was noted on slit-lamp examination. On further investigation, she was found to have a previously unsuspected low-grade multiple myeloma. We established the nature of the corneal deposits with corneal epithelial biopsy histopathology and electron microscopy. It is very rare for multiple myeloma to present in this fashion. Ophthalmologists should be aware that such a presentation may rarely be due to systemic multiple myeloma. PMID:24812487

  9. Treatment of Multiple Myeloma: A Comprehensive Review

    PubMed Central

    Kyle, Robert A.; Rajkumar, S. Vincent

    2014-01-01

    Multiple myeloma (MM) is a neoplastic plasma cell disorder that results in end-organ damage (hypercalcemia, renal insufficiency, anemia, or skeletal lesions). Patients should not be treated unless they have symptomatic (end-organ damage) MM. They should be classified as having high-risk or standard-risk disease. Patients are classified as high risk in the presence of hypodiploidy or deletion of chromosome 13 (del[13]) with conventional cytogenetics, the presence of t(4:14), t(14;16), t(14;20) translocations or del(17p) with fluorescence in situ hybridization. High-risk disease accounts for about 25% of patients with symptomatic MM. If the patient is deemed eligible for an autologous stem cell transplantation (ASCT), 3 or 4 cycles of lenalidomide and low-dose dexamethasone, or bortezomib and dexamethasone, or thalidomide and dexamethasone are reasonable choices. Stem cells should then be collected and one may proceed with an ASCT. If the patient has a complete response or a very good partial response (VGPR), the patient may be followed without maintenance therapy. If the patient has a less than VGPR, a second ASCT is encouraged. If the patient is in the high-risk group, a bortezomib-containing regimen to maximum response followed by 2 additional cycles of therapy is a reasonable approach. Lenalidomide and low-dose dexamethasone is another option for maintenance until progression. If the patient is considered ineligible for an ASCT, then melphalan, prednisone, and thalidomide is suggested for the standard-risk patient, and melphalan, prednisone, and bortezomib (MPV) for the high-risk patient. Treatment of relapsed or refractory MM is covered. The novel therapies—thalidomide, bortezomib, and lenalidomide—have resulted in improved survival rates. The complications of MM are also described. Multiple myeloma is a plasma cell neoplasm that is characterized by a single clone of plasma cells producing a monoclonal protein (M-protein). The malignant proliferation of

  10. Pyoderma gangrenosum due to lenalidomide use for multiple myeloma.

    PubMed

    Dasanu, Constantin A; Bockorny, Bruno; Alexandrescu, Doru T

    2015-12-01

    Pyoderma gangrenosum has been described in association with multiple myeloma and usually affects patients with active/untreated disease. This dermatologic condition was shown to resolve after successful anti-myeloma therapy. We report herein occurrence of pyoderma gangrenosum involving bilateral knees in a patient with multiple myeloma responding to lenalidomide therapy. Previous papers claimed usefulness of thalidomide and its newer derivatives for the therapy of this neutrophilic dermatosis. Occurrence of pyoderma gangrenosum in a myeloma patient responding to lenalidomide would argue against its effectiveness in treating this skin condition. Moreover, the clinical setting suggested that lenalidomide either induced or contributed to the occurrence of pyoderma gangrenosum in our patient. If our hypothesis is correct, we expect more reports of pyoderma gangrenosum with the use of this class of pharmaceuticals.

  11. 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.

  12. Multiple myeloma: practice patterns across Europe.

    PubMed

    Raab, Marc S; Cavo, Michele; Delforge, Michel; Driessen, Christoph; Fink, Leah; Flinois, Alain; Gonzalez-McQuire, Sebastian; Safaei, Reza; Karlin, Lionel; Mateos, Maria-Victoria; Schoen, Paul; Yong, Kwee

    2016-10-01

    Real-world data describing management of patients with multiple myeloma are limited. A European (Belgium, France, Germany, Italy, Spain, Switzerland, UK) observational chart review was conducted to address this. Physicians completed questionnaires for every patient seen during a 2-4-week observation period, regardless of treatment status. A total of 435 physicians completed 7635 cross-sectional chart reviews. Overall, 47% of patients were undergoing anti-tumour drug treatment, 42% had previously received ≥1 line of treatment and 12% had never received anti-tumour drug treatment. Of the patients treated by oncologists, onco-haematologists or internists, 95% received, or were expected to receive, at least one line of anti-tumour drug treatment, 61% received ≥2 lines of therapy and 38% received ≥3 lines. Except in the UK, the most commonly used induction therapies contained bortezomib (48%); lenalidomide was the most commonly used first-line maintenance therapy (45%) and second- and third-line agent overall (60% and 52% of patients at those lines, respectively). Bortezomib retreatment was used in 47% of patients who received it first line. Treatment patterns became more diverse with subsequent treatment lines. This study provides insight into real-world treatment patterns in Europe. While treatment practices are broadly similar across countries, some notable differences in the agents used exist. © 2016 John Wiley & Sons Ltd.

  13. Characterization of clonogenic multiple myeloma cells

    PubMed Central

    Matsui, William; Huff, Carol Ann; Wang, Qiuju; Malehorn, Matthew T.; Barber, James; Tanhehco, Yvette; Smith, B. Douglas; Civin, Curt I.; Jones, Richard J.

    2012-01-01

    The identity of the cells responsible for the initiation and maintenance of multiple myeloma (MM) remains unclear largely because of the difficulty growing MM cells in vitro and in vivo. MM cell lines and clinical specimens are characterized by malignant plasma cells that express the cell surface antigen syndecan-1 (CD138); however, CD138 expression is limited to terminally differentiated plasma cells during B-cell development. Moreover, circulating B cells that are clonally related to MM plasma cells have been reported in some patients with MM. We found that human MM cell lines contained small (< 5%) subpopulations that lacked CD138 expression and had greater clonogenic potential in vitro than corresponding CD138+ plasma cells. CD138− cells from clinical MM samples were similarly clonogenic both in vitro and in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, whereas CD138+ cells were not. Furthermore, CD138− cells from both cell lines and clinical samples phenotypically resembled postgerminal center B cells, and their clonogenic growth was inhibited by the anti-CD20 monoclonal antibody rituximab. These data suggest that MM “stem cells” are CD138− B cells with the ability to replicate and subsequently differentiate into malignant CD138+ plasma cells. PMID:14630803

  14. Characterization of clonogenic multiple myeloma cells.

    PubMed

    Matsui, William; Huff, Carol Ann; Wang, Qiuju; Malehorn, Matthew T; Barber, James; Tanhehco, Yvette; Smith, B Douglas; Civin, Curt I; Jones, Richard J

    2004-03-15

    The identity of the cells responsible for the initiation and maintenance of multiple myeloma (MM) remains unclear largely because of the difficulty growing MM cells in vitro and in vivo. MM cell lines and clinical specimens are characterized by malignant plasma cells that express the cell surface antigen syndecan-1 (CD138); however, CD138 expression is limited to terminally differentiated plasma cells during B-cell development. Moreover, circulating B cells that are clonally related to MM plasma cells have been reported in some patients with MM. We found that human MM cell lines contained small (< 5%) subpopulations that lacked CD138 expression and had greater clonogenic potential in vitro than corresponding CD138+ plasma cells. CD138- cells from clinical MM samples were similarly clonogenic both in vitro and in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, whereas CD138+ cells were not. Furthermore, CD138- cells from both cell lines and clinical samples phenotypically resembled postgerminal center B cells, and their clonogenic growth was inhibited by the anti-CD20 monoclonal antibody rituximab. These data suggest that MM "stem cells" are CD138- B cells with the ability to replicate and subsequently differentiate into malignant CD138+ plasma cells.

  15. 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

  16. Multiple Myeloma Genomics: A Systematic Review.

    PubMed

    Weaver, Casey J; Tariman, Joseph D

    2017-08-01

    This integrative review describes the genomic variants that have been found to be associated with poor prognosis in patients diagnosed with multiple myeloma (MM). Second, it identifies MM genetic and genomic changes using next-generation sequencing, specifically whole-genome sequencing or exome sequencing. A search for peer-reviewed articles through PubMed, EBSCOhost, and DePaul WorldCat Libraries Worldwide yielded 33 articles that were included in the final analysis. The most commonly reported genetic changes were KRAS, NRAS, TP53, FAM46C, BRAF, DIS3, ATM, and CCND1. These genetic changes play a role in the pathogenesis of MM, prognostication, and therapeutic targets for novel therapies. MM genetics and genomics are expanding rapidly; oncology nurse clinicians must have basic competencies in genetics and genomics to help patients understand the complexities of genetic and genomic alterations and be able to refer patients to appropriate genomic professionals if needed. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Multiple Myeloma and the immune microenvironment.

    PubMed

    Kawano, Yawara; Roccaro, Aldo M; Azzi, Jamil; Ghobrial, Irene M

    2017-02-13

    One of the great advances in the field of cancer therapy in recent years is the emergence of immune therapies. Immune therapies, especially immune checkpoint inhibitors, have shown promising results in pre-clinical models and clinical trials of solid tumors, such as melanoma, breast cancer and lung cancer. Therapeutic strategies targeting the immune microenvironment have also been applied to hematological malignancies such as multiple myeloma (MM), a plasma cell neoplasia characterized by clonal expansion of malignant plasma cells mainly in the bone marrow (BM). MM is associated with both cellular and humoral immune deficiencies, indicating that the evolution of the disease from a precursor state (monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (sMM)) is associated with an immunosuppressive milieu that fosters immune escape and tumor growth. Despite significant advances in treatment, MM is mostly an incurable diseases. Therefore, there is an urgent need of novel therapeutic agents that not only target the tumor clone but also the MM immune microenvironment. However, the complexity of the BM microenvironment and heterogeneity of tumor cell clones make it a difficult task for developing appropriate immune therapies of MM. In this article we review the current knowledge of the interaction between malignant plasma cells and the bone marrow immune microenvironment during disease progression. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Antibody-Based Therapies in Multiple Myeloma

    PubMed Central

    Tai, Yu-Tzu; Anderson, Kenneth C.

    2011-01-01

    The unmet need for improved multiple myeloma (MM) therapy has stimulated clinical development of monoclonal antibodies (mAbs) targeting either MM cells or cells of the bone marrow (BM) microenvironment. In contrast to small-molecule inhibitors, therapeutic mAbs present the potential to specifically target tumor cells and directly induce an immune response to lyse tumor cells. Unique immune-effector mechanisms are only triggered by therapeutic mAbs but not by small molecule targeting agents. Although therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, the advancement of genetic recombination for humanizing rodent mAbs has allowed large-scale production and designation of mAbs with better affinities, efficient selection, decreasing immunogenicity, and improved effector functions. These advancements of antibody engineering technologies have largely overcome the critical obstacle of antibody immunogenicity and enabled the development and subsequent Food and Drug Administration (FDA) approval of therapeutic Abs for cancer and other diseases. PMID:22046572

  19. Enhancing cytokine-induced killer cell therapy of multiple myeloma.

    PubMed

    Liu, Chunsheng; Suksanpaisan, Lukkana; Chen, Yun-Wen; Russell, Stephen J; Peng, Kah-Whye

    2013-06-01

    Cytokine-induced killer (CIK) cells are in clinical testing against various tumor types, including multiple myeloma. In this study, we show that CIK cells have activity against subcutaneous and disseminated models of human myeloma (KAS-6/1), which can be enhanced by infecting the CIK cells with an oncolytic measles virus (MV) or by pretreating the myeloma cells with ionizing radiation (XRT). KAS-6/1 cells were killed by coculture with CIK or MV-infected CIK (CIK/MV) cells, and the addition of an anti-NKG2D antibody inhibited cytolysis by 50%. However, human bone marrow stromal cells can reduce CIK and CIK/MV mediated killing of myeloma cells (RPMI 8226, JJN-3 and MM1). In vivo, CIK and CIK/MV prolonged the survival of mice with systemic myeloma, although CIK/MV showed enhanced antitumor activity compared with CIK. Irradiation of the KAS-6/1 cells induced mRNA and protein expression of NKG2D ligands, MICA, and MICB in a dose-dependent manner and enhanced delivery of CIK/MV to the irradiated tumors. In both subcutaneous and disseminated myeloma models, XRT at 2 Gy resulted in superior prolongation of the survival of mice given CIK/MV therapy compared with CIK/MV with no XRT. This study demonstrates the potential of CIK against myeloma and that the combination of virotherapy with radiation could be used to further enhance therapeutic outcome using CIK cells.

  20. Serum free light chains for monitoring multiple myeloma.

    PubMed

    Mead, G P; Carr-Smith, H D; Drayson, M T; Morgan, G J; Child, J A; Bradwell, A R

    2004-08-01

    Monoclonal immunoglobulin free light chains (FLC) are found in the serum and urine of patients with a number of B-cell proliferative disorders, including multiple myeloma. Automated immunoassays, which can measure FLC in serum, are useful for the diagnosis and monitoring of light chain (AL) amyloidosis, Bence Jones myeloma and non-secretory myeloma patients. We report the results of a study investigating the utility of serum FLC measurements in myeloma patients producing monoclonal intact immunoglobulin proteins. FLC concentrations were measured in presentation sera from 493 multiple myeloma patients with monoclonal, intact immunoglobulin proteins. Serial samples were assayed from 17 of these patients and the FLC measurements were compared with other disease markers. Serum FLC concentrations were abnormal in 96% of patients at presentation. FLC concentrations fell more rapidly in response to treatment than intact immunoglobulin G (IgG) and showed greater concordance with serum beta2 microglobulin concentrations and bone marrow plasma cell assessments. It was concluded that serum FLC assays could be used to follow the disease course in nearly all multiple myeloma patients. In addition, because of their short serum half-life, changes in serum FLC concentrations provide a rapid indication of the response to treatment.

  1. A transplant "immunome" screening platform defines a targetable epitope fingerprint of multiple myeloma.

    PubMed

    Schieferdecker, Aneta; Oberle, Anna; Thiele, Benjamin; Hofmann, Fabian; Göthel, Markus; Miethe, Sebastian; Hust, Michael; Braig, Friederike; Voigt, Mareike; von Pein, Ute-Marie; Koch-Nolte, Friedrich; Haag, Friedrich; Alawi, Malik; Indenbirken, Daniela; Grundhoff, Adam; Bokemeyer, Carsten; Bacher, Ulrike; Kröger, Nicolaus; Binder, Mascha

    2016-06-23

    Multiple myeloma (MM) is a hematological cancer for which immune-based treatments are currently in development. Many of these rely on the identification of highly disease-specific, strongly and stably expressed antigens. Here, we profiled the myeloma B-cell immunome both to explore its predictive role in the context of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and to identify novel immunotherapeutic targets. We used random peptide phage display, reverse immunization, and next-generation sequencing-assisted antibody phage display to establish a highly myeloma-specific epitope fingerprint targeted by B-cell responses of 18 patients in clinical remission. We found that allogeneic HSCT more efficiently allowed production of myeloma-specific antibodies compared with autologous HSCT and that a highly reactive epitope recognition signature correlated with superior response to treatment. Next, we performed myeloma cell surface screenings of phage-displayed patient transplant immunomes. Although some of the screenings yielded clear-cut surface binders, the majority of screenings did not, suggesting that many of the targeted antigens may in fact not be accessible to the B-cell immune system in untreated myeloma cells. This fit well with the identification of heat-shock proteins as a class of antigens that showed overall the broadest reactivity with myeloma patient sera after allogeneic HSCT and that may be significantly translocated to the cell surface upon treatment as a result of immunogenic cell death. Our data reveal a disease-specific epitope signature of MM that is predictive for response to treatment. Mining of transplant immunomes for strong myeloma surface binders may open up avenues for myeloma immunotherapy. © 2016 by The American Society of Hematology.

  2. 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

  3. Genomic analysis of high-risk smoldering multiple myeloma.

    PubMed

    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

    2012-09-01

    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).

  4. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.

    PubMed

    Kyle, Robert A; Remstein, Ellen D; Therneau, Terry M; Dispenzieri, Angela; Kurtin, Paul J; Hodnefield, Janice M; Larson, Dirk R; Plevak, Matthew F; Jelinek, Diane F; Fonseca, Rafael; Melton, Lee Joseph; Rajkumar, S Vincent

    2007-06-21

    Smoldering (asymptomatic) multiple myeloma is an asymptomatic plasma-cell proliferative disorder associated with a high risk of progression to symptomatic multiple myeloma or amyloidosis. Prognostic factors for the progression and outcome of this disease are unclear. We searched a computerized database and reviewed the medical records of all patients at Mayo Clinic who fulfilled the criteria of the International Myeloma Working Group for the diagnosis of smoldering multiple myeloma between 1970 and 1995. Bone marrow aspirate and biopsy specimens were studied, and patients were followed throughout the course of disease. During the 26-year period, 276 patients fulfilled the criteria for smoldering multiple myeloma. During 2131 cumulative person-years of follow-up, symptomatic multiple myeloma or amyloidosis developed in 163 persons (59%). The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years; the cumulative probability of progression was 73% at 15 years. At diagnosis, significant risk factors for progression included the serum level and type of monoclonal protein, the presence of urinary light chain, the extent and pattern of bone marrow involvement, and the reduction in uninvolved immunoglobulins. The proportion of plasma cells in the bone marrow and the serum monoclonal protein level were combined to create a risk-stratification model with three distinct prognostic groups. The risk of progression from smoldering multiple myeloma to symptomatic disease is related to the proportion of bone marrow plasma cells and the serum monoclonal protein level at diagnosis. Copyright 2007 Massachusetts Medical Society.

  5. Targeting aurora kinases as therapy in multiple myeloma

    PubMed Central

    Shi, Yijiang; Reiman, Tony; Li, Weiqun; Maxwell, Christopher A.; Sen, Subrata; Pilarski, Linda; Daniels, Tracy R.; Penichet, Manuel L.; Feldman, Rick

    2007-01-01

    The aurora kinases facilitate transit from G2 through cytokinesis and, thus, are targets in cancer therapy. Multiple myeloma (MM) is a malignancy characterized by genetic instability, suggesting a disruption of checkpoints that arrest cells at G2M when injury to the mitotic machinery occurs. Since deficient checkpoints would prevent cell cycle arrest and may render cells susceptible to apoptosis in mitosis and since aurora kinases are intermediaries in checkpoint pathways, we tested antimyeloma effects of 2 agents that inhibit aurora kinases. Both inhibited growth of MM lines and primary myeloma samples at nanomolar concentrations while having less of an effect on proliferating lymphocytes and hematopoietic cells. MM cells were not protected by IL-6 or activating mutations of Ras. Antimyeloma effects included induction of tetraploidy followed by apoptosis. Apoptosis correlated with inhibition of aurora activity as shown by reduction of histone 3B phosphorylation. Ectopic expression of aurora A protected MM cells against aurora inhibitors but had no effect on apoptosis induced by bortezomib. As expression of RHAMM in MM contributes to genetic instability, we tested effects of RHAMM. RHAMM overexpression enhanced sensitivity to apoptosis and RHAMM silencing decreased sensitivity. These results suggest potential for aurora kinase inhibitors in MM especially in patients in whom RHAMM is overexpressed. PMID:17213289

  6. Neuropathy in multiple myeloma treated with thalidomide: a prospective study.

    PubMed

    Plasmati, R; Pastorelli, F; Cavo, M; Petracci, E; Zamagni, E; Tosi, P; Cangini, D; Tacchetti, P; Salvi, F; Bartolomei, I; Michelucci, R; Tassinari, C A

    2007-08-07

    Thalidomide is effective as a first-line therapy for the treatment of multiple myeloma (MM), but its use is limited by peripheral neurotoxicity. To study the occurrence of both myeloma-related neuropathy and thalidomide-induced neuropathy in 31 patients with newly diagnosed MM. Clinical and electrophysiologic examinations were performed in 31 patients with newly diagnosed MM before and after 4 months of therapy with thalidomide (200 mg/day, total dose: 21 g) aimed at debulking MM, before autologous transplantation. After transplantation, the patients took thalidomide, 200 mg/day for another 3 months (total dose over three months: 18 g) and then underwent a final clinical and electrophysiologic checkup. At baseline, four patients presented a mild sensorimotor peripheral neuropathy related to MM, which tended to worsen slightly during treatment with thalidomide. At the end of treatment, 83% of the patients had clinical and electrophysiologic evidence of a mild sensory rather than motor, axonal, length-dependent polyneuropathy, whereas 100% of the patients showed improvement to the basic pathology (>or=partial response). Peripheral neuropathy, sometimes subclinical, and mild in our patients, is a common, early side effect of thalidomide therapy. The high doses (21 g) used in all patients for a relatively short time (4 months) rule out any correlations between neuropathy, total dose, and duration of treatment.

  7. Integrated molecular profiling of SOD2 expression in multiple myeloma.

    PubMed

    Hurt, Elaine M; Thomas, Suneetha B; Peng, Benjamin; Farrar, William L

    2007-05-01

    Reactive oxygen species are known to be involved in several cellular processes, including cell signaling. SOD2 is a key enzyme in the conversion of reactive oxygen species and has been implicated in a host of disease states, including cancer. Using an integrated, whole-cell approach encompassing epigenetics, genomics, and proteomics, we have defined the role of SOD2 in multiple myeloma. We show that the SOD2 promoter is methylated in several cell lines and there is a correlative decrease in expression. Furthermore, myeloma patient samples have decreased SOD2 expression compared with healthy donors. Overexpression of SOD2 results in decreased proliferation and altered sensitivity to 2-methoxyestradiol-induced DNA damage and apoptosis. Genomic profiling revealed regulation of 65 genes, including genes involved in tumorigenesis, and proteomic analysis identified activation of the JAK/STAT pathway. Analysis of nearly 400 activated transcription factors identified 31 transcription factors with altered DNA binding activity, including XBP1, NFAT, forkhead, and GAS binding sites. Integration of data from our gestalt molecular analysis has defined a role for SOD2 in cellular proliferation, JAK/STAT signaling, and regulation of several transcription factors.

  8. A case of multiple myeloma in a poultry worker.

    PubMed

    Jung, Pil Kyun; Kim, Inah; Park, Inhyo; Kim, Chinyon; Kim, Eun-A; Roh, Jaehoon

    2014-01-01

    Livestock breeders including poultry workers are exposed to various agricultural chemicals including pesticides and/or organic solvents. Multiple myeloma is a rare disease in Korea, and few reports have investigated the influence of occupational exposures on multiple myeloma occurrence. A 61-year-old male poultry farm worker presented with bone pain and generalized weakness. A bone marrow biopsy was performed, and he was diagnosed with multiple myeloma. The patient had worked in a poultry farm for 16 years and was exposed to various pesticides and organic solvents such as formaldehyde without any proper personal protective equipment. Results of the work reenactment revealed that the concentration of formaldehyde (17.53 ppm) greatly exceeded the time-weighted average (0.5 ppm) and short-term exposure limit (1.0 ppm) suggested in the Korean Industrial Safety and Health Act. This case report suggests that poultry workers may be exposed to high levels of various hazardous chemicals including pesticides and/or organic solvents. Numerous previous studies have suggested an association between multiple myeloma and exposure to agricultural chemicals; thus, multiple myeloma in this patient might have resulted from the prolonged, high exposure to these chemicals.

  9. Jaw avascular osteonecrosis after treatment of multiple myeloma with zoledronate.

    PubMed

    Lobato, J V; Maurício, A C; Rodrigues, J M; Cavaleiro, M V; Cortez, P P; Xavier, L; Botelho, C; Hussain, N Sooraj; Santos, J D

    2008-01-01

    Multiple myeloma, the second most common haematopoietic cancer, which represents the collection of plasma-cell neoplasms that invariably becomes fatal when self-renewing myeloma cells begin unrestrained proliferation. The major clinical manifestation of multiple myeloma is related to the loss of bone through osteolysis. This can lead to pathologic fractures, spinal cord compression, hypercalcaemia, and pain. It is also a major cause of morbidity and mortality in these patients, who frequently require radiation therapy, surgery and analgesic medications. Bisphosphonates are specific inhibitors of osteoclastic activity, and are currently used to prevent bone complications and to treat malignant hypercalcaemia in patients with multiple myeloma, or bone metastases from breast and prostate cancers. Hence, osteonecrosis of the mandible has been reported in three patients from Centro Hospitalar de Vila Nova de Gaia (CHVNG) with multiple myeloma treated for over 18-48 months with intravenous zoledronate, commonly prescribed for multiple myeloma therapy. Although, this report alerts clinicians about the potential complication of bone necrosis in patients receiving bisphosphonate therapy, many questions remain concerning the underlying pathogenesis of this process. The medical and dental records of three patients with multiple myeloma, who were treated in CHVNG in the past 4 years, were reviewed. These three patients presented exposed bone and osteonecrosis of the mandible, and shared one common clinical feature: all of them were treated with bisphosphonate zoledronate, administered intravenously for long periods. Sequential orthopantomograms (OPGs) and histological evaluation have been analysed from the biopsies of the non healing dental extraction sites of these patients. After a routine dental extraction, these patients developed avascular osteonecrosis of the mandible and secondary bone infection with Actinomyces israelii (actinomycotic osteomyelitis), with no evidence

  10. New cancers after autotransplantations for multiple myeloma.

    PubMed

    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 N

    2015-04-01

    We describe baseline incidence and risk factors for new cancers in 4161 persons receiving autotransplants for multiple myeloma in the United States from 1990 to 2010. Observed incidence of invasive new cancers was compared with expected incidence relative to the US population. The cohort represented 13,387 person-years at-risk. In total, 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% confidence interval [CI], 2.09 to 3.17), 4.2% (95% CI, 3.49 to 5.00), and 6.1% (95% CI, 5.08 to 7.24) at 3, 5, and 7 years, respectively. The incidence of new cancers in the autotransplantation cohort was similar to age-, race-, and gender-adjusted comparison subjects with an observed/expected (O/E) ratio of 1.00 (99% CI, .81 to 1.22). However, acute myeloid leukemia and melanoma were observed at higher than expected rates with O/E ratios of 5.19 (99% CI, 1.67 to 12.04; P = .0004), and 3.58 (99% CI, 1.82 to 6.29; P < .0001), respectively. Obesity, older age, and male gender were associated with increased risks of new cancers in multivariate analyses. This large data set provides a baseline for comparison and defines the histologic type specific risk for new cancers in patients with MM receiving postautotransplantation therapies, such as maintenance.

  11. Sequential or combination therapy for multiple myeloma.

    PubMed

    Nooka, Ajay; Lonial, Sagar

    2012-10-01

    In myeloma management, whether to offer sequential or combination therapies has largely remained elusive, partly for the reason that there are no conclusive studies evaluating this question and partly owing to the paradigm shift in myeloma outcomes over the last decade raising the same question again, but now in a different context with active agents such as immunomodulatory drugs and proteasome inhibitors being available. Historically, in myeloma, combination cytotoxic chemotherapy compared with the standard-of-care melphalan and prednisone regimen resulted in similar response rates, raising the question of efficacy of the cytotoxic combination therapies with high toxicities and the preference for sequential therapies in order to lower the toxicity of the chosen treatment. However, with the use of more active novel agents with favorable toxicity profiles such as bortezomib, thalidomide and lenalidomide, re-evaluation of this question is necessary.

  12. Osteoblastic niche supports the growth of quiescent multiple myeloma cells

    PubMed Central

    Chen, Zheng; Orlowski, Robert Z.; Wang, Michael; Kwak, Larry

    2014-01-01

    The heterogeneity of multiple myeloma (MM) contributes to variable responses to therapy. In this study, we aim to correlate the heterogeneity of MM to the presence of quiescent cells using the PKH26 dye. We tracked the rare quiescent cells in different niches of the bone marrow by allowing the cells to cycle in vivo. Surprisingly, quiescent PKH+ MM cells prefer to reside within the osteoblastic niches of the bone marrow (PKH+/OS) rather than the vascular (VS) niches or the spleen. These cells (PKH+/OS) displayed enhanced stemlike properties by forming colonies in semisolid medium. PKH+ cells were highly tumorigenic compared with PKH– cells and were resistant to a variety of drugs. However, the levels of drug resistance were somewhat similar regardless of where the PKH+ cells were isolated. Our data indicate that osteoblastic niches support the growth of quiescent PKH+ cells and allow them to have stemlike functions. PMID:24425802

  13. 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

  14. Molecular pathogenesis of multiple myeloma: basic and clinical updates.

    PubMed

    Chesi, Marta; Bergsagel, P Leif

    2013-03-01

    Multiple myeloma is divided into two distinct genetic subtypes based on chromosome content. Hyperdiploid myeloma is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21, and lacks recurrent immunoglobulin gene translocations. Non-hyperdiploid myeloma in contrast is characterized by chromosome translocations t(4;14), t(14;16), t(14;20), t(6;14) and t(11;14). A unifying event in the pathogenesis of multiple myeloma is the dysregulated expression of a cyclin D gene, either directly by juxtaposition to an immunoglobulin enhancer, as a result of ectopic expression of a MAF family transcription factor, or indirectly by as yet unidentified mechanisms. Secondary genetic events include rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, a promiscuous array of mutations that activate NFkB and deletions of 17p. Among the poor-risk genetic features are t(4;14), t(14;16), t(14;20), del 17p and gains of 1q. Available evidence supports the use of a risk-stratified approach to the treatment of patients with multiple myeloma, with the early and prolonged use of bortezomib particularly in patients with t(4;14) and del 17p.

  15. [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.

  16. Molecular pathogenesis of multiple myeloma: basic and clinical updates

    PubMed Central

    Chesi, Marta

    2014-01-01

    Multiple myeloma is divided into two distinct genetic subtypes based on chromosome content. Hyperdiploid myeloma is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21, and lacks recurrent immunoglobulin gene translocations. Non-hyperdiploid myeloma in contrast is characterized by chromosome translocations t(4;14), t(14;16), t(14;20), t(6;14) and t(11;14). A unifying event in the pathogenesis of multiple myeloma is the dysregulated expression of a cyclin D gene, either directly by juxtaposition to an immunoglobulin enhancer, as a result of ectopic expression of a MAF family transcription factor, or indirectly by as yet unidentified mechanisms. Secondary genetic events include rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, a promiscuous array of mutations that activate NFkB and deletions of 17p. Among the poor-risk genetic features are t(4;14), t(14;16), t(14;20), del 17p and gains of 1q. Available evidence supports the use of a risk-stratified approach to the treatment of patients with multiple myeloma, with the early and prolonged use of bortezomib particularly in patients with t(4;14) and del 17p. PMID:23456262

  17. Unrelated stem cell transplantation for patients with multiple myeloma.

    PubMed

    Kröger, Nicolaus

    2010-11-01

    The role of allogeneic stem cell transplantation (SCT) in treatment of myeloma patients is still controversial. Meanwhile, the numbers of unrelated SCT for hematological diseases in Europe are higher than for human leukocyte antigen (HLA)-identical sibling transplantations, but in multiple myeloma only 39% of the allogeneic transplantations are performed from unrelated donors and only a minority were done within prospective clinical trials. The few published data of unrelated SCT in multiple myeloma reported a higher treatment-related mortality for standard myeloablative conditioning in comparison to reduced-intensity conditioning. Despite the heterogeneous patient selection in the trial, lower nonrelapse mortality and improved survival can be achieved by careful donor selection (10/10 HLA-alleles, male donor). Natural killer-alloreactivity might play a role, but conclusive data are lacking. Transplantation in more advanced or refractory patients is associated with an inferior outcome. The results of an unrelated SCT seem to be comparable to those of HLA-identical siblings, but a direct comparison is lacking so far. Unrelated SCT in multiple myeloma is feasible, but prospective clinical trials using unrelated stem cell donors are urgently needed to define the role of an unrelated SCT in multiple myeloma in the era of novel agents.

  18. Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche

    PubMed Central

    Bulfamante, Gaetano; Falleni, Monica; Tosi, Delfina; Todoerti, Katia; Lazzari, Elisa; Crews, Leslie A.; Jamieson, Catriona H.M.; Ravaioli, Sara; Baccianti, Francesco; Garavelli, Silvia; Platonova, Natalia; Neri, Antonino; Chiaramonte, Raffaella

    2016-01-01

    Multiple myeloma cell growth relies on intrinsic aggressiveness, due to a high karyotypic instability, or on the support from bone marrow (BM) niche. We and other groups have provided evidences that Notch signaling is related to tumor cell growth, pharmacological resistance, localization/recirculation in the BM and bone disease. This study indicates that high gene expression levels of Notch signaling members (JAG1, NOTCH2, HES5 and HES6) correlate with malignant progression or high-risk disease, and Notch signaling may participate in myeloma progression by increasing the BM levels of interleukin-6 (IL-6), a major player in myeloma cell growth and survival. Indeed, in vitro results, confirmed by correlation analysis on gene expression profiles of myeloma patients and immunohistochemical studies, demonstrated that Notch signaling controls IL-6 gene expression in those myeloma cells capable of IL-6 autonomous production as well as in surrounding BM stromal cells. In both cases Notch signaling activation may be triggered by myeloma cell-derived Jagged ligands. The evidence that Notch signaling positively controls IL-6 in the myeloma-associated BM makes this pathway a key mediator of tumor-directed reprogramming of the bone niche. This work strengthens the rationale for a novel Notch-directed therapy in multiple myeloma based on the inhibition of Jagged ligands. PMID:27463014

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

    USDA-ARS?s Scientific Manuscript database

    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...

  20. CCR10/CCL27 crosstalk contributes to failure of proteasome-inhibitors in multiple myeloma

    PubMed Central

    Thangavadivel, Shanmugapriya; Zelle-Rieser, Claudia; Olivier, Angelika; Postert, Benno; Untergasser, Gerold; Kern, Johann; Brunner, Andrea; Gunsilius, Eberhard; Biedermann, Rainer; Hajek, Roman; Pour, Ludek; Willenbacher, Wolfgang; Greil, Richard; Jöhrer, Karin

    2016-01-01

    The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines. In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor. From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients. PMID:27732933

  1. 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.

  2. Primary laryngeal localization of multiple myeloma: A case report

    PubMed Central

    Allegra, Eugenia; Marino, Nicolò; Modica, Domenico; Emmanuele, Carmela; Saita, Vincenzo

    2017-01-01

    Multiple myeloma is a lymphoproliferative disease that may involve the bone marrow as well as extramedullary soft tissues. However, laryngeal localization of multiple myeloma is extremely rare. We herein present the case of a 68-year-old male patient with a history of dyspnea, dysphonia and dysphagia. Laryngoscopic examination revealed a lesion involving the right glottis and right vestibular (false) vocal fold, with absence of ipsilateral laryngeal motility and constriction of the airway. Computed tomography and magnetic resonance imaging revealed a gross swelling infiltrating the right glottis and right false vocal fold, sized 33×19×33 mm, with sub-centimeter laterocervical lymph nodes bilaterally. Careful integration of the clinical manifestations with the radiological and pathological data led to the diagnosis of multiple myeloma. Given the rarity of this localization, the purpose of this study was to increase knowledge of this disease among ear, nose and throat specialists, in order to enable a more timely diagnosis. PMID:28357083

  3. Impaired NHEJ function in Multiple Myeloma

    PubMed Central

    Yang, Clara; Toor, Amir A.; Singh, Sheetal; Betti, Christopher; Vaughan, Andrew

    2009-01-01

    Multiple Myeloma (MM) is characterized by multiple chromosomal aberrations. To assess the contribution of DNA repair to this phenotype, ionizing radiation was used to induce DNA double strand breaks in three MM cell lines. Clonogenic survival assays showed U266 (SF4= 15.3+6.4%) and RPMI 8226 (SF4=12.6.0+1.7%) were radiation sensitive while OPM2 was resistant (SF4=78.9+4.1%). Addition of the DNA-PK inhibitor NU7026 showed the expected suppression in radiation survival in OPM2 but increased survival in both radiation sensitive cell lines. To examine NHEJ repair in these lines, the ability of protein extracts to support in vitro DNA repair was measured. Among the three MM cell lines analyzed, RPMI 8226 demonstrated impaired blunt ended DNA ligation using a ligation mediated PCR technique. In a bacterial based functional assay to rejoin a DNA break within the β-galactosidase gene, RPMI 8226 demonstrated a four fold reduction in rejoining fidelity compared to U266, with OPM2 showing an intermediate capacity. Ionizing radiation induced a robust γ-H2AX response in OPM2 but only a modest increase in each radiation sensitive cell line perhaps related to the high level of γ-H2AX in freshly plated cells. Examination of γ-H2AX foci in RPMI 8226 cells confirmed data from Western blots where a significant number of foci were present in freshly plated untreated cells which diminished over 24 h of culture. Based on the clonogenic survival and functional repair assays, all three cell lines exhibited corrupt NHEJ repair. We conclude that suppression of aberrant NHEJ function using the DNA-PK inhibitor NU7026 may facilitate access of DNA ends to an intact homologous recombination repair pathway, paradoxically increasing survival after irradiation. These data provide insight into the deregulation of DNA repair at the site of DNA breaks in MM that may underpin the characteristic genomic instability of this disease. PMID:19028508

  4. A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells.

    PubMed

    Gullà, Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia; Morelli, Eugenio; Amodio, Nicola; Botta, Cirino; Pitari, Maria Rita; Lio, Santo Giovanni; Britti, Domenico; Stamato, Maria Angelica; Hideshima, Teru; Munshi, Nikhil C; Anderson, Kenneth C; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2016-03-01

    The onset of drug resistance is a major cause of treatment failure in multiple myeloma. Although increasing evidence is defining the role of miRNAs in mediating drug resistance, their potential activity as drug-sensitizing agents has not yet been investigated in multiple myeloma. Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory multiple myeloma cells to melphalan. miR-221/222 expression inversely correlated with melphalan sensitivity of multiple myeloma cells. Inhibition of miR-221/222 overcame melphalan resistance and triggered apoptosis of multiple myeloma cells in vitro, in the presence or absence of human bone marrow (BM) stromal cells. Decreased multiple myeloma cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ABC transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory multiple myeloma xenografts with systemic locked nucleic acid (LNA) inhibitors of miR-221 (LNA-i-miR-221) plus melphalan overcame drug resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice. Taken together, our findings provide the proof of concept that LNA-i-miR-221 can reverse melphalan resistance in preclinical models of multiple myeloma, providing the framework for clinical trials to overcome drug resistance, and improve patient outcome in multiple myeloma. ©2015 American Association for Cancer Research.

  5. Treatment of relapsed and refractory multiple myeloma.

    PubMed

    Singhal, Seema; Mehta, Jayesh

    2003-06-01

    The definition of relapsed and refractory myeloma was straightforward when melphalan-prednisone constituted the mainstay of treatment and high-dose therapy with transplantation was rarely used in myeloma. However, several advances have occurred in the treatment of myeloma over the past decade. Most notably, high-dose therapy and transplantation have become broadly applicable, thalidomide has become available as effective salvage therapy, and several investigational agents with novel mechanisms of action appear to be very promising. Because of the differing properties of some of these agents, it is often possible to control the disease with an alternative treatment approach after the failure of one therapy. Some data indicate that combinations of these agents work when the drugs have failed individually. Therefore, refractory myeloma indicates disease unresponsive to the most recent therapy administered. Broadly, the salvage approaches that are used in patients with refractory or relapsed disease include high-dose dexamethasone, high-dose chemotherapy with autotransplantation, allogeneic hematopoietic stem cell transplantation, thalidomide-based therapies, and novel/investigational agents. The appropriate therapy for a given situation depends on the nature of the disease, age, organ function, bone marrow function, prior treatment, the availability of stem cell donors, and access to novel agents. A therapeutic trial of thalidomide is essential at some stage of the disease in all patients. High-dose therapy with autotransplantation is needed at some stage of the disease in most patients younger than 65 to 70 years.

  6. Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo.

    PubMed

    Schmidmaier, R; Mörsdorf, K; Baumann, P; Emmerich, B; Meinhardt, G

    2006-01-01

    Multiple myeloma is an incurable disease and patients eventually die of disease progression due to drug resistance. VLA-4 (very late antigen 4), VCAM (vascular adhesion molecule), LFA-1 (leukocyte function-associated antigen 1), and ICAM-1 (intercellular adhesion molecule 1)-mediated adhesion of myeloma cells to bone marrow stromal cells induces primary multidrug resistance in vitro. Based on these preclinical data we hypothesized that myeloma cells with strong adhesion - due to strong expression of adhesion molecules on the cell surface - are selected by chemotherapy in patients. To prove this hypothesis we determined the expression levels of adhesion molecules in 31 multiple myeloma patients by flow cytometry. A 3-color stain with CD38, CD138 and antibodies against VLA-4, ICAM-1, LFA-1, and VCAM was performed. The patients were either at diagnosis (chemo-naive; n=17) or at relapse (pre-treated; n=15). Furthermore, the response to the next chemotherapy of chemo-naive patients was correlated with the expression levels of adhesion molecules. ICAM-1, VLA-4, and VCAM expression was higher in pre-treated patients than in chemo-naive patients and the expression levels increased with the number of chemotherapy regimens. Primarily multidrug-resistant patients had significantly higher expression levels of VLA-4 and ICAM-1 than responders. This study suggests that multiple myeloma cells expressing high levels of VLA-4 and ICAM-1 are drug resistant and that such a subpopulation of cells is selected by chemotherapy.

  7. [Advances of CRBN in Immunomodulatory Drugs for Multiple Myeloma-Review].

    PubMed

    An, Ran; Hou, Jian

    2016-12-01

    Multiple myeloma is a plasma cell malignant clone proliferation diseases and has been remained incurable. In the resent years, the widespread application of immunomodulatory drugs (IMiD) have made a great progress in the treatment of multiple myeloma, greatly improved the complete remission rate and prolonged the overall survival of MM patients. According to recent researches, CRBN (cereblon) plays an important role in mediating anti-myeloma effects of IMiD, and its expression correlated with the effect of IMiD treatment and the prognosis of multiple myeloma. The discovery of CRBN not only deepened the understanding the molecular pharmacological mechanisms of IMiD, but also provide new insights into the novel therapeutic targets and therapeutic strategies for myeloma. This review focuses on the research advances of effectiveness and related mechanisms of CRBN and IMiD for MM, the concrete problems discussing in this review are discover of CRBN, therapeutic effect of CRBN and IMiD, mechnism of CRBN in IMiD treatment for MM, and so on.

  8. Pomalidomide in heavily pretreated refractory multiple myeloma: a case report.

    PubMed

    Palmas, Angelo; Piras, Giovanna; Uras, Antonella; Asproni, Rosanna; Murineddu, Marco; Monne, Maria; Stradoni, Roberta; Latte, Giancarlo

    2017-02-01

    We present the case of a 70-year-old man diagnosed with multiple myeloma in 2008, who after four therapy lines initiated a fifth-line treatment with pomalidomide (4 mg orally, days 1-21 of a 28-day cycle) and low-dose dexamethasone (40 mg weekly orally). The patient was treated with pomalidomide for almost 2 years achieving a complete remission after 12 cycles. Complete remission was maintained for 9 months. This case illustrates the potential of pomalidomide plus low-dose dexamethasone to overcome multiple myeloma refractoriness inducing a quick and very prolonged remission.

  9. Comparative genomic hybridisation identifies two variants of smoldering multiple myeloma.

    PubMed

    Rosiñol, Laura; Carrió, Ana; Bladé, Joan; Queralt, Rosa; Aymerich, Marta; Cibeira, Ma Teresa; Esteve, Jordi; Rozman, Maria; Campo, Elías; Montserrat, Emili

    2005-09-01

    Two variants of smoldering multiple myeloma (SMM) have been recognised: (i) an evolving type, characterised by a progressive increase in the M-protein size and short time to progression to overt multiple myeloma (MM) and (ii) a non-evolving type, with a long-lasting, stable M-protein and longer time to progression. Comparative genomic hybridisation (CGH) analyses in both subtypes of SMM (seven evolving and eight non-evolving SMM) were performed. Evolving SMM showed cytogenetic changes consistent with those found in de novo symptomatic MM (1q gains, chromosome 13 deletions) while the non-evolving variant showed no 1q gains and deletions were uncommon.

  10. [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.

  11. Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma.

    PubMed

    Xu, Linlin; Mohammad, Khalid S; Wu, Hao; Crean, Colin; Poteat, Bradley; Cheng, Yinghua; Cardoso, Angelo A; Machal, Christophe; Hanenberg, Helmut; Abonour, Rafat; Kacena, Melissa A; Chirgwin, John; Suvannasankha, Attaya; Srour, Edward F

    2016-12-01

    Multiple myeloma is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here, we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in multiple myeloma cell lines and primary bone marrow cells from patients. CD166(+) multiple myeloma cells homed more efficiently than CD166(-) cells to the bone marrow of engrafted immunodeficient NSG mice. CD166 silencing in multiple myeloma cells enabled longer survival, a smaller tumor burden, and less osteolytic lesions, as compared with mice bearing control cells. CD166 deficiency in multiple myeloma cell lines or CD138(+) bone marrow cells from multiple myeloma patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Furthermore, CD166 deficiency in multiple myeloma cells also reduced the formation of osteolytic disease in vivo after intratibial engraftment. Mechanistic investigation revealed that CD166 expression in multiple myeloma cells inhibited osteoblastogenesis of bone marrow-derived osteoblast progenitors by suppressing Runx2 gene expression. Conversely, CD166 expression in multiple myeloma cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in multiple myeloma cell homing to the bone marrow and multiple myeloma progression, rationalizing its further study as a candidate therapeutic target for multiple myeloma treatment. Cancer Res; 76(23); 6901-10. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. 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.

  13. SGK Kinase Activity in Multiple Myeloma Cells Protects against ER Stress Apoptosis via a SEK-Dependent Mechanism.

    PubMed

    Hoang, Bao; Shi, Yijiang; Frost, Patrick J; Mysore, Veena; Bardeleben, Carolyne; Lichtenstein, Alan

    2016-04-01

    To assess the role of the serum and glucocorticoid-regulated kinase (SGK) kinase in multiple myeloma, we ectopically expressed wild type or a phosphomimetic version of SGK into multiple myeloma cell lines. These cells were specifically resistant to the ER stress inducers tunicamycin, thapsigargin, and bortezomib. In contrast, there was no alteration of sensitivity to dexamethasone, serum starvation, or mTORC inhibitors. Mining of genomic data from a public database indicated that low baseline SGK expression in multiple myeloma patients correlated with enhanced ability to undergo a complete response to subsequent bortezomib treatment and a longer time to progression and overall survival following treatment. SGK overexpressing multiple myeloma cells were also relatively resistant to bortezomib in a murine xenograft model. Parental/control multiple myeloma cells demonstrated a rapid upregulation of SGK expression and activity (phosphorylation of NDRG-1) during exposure to bortezomib and an SGK inhibitor significantly enhanced bortezomib-induced apoptosis in cell lines and primary multiple myeloma cells. In addition, a multiple myeloma cell line selected for bortezomib resistance demonstrated enhanced SGK expression and SGK activity. Mechanistically, SGK overexpression constrained an ER stress-induced JNK proapoptotic pathway and experiments with a SEK mutant supported the notion that SGK's protection against bortezomib was mediated via its phosphorylation of SEK (MAP2K4) which abated SEK/JNK signaling. These data support a role for SGK inhibitors in the clinical setting for myeloma patients receiving treatment with ER stress inducers like bortezomib. Enhanced SGK expression and activity in multiple myeloma cells contributes to resistance to ER stress, including bortezomib challenge. ©2016 American Association for Cancer Research.

  14. Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients.

    PubMed

    Bianco, Mimma; Gasparri, Anna Maria; Colombo, Barbara; Curnis, Flavio; Girlanda, Stefania; Ponzoni, Maurilio; Bertilaccio, Maria Teresa Sabrina; Calcinotto, Arianna; Sacchi, Angelina; Ferrero, Elisabetta; Ferrarini, Marina; Chesi, Marta; Bergsagel, P Leif; Bellone, Matteo; Tonon, Giovanni; Ciceri, Fabio; Marcatti, Magda; Caligaris-Cappio, Federico; Corti, Angelo

    2016-04-01

    Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma, a neoplastic disease characterized by abnormal proliferation of malignant plasma cells in the bone marrow (BM). Cleavage of the N- and C-terminal regions of circulating chromogranin A (CgA, CHGA), classically an antiangiogenic protein, can activate latent antiangiogenic and proangiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in multiple myeloma patients and the subsequent implications for disease progression. We show that the ratio of pro/antiangiogenic forms of CgA is altered in multiple myeloma patients compared with healthy subjects and that this ratio is higher in BM plasma compared with peripheral plasma, suggesting enhanced local cleavage of the CgA C-terminal region. Enhanced cleavage correlated with increased VEGF and FGF2 BM plasma levels and BM microvascular density. Using the Vk*MYC mouse model of multiple myeloma, we further demonstrate that exogenously administered CgA was cleaved in favor of the proangiogenic form and was associated with increased microvessel density. Mechanistic studies revealed that multiple myeloma and proliferating endothelial cells can promote CgA C-terminal cleavage by activating the plasminogen activator/plasmin system. Moreover, cleaved and full-length forms could also counter balance the pro/antiangiogenic activity of each other in in vitro angiogenesis assays. These findings suggest that the CgA-angiogenic switch is activated in the BM of multiple myeloma patients and prompt further investigation of this CgA imbalance as a prognostic or therapeutic target. Cancer Res; 76(7); 1781-91. ©2016 AACR. ©2016 American Association for Cancer Research.

  15. Carfilzomib boosted combination therapy for relapsed multiple myeloma

    PubMed Central

    Steiner, Raphael E; Manasanch, Elisabet E

    2017-01-01

    Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome, the proteolytic core particle within the 26S proteasome, resulting in the accumulation of proteasome substrates and ultimately growth arrest and apoptosis of tumor cells. The development and ultimate approval of this medication by regulatory agencies has been an important step toward improving clinical outcomes in multiple myeloma. Although initially approved as a single agent for the treatment of multiply relapsed and/or refractory myeloma, in the USA, it is now widely used in the early relapse setting in combination with lenalidomide and dexamethasone. Carfilzomib has also been studied in combination with second-generation immunomodulatory drugs, histone deacetylase inhibitors, alkylating agents and other novel medications. In this review article, we will discuss the efficacy, safety, tolerability and quality of life of carfilzomib-based combination therapies, as well as novel agents, for relapsed multiple myeloma. PMID:28243125

  16. Carfilzomib boosted combination therapy for relapsed multiple myeloma.

    PubMed

    Steiner, Raphael E; Manasanch, Elisabet E

    2017-01-01

    Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome, the proteolytic core particle within the 26S proteasome, resulting in the accumulation of proteasome substrates and ultimately growth arrest and apoptosis of tumor cells. The development and ultimate approval of this medication by regulatory agencies has been an important step toward improving clinical outcomes in multiple myeloma. Although initially approved as a single agent for the treatment of multiply relapsed and/or refractory myeloma, in the USA, it is now widely used in the early relapse setting in combination with lenalidomide and dexamethasone. Carfilzomib has also been studied in combination with second-generation immunomodulatory drugs, histone deacetylase inhibitors, alkylating agents and other novel medications. In this review article, we will discuss the efficacy, safety, tolerability and quality of life of carfilzomib-based combination therapies, as well as novel agents, for relapsed multiple myeloma.

  17. A Rare Case of Multiple Myeloma with Biclonal Gammopathy

    PubMed Central

    Banerjee, Abhik; Christy, Alap Lukiyas

    2016-01-01

    Multiple myeloma is a debilitating malignancy arising from plasma cells. These malignant plasma cells called myeloma cells proliferate and infiltrate the bone marrow. The disease is characterized by the presence of a monoclonal protein in plasma and/or the urine. In this report, we present a case of biclonal multiple myeloma which showed two M bands on serum protein electrophoresis. The patient had elevated serum IgA and IgG levels. To reveal the nature of M bands or clonality, serum Immunofixation study was performed which revealed IgA with Lambda and IgG with Kappa light chains. Such pattern is very rare if we consider the various immunofixation patterns observed in different gammopathies. PMID:28208846

  18. 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

  19. Elderly patients with multiple myeloma: towards a frailty approach?

    PubMed

    Zweegman, Sonja; Engelhardt, Monika; Larocca, Alessandra

    2017-09-01

    To describe how to better identify frail multiple myeloma patients and to treat them appropriately. Proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, and immunomodulatory agents (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, have significantly improved the outcome of multiple myeloma patients in the last decade. However, both in clinical trials and in daily clinical practice, elderly multiple myeloma patients have shown lesser benefit. This is mainly due to less stringent use of proteasome inhibitors and IMiDs, increased toxicity, and subsequent early discontinuation of therapy in elderly. Multiple myeloma typically affects elderly patients. Approximately one-third of patients are older than 75 years at diagnosis. Moreover, at least 30% are frail, both due to disease-related symptoms and (age-related) decline in physical capacity, presence of comorbidities, frailty, polypharmacy, nutritional status, and cognitive impairment. Treatment regimens that are investigated in clinical trials for transplant-ineligible patients have largely been investigated in fit, rather than frail patients, the latter being typically excluded or highly underrepresented therein. Data on the feasibility and efficacy of current standards of care are therefore lacking in frail patients. Preliminary data suggest a higher toxicity and discontinuation rate, loss of efficacy, and impaired quality of life in frail patients. Geriatric assessment helps to identify frail patients according to their functional and cognitive status. Both the International Myeloma Working Group (IMWG)-frailty index and Revised Myeloma Comorbidity Index constitute recently proposed algorithms that easily identify intermediate-fit and frail patients. Ongoing and future clinical trials, specifically designed for frail patients, will hopefully define frailty-directed treatment selection.

  20. Elevated Translation Initiation Factor eIF4E Is an Attractive Therapeutic Target in Multiple Myeloma.

    PubMed

    Li, Shirong; Fu, Jing; Lu, Caisheng; Mapara, Markus Y; Raza, Shahzad; Hengst, Ulrich; Lentzsch, Suzanne

    2016-04-01

    eIF4E is the key regulator of protein translation and critical for translation. The oncogenic potential of tumorigenesis, which is highly contingent on cap-dependent eIF4E, also arises from the critical role in the nuclear export and cytosolic translation of oncogenic transcripts. Inhibition of Exportin1 (XPO1), which is the major nuclear export protein for eIF4E-bound oncoprotein mRNAs, results in decreased tumor cell growth in vitro and in vivo, suggesting that eIF4E is critical in multiple myeloma. Indeed, we found that eIF4E is overexpressed in myeloma cell lines and primary myeloma cells compared with normal plasma cells. Although stable overexpression of eIF4E in multiple myeloma cells significantly increases tumorigenesis, knockdown of eIF4E impairs multiple myeloma tumor progression in a human xenograft mouse model. Using a tet-on-inducible eIF4E-knockdown system, eIF4E downregulation blocks multiple myeloma tumor growth in vivo, correlating with decreased eIF4E expression. Further overexpression and knockdown of eIF4E revealed that eIF4E regulates translation of mRNAs with highly complex 5'-untranslated regions, such as c-MYC and C/EBPβ, and subsequently proliferation in multiple myeloma cells, but not in nonmalignant bone marrow stromal cells. Because many transcription factors that are critical for multiple myeloma proliferation exhibit a higher dependency on protein translation, eIF4E is an ideal and selective tool to target multiple myeloma cell growth. Mol Cancer Ther; 15(4); 711-9. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. 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

  2. [PET-CT for nuclear medicine diagnostics of multiple myeloma].

    PubMed

    Dimitrakopoulou-Strauss, A

    2014-06-01

    Functional or morphofunctional imaging modalities are used in myeloma patients for the diagnosis and therapy management within research protocols. Despite new staging criteria, which take into account the viability of a myeloma lesion, positron emission tomography (PET) is not used routinely. The impact of PET is therefore open. The role of PET and PET computed tomography (PET-CT) for the diagnosis and therapy management is discussed. The use of PET with 18F-fluorodeoxyglucose (FDG) allows the measurement of viable myeloma lesions and correlates with the stage of disease. A negative FDG examination correlates with a better prognosis. Furthermore, the number of focal lesions as well as the whole functional volume of myeloma lesions in FDG have a prognostic impact. Several studies have demonstrated the impact of FDG for the assessment of therapy monitoring and show that FDG is an earlier indicator for therapy response as compared to magnetic resonance imaging (MRI). The CT component of the new hybrid systems allows the assessment of osteolytic lesions in CT and their viability in FDG. The combination of PET with an MRT scanner allows the simultaneous measurement of bone marrow infiltration, focal lesions and their viability. The use of modern hybrid scanners, such as PET-CT and PET-MRT facilitates the simultaneous measurement of viable myeloma lesions, osteolytic lesions and bone marrow infiltration in the whole body; therefore, it is expected that these imaging modalities will play a greater role both in diagnosis and therapy management.

  3. Circulating osteopontin: a dual marker of bone destruction and angiogenesis in patients with multiple myeloma

    PubMed Central

    2011-01-01

    The matrix protein osteopontin has been shown to be a marker of osteoclastic activity in multiple myeloma patients, as well as a regulator of angiogenesis. We measured serum levels of osteopontin in 50 untreated multiple myeloma patients (in 25, also after treatment) and examined the relation to markers of osteolytic and angiogenic activity. The median (range) of serum osteopontin was 85 (5-232) in the patient group vs. 36 (2-190) ng/ml in the control group. Serum osteopontin levels were significantly higher in patients with advanced stage or grade of myeloma disease. All patients with serum osteopontin levels >100 ng/ml had advanced stage (II or III) or high grade bone disease, whereas stage I or low grade patients had serum osteopontin levels <100ng/ml. Serum osteopontin levels significantly decreased after treatment. There was a positive correlation of osteopontin with the bone turnover marker N-terminal propeptide of procollagen type I (NTx) and the angiogenic markers vascular endothelial growth factor (VEGF) and bone marrow microvessel density (r: 0.35, 0.47 and 0.30 respectively, p < 0.05). These results support osteopontin as a dual marker of bone destruction and angiogenic activity in myeloma patients. Osteopontin represents a useful biomarker for monitoring myeloma disease activity. PMID:21548993

  4. A concise revised Myeloma Comorbidity Index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients

    PubMed Central

    Engelhardt, Monika; Domm, Anne-Saskia; Dold, Sandra Maria; Ihorst, Gabriele; Reinhardt, Heike; Zober, Alexander; Hieke, Stefanie; Baayen, Corine; Müller, Stefan Jürgen; Einsele, Hermann; Sonneveld, Pieter; Landgren, Ola; Schumacher, Martin; Wäsch, Ralph

    2017-01-01

    With growing numbers of elderly multiple myeloma patients, reliable tools to assess their vulnerability are required. The objective of the analysis herein was to develop and validate an easy to use myeloma risk score (revised Myeloma Comorbidity Index) that allows for risk prediction of overall survival and progression-free survival differences in a large patient cohort. We conducted a comprehensive comorbidity, frailty and disability evaluation in 801 consecutive myeloma patients, including comorbidity risks obtained at diagnosis. The cohort was examined within a training and validation set. Multivariate analysis determined renal, lung and Karnofsky Performance Status impairment, frailty and age as significant risks for overall survival. These were combined in a weighted revised Myeloma Comorbidity Index, allowing for the identification of fit (revised Myeloma Comorbidity Index ≤3 [n=247, 30.8%]), intermediate-fit (revised Myeloma Comorbidity Index 4–6 [n=446, 55.7%]) and frail patients (revised Myeloma Comorbidity Index >6 [n=108, 13.5%]): these subgroups, confirmed via validation analysis, showed median overall survival rates of 10.1, 4.4 and 1.2 years, respectively. The revised Myeloma Comorbidity Index was compared to other commonly used comorbidity indices (Charlson Comorbidity Index, Hematopoietic Cell Transplantation-Specific Comorbidity Index, Kaplan-Feinstein Index): if each were divided in risk groups based on 25% and 75% quartiles, highest hazard ratios, best prediction and Brier scores were achieved with the revised Myeloma Comorbidity Index. The advantages of the revised Myeloma Comorbidity Index include its accurate assessment of patients’ physical conditions and simple clinical applicability. We propose the revised Myeloma Comorbidity Index to be tested with the “reference” International Myeloma Working Group frailty score in multicenter analyses and future clinical trials. The study was registered at the German Clinical Trials Register

  5. New tools for diagnosis and monitoring of multiple myeloma.

    PubMed

    San-Miguel, Jesús F; Paiva, Bruno; Gutiérrez, Norma C

    2013-01-01

    This article reviews the most relevant techniques currently used for the evaluation of patients with multiple myeloma. Although bone marrow morphologic examination and electrophoretic analysis of the monoclonal paraprotein and conventional x-rays remain the "gold standard" techniques for fast, accurate, and cost-effective diagnosis, other assays such as molecular cytogenetics, immunophenotyping, MRI, and PET-CT may contribute to a better assessment of patients with myeloma. Here, we will discuss not only the contribution of each technique to differential diagnosis of monoclonal gammopathies, but also the value of each parameter for determining prognosis and for monitoring treatment efficacy. In addition, possible technical pitfalls inherent to each technique will be analyzed.

  6. Plasmablastic multiple myeloma following clear cell renal cell carcinoma

    PubMed Central

    Padhi, Somanath; Mokkappan, Sudhagar; Varghese, Renu G’ Boy; Veerappan, Ilangovan

    2014-01-01

    We aim to describe the clinicohaematological profile of an elderly male with plasmablastic multiple myeloma (MM) (IgG λ, International System Stage II) with an unfavourable outcome following chemotherapy. The serum interleukin-6 level was found to be markedly elevated (2464 pg/mL, reference; <50 pg/mL). Thirty-six months prior to MM diagnosis, he underwent left radical nephrectomy for a stage III (pT3N0M0) clear cell renal cell carcinoma (RCC, Fuhrman grade 2). The unique MM-RCC association, shared risk factors, myeloma pathobiology and clinical implications are discussed with a brief literature review. PMID:25103318

  7. Microenvironment drug resistance in multiple myeloma: emerging new players

    PubMed Central

    Solimando, Antonio Giovanni; Ruggieri, Simona; Annese, Tiziana; Nico, Beatrice; Fumarulo, Ruggiero; Vacca, Angelo; Frassanito, Maria Antonia

    2016-01-01

    Multiple myeloma (MM) drug resistance (DR) is a multistep transformation process based on a powerful interplay between bone marrow stromal cells and MM cells that allows the latter to escape anti-myeloma therapies. Here we present an overview of the role of the bone marrow microenvironment in both soluble factors-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR), focusing on the role of new players, namely miRNAs, exosomes and cancer-associated fibroblasts. PMID:27474171

  8. MUSCULOSKELETAL PRESENTATION OF MULTIPLE MYELOMA AT GENERAL HOSPITAL DOUALA, CAMEROON.

    PubMed

    Doualla-Bija, M; Ndongho, E N; Oben, D T; Namme, H L; Mbanya, D

    2014-09-01

    Background: very little is known about musculoskeletal features of multiple myeloma (MM) in Africa. To describe the musculoskeletal features of multiple myeloma at presentation in a tertiary health care centre in sub-Saharan Africa. A Cross sectional observational study. The Douala General Hospital, Cameroon from 2007 to 2013. A patient was said to have MM according the current international consensus criteria for diagnosis and staging of MM. Patients with monoclonal gammopathy of undetermined significance, solitary plamocytoma and other haematologic malignancies were excluded. A total of 62 patients were diagnosed with multiple myeloma, 63% were female. Mean age was 57 ± 12,1 (19-81) years. Musculoskeletal presentation included spine bone pains (75.6%); vertebral fracture with spinal cord compression in 46.8 %. Other clinical features at presentation included anaemia (70.93%), and nephropathy (17.74%). The average percentage of bone marrow plasmacytosis at diagnosis was 33% and Immunoglobulin G was found in 86% of patients. Sixty three per cent of patients were diagnosed at stage III of the disease. Presence of bone pain and anaemia should alert the clinician to investigate along the lines of multiple myeloma. Majority of the patients have osteolytic lesions and pathologic fractures at the time of diagnosis.

  9. How is patient care for multiple myeloma advancing?

    PubMed

    Genadieva Stavric, Sonja; Bonello, Francesca; Bringhen, Sara; Boccadoro, Mario; Larocca, Alessandra

    2017-06-01

    Treatment of multiple myeloma has undergone profound changes in the past years thanks to the increased understanding of the biology of the disease and the new treatment options. New drugs and effective approaches are currently available for the treatment of multiple myeloma, including immunomodulatory agents, proteasome inhibitors and autologous stem cell transplantation. Areas covered: We have described the recent updated criteria to start treatment in multiple myeloma and summarized clinical data from major studies including most recent agents. Particularly, results with pomalidomide, carfilzomib, ixazomib, monoclonal antibodies such as elotuzumab, daratumumab, and checkpoint inhibitors have been reported. Both transplant and non-transplant settings have been covered. Expert commentary: Despite the successful improvement in overall survival and time to relapse, multiple myeloma still remains incurable. Therefore, there is still an unmet need for new treatment strategies with novel mechanisms of action, like monoclonal antibodies, novel immunomodulators, and novel proteasome inhibitors. Implementation of these novel drugs in rationally designed therapies with a good balance of efficacy and safety should be carefully considered in order to improve outcome.

  10. [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.

  11. 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.

  12. Intracellular glutathione determines bortezomib cytotoxicity in multiple myeloma cells

    PubMed Central

    Starheim, K K; Holien, T; Misund, K; Johansson, I; Baranowska, K A; Sponaas, A-M; Hella, H; Buene, G; Waage, A; Sundan, A; Bjørkøy, G

    2016-01-01

    Multiple myeloma (myeloma in short) is an incurable cancer of antibody-producing plasma cells that comprise 13% of all hematological malignancies. The proteasome inhibitor bortezomib has improved treatment significantly, but inherent and acquired resistance to the drug remains a problem. We here show that bortezomib-induced cytotoxicity was completely dampened when cells were supplemented with cysteine or its derivative, glutathione (GSH) in ANBL-6 and INA-6 myeloma cell lines. GSH is a major component of the antioxidative defense in eukaryotic cells. Increasing intracellular GSH levels fully abolished bortezomib-induced cytotoxicity and transcriptional changes. Elevated intracellular GSH levels blocked bortezomib-induced nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2)-associated stress responses, including upregulation of the xCT subunit of the Xc- cystine-glutamate antiporter. INA-6 cells conditioned to increasing bortezomib doses displayed reduced bortezomib sensitivity and elevated xCT levels. Inhibiting Xc- activity potentiated bortezomib-induced cytotoxicity in myeloma cell lines and primary cells, and re-established sensitivity to bortezomib in bortezomib-conditioned cells. We propose that intracellular GSH level is the main determinant of bortezomib-induced cytotoxicity in a subset of myeloma cells, and that combined targeting of the proteasome and the Xc- cystine-glutamate antiporter can circumvent bortezomib resistance. PMID:27421095

  13. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

    PubMed Central

    Bolli, Niccolo; Avet-Loiseau, Hervé; Wedge, David C.; Van Loo, Peter; Alexandrov, Ludmil B.; Martincorena, Inigo; Dawson, Kevin J.; Iorio, Francesco; Nik-Zainal, Serena; Bignell, Graham R.; Hinton, Jonathan W.; Li, Yilong; Tubio, Jose M.C.; McLaren, Stuart; O' Meara, Sarah; Butler, Adam P.; Teague, Jon W.; Mudie, Laura; Anderson, Elizabeth; Rashid, Naim; Tai, Yu-Tzu; Shammas, Masood A.; Sperling, Adam S.; Fulciniti, Mariateresa; Richardson, Paul G.; Parmigiani, Giovanni; Magrangeas, Florence; Minvielle, Stephane; Moreau, Philippe; Attal, Michel; Facon, Thierry; Futreal, P Andrew; Anderson, Kenneth C.; Campbell, Peter J.; Munshi, Nikhil C.

    2014-01-01

    Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment. PMID:24429703

  14. Prognostic indicators of lenalidomide for multiple myeloma: consensus and controversy.

    PubMed

    Kuroda, Junya; Kobayashi, Tsutomu; Taniwaki, Masafumi

    2015-01-01

    The long-term outcome of multiple myeloma (MM) has been greatly improved through new agents, one being lenalidomide (LEN). Based upon the findings of in vitro experiments, its mode of action against MM occurs through a combination of direct tumoricidal effects on myeloma cells, modulatory effects on tumor immunity and tumor microenvironment-regulatory effects. However, it has not been clearly defined whether the clinical response and long-term outcome of MM with LEN treatment truly reflect the mechanisms of action of LEN proposed by in vitro studies. To ascertain what is known and what remains to be elucidated with LEN, we review the current literature on the mode of action of LEN in association with myeloma pathophysiology, and discuss the prognostic indicators in the treatment of MM with LEN.

  15. Prediagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the Multiple Myeloma Cohort Consortium

    PubMed Central

    Neuhouser, Marian L.; Rosner, Bernard; Albanes, Demetrius; Buring, Julie E.; Giles, Graham G.; Lan, Qing; Lee, I-Min; Purdue, Mark P.; Rothman, Nathaniel; Severi, Gianluca; Yuan, Jian-Min; Anderson, Kenneth C.; Pollak, Michael; Rifai, Nader; Hartge, Patricia; Landgren, Ola; Lessin, Lawrence; Virtamo, Jarmo; Wallace, Robert B.; Manson, JoAnn E.; Colditz, Graham A.

    2012-01-01

    Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤ 3, 4- ≤ 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P = .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR ≤ 3 years, 95% CI, 1.4, 1.1-1.9, P = .01; OR4- ≤ 6 years, 95% CI, 1.4, 1.1-1.7, P = .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma. PMID:23074271

  16. Prediagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the Multiple Myeloma Cohort Consortium.

    PubMed

    Birmann, Brenda M; Neuhouser, Marian L; Rosner, Bernard; Albanes, Demetrius; Buring, Julie E; Giles, Graham G; Lan, Qing; Lee, I-Min; Purdue, Mark P; Rothman, Nathaniel; Severi, Gianluca; Yuan, Jian-Min; Anderson, Kenneth C; Pollak, Michael; Rifai, Nader; Hartge, Patricia; Landgren, Ola; Lessin, Lawrence; Virtamo, Jarmo; Wallace, Robert B; Manson, JoAnn E; Colditz, Graham A

    2012-12-13

    Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤ 3, 4- ≤ 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P = .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR (≤ 3 years), 95% CI, 1.4, 1.1-1.9, P = .01; OR(4- ≤ 6 years), 95% CI, 1.4, 1.1-1.7, P = .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma.

  17. Monitoring multiple myeloma by quantification of recurrent mutations in serum.

    PubMed

    Rustad, Even Holth; Coward, Eivind; Skytøen, Emilie R; Misund, Kristine; Holien, Toril; Standal, Therese; Børset, Magne; Beisvag, Vidar; Myklebost, Ola; Meza-Zepeda, Leonardo A; Dai, Hong Yan; Sundan, Anders; Waage, Anders

    2017-07-01

    Circulating tumor DNA is a promising biomarker to monitor tumor load and genome alterations. We explored the presence of circulating tumor DNA in multiple myeloma patients and its relation to disease activity during long-term follow-up. We used digital droplet polymerase chain reaction analysis to monitor recurrent mutations, mainly in mitogen activated protein kinase pathway genes NRAS, KRAS and BRAF Mutations were identified by next-generation sequencing or polymerase chain reaction analysis of bone marrow plasma cells, and their presence analyzed in 251 archived serum samples obtained from 20 patients during a period of up to 7 years. In 17 of 18 patients, mutations identified in bone marrow during active disease were also found in a time-matched serum sample. The concentration of mutated alleles in serum correlated with the fraction in bone marrow plasma cells (r=0.507, n=34, P<0.002). There was a striking covariation between circulating mutation levels and M protein in ten out of 11 patients with sequential samples. When relapse evaluation by circulating tumor DNA and M protein could be directly compared, the circulating tumor DNA showed relapse earlier in two patients (3 and 9 months), later in one patient (4 months) and in three patients there was no difference. In three patients with transformation to aggressive disease, the concentrations of mutations in serum increased up to 400 times, an increase that was not seen for the M protein. In conclusion, circulating tumor DNA in myeloma is a multi-faceted biomarker reflecting mutated cells, total tumor mass and transformation to a more aggressive disease. Its properties are both similar and complementary to M protein. Copyright© 2017 Ferrata Storti Foundation.

  18. CUL4A as a marker and potential therapeutic target in multiple myeloma.

    PubMed

    Yang, Yougang; Wang, Shanan; Li, Jinghong; Qi, Shipeng; Zhang, Debing

    2017-07-01

    Multiple myeloma is the most common cause of death of hematological malignancy worldwide. Cullin 4A has been proposed as oncogene in several types of human cancer, but the expression and function of cullin 4A in multiple myeloma remain unclear. Here, we demonstrate that cullin 4A plays an oncogenic role in multiple myeloma development. The expression of cullin 4A was detected by quantitative real-time polymerase chain reaction in multiple myeloma patients and multiple myeloma cell lines. In addition, silencing of cullin 4A with small interfering RNA was performed in human multiple myeloma cells, and the impact on proliferation, cell cycle, apoptosis, migration, and invasion of the multiple myeloma cells was analyzed. We found that the level of cullin 4A in serum samples was significantly upregulated in patients with multiple myeloma compared with healthy control subjects. Knockdown of cullin 4A via small interfering RNA inhibited the proliferation of the multiple myeloma cell lines by delaying cell-cycle progression and increasing apoptosis. cullin 4A downregulation inhibited multiple myeloma cell migration and invasion in vitro. Our results suggested that cullin 4A could be a promising therapy target in multiple myeloma patients.

  19. Recurrent extramedullary plasmacytoma in asymptomatic multiple myeloma: a case report.

    PubMed

    Schols, Saskia E M; Tick, Lidwine L W

    2015-02-19

    The gross majority of extramedullary plasmacytomas arise in the lymphatic tissue of the upper respiratory tract. On average, one third of patients with a solid plasmacytoma will develop multiple myeloma, resulting in a worse clinical outcome. We describe a case of rapid recurrent extramedullary plasmacytomas in the background of an asymptomatic multiple myeloma. A 71-year-old, white Caucasian woman presented with three extramedullary plasmacytomas occurring within a short time period. The third plasmacytoma was accompanied by progressive cervical pain and swallow dysfunction. Additional immunostaining test results were negative for CD56 and showed high MIB-1 expression in the extramedullary plasmacytoma and low MIB-1 expression in the bone marrow. A conventional swallow X-ray did not show any obstruction, however a magnetic resonance imaging scan of her cervical backbone revealed an extramedullary plasmacytoma, threatening her spinal cord. A short course of radiation therapy alleviated her pain and during almost a two-year follow-up period, the multiple myeloma remained asymptomatic, despite the rise in immunoglobulin A lambda levels. After the appearance of the third plasmacytoma, systemic chemotherapy was started to prevent the development of a fourth plasmacytoma, despite the asymptomatic character of the multiple myeloma. In this case report we describe the rapid appearance of extramedullary plasmacytomas in the background of an asymptomatic multiple myeloma. An immunohistochemical analysis was negative for CD56 and showed high MIB-1 expression in the extramedullary plasmacytoma and low MIB-1 expression in the bone marrow, contributing to the potential underlying pathophysiology of the recurrent extramedullary plasmacytomas and their genetic changes. Systemic chemotherapy was started and no fourth extramedullary plasmacytoma has developed since.

  20. Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology.

    PubMed

    Kumar, Shaji K; Callander, Natalie S; Alsina, Melissa; Atanackovic, Djordje; Biermann, J Sybil; Chandler, Jason C; Costello, Caitlin; Faiman, Matthew; Fung, Henry C; Gasparetto, Cristina; Godby, Kelly; Hofmeister, Craig; Holmberg, Leona; Holstein, Sarah; Huff, Carol Ann; Kassim, Adetola; Liedtke, Michaela; Martin, Thomas; Omel, James; Raje, Noopur; Reu, Frederic J; Singhal, Seema; Somlo, George; Stockerl-Goldstein, Keith; Treon, Steven P; Weber, Donna; Yahalom, Joachim; Shead, Dorothy A; Kumar, Rashmi

    2017-02-01

    Multiple myeloma (MM) is caused by the neoplastic proliferation of plasma cells. These neoplastic plasma cells proliferate and produce monoclonal immunoglobulin in the bone marrow causing skeletal damage, a hallmark of multiple myeloma. Other MM-related complications include hypercalcemia, renal insufficiency, anemia, and infections. The NCCN Multiple Myeloma Panel members have developed guidelines for the management of patients with various plasma cell dyscrasias, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenström's macroglobulinemia. The recommendations specific to the diagnosis and treatment of patients with newly diagnosed MM are discussed in this article.

  1. Phenotypic detection of clonotypic B cells in multiple myeloma by specific immunoglobulin ligands reveals their rarity in multiple myeloma.

    PubMed

    Trepel, Martin; Martens, Victoria; Doll, Christian; Rahlff, Janina; Gösch, Barbara; Loges, Sonja; Binder, Mascha

    2012-01-01

    In multiple myeloma, circulating "clonotypic" B cells, that express the immunoglobulin rearrangement of the malignant plasma cell clone, can be indirectly detected by PCR. Their role as potential "feeder" cells for the malignant plasma cell pool remains controversial. Here we established for the first time an approach that allows direct tracking of such clonotypic cells by labeling with patient-specific immunoglobulin ligands in 15 patients with myeloma. Fifty percent of patients showed evidence of clonotypic B cells in blood or bone marrow by PCR. Epitope-mimicking peptides from random libraries were selected on each patient's individual immunoglobulin and used as ligands to trace cells expressing the idiotypic immunoglobulin on their surface. We established a flow cytometry and immunofluorescence protocol to track clonotypic B cells and validated it in two independent monoclonal B cell systems. Using this method, we found clonotypic B cells in only one out of 15 myeloma patients. In view of the assay's validated sensitivity level of 10(-3), this surprising data suggests that the abundance of such cells has been vastly overestimated in the past and that they apparently represent a very rare population in myeloma. Our novel tracing approach may open perspectives to isolate and analyze clonotypic B cells and determine their role in myeloma pathobiology.

  2. Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance.

    PubMed

    Skrtić, Anita; Korać, Petra; Krišto, Delfa Radić; Ajduković Stojisavljević, Radmila; Ivanković, Davor; Dominis, Mara

    2010-12-01

    Notch signaling is implicated in the pathogenesis of multiple myeloma expressing high level of active Notch proteins NOTCH1 and JAGGED1 in tumor plasma cells. We investigated expression of NOTCH1 and JAGGED1 in bone marrow trephine biopsies of 80 newly diagnosed multiple myeloma and 20 monoclonal gammopathy of undetermined significance patients using immunohistochemical methods. The number of positive tumor cells was counted per 1000 tumor cells and the intensity of staining was assessed semi quantitatively. Multiple myelomas expressed NOTCH1 in 92.31% (72/78) and JAGGED1 in 92.21% (71/77) cases. NOTCH1 staining was strong in the majority of cases (59.7%), whereas JAGGED1 was predominately weak (67.6% of cases). In contrast, both markers were negative in all monoclonal gammopathy of undetermined significance cases. However, upon progression of disease from monoclonal gammopathy of undetermined significance to multiple myeloma (seen in 4 patients), analysis of the subsequent bone marrow biopsy showed weak expression of both markers in tumorous plasma cells. Immunohistochemistry results were compared with the pattern of bone marrow infiltration, plasma cell differentiation, and the presence of t(11;14)(q13,q32), t(14;16)(q32;q23),and t(4;14)(p16.3;q23) and overall survival in multiple myeloma patients. A significant correlation was found between strong NOTCH1 staining in multiple myeloma plasma cells and the diffuse type of bone marrow infiltration (P = .002) and an immature morphologic type of plasma cells (P = .043). After a median follow-up of 20.3 months, in multiple myeloma patients no difference in overall survival between NOTCH1 (P = .484) and JAGGED1 (P = .822) positive and negative cases were found. In conclusion, our results indicate importance of NOTCH1 and JAGGED1 expression in plasma cell neoplasia and a possible diagnostic value of their immunohistochemical evaluation of bone marrow infiltrates for multiple myeloma.

  3. 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

  4. 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). Copyright© Ferrata Storti Foundation.

  5. 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

  6. Is it time for preemptive drug treatment of asymptomatic (smoldering) multiple myeloma?

    PubMed

    Fawole, Adewale; Abonour, Rafat; Stender, Michael; Shatavi, Seerin; Gaikazian, Susanna; Anderson, Joseph; Jaiyesimi, Ishmael

    2015-01-01

    Asymptomatic (smoldering) multiple myeloma is a heterogeneous plasma cell proliferative disorder with a variable rate of progression to active multiple myeloma or related disorders. Hypercalcemia, renal insufficiency, anemia, bone lesions or recurrent bacterial infections characterize active multiple myeloma. Some patients with asymptomatic myeloma develop active disease rapidly, and others can stay asymptomatic for many years. Those who are likely to progress within the first 2 years of diagnosis have been categorized as having high-risk disease. The availability of novel agents in the treatment of active multiple myeloma and our better understanding of the heterogeneity of asymptomatic multiple myeloma have spurred interest in the early treatment of these patients. We have reviewed the current proposed definitions of high-risk asymptomatic multiple myeloma, the concerns about future therapy in view of the transient nature, remissions and toxicities of the therapies, and the eventual relapses that characterize this incurable disease.

  7. [Analysis of cell morphology and immunophenotypic characteristics in 47 cases of multiple myeloma].

    PubMed

    Su, Xian-Du; Lin, Rong; Xu, Xiao-Lan; Chen, Xu; Zhan, Wen-Li; Zheng, Jin-Pu; Fan, Chang-Ling

    2015-02-01

    This study was to investigate the cell morphology and cell immune phenotypic characteristics in patients with multiple myeloma (MM). The flow cytometry with multiparametric direct immunofluorescence technique, and CD45/SSC and CD38(+)(+)/CD138(+) gating were used to measure cell markers CD138, CD38, CD56, CD117, CD3, CD13, CD33, CD19, CD7, CD20, CD22, CD34, CD28 in 47 MM patients. At the same time the morphology examination of bone marrow cells was performed. The suspicious myeloma cell ratio in MM patients was 9.42%-74.25% detected by flow cytometry, moreover, the myeloma cell ratio detected by morphology examination was 11.0%-80.6%, there was a good correlation between the two detection methods (r(2) = 0.54, P < 0.001). The ratio of antigen positive expression was as follows: 74.46% for CD138, 100% for CD38, 57.44% for CD56, 40.42% for CD117, 6.38% for CD13, 19.15% for CD33, 8.51% for CD20, 27.66% for CD28, 2.12% for CD22, 4.25% for CD34, 0% for CD3, 0% for CD19, 0% for CD7. CD45/SSC and CD38(+)/CD138(+) gating technique can accurately gate multiple myeloma cell sets which need analysis, the majority of myeloma cells expreses CD138, CD38, CD56 antigens. The immunophenotypic analysis combined with the cell morphology examination more contribute to the diagnosis and differential diagnosis of multiple myeloma.

  8. Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients.

    PubMed

    Ghermezi, Michael; Li, Mingjie; Vardanyan, Suzie; Harutyunyan, Nika Manik; Gottlieb, Jillian; Berenson, Ariana; Spektor, Tanya M; Andreu-Vieyra, Claudia; Petraki, Sophia; Sanchez, Eric; Udd, Kyle; Wang, Cathy S; Swift, Regina A; Chen, Haiming; Berenson, James R

    2017-04-01

    B-cell maturation antigen is expressed on plasma cells. In this study, we have identified serum B-cell maturation antigen as a novel biomarker that can monitor and predict outcomes for multiple myeloma patients. Compared to healthy donors, patients with multiple myeloma showed elevated serum B-cell maturation antigen levels (P<0.0001). Serum B-cell maturation antigen levels correlated with the proportion of plasma cells in bone marrow biopsies (Spearman's rho = 0.710; P<0.001), clinical status (complete response vs partial response, P=0.0374; complete response vs progressive disease, P<0.0001), and tracked with changes in M-protein levels. Among patients with non-secretory disease, serum B-cell maturation antigen levels correlated with bone marrow plasma cell levels and findings from positron emission tomography scans. Kaplan-Meier analysis demonstrated that serum B-cell maturation antigen levels above the median levels were predictive of a shorter progression-free survival (P=0.0006) and overall survival (P=0.0108) among multiple myeloma patients (n=243). Specifically, patients with serum B-cell maturation antigen levels above the median level at the time of starting front-line (P=0.0043) or a new salvage therapy (P=0.0044) were found to have shorter progression-free survival. Importantly, serum B-cell maturation antigen levels did not show any dependence on renal function and maintained independent significance when tested against other known prognostic markers for multiple myeloma such as age, serum β2 microglobulin, hemoglobin, and bone disease. These data identify serum B-cell maturation antigen as a new biomarker to manage multiple myeloma patients. Copyright© Ferrata Storti Foundation.

  9. 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

  10. Differences in the distribution of cytogenetic subtypes between multiple myeloma patients with and without a family history of monoclonal gammopathy and multiple myeloma.

    PubMed

    Greenberg, Alexandra J; Cousin, Margot; Kumar, Shaji; Ketterling, Rhett P; Knudson, Ryan A; Larson, Dirk; Colby, Colin; Scott, Christopher; Vachon, Celine M; Rajkumar, S Vincent

    2013-09-01

    We previously reported an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of MGUS and multiple myeloma patients. Here, we examine whether primary cytogenetic categories of myeloma differ between patients with and without a family history of MGUS or myeloma. We studied 201 myeloma patients with available data on family history and molecular cytogenetic classification. Myeloma with trisomies was more common in probands who had an affected first-degree relative with MGUS or myeloma compared with those without a family history (46.9% vs. 33.5%, P = 0.125); however, the difference was not statistically significant. Additional studies on the cytogenetic types of myeloma associated with familial tendency are needed.

  11. IAP antagonists induce anti-tumor immunity in multiple myeloma

    PubMed Central

    Chesi, Marta; Mirza, Noweeda N.; Garbitt, Victoria M.; Sharik, Meaghen E.; Dueck, Amylou C.; Asmann, Yan W.; Akhmetzyanova, Ilseyar; Kosiorek, Heidi E.; Calcinotto, Arianna; Riggs, Daniel L.; Keane, Niamh; Ahmann, Greg J.; Morrison, Kevin M.; Fonseca, Rafael; Lacy, Martha Q.; Dingli, David; Kumar, Shaji K.; Ailawadhi, Sikander; Dispenzieri, Angela; Buadi, Francis; Gertz, Morie A.; Reeder, Craig B.; Lin, Yi; Chanan-Khan, Asher Alban; Stewart, A. Keith; Fooksman, David; Bergsagel, P. Leif

    2017-01-01

    The cellular inhibitor of apoptosis cIAP1 and −2 are amplified in about 3% of cancers, and were identified in multiple malignancies as potential therapeutic targets due to their role in evasion of apoptosis. Consequently, small molecule IAP antagonists, like LCL161, have entered clinical trials for their ability to induce TNF-mediated apoptosis of cancer cells. However, cIAP1 and −2 are recurrently homozygously deleted in multiple myeloma resulting in constitutive activation of the non-canonical NFkB pathway. It was therefore counterintuitive to observe a robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and patients with relapsed-refractory myeloma, where addition of cyclophosphamide resulted in a median progression free survival of 10 months. This effect is not due to direct induction of tumor cell death, but rather to upregulation of a tumor cell autonomous type I interferon signaling and a strong inflammatory response with activation of macrophages and dendritic cells resulting in phagocytosis of tumor cells. Treatment with LCL161 established long-term anti-tumor protection and cure in a fraction of transgenic Vk*MYC mice. Remarkably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all treated mice. PMID:27841872

  12. 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

  13. 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

  14. A monoclonal gammopathy precedes multiple myeloma in most patients

    PubMed Central

    Abadie, Jude; Verma, Pramvir; Howard, Robin S.; Kuehl, W. Michael

    2009-01-01

    Preexisting plasma cell disorders, monoclonal gammopathy of undetermined significance, or smoldering myeloma are present in at least one-third of multiple myeloma patients. However, the proportion of patients with a preexisting plasma cell disorder has never been determined by laboratory testing on prediagnostic sera. We cross-referenced our autologous stem cell transplantation database with the Department of Defense Serum Repository. Serum protein electrophoresis, immunofixation electrophoresis, and serum free light-chain analysis were performed on all sera collected 2 or more years before diagnosis to detect a monoclonal gammopathy (M-Ig). In 30 of 90 patients, 110 prediagnostic samples were available from 2.2 to 15.3 years before diagnosis. An M-Ig was detected initially in 27 of 30 patients (90%, 95% confidence interval, 74%-97%); by serum protein electrophoresis and/or immunofixation electrophoresis in 21 patients (77.8%), and only by serum free light-chain analysis in 6 patients (22.2%). Four patients had only one positive sample within 4 years before diagnosis, with all preceding sera negative. All 4 patients with light-chain/nonsecretory myeloma evolved from a light-chain M-Ig. A preexisting M-Ig is present in most multiple myeloma patients before diagnosis. Some patients progress rapidly through a premalignant phase. Light-chain detected M-Ig is a new entity that requires further study. PMID:19234139

  15. 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

  16. New drugs in multiple myeloma - role of carfilzomib and pomalidomide.

    PubMed

    Jurczyszyn, Artur; Legieć, Wojciech; Helbig, Grzegorz; Hus, Marek; Kyrcz-Krzemień, Sławomira; Skotnicki, Aleksander B

    2014-01-01

    Carfilzomib (CFZ), an epoxyketone with specific chymotrypsin-like activity, is a second-generation proteasome inhibitor with significant activity in patients with relapsed and refractory multiple myeloma. On July 20, 2012, the US Food and Drug Administration approved CFZ to treat patients with multiple myeloma who have received at least two prior therapies including bortezomib (BORT) and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Cytogenetic abnormalities did not appear to have a significant impact on the CFZ activity. Carfilzomib was well tolerated and demonstrated promising efficacy in patients with renal insufficiency. Pomalidomide (POM) (CC-4047) is a novel immunomodulatory derivative (IMID) with a stronger in vitro anti-myeloma effect compared with "older" IMIDs - thalidomide and lenalidomide (LEN). On February 8, 2013, the US Food and Drug Administration approved POM (Pomalyst, Celgene) for the treatment of MM patients who have received at least two prior therapies including LEN and BORT and have demonstrated progression on or within 60 days of completion of the last therapy. Pomalidomide is a novel IMID with significant anti-myeloma activity and manageable toxicity. This compound has shown high efficacy in MM patients who were resistant to prior use of LEN/BORT as well as in patients with a high-risk cytogenetic profile. Carfilzomib and POM have very high efficacy and will be used also in first line therapy in future.

  17. Smoldering multiple myeloma: to treat or not to treat.

    PubMed

    Gentile, Massimo; Offidani, Massimo; Vigna, Ernesto; Corvatta, Laura; Recchia, Anna Grazia; Morabito, Lucio; Martino, Massimo; Morabito, Fortunato; Gentili, Silvia

    2015-04-01

    Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of ≥ 30 g/l serum M-protein and/or ≥ 10% bone marrow plasma cell infiltration. The progression risk to active multiple myeloma (MM) is not uniform, and several prognostic parameters are useful for identifying patients at high risk of progression. A watch-and-wait approach has been the standard of care up to now. However, recently, it has been demonstrated that a subset of high-risk cases can benefit from early treatment with new drugs. In this editorial, we focus on SMM and evaluate the diagnostic work-up and the prognostic factors predicting progression to symptomatic MM. We also review the studies in which the role of early treatment has been evaluated for patients with SMM. After the update performed by the International Myeloma Working Group regarding MM diagnosis, it is now time to change the therapeutic paradigm for this disease. While "ultra high-risk" myeloma should now be considered as active MM, for low-risk patients the "watch-and-wait" strategy is still recommended. More caution is needed for the high-risk group: physicians should continue monitoring patients using every tool now available while waiting for results from ongoing trials that will establish if this group will benefit from an early intervention.

  18. Controversies in multiple myeloma: Evidence-based update.

    PubMed

    Ahn, Inhye E; Mailankody, Sham

    2016-12-01

    The US Food and Drug Administration (FDA) approved 10 new drugs for the treatment of multiple myeloma (MM) over the last two decades. The influx of new anti-myeloma agents with high efficacy and acceptable tolerability add complexity to the clinical decision-making process. First, treatment of smoldering multiple myeloma (SMM) remains investigational to date, although a randomized trial showed a survival gain in high-risk patients receiving lenalidomide. Second, in newly diagnosed MM, the majority of contemporary induction regimens have been studied in single-arm trials or compared to an older regimen, which complicates evidence-based treatment selection. Third, the role of consolidation chemotherapy followed by autologous stem cell transplant (ASCT) needs to be revisited in the context of highly effective agents, as newer regimens- such as carfilzomib, lenalidomide, and dexamethasone-are able to achieve extremely deep responses equivalent to or exceeding those seen after conventional induction and ASCT. Fourth, risks and benefits of maintenance therapy should also be redefined and individualized, as long-term survival and safety data accumulate. Here we selected four clinical settings where controversies exist, reviewed evidences behind conflicting treatment strategies, and asked myeloma experts to discuss evidence-based recommendations. Copyright © 2016 Elsevier. All rights reserved.

  19. MGUS and Smoldering Multiple Myeloma: Diagnosis and Epidemiology.

    PubMed

    Mateos, María-Victoria; Landgren, Ola

    Monoclonal gammopathy of undetermined significance (MHUS) is characterized by the presence of a serum M-protein less than 3 g/dL, less than 10 % clonal plasma cells in the bone marrow, and the absence of myeloma-defining event. Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of ≥3 g/dL serum M-protein and/or 10-60 % bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to multiple myeloma (MM) requiring therapy varies greatly for individual patients, but it is uniform and 1 % per year for MGUS, while higher (10 % per year) and not uniform for SMM patients. The definition of MM was recently revisited patients previously labeled as SMM with a very high risk of progression (80-90 % at 2 years) were included in the updated definition of MM requiring therapy. The standard of care is observation for MGUS patients and although this also applies for SMM, a recent randomized trial targeting high-risk SMM showed that early intervention was associated with better progression-free and overall survival. Biomarkers have become an integrated part of diagnostic criteria for MM requiring therapy, as well as clinical risk stratification of patients with SMM. This paper reviews and discusses clinical implications for MGUS and SMM patients.

  20. 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.

  1. 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.

  2. 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.

  3. From myeloma precursor disease to multiple myeloma: new diagnostic concepts and opportunities for early intervention.

    PubMed

    Landgren, Ola; Kyle, Robert A; Rajkumar, S Vincent

    2011-03-15

    Since monoclonal gammopathy of undetermined significance (MGUS) was first described more than 30 years ago, the definition of the entity has evolved. Today, 3 distinct clinical MGUS subtypes have been defined: non-immunoglobulin M (IgM; IgG or IgA) MGUS, IgM MGUS, and light chain MGUS. Each clinical MGUS subtype is characterized by unique intermediate stages and progression events. Although we now have strong evidence that multiple myeloma is consistently preceded by a precursor state at the molecular level, there is urgent need to better understand mechanisms that regulate transformation from precursor to full-blown multiple myeloma. In the future, if such knowledge was available, it would allow clinicians to define high-risk and low-risk precursor patients for a more tailored clinical management. Also, it would provide insights on the individual patient's disease biology, which, in turn, can be used for targeted and more individualized treatment strategies. On the basis of current clinical guidelines, patients diagnosed with MGUS and smoldering myeloma should not be treated outside of clinical trials. In the near future, it seems reasonable to believe that high-risk precursor patients will likely become candidates for early treatment strategies. In this review, we discuss novel insights from recent studies and propose future directions of relevance for clinical management and research studies.

  4. Evolutionary Dynamics of Tumor-Stroma Interactions in Multiple Myeloma

    PubMed Central

    Sartakhti, Javad Salimi; Manshaei, Mohammad Hossein; Bateni, Soroosh; Archetti, Marco

    2016-01-01

    Cancer cells and stromal cells cooperate by exchanging diffusible factors that sustain tumor growth, a form of frequency-dependent selection that can be studied in the framework of evolutionary game theory. In the case of multiple myeloma, three types of cells (malignant plasma cells, osteoblasts and osteoclasts) exchange growth factors with different effects, and tumor-stroma interactions have been analysed using a model of cooperation with pairwise interactions. Here we show that a model in which growth factors have autocrine and paracrine effects on multiple cells, a more realistic assumption for tumor-stroma interactions, leads to different results, with implications for disease progression and treatment. In particular, the model reveals that reducing the number of malignant plasma cells below a critical threshold can lead to their extinction and thus to restore a healthy balance between osteoclast and osteoblast, a result in line with current therapies against multiple myeloma. PMID:28030607

  5. [Imaging in smoldering (asymptomatic) multiple myeloma. Past, present and future].

    PubMed

    Bhutani, M; Landgren, O

    2014-06-01

    Emerging clinical trial data support treatment of high-risk smoldering multiple myeloma (SMM) upon diagnosis, and not only at the time of progression to symptomatic complications (multiple myeloma). Early detection of bone and/or bone marrow involvement by sensitive imaging modalities may help define SMM patients at a high risk of progression. Current (2011) consensus guidelines recognize skeletal survey as a cornerstone modality for assessment of bone involvement at initial diagnosis and during follow-up of SMM. Skeletal survey has severe limitations related to underdetection of bone lesions and also provides no information on bone marrow abnormalities. Modern imaging strategies such as fluorodeoxyglucose positron-emission tomography/CT (FDG PET/CT) and MRI, in conjunction with functional innovations, provide improved estimates of global abnormalities in the bone marrow and bone compartments. These methods have the potential to objectively quantify early transformation from SMM to multiple myeloma. Although frequently used for staging and risk prognostication in multiple myeloma, modern imaging techniques have only been evaluated to a limited extent in SMM. Scant data in SMM indicate the prognostic value of two or more MRI-detected focal bone marrow abnormalities, which, if present, predict rapid progression to multiple myeloma. Data evaluating the role of FDG PET/CT in detecting early bone marrow abnormalities as an aid to predicting risk or directing treatment in SMM is currently lacking. The superior specificity and sensitivity of modern imaging techniques compared to skeletal survey suggest that these should have a place in standard practice management of patients at a high risk of SMM progression. The model imaging of the future should be an all-in-one strategy offering high diagnostic performance for bone marrow abnormalities and low-volume bone lesions, as well as allowing monitoring by minimizing radiation exposure and the need for contrast agents. Newer

  6. IL-21 and other serum proinflammatory cytokine levels in patients with multiple myeloma at diagnosis.

    PubMed

    Mehtap, O; Atesoglu, E B; Tarkun, P; Hacihanefioglu, A; Dolasik, I; Musul, M M

    2014-01-01

    IL-6, IL1-β, TNF-α and IL-21 have been identified in the growth, progression and dissemination of multiple myeloma. To dte, there is no published data about serum levels of IL-21 in patients with multiple myeloma. In the present study we have investigated circulating levels of cytokines, such as IL-6, IL-1β, TNF-α, IL-21 and the association of these levels with the disease stage in newly diagnosed multiple myeloma patients. Twenty healthy controls and 44 newly diagnosed multiple myeloma patients were evaluated. Patients were classified according to Durie-Salmon criteria, international staging system (ISS) and bone disease. Quantification of cytokine levels in serum were performed by using ELISA. The levels of cytokines in patients' serum are found elevated than healthy controls. However, only the serum levels of IL-1β and TNF-α were found statistically significant. TNF-α levels of patients with ISS stage 3 were significantly higher than patients with ISS stage 1 and 2 (P 0.000). IL-1β was significantly elevated in advanced stage patients (stage II-III) (P 0.040). There was no correlation between IL-1β, TNF-α, IL-21 levels and bone lesions. IL-6 levels were significantly elevated who have at least three visible lytic bone lesions and/or bone fracture in comparison to patients who have one or two visible or no visible lytic bone lesions (P 0.048). It appears that there is no association of serum IL-21 level with multiple myeloma in contrast to the other cytokines such as IL-6, IL-1β, TNF-α.

  7. Experimental Approaches in the Treatment of Multiple Myeloma

    PubMed Central

    Khan, Saad A.; Cohen, Adam D.

    2011-01-01

    Myeloma therapy has undergone significant advances in recent years resulting in a marked improvement in survival. Knowledge of the active pathways involved in myeloma pathogenesis has led to the discovery of novel agents and greatly expanded the potential armamentarium available for treatment. This better understanding of the disease and resistance mechanisms has resulted in new agent classes that are being evaluated in preclinical and early clinical studies. In addition, dosing for existing agents is being optimized, and they are being given in new combinations. In this article, we review experimental agents that are showing promise in multiple myeloma treatment. New biological agents in clinical trials hold the promise of efficacy through novel mechanisms of action, with a significant reduction of dose-limiting toxicities compared with classic cytotoxic chemotherapeutics. Second-generation proteasome inhibitors and immunomodulatory agents are furthest along in clinical development, and histone deacetylase inhibitors, heat shock protein 90 inhibitors, Akt inhibitors and monoclonal antibodies are some of the other agents entering later-phase clinical trials. We also review developments in targeting the myeloma stem cell as an exciting new treatment direction. PMID:23556091

  8. Therapy for Relapsed Multiple Myeloma: Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy

    PubMed Central

    Dingli, David; Ailawadhi, Sikander; Bergsagel, P. Leif; Buadi, Francis K.; Dispenzieri, Angela; Fonseca, Rafael; Gertz, Morie A.; Gonsalves, Wilson I.; Hayman, Susan R.; Kapoor, Prashant; Kourelis, Taxiarchis; Kumar, Shaji K.; Kyle, Robert A.; Lacy, Martha Q.; Leung, Nelson; Lin, Yi; Lust, John A.; Mikhael, Joseph R.; Reeder, Craig B.; Roy, Vivek; Russell, Stephen J.; Sher, Taimur; Stewart, A. Keith; Warsame, Rahma; Zeldenrust, Stephen R.; Rajkumar, S. Vincent; Chanan Khan, Asher A.

    2017-01-01

    Life expectancy in patients with multiple myeloma is increasing because of the availability of an increasing number of novel agents with various mechanisms of action against the disease. However, the disease remains incurable in most patients because of the emergence of resistant clones, leading to repeated relapses of the disease. In 2015, 5 novel agents were approved for therapy for relapsed multiple myeloma. This surfeit of novel agents renders management of relapsed multiple myeloma more complex because of the occurrence of multiple relapses, the risk of cumulative and emergent toxicity from previous therapies, as well as evolution of the disease during therapy. A group of physicians at Mayo Clinic with expertise in the care of patients with multiple myeloma regularly evaluates the evolving literature on the biology and therapy for multiple myeloma and issues guidelines on the optimal care of patients with this disease. In this article, the latest recommendations on the diagnostic evaluation of relapsed multiple myeloma and decision trees on how to treat patients at various stages of their relapse (off study) are provided together with the evidence to support them. PMID:28291589

  9. Therapy for Relapsed Multiple Myeloma: Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy.

    PubMed

    Dingli, David; Ailawadhi, Sikander; Bergsagel, P Leif; Buadi, Francis K; Dispenzieri, Angela; Fonseca, Rafael; Gertz, Morie A; Gonsalves, Wilson I; Hayman, Susan R; Kapoor, Prashant; Kourelis, Taxiarchis; Kumar, Shaji K; Kyle, Robert A; Lacy, Martha Q; Leung, Nelson; Lin, Yi; Lust, John A; Mikhael, Joseph R; Reeder, Craig B; Roy, Vivek; Russell, Stephen J; Sher, Taimur; Stewart, A Keith; Warsame, Rahma; Zeldenrust, Stephen R; Rajkumar, S Vincent; Chanan Khan, Asher A

    2017-04-01

    Life expectancy in patients with multiple myeloma is increasing because of the availability of an increasing number of novel agents with various mechanisms of action against the disease. However, the disease remains incurable in most patients because of the emergence of resistant clones, leading to repeated relapses of the disease. In 2015, 5 novel agents were approved for therapy for relapsed multiple myeloma. This surfeit of novel agents renders management of relapsed multiple myeloma more complex because of the occurrence of multiple relapses, the risk of cumulative and emergent toxicity from previous therapies, as well as evolution of the disease during therapy. A group of physicians at Mayo Clinic with expertise in the care of patients with multiple myeloma regularly evaluates the evolving literature on the biology and therapy for multiple myeloma and issues guidelines on the optimal care of patients with this disease. In this article, the latest recommendations on the diagnostic evaluation of relapsed multiple myeloma and decision trees on how to treat patients at various stages of their relapse (off study) are provided together with the evidence to support them. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  10. Incidence of contrast-induced nephropathy in patients with multiple myeloma undergoing contrast-enhanced CT.

    PubMed

    Pahade, Jay K; LeBedis, Christina A; Raptopoulos, Vassilios D; Avigan, David E; Yam, Chun S; Kruskal, Jonathan B; Pedrosa, Ivan

    2011-05-01

    The purpose of this article is to evaluate the incidence of contrast-induced nephropathy (CIN) and the effects of associated risk factors in patients with multiple myeloma undergoing contrast-enhanced CT (CECT) with IV administration of nonionic iodinated contrast agent. This retrospective review of medical records identified patients with a diagnosis of myeloma who underwent a CECT examination of the chest, abdomen, or pelvis between January 1, 2005, and December 1, 2008. Analysis for CIN, as defined by an increase in creatinine level after the CECT examination of 25% or more, or of 0.5 mg/dL, compared with the level before the CECT examination, both within 48 hours and within 7 days, was performed. Statistical correlations between the development of CIN and creatinine level before CECT examination, patient location, type and amount of contrast agent, blood urea nitrogen-creatinine ratio, history of diabetes, hypercalcemia, Bence Jones proteinuria, β(2)-microglobulin level, albumin level, International Myeloma Staging System stage, and history of myeloma provided at the time the CT examination was ordered were calculated. Forty-six patients who completed 80 unique examinations were included; their average creatinine level before CECT examination was 0.97 mg/dL. There was no significant difference in the average creatinine levels before CT examination between patients without and those with CIN. Four (5%) and 12 (15%) patients developed CIN within 48 hours and 7 days, respectively. Only serum β(2)-microglobulin level showed a statistically significant (p = 0.03) correlation with the development of CIN. The incidence of CIN in patients with multiple myeloma with a normal creatinine level is low and correlates with β(2)-microglobulin levels. The administration of contrast agent in this patient population is safe but should be based on the potential benefit of the examination and the expected low risk of developing CIN.

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

    PubMed Central

    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

    2016-01-01

    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

  12. Current approaches to the initial treatment of symptomatic multiple myeloma

    PubMed Central

    Jasielec, Jagoda K; Jakubowiak, Andrzej J

    2013-01-01

    SUMMARY The treatment of newly diagnosed multiple myeloma has dramatically changed since the emergence of proteasome inhibitors and immunomodulatory drugs. Front-line combination regimens incorporating novel drugs such as thalidomide, bortezomib and lenalidomide, have significantly improved response rates and are the standard of care for induction regimens. Although the timing and role of autologous stem cell transplant are now being questioned, it remains an important part of the treatment paradigm in eligible patients. In addition, the concept of extended sequential therapy has recently emerged, including consolidation and/or maintenance in both the post-transplant setting and in nontransplant candidates. In this article we focus on management strategies in newly diagnosed multiple myeloma, including choice of induction regimens in transplant-eligible and -ineligible patients, as well as the role of autologous stem cell transplant, consolidation therapy and maintenance therapy. PMID:24286003

  13. Atypical progression of multiple myeloma with extensive extramedullary disease.

    PubMed Central

    Jowitt, S N; Jacobs, A; Batman, P A; Sapherson, D A

    1994-01-01

    Multiple myeloma is a neoplastic disorder caused by the proliferation of a transformed B lymphoid progenitor cell that gives rise to a clone of immunoglobulin-secreting cells. Other plasma cell tumours include solitary plasmacytoma of bone (SPB) and extramedullary plasmacytomas (EMP). Despite an apparent common origin there exist pathological and clinical differences between these neoplasms and the association between them is not completely understood. A case of IgG multiple myeloma that presented with typical clinical and laboratory features, including a bone marrow infiltrated by well differentiated plasma cells, is reported. The tumour had an unusual evolution, with the development of extensive extramedullary disease while maintaining mature histological features. Images PMID:8163701

  14. Multiple myeloma with associated polyneuropathy in a German shepherd dog.

    PubMed

    Villiers, E; Dobson, J

    1998-05-01

    A 12-year-old female, neutered German shepherd dog developed progressive hindlimb followed by forelimb ataxia leading to tetraplegia. Neurological examination suggested lower motor dysfunction. Biochemical evaluation revealed a monoclonal hypergammaglobulinaemia, hypoalbuminaemia and hypercalcaemia. Multiple lytic lesions were identified radiographically in numerous bones. A bone marrow aspirate confirmed the diagnosis of multiple myeloma, with large numbers of plasma cells seen in clusters. An electromyogram revealed positive sharp waves and fibrillation potentials in the skeletal muscles of the limbs, suggesting a polyneuropathy. The dog was treated with chemotherapy using melphalan and prednisolone. Both the hypergammaglobulinaemia and the polyneuropathy resolved and the dog had normal motor function four weeks after commencing treatment. Polyneuropathy may occur as a paraneoplastic syndrome secondary to myeloma, and in this case was reversible following treatment of the underlying disease.

  15. Multiple myeloma associated with an Evan’s syndrome

    PubMed Central

    Bechir, Achour; Haifa, Regaieg; Nesrine, Ben Sayed; Emna, Bouslema; Senda, Mejdoub; Asma, Achour; Amina, Bouatay Bouzouita; Mrabet, Senda; Yosra, Ben Youssef; Mondher, Kortas; Abderrahim, Khelif

    2016-01-01

    Auto-immun events are rare in multiple myeloma (MM). Here, we report one MM case complicated by Evans syndrome (Autoimmun hemolytic anemia (AIHA) associated with thrombocytopenia). A 52-year-old man was admitted in nephrology department with severe anemia, renal insufficiency and hypergamma globulinemia. Laboratory exams showed acute hemolysis due to an IgG warm autoantibody. Serum electrophoresis revealed the presence of a monoclonal IgG protein and urinary M protein was 2g/day. A whole body CT-Scan showed osteolytic lesions of vertebral body of C5, D4, L3, L4 and the left iliac wing. The diagnosis of multiple myeloma and Evan's syndrome was made, we underwent chemotherapy by BTD (bortezomib-thalidomide-dexamethasone) and continuous corticosteroid therapy but unfortunately the patient died secondary of a Lactic acidosis. The relationship between MM and hemolysis remain unclear. PMID:28292089

  16. The hyponatramia of multiple myeloma is true and not pseudohyponatramia.

    PubMed

    Sachs, Jeffrey; Fredman, Brian

    2006-01-01

    The hyponatremia found in multiple myeloma and which is associated with a reduced anion gap (ag) is considered to be pseudohyponatremia due to the displacement of water by the high globulin content in the blood. Serum proteins participate in acid-base balance. Stewart and other authors in their approach to acid-base interpretation acknowledge electrical neutrality as a fundamental characteristic of body fluids. Furthermore, they have shown that both the strong ion difference (SID) and protein, specifically, negatively-charged albumin affect hydrogen ion concentration (H(+)) in the body--i.e., for example an increase in SID leads to a decrease in H(+) and a decrease in albumin leads to a similar effect. The M proteins of multiple myeloma are positively charged. As a result they cause a decrease in sodium levels and the anion gap and thus a true hyponatremia.

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

    PubMed

    Rajan, A M; Rajkumar, S V

    2015-10-30

    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.

  18. 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

  19. 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.

  20. Non-secretory multiple myeloma: from biology to clinical management

    PubMed Central

    Dupuis, Megan Murray; Tuchman, Sascha A

    2016-01-01

    Multiple myeloma (MM) is the second most common hematologic malignancy in the US. It is typically characterized by production of large amounts of defective immunoglobulin (Ig). Diagnosing MM and monitoring treatment response, including eventual relapse, are largely based on sequential measurements of Ig. However, a small subset of MM called non-secretory multiple myeloma (NSMM) produces no detectable Ig. This subset of true NSMM has become even smaller over time, as the advent of the serum free light chain assay has resulted in the majority of NSMM patients being recategorized as light-chain MM – that is, MM cells that produce only the light-chain component of Ig. True forms of NSMM, meaning MM that secretes no monoclonal proteins whatsoever, constitute a distinct entity that is reviewed; definition of NSMM using current detection methods, discuss the biology underpinning NSMM development, and share recommendations for how NSMM should be managed clinically with respect to detection, treatment, and monitoring. PMID:28008276

  1. Generalized livedo reticularis associated with monoclonal cryoglobulinemia and multiple myeloma.

    PubMed

    Requena, Luis; Kutzner, Heinz; Angulo, Jorge; Renedo, Guadalupe

    2007-02-01

    Cryoglobulins are detected in a wide variety of diseases, including malignancies, infections and systemic autoimmune diseases. Classically, monoclonal cryoglobulinemia is associated with hematologic malignancies, whereas mixed cryoglobulinemias are reported in association with hepatitis C virus infections or autoimmune diseases. We present a patient with generalized livedo reticularis as the first manifestation of monoclonal cryoglobulinemia and multiple myeloma. Histopathology demonstrated that nearly all small blood vessels of the upper and deep dermis, as well as the capillaries of the fat lobule, were filled with homogeneous, eosinophilic material that corresponded to monoclonal cryoglobulin deposits within the vascular lumina. Our case of livedo reticularis associated with monoclonal cryoglobulinemia and multiple myeloma was exceptional, because the mottled cyanotic discoloration of the skin with a reticular pattern was generalized, covering most of the skin surface. We have not found previous report of similar cases. Therefore, we recommend that dermatologists be made aware of the significance of this diagnosis.

  2. Consolidation in multiple myeloma – current status and perspectives

    PubMed Central

    Rzepecki, Piotr

    2014-01-01

    Although multiple myeloma (MM) is still considered an incurable disease, the treatment philosophy is changing due to the introduction of novel agents. Standard treatment consists of an induction phase and autologous stem cell transplantation in patients under 65–70 years. Prolonged treatment (consolidation and/or maintenance) is being introduced in many countries. We present a review of clinical trials dedicated to consolidation treatment in multiple myeloma. Bortezomib, lenalidomide and carfilzomib in different combinations were tested in the trials mentioned below. Although they did not prolong overall survival, the data are very promising. Three very important large clinical trials are still in progress. The results might help to establish the actual value of consolidation treatment. PMID:25477752

  3. 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

  4. Initial genome sequencing and analysis of multiple myeloma

    PubMed Central

    Chapman, Michael A.; Lawrence, Michael S.; Keats, Jonathan J.; Cibulskis, Kristian; Sougnez, Carrie; Schinzel, Anna C.; Harview, Christina L.; Brunet, Jean-Philippe; Ahmann, Gregory J.; Adli, Mazhar; Anderson, Kenneth C.; Ardlie, Kristin G.; Auclair, Daniel; Baker, Angela; Bergsagel, P. Leif; Bernstein, Bradley E.; Drier, Yotam; Fonseca, Rafael; Gabriel, Stacey B.; Hofmeister, Craig C.; Jagannath, Sundar; Jakubowiak, Andrzej J.; Krishnan, Amrita; Levy, Joan; Liefeld, Ted; Lonial, Sagar; Mahan, Scott; Mfuko, Bunmi; Monti, Stefano; Perkins, Louise M.; Onofrio, Robb; Pugh, Trevor J.; Vincent Rajkumar, S.; Ramos, Alex H.; Siegel, David S.; Sivachenko, Andrey; Trudel, Suzanne; Vij, Ravi; Voet, Douglas; Winckler, Wendy; Zimmerman, Todd; Carpten, John; Trent, Jeff; Hahn, William C.; Garraway, Levi A.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Golub, Todd R.

    2013-01-01

    Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the dataset. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signaling was suggested by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. PMID:21430775

  5. Risk of vertebral compression fractures in multiple myeloma patients

    PubMed Central

    Anitha, D.; Thomas, Baum; Jan, Kirschke S.; Subburaj, Karupppasamy

    2017-01-01

    Abstract The purpose of this study was to develop and validate a finite element (FE) model to predict vertebral bone strength in vitro using multidetector computed tomography (MDCT) images in multiple myeloma (MM) patients, to serve as a complementing tool to assess fracture risk. In addition, it also aims to differentiate MM patients with and without vertebral compression fractures (VCFs) by performing FE analysis on vertebra segments (T1–L5) obtained from in vivo routine MDCT imaging scans. MDCT-based FE models were developed from the in vitro vertebrae samples and were then applied to the in vivo vertebrae segments of MM patients (n = 4) after validation. Predicted fracture load using FE models correlated significantly with experimentally measured failure load (r = 0.85, P < 0.001). Interestingly, an erratic behavior was observed in patients with fractures (n = 2) and a more gradual change in FE-predicted strength values in patients without fractures (n = 2). Severe geometric deformations were also observed in models that have already attained fractures. Since BMD is not a reliable parameter for fracture risk prediction in MM subjects, it is necessary to use advanced tools such as FE analysis to predict individual fracture risk. If peaks are observed between adjacent segments in an MM patient, it can be safe to conclude that the spine is experiencing regions of structural instability. Such an FE visualization may have therapeutic consequences to prevent MM associated vertebral fractures. PMID:28079810

  6. Subcutaneous bortezomib for multiple myeloma treatment: patients' benefits.

    PubMed

    Petrucci, Maria Teresa; Finsinger, Paola; Chisini, Marta; Gentilini, Fabiana

    2014-01-01

    The use of novel agents such as thalidomide, lenalidomide, and bortezomib has considerably improved the outcome of multiple myeloma patients. Besides greater biological activity, these drugs unfortunately have also been associated with greater toxicity. To evaluate the positive effect on the quality of life of patients, driven by both the tolerability and antimyeloma activity of bortezomib, we analyzed data that have been published concerning different strategies used to improve its tolerability as once weekly and/or subcutaneous administration.

  7. MicroRNAs: New Players in Multiple Myeloma

    PubMed Central

    Pichiorri, Flavia; De Luca, Luciana; Aqeilan, Rami I.

    2011-01-01

    MicroRNAs (miRNAs) are short non-coding RNAs that play critical roles in numerous cellular processes through post-transcriptional regulating functions. The aberrant role of miRNAs has been reported in a number of hematopoietic malignancies including multiple myeloma (MM). In this review we summarize the current knowledge on roles of miRNAs in the pathogenesis of MM. PMID:22303318

  8. MicroRNAs: New Players in Multiple Myeloma.

    PubMed

    Pichiorri, Flavia; De Luca, Luciana; Aqeilan, Rami I

    2011-01-01

    MicroRNAs (miRNAs) are short non-coding RNAs that play critical roles in numerous cellular processes through post-transcriptional regulating functions. The aberrant role of miRNAs has been reported in a number of hematopoietic malignancies including multiple myeloma (MM). In this review we summarize the current knowledge on roles of miRNAs in the pathogenesis of MM.

  9. Subcutaneous bortezomib for multiple myeloma treatment: patients’ benefits

    PubMed Central

    Petrucci, Maria Teresa; Finsinger, Paola; Chisini, Marta; Gentilini, Fabiana

    2014-01-01

    The use of novel agents such as thalidomide, lenalidomide, and bortezomib has considerably improved the outcome of multiple myeloma patients. Besides greater biological activity, these drugs unfortunately have also been associated with greater toxicity. To evaluate the positive effect on the quality of life of patients, driven by both the tolerability and antimyeloma activity of bortezomib, we analyzed data that have been published concerning different strategies used to improve its tolerability as once weekly and/or subcutaneous administration. PMID:25045252

  10. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

    PubMed

    Stewart, A Keith; Rajkumar, S Vincent; Dimopoulos, Meletios A; Masszi, Tamás; Špička, Ivan; Oriol, Albert; Hájek, Roman; Rosiñol, Laura; Siegel, David S; Mihaylov, Georgi G; Goranova-Marinova, Vesselina; Rajnics, Péter; Suvorov, Aleksandr; Niesvizky, Ruben; Jakubowiak, Andrzej J; San-Miguel, Jesus F; Ludwig, Heinz; Wang, Michael; Maisnar, Vladimír; Minarik, Jiri; Bensinger, William I; Mateos, Maria-Victoria; Ben-Yehuda, Dina; Kukreti, Vishal; Zojwalla, Naseem; Tonda, Margaret E; Yang, Xinqun; Xing, Biao; Moreau, Philippe; Palumbo, Antonio

    2015-01-08

    Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

  11. MMSA-1 expression pattern in multiple myeloma and its clinical significance.

    PubMed

    Meng, Shan; Lu, Chenyang; Zhang, Wanggang; Shen, Wenjun; Wei, Yongchang; Su, Dan; Zhou, Fuling

    2016-11-01

    Multiple myeloma-associated antigen-1 (MMSA-1) is a novel multiple myeloma (MM)-associated antigen which has been recently identified. Herein, we have tried to examine its clinical significance by studying the relationship between its expression and selected clinicopathological features. We extracted mononuclear cells from the bone marrow of MM patients and healthy donors and compared the MMSA-1 expression by RT-PCR and Western blot analysis. In addition, we also analyzed MMSA-1 expression in patients that were grouped based on selected clinical parameters. Moreover, the impact of MMSA-1 on patients' survival was also explored. MMSA-1 mRNA and protein were significantly upregulated in MM patients in comparison with healthy donors. Moreover, among the newly diagnosed and relapsed/refractory patients, the MMSA-1 expression was higher in relapsed/refractory patients. In addition, MMSA-1 mRNA expression not only showed significantly higher correlation with clinical parameters such as age, Durie and Salmon stage, bone lesion condition, albumin, creatinine and lactate dehydrogenase but also has a close relationship with myeloma bone disease-related cytokines, genetic abnormalities and treatment response. Multivariate COX analysis predicted MMSA-1 and LDH levels to be independently associated with a poor progression-free survival and overall survival in myeloma patients. Our findings provide initial proof of concept that MMSA-1 is a potent gene that is specifically expressed in MM patients and could be a feasible biomarker and independent prognostic factor.

  12. A novel multi-epitope vaccine from MMSA-1 and DKK1 for multiple myeloma immunotherapy.

    PubMed

    Lu, Chenyang; Meng, Shan; Jin, Yanxia; Zhang, Wanggang; Li, Zongfang; Wang, Fang; Wang-Johanning, Feng; Wei, Yongchang; Liu, Hailing; Tu, Honglei; Su, Dan; He, Aili; Cao, Xingmei; Zhou, Fuling

    2017-08-01

    The identification of novel tumour-associated antigens is urgently needed to improve the efficacy of immunotherapy for multiple myeloma (MM). In this study, we identified a membrane protein MMSA-1 (multiple myeloma special antigen-1) that was specifically expressed in MM and exhibited significantly positive correlation with MM. We then identified HLA-A*0201-restricted MMSA-1 epitopes and tested their cytotoxic T lymphocyte (CTL) response. The MMSA-1 epitope SLSLLTIYV vaccine was shown to induce an obvious CTL response in vitro. To improve the immunotherapy, we constructed a multi-epitope peptide vaccine by combining epitopes derived from MMSA-1 and Dickkopf-1 (DKK1). The effector T cells induced by multi-epitope peptide vaccine-loaded dendritic cells lysed U266 cells more effectively than MMSA-1/DKK1 single-epitope vaccine. In myeloma-bearing severe combined immunodeficient mice, the multi-epitope vaccine improved the survival rate significantly compared with single-epitope vaccine. Consistently, multi-epitope vaccine decreased the tumour volume greatly and alleviated bone destruction. The frequencies of CD4(+) and CD8(+) T cells was significantly increased in mouse blood induced by the multi-epitope vaccine, indicating that it inhibits myeloma growth by changing T cell subsets and alleviating immune paralysis. This study identified a novel peptide from MMSA-1 and the multi-epitope vaccine will be used to establish appropriate individualized therapy for MM. © 2017 John Wiley & Sons Ltd.

  13. Disseminated growth of murine plasmacytoma: similarities to multiple myeloma.

    PubMed

    Roschke, V; Hausner, P; Kopantzev, E; Pumphrey, J G; Riminucci, M; Hilbert, D M; Rudikoff, S

    1998-02-01

    Murine plasma cell tumors share a number of common features with human multiple myeloma, suggesting their possible use as a model for this disease. However, one major difference between the two is the peritoneal localization of murine tumors as opposed to bone marrow residence of malignant plasma cells in early stages of multiple myeloma. We have thus examined the ability of murine plasmacytoma to produce disseminated growth similar to that seen in myeloma or other lymphoid neoplasias. Of four murine cell lines evaluated, all were demonstrated to effect highly metastatic disease involving multiple organs, although variation was observed between lines. A temporal analysis was accordingly performed with the S107 line to assess the pattern of cellular localization. Both light microscopy and PCR analysis revealed that engraftment of plasma cells occurs first in the bone marrow, followed by dissemination to other sites including the spleen, lung, and liver. Cells passaged in vivo through the bone marrow display an entirely different metastatic pattern with no homing preference to bone marrow or any other organ, suggesting the occurrence of a phenotypic change. Microscopic osteolytic lesions were observed adjacent to plasma cell tumor masses in the bone marrow, indicating early stages of bone disease. These findings demonstrate previously unrecognized similarities between the murine and human diseases and suggest the use of this in vivo model for experimental approaches to the treatment of human disease.

  14. 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.

  15. Invasive granulomatous cryptococcal sinusitis in an adult with multiple myeloma.

    PubMed

    Ferraro, Richard A; Ivanidze, Jana; Margolskee, Elizabeth; Tsang, Hamilton; Sconomiglio, Theresa; Jhanwar, Yuliya S

    We report a case of cryptococcal sinusitis, a rare presentation of Cryptococcus neoformans infection in a patient with multiple myeloma. The objective of this case report is to highlight the utility of structural and functional imaging modalities in the differential diagnosis of sinonasal soft tissue masses in the immunocompromised patient population. PET-CT was the first imaging modality in this patient, who presented for routine follow-up staging of multiple myeloma, and was asymptomatic at the time of his presentation. PET-CT findings prompted further evaluation with MRI, to aid in the differential diagnosis with respect to a neoplastic versus infectious etiology. Ultimately, surgical excision with histopathology was required to provide definitive diagnosis. Final histopathology displayed yeast-organism staining consistent with Cryptococcus neoformans/gatti. The patient subsequently underwent treatment for this infection, along continued treatment for multiple myeloma. To our knowledge this is the first known case of cryptococcal sinusitis in a patient with neoplastic disease. Imaging represents an important tool to differentiate fungal infection from neoplasm in the immunocompromised patient population. As the population of immunocompromised patients continues to grow, the relevance of this diagnosis as well as the use of alternative imaging modalities is becoming more important in clinical practice.

  16. [Systemic amyloidosis associated with IgD-λ multiple myeloma].

    PubMed

    Nagamachi, Yasuhiro; Yamauchi, Naofumi; Muramatsu, Hirohito; Inomata, Hidetoshi; Nozawa, Eri; Koyama, Ryuzo; Ihara, Koji; Nishisato, Takuji; Yamada, Hideyuki; Yano, Tomohiro; Kikuchi, Shohei; Hirako, Tasuku; Kitaoka, Keisuke; Ono, Kaoru; Ihara, Hideyuki; Kato, Junji

    2011-12-01

    We describe here a case of systemic amyloidosis associated with IgD multiple myeloma. A 59-year-old man was admitted to our hospital in April 2009, because of macroglossia and swelling in both wrists and fingers. He had difficulty moving his limbs and was aware of peripheral neuropathy. Skin biopsy revealed extensive deposition of amyloidosis, which was positive by Congo red staining. Laboratory findings were as follows: serum electrophoresis revealed IgD λ monoclonal protein, and Bence-Jones protein was detected. Monoclonal IgD protein had a concentration of 727 mg/dl, and a bone marrow aspiration revealed 49.6% of plasma cells. These findings led to a diagnosis of IgD multiple myeloma with systemic amyloidosis. The patient was treated with MP (melphalan and methylprednisolone), high-dose dexamethasone and VAD therapy (vincristine, adriamycin and dexamethasone), but systemic amyloidosis progressed, and his general condition deteriorated. Coexistence of IgD multiple myeloma and systemic amyloidosis is rare, and accumulation of case reports is needed to gain a better understanding of this condition.

  17. Medical history and the risk of multiple myeloma.

    PubMed Central

    Gramenzi, A.; Buttino, I.; D'Avanzo, B.; Negri, E.; Franceschi, S.; La Vecchia, C.

    1991-01-01

    The relationship between various diseases and immunisations and the risk of multiple myeloma was analysed using data from a hospital-based case-control study conducted in Northern Italy on 117 patients with multiple myeloma and 477 controls. Associations were observed for clinical history of scarlet fever (relative risk, RR = 2.0; 95% confidence interval, CI = 1.1-3.9), tuberculosis (RR = 2.3%; 95% CI = 0.9-5.7) and BCG immunisation (RR = 3.0; 95% CI = 1.4-6.4). The relative risk was 1.8 (95% CI = 0.9-3.5) for episodes of Herpes zoster infection, but most of the excess cases occurred within 10 years of diagnosis, suggesting that this might have been an early manifestation of the disease. No association emerged for common childhood viral infections or any other immunisation practice. When various classes of infectious or inflammatory diseases were grouped together according to their aetiology, there was a significant positive association with chronic bacterial illnesses (RR = 1.8; 95% CI = 1.1-2.8), and the relative risk estimates increased with the number of bacterial diseases. The trend in risk with number of diseases was significant (chi 21 = 4.5, P = 0.03). A negative association was found between allergic conditions and risk of multiple myeloma (RR = 0.6; 95% CI = 0.3-1.0). PMID:2039702

  18. Sacroplasty for local or massive localization of multiple myeloma.

    PubMed

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

    2010-12-01

    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.

  19. 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

  20. 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.

  1. 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.

  2. Renal complications in multiple myeloma and related disorders: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board.

    PubMed

    Faiman, Beth M; Mangan, Patricia; Spong, Jacy; Tariman, Joseph D

    2011-08-01

    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, if not reversed, will adversely affect 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 because of light chain cast nephropathy. Kidney failure in patients with presumed multiple myeloma also may 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 has developed practice recommendations for screening renal function, identifying positive and negative contributing risk and environmental factors, selecting appropriate therapies and supportive care measures to decrease progression to ESRD, and enacting dialysis to reduce and manage renal complications in patients with multiple myeloma.

  3. Flow cytometric evaluation of bone marrow plasma cells using CD19, CD45, CD56, CD38, and CD138 and correlation with bone marrow infiltration ratio in multiple myeloma patients.

    PubMed

    Kara, Ismail O; Sahin, Berksoy; Paydas, Semra; Cetiner, Salih

    2004-11-01

    To examine the co-expression of CD19, CD45, CD38, CD56, and CD138 molecules in plasma cells of bone marrow (BM) aspirates and their relation with BM infiltration, and treatment in patients with multiple myeloma by flow cytometry. Forty BM aspirate samples were assessed from 40 patients at diagnosis and on follow-up at the Medical Oncology Department, Cukurova University, Balcali Hospital, Turkey, between 2002 and 2004. The mean age was 56.83 +/- 9.1 and male:female ratio was 2.6. All patients received at least 4 courses of VAD(vincristine, adriamycin, dexamethasone) regimens and 20 of them were also treated with high dose melphalan and peripheral autologous stem cell transplantation. The median follow-up period was 19.1 +/- 22.7 months. Using light microscopy the BM smears stained with hematoxylin and eosin from patients on follow up were classified into one of 3 categories, complete remission (CR) (<5%), partial remission (PR) (>5% and <30%), and extensive infiltration (EI) (>30%). According to infiltration ratio 23 were evaluated CR, 2 were PR and 15 were EI. The mean value of CD19 was 6.01 +/- 9.5%, CD56 = 9.9 +/- 6.8%, CD138 = 8.6 +/- 5.6%, CD45 = 84.2 +/- 22.3% and CD38 = 59.5 +/- 25.4%. The flow cytometric analyses revealed that only the mean value of CD38 and CD45 expression were significantly high. We correlated infiltration ratio with each parametric and found statistically significant relations. We also correlated independent variables with each other and found a relation between CD38 and CD19 (p=0.005). We also defined the groups whether treated with peripheral autologous transplantation or not and compared the independent variables between them, in which CD138 was statistically significant (p=0.02). We suggest BM plasma cells expressed mainly by CD38 and CD45 may have a role in generation of BM plasma cells and that CD138 expression may be considered in follow-up for minimal residual disease after autologous transplantation in myeloma patients.

  4. Consensus in the Management of Multiple Myeloma in India at Myeloma State of the Art 2016 Conference.

    PubMed

    Yanamandra, Uday; Khattry, Navin; Kumar, Shaji; Raje, Noopur; Jain, Arihant; Jagannath, Sundar; Menon, Hari; Kumar, Lalit; Varma, Neelam; Varma, Subhash; Saikia, Tapan; Malhotra, Pankaj

    2017-03-01

    The science of multiple myeloma (MM) and related plasma cell disorders is rapidly evolving with increased understanding of the disease biology and recent approval of the newer drugs widening the therapeutic armamentarium. Despite multiple international guidelines regarding the management of this disease, the practice of managing MM is not uniform amongst Indian physicians. There are challenges in management which are unique to the Indian patients. This review discusses these challenges and the consensus of the nation-wide experts in dealing with the same. We also briefly highlighted the perspective of international experts as discussed in the Myeloma State of the Art conference held in September 2016 at PGI, Chandigarh. An Indian Myeloma Academic Groupe (IMAGe) group was formed to strengthen the research, create awareness about myeloma and related disorders and form consensus guidelines/ recommendations that can be adapted to the Indian Scenario.

  5. Immunomodulatory Drugs (IMiDs) in Multiple Myeloma.

    PubMed

    Raza, Shahzad; Safyan, Rachael A; Suzanne, Lentzsch

    2017-02-13

    Multiple myeloma (MM) is a plasma cell neoplasm that is incurable with conventional therapy. However, the treatment of MM has dramatically changed since the emergence of immunomodulatory drugs and proteasome inhibitors. The improvements in survival are linked to a deeper understanding of the molecular mechanisms of the disease. Thalidomide, although highly active in MM, is associated with considerable toxicity, particularly in older patients. Immunomodulatory drugs (IMiDs) are structural and functional analogues of thalidomide that represent a promising new class of immunomodulators for treatment of a variety of inflammatory, autoimmune, and neoplastic diseases. Lenalidomide, a second generation IMiD, is more potent and has a better toxicity profile than thalidomide. It is commonly used in newly-diagnosed multiple myeloma, relapse refractory myeloma and as maintenance therapy after autologous stem cell transplantation (ASCT). Pomalidomide, a third generation IMiD, is 10 times more potent than lenalidomide and has already shown impressive results in patients who are heavily pre-treated and refractory to both lenalidomide and bortezomib. Here we provide a comprehensive review on IMiDs including molecular mechanisms, recent advances in therapeutic applications and management of toxicities in the treatment of MM.

  6. ERG expression in multiple myeloma-A potential diagnostic pitfall.

    PubMed

    Knief, Juliana; Reddemann, Katharina; Gliemroth, Jan; Brede, Swantje; Bartscht, Tobias; Thorns, Christoph

    2017-02-01

    ERG expression has been described as a frequent event in prostate cancer indicating poor prognosis and promoting oncogenesis. It has also been demonstrated in Ewing's sarcoma, acute myeloid leukemia and acute T-lymphoblastic leukemia but could not be found in other epithelial tumors, Hodgkin's or Non-Hodgkin's lymphoma. We aimed to analyze ERG expression in multiple myeloma, following an index case of a patient with metastases of unknown origin in the spine strongly expressing ERG, which were thought to be of prostatic origin but turned out to be plasmacytic lesions. We subsequently selected 12 formalin-fixed, paraffin-embedded tissue samples of multiple myeloma from our archives and performed immunohistochemical staining for ERG. All 12 analyzed cases showed strong nuclear expression of ERG in >90% of tumor cells (myeloma cells). This report highlights a potential and critical diagnostic pitfall in biopsy specimens where morphology is only of limited assistance in reaching the correct diagnosis. It urges pathologists to exercise caution in cases where strong ERG-positivity implicates the presence of a prostatic neoplasia and illustrates the need for further immunohistochemical examination. Copyright © 2016 Elsevier GmbH. All rights reserved.

  7. COMPARISON OF TWIN AND AUTOLOGOUS TRANSPLANTS FOR MULTIPLE MYELOMA

    PubMed Central

    Bashey, Asad; Pérez, Waleska S.; Zhang, Mei-Jie; Anderson, Kenneth C.; Ballen, Karen; Berenson, James R.; To, L. Bik; Fonseca, Rafael; Freytes, César O.; Gale, Robert Peter; Gibson, John; Giralt, Sergio A.; Kyle, Robert A.; Lazarus, Hillard M.; Maharaj, Dipnarine; McCarthy, Philip L.; Milone, Gustavo A.; Nimer, Stephen; Pavlovsky, Santiago; Reece, Donna E.; Schiller, Gary; Vesole, David H.; Hari, Parameswaran

    2008-01-01

    Relapse is the overwhelming cause of treatment-failure after autologous transplantation for multiple myeloma (MM). For patients with a syngeneic donor, twin transplants provide a healthy graft that is free of myeloma. The relative impact of the graft on post-transplant relapse can be estimated by comparing risk of relapse after hematopoietic cell transplantation from genetically-identical twins vs. autotransplants since confounding differences in minor or major histocompatibility antigens are absent in the syngeneic transplant setting. Outcomes of 43 subjects who received twin transplants for MM were compared to 170 matched autotransplant recipients reported to the CIBMTR. Multivariate analysis was performed by fitting a Cox model stratified on matched-pairs. The matched transplant patients studied were similar with respect to subject-, disease- and transplant-related characteristics. Cumulative incidence of relapse/progression was significantly lower and progression-free survival was significantly higher following twin transplants. In multivariate analysis, the probability of relapse/progression was lower in twins (relative risk, RR=0.49, 95% confidence interval (CI) 0.28 – 0.86, p=0.011). Twin transplants have a significantly lower relapse risk than autotransplants in multiple myeloma suggesting that graft composition may impact outcomes following high-dose chemotherapy. PMID:18804041

  8. Smoldering multiple myeloma: when to observe and when to treat?

    PubMed

    Mateos, María-Victoria; San Miguel, Jesús-F

    2015-01-01

    Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of at least 3 g/dL of serum M-protein and/or 10% to 60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to active multiple myeloma (MM) is not uniform and several markers are useful for identifying patients at high risk of progression. The definition of the disease has recently been revisited and patients with asymptomatic MM at 80% to 90% of progression risk at 2 years are now considered to have MM. Although the current standard of care is not to treat, a randomized trial in patients with high-risk SMM that compared early treatment versus observation demonstrated that early intervention resulted in substantial benefits in terms of time to progression and overall survival (OS). These findings highlight the need to follow a correct diagnosis by an accurate risk stratification to plan an optimized follow-up according to the risk of disease progression.

  9. Smoldering Multiple Myeloma: Who and When to Treat.

    PubMed

    Mateos, María-Victoria; González-Calle, Verónica

    2017-06-23

    Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by the presence of ≥ 3 g/dL serum M-protein and/or 10% to 60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to active multiple myeloma (MM) is not uniform, and several markers are useful for identifying patients at high risk of progression. The definition of the disease has recently been revisited and asymptomatic MMs at 80% to 90% of progression risk at 2 years are now considered to be active MM candidates for treatment. In the future, more precise biomarkers are necessary for accurate risk stratification to plan an optimized follow-up according to the risk of progression, as well as to expand the group of patients that can obtain a benefit if they receive early treatment. A phase 3, randomized trial in high-risk patients with SMM comparing early treatment versus observation has shown a significant benefit in terms of time to progression and overall survival for early intervention and confirmatory clinical trials will definitively contribute to establish the early treatment as standard of care in high-risk SMM. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Bone Disease in Multiple Myeloma: Pathophysiology and Management

    PubMed Central

    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. PMID:25187738

  11. Management of multiple myeloma in resource-constrained settings.

    PubMed

    Kumar, Lalit; Kumar Sahoo, Ranjit

    2016-12-01

    The prognosis of patients with multiple myeloma (MM) has improved significantly in the past two decades. This is attributed to use of novel agents for induction, high-dose chemotherapy and autologous stem cell transplantation (ASCT), maintenance therapy, and improved supportive care. Currently, evidence-based management guidelines/recommendations developed by International societies/groups are being followed partially in low-resource settings. Lack of quality diagnostics (eg, cytogenetics/fluorescence in situ hybridization (FISH), serum free light chains), novel therapeutics, and trained manpower, and limited financial resources are key challanges. An optimal utilization of available resources with continued educational activities of treating physicians focused on improving knowledge in the management of such patients may be a way forward to improve the outcome of myeloma patients in these countries. Our current approach to the management of this disease is presented here through a discussion of clinical vignettes. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. CD52 is not a promising immunotherapy target for most patients with multiple myeloma.

    PubMed

    Westermann, Jörg; Maschmeyer, Georg; van Lessen, Antje; Dörken, Bernd; Pezzutto, Antonio

    2005-10-01

    The aim of our study was to evaluate CD52 as a target molecule for antibody therapy for multiple myeloma. Twenty consecutive bone marrow samples from myeloma patients were studied by flow cytometry using antibodies against CD45, CD38, CD138, CD3, CD19, and CD52. Most myeloma cells did not express CD52; CD52 expression was found only in a small subpopulation of plasma cells with a CD45+CD38++ phenotype. In contrast, the major fraction of myeloma cells (CD45-CD38++) was CD52-. Treatment of myeloma patients with anti-CD52 antibodies with the aim to reduce the number of myeloma cells in the CD45+CD38++ subfraction, which possibly contains a proliferative progenitor cell pool, would be at best a highly experimental approach. We conclude that CD52 is not a promising target for antibody-based therapies for most patients with multiple myeloma.

  13. Incidence of multiple myeloma in Olmsted County, Minnesota: Trend over 6 decades.

    PubMed

    Kyle, Robert A; Therneau, Terry M; Rajkumar, S Vincent; Larson, Dirk R; Plevak, Matthew F; Melton, L Joseph

    2004-12-01

    Previous studies have indicated that the incidence and mortality rates for multiple myeloma have increased in the United States. The authors reported on the incidence of multiple myeloma in Olmsted County, Minnesota, between 1991 and 2001 and on trends in multiple myeloma incidence over the last 56 years. Using the files of the Mayo Clinic and the Olmsted Medical Center (Rochester, MN), the authors identified all residents of Olmsted County who had multiple myeloma, suspected myeloma, or a related disorder. Reports of all laboratory determinations, in addition to autopsy findings and death certificates, were obtained. The criteria for the diagnosis of multiple myeloma have not changed during the last 6 decades. All but 1 of the 47 residents with multiple myeloma first diagnosed between 1991 and 2001 were recognized antemortem. Fifty-five percent had a previous monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma before multiple myeloma was diagnosed. From 1991 to 2001, the overall annual incidence rate, age-adjusted to the 2000 U.S. population, was 4.3 per 100,000 (95% confidence interval, 3.0-5.5 per 100,000). Poisson regression analysis showed no statistically significant trend in Olmsted County incidence rates over 56 years. In similar fashion, the authors adjusted multiple myeloma incidence rates from nine other studies worldwide for which adequate data were available and documented similar findings in each case, except for one study that included patients with smoldering multiple myeloma. The overall incidence of multiple myeloma in Olmsted County, Minnesota, has not changed in almost 6 decades. The apparent increase in incidence elsewhere is unexplained but probably is attributable to improvements in diagnostic techniques, particularly in older patients. (c) 2004 American Cancer Society

  14. Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease

    PubMed Central

    Garcia-Gomez, Antonio; Las Rivas, Javier De; Ocio, Enrique M.; Díaz-Rodríguez, Elena; Montero, Juan C.; Martín, Montserrat; Blanco, Juan F.; Sanchez-Guijo, Fermín M.; Pandiella, Atanasio; San Miguel, Jesús F.; Garayoa, Mercedes

    2014-01-01

    Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease. PMID:25268740

  15. Monitoring multiple myeloma by next-generation sequencing of V(D)J rearrangements from circulating myeloma cells and cell-free myeloma DNA.

    PubMed

    Oberle, Anna; Brandt, Anna; Voigtlaender, Minna; Thiele, Benjamin; Radloff, Janina; Schulenkorf, Anita; Alawi, Malik; Akyüz, Nuray; März, Manuela; Ford, Christopher T; Krohn-Grimberghe, Artus; Binder, Mascha

    2017-02-09

    Recent studies suggest that circulating tumor cells and cell-free DNA may represent powerful non-invasive tools for disease monitoring in patients with solid and hematological malignancies. Here, we conducted a pilot study in 27 myeloma patients to explore the clonotypic V(D)J rearrangement for monitoring of circulating myeloma cells (cmc-V(D)J) and cell-free myeloma DNA (cfm-V(D)J). Next-generation sequencing was used to define the myeloma V(D)J rearrangement and for subsequent peripheral blood tracking after treatment initiation. Positivity for cmc-/cfm-V(D)J was associated with conventional remission status (p<0.001) and 91% of non-responders/progressors versus 41% of responders had evidence of persistent cmc-/cfm-V(D)J (p<0.001). About half of the partial responders showed complete clearance of cmc-/cfm-V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover and therefore decline more rapidly after initiation of effective treatment. Positivity for cmc- and cfm-V(D)J was associated with each other (p=0.042), but in 30% discordant. This indicated that cfm-V(D)J may not be generated entirely by circulating myeloma cells and may reflect overall tumor burden. Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma.

  16. Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease.

    PubMed

    Garcia-Gomez, Antonio; De Las Rivas, Javier; Ocio, Enrique M; Díaz-Rodríguez, Elena; Montero, Juan C; Martín, Montserrat; Blanco, Juan F; Sanchez-Guijo, Fermín M; Pandiella, Atanasio; San Miguel, Jesús F; Garayoa, Mercedes

    2014-09-30

    Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease.

  17. Occupation, pesticide exposure and risk of multiple myeloma.

    PubMed

    Baris, Dalsu; Silverman, Debra T; Brown, Linda Morris; Swanson, G Marie; Hayes, Richard B; Schwartz, Ann G; Liff, Jonathan M; Schoenberg, Janet B; Pottern, Linda M; Greenberg, Raymond S; Stewart, Patricia A

    2004-06-01

    This population-based case-control study examined the relationship between occupation, living or working on a farm, pesticide exposure, and the risk of multiple myeloma. The study included 573 persons newly diagnosed with myeloma and 2131 controls. Information was obtained on sociodemographic factors, occupational history, and history of living and working on a farm. Occupational and industrial titles were coded by standardized classification systems. A job-exposure matrix was developed for occupational pesticide exposure. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression. Farmers and farm workers had odds ratios of 1.9 (95% CI 0.8-4.6) and 1.4 (95% CI 0.8-2.3), respectively. An odds ratio of 1.7 (95% CI 1.0-2.7) was observed for sheep farm residents or workers, whereas no increased risks were found for cattle, beef, pig, or chicken farm residents or workers. A modestly increased risk was observed for pesticides (OR 1.3, 95% CI 0.9-1.8). Significantly increased risks were found for pharmacists, dieticians and therapists (OR 6.1, 95% CI 1.7-22.5), service occupations (OR 1.3, 95% CI 1.02-1.7), roofers (OR 3.3, 95% CI 1.1-9.8), precision printing occupations (OR 10.1, 95% CI 1.03-99.8), heating equipment operators (OR 4.7, 95% CI 1.4-15.8), and hand molders and casters (OR 3.0, 95% CI 1.0-8.4). A modest increased risk of multiple myeloma is suggested for occupational pesticide exposure. The increased risk for sheep farm residents or workers indicates that certain animal viruses may be involved in myeloma risk.

  18. Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients.

    PubMed

    Rettig, M B; Ma, H J; Vescio, R A; Põld, M; Schiller, G; Belson, D; Savage, A; Nishikubo, C; Wu, C; Fraser, J; Said, J W; Berenson, J R

    1997-06-20

    Kaposi's sarcoma-associated herpesvirus (KSHV) was found in the bone marrow dendritic cells of multiple myeloma patients but not in malignant plasma cells or bone marrow dendritic cells from normal individuals or patients with other malignancies. In addition the virus was detected in the bone marrow dendritic cells from two out of eight patients with monoclonal gammopathy of undetermined significance (MGUS), a precursor to myeloma. Viral interleukin-6, the human homolog of which is a growth factor for myeloma, was found to be transcribed in the myeloma bone marrow dendritic cells. KSHV may be required for transformation from MGUS to myeloma and perpetuate the growth of malignant plasma cells.

  19. 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

  20. Dynamic interplay between bone and multiple myeloma: emerging roles of the osteoblast.

    PubMed

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

    2015-06-01

    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.

  1. Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells.

    PubMed

    Das, Deepika Sharma; Das, Abhishek; Ray, Arghya; Song, Yan; Samur, Mehmet Kemal; Munshi, Nikhil C; Chauhan, Dharminder; Anderson, Kenneth C

    2017-08-01

    Purpose: The ubiquitin proteasome pathway is a validated therapeutic target in multiple myeloma. Deubiquitylating enzyme USP1 participates in DNA damage response and cellular differentiation pathways. To date, the role of USP1 in multiple myeloma biology is not defined. In the present study, we investigated the functional significance of USP1 in multiple myeloma using genetic and biochemical approaches.Experimental Design: To investigate the role of USP1 in myeloma, we utilized USP1 inhibitor SJB3-019A (SJB) for studies in myeloma cell lines and patient multiple myeloma cells.Results: USP1-siRNA knockdown decreases multiple myeloma cell viability. USP1 inhibitor SJB selectively blocks USP1 enzymatic activity without blocking other DUBs. SJB also decreases the viability of multiple myeloma cell lines and patient tumor cells, inhibits bone marrow plasmacytoid dendritic cell-induced multiple myeloma cell growth, and overcomes bortezomib resistance. SJB triggers apoptosis in multiple myeloma cells via activation of caspase-3, caspase-8, and caspase-9. Moreover, SJB degrades USP1 and downstream inhibitor of DNA-binding proteins as well as inhibits DNA repair via blockade of Fanconi anemia pathway and homologous recombination. SJB also downregulates multiple myeloma stem cell renewal/survival-associated proteins Notch-1, Notch-2, SOX-4, and SOX-2. Moreover, SJB induced generation of more mature and differentiated plasma cells. Combination of SJB and HDACi ACY-1215, bortezomib, lenalidomide, or pomalidomide triggers synergistic cytotoxicity.Conclusions: Our preclinical studies provide the framework for clinical evaluation of USP1 inhibitors, alone or in combination, as a potential novel multiple myeloma therapy. Clin Cancer Res; 23(15); 4280-9. ©2017 AACR. ©2017 American Association for Cancer Research.

  2. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma.

    PubMed

    Zhu, Yuan Xiao; Kortuem, K Martin; Stewart, A Keith

    2013-04-01

    Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance.

  3. Patients With Multiple Myeloma Have More Complications After Surgical Treatment of Hip Fracture

    PubMed Central

    Park, Kwan Jun; Menendez, Mariano E.; Mears, Simon C.

    2016-01-01

    Objectives: Bone lesions from multiple myeloma may lead to pathological fracture of the proximal femur, requiring either fixation or arthroplasty. Little is known about the impact of multiple myeloma on hip fracture care. We investigated whether the patients with multiple myeloma undergoing surgical treatment of hip fractures would be at increased risk for adverse outcomes versus patients who sustain a hip fracture without multiple myeloma. Methods: Using discharge records from the Nationwide Inpatient Sample (2002-2011), we identified 2 440 513 patients older than 50 years of age with surgically treated hip fractures. Of which, 4011 (0.2%) were found to have multiple myeloma. We compared perioperative outcomes between the patients with multiple myeloma and the nonmultiple myeloma patients using multivariable logistic regression modeling. Results: Patients with multiple myeloma were more likely to have several postoperative complications, such as in-hospital pneumonia (odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.14-1.51), sepsis (OR: 1.72, 95% CI: 1.32-2.25), surgical site infection (OR: 1.66, 95% CI: 1.38-2.00), and acute renal failure (OR: 1.28, 95% CI: 1.14-1.43). We found that myeloma was not associated with increased inpatient mortality, myocardial infarction, respiratory failure, thromboembolic events, or pulmonary embolism. Conclusion: Patients with multiple myeloma are at increased risk for immediate postoperative complications following surgical treatment of hip fractures including in-hospital pneumonia, surgical site infection, and acute renal failure but not hospital mortality, when compared to hip fracture patients without multiple myeloma. Perioperative management of hip fractures in patients with myeloma may be optimized by increased awareness of these risks in this subset of patients. PMID:27551575

  4. Recent advances in the mangement of multiple myeloma.

    PubMed

    Kumar, Lalit; Vikram, P; Kochupillai, V

    2006-01-01

    The management of multiple myeloma has undergone a major change during the past decade. Currently, patients < 65 years of age with advanced disease (stage II-III) are best treated with initial chemotherapy (3-4 cycles of vincristine, adriamycin and dexamethasone, or vincristine, adriamycin and methyl prednisolone, or thalidomide and dexamethasone followed by high dose chemotherapy with autologous peripheral blood stem cell transplantation. More than 50% of patients achieve complete response following this approach. The results of a number of nonrandomized and randomized studies indicate that treatment with high dose chemotherapy followed by autologous peripheral blood stem cell transplantation is associated with improved overall and event-free survival compared with conventional chemotherapy. The absence of chromosome 13 abnormalities, serum albumin levels > 3.5 g/dl and low serum b-2 microglobulin are associated with a better outcome. Almost all patients with significant bone disease or osteoporosis are candidates for therapy with bisphosphonates. About one-third of patients with relapsed or refractory myeloma benefit from therapy with thalidomide or bortezomib (a proteosome inhibitor). Recent work in the immunotherapy of myeloma suggests that some novel immune-based approaches might be useful in the management. The application of cytogenetics and molecular genetics, especially gene expression profiling, are likely to be areas of active research in future studies.

  5. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma.

    PubMed

    Lin, Pei; Owens, Rebecca; Tricot, Guido; Wilson, Carla S

    2004-04-01

    Bone marrow aspirates from 306 patients with multiple myeloma were analyzed by flow cytometric immunophenotyping. The plasma cells (PCs) were identified by their characteristic light scatter distribution and reactivity patterns to CD138, CD38, and CD45. Monoclonality was confirmed by immunoglobulin light chain analysis. The immunophenotypic profile of the PCs was determined with a panel of antibodies. Moderate to bright expression of CD56, CD117, CD20, CD45, and CD52 was detected in 71.7%, 17.8%, 9.3%, 8.8%, and 5.2% of cases, respectively. These antigens were expressed by a distinct subpopulation of the PCs in 6.3%, 2.2%, 3.7%, 2.9%, and 2.6% of additional cases. CD19 was negative in more than 99% of cases. The combination of CD38 and CD138 was superior to CD38 alone for identifying CD45+ myeloma and separating CD20+ myeloma from B-cell lymphoma. PC immunophenotyping might be useful for detecting minimal residual disease in cases with aberrant antigen expression and for selection of therapeutic agents that have specific membrane targets.

  6. Impact of pomalidomide therapy in multiple myeloma: a recent survey.

    PubMed

    Kumar, Arvind; Porwal, Mayur; Verma, Ankita; Mishra, Arun K

    2014-12-01

    Pomalidomide (Pomalyst(®)) is a synthetic compound derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects and third drug in the class of immunomodulatory drugs. Pomalidomide is under global development with Celgene Corporation, was approved by the U.S. Food and Drug Administration on February 8, 2013 to treat patients with relapsed and refractory multiple myeloma (MM) who have received at least two prior therapies including bortezomib and lenalidomide. In October 2009, it has found orphan designation for the treatment of relapsed and refractory MM by the EMA, and on August 2013, marketing authorization has issued in Europe by gaining a positive response. It inhibits myeloma cell growth and angiogenesis directly. Pomalidomide is the latest myeloma cell growth inhibitor to be approved in both USA and EU. The predominant side effects are thrombocytopenia, neuropathy, and deep vein thrombosis. Pomalidomide is also being investigated in patients with amyloidosis, prostate cancer, small cell lung cancer, pancreatic cancer, graft-versus-host disease, and Waldenstrom's macroglobulinemia. This article reviews the available information on pomalidomide with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, pre-clinical studies, and clinical trials.

  7. Chimeric Antigen Receptor T-cell Therapies for Multiple Myeloma.

    PubMed

    Mikkilineni, Lekha; Kochenderfer, James N

    2017-09-19

    Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T-cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR T-cells against leukemia and lymphoma has encouraged development of CAR T-cell therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells. CAR T-cells targeting B-cell maturation antigen have demonstrated significant anti-myeloma activity in early clinical trials. Toxicities in these trials, including cytokine-release syndrome, have been similarto toxicities observed in CAR T-cell trials for leukemia. Targeting postulated CD19(+) myeloma stem cells with anti-CD19 CAR T-cells is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte-activating molecule 7 (SLAMF7), and kappa light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of more than one antigen might often be required for effective treatment of MM with CAR T cells. Integration of CAR T cells with other myeloma therapies is an important area of future research. CAR T cell therapies for MM are at an early stage of development but have great promise to improve MM treatment. Copyright © 2017 American Society of Hematology.

  8. [Immunophenotype in multiple myeloma cells detected by multiparameter flow cytometry].

    PubMed

    Cao, Fang-Fang; Chen, Fang; Hu, Yan-Ping; Zhang, Ji-Hong

    2012-06-01

    This study was purposed to investigate the immunophenotypic characteristics in multiple myeloma (MM) cells and their significance. Thirty three cases of MM and 12 cases of reactive plasmacytosis (as control group) were enrolled in the study. The expressions of surface antigens in MM cells were detected with flow cytometry by using direct immunofluorescent technique and gating method of CD38/SSC and were confirmed with morphologic observation of myeloma cells. The results indicated that the proportion of myeloma cells detected by morphologic examination was 6.0% - 76.0%. With CD38/SSC gating method, a cluster of CD38 bright positive cells could be detected in their scatter plot, the proportion ranged from 0.99% to 57.54%. Most phenotype of MM was 38(st+)CD138(+)CD19(-)CD56(+) (78.8%). While the expressions of CD20, CD33, CD117, HLA-DR were seen in some MM patients, the positive rates were 12.1%, 15.2%, 30.3%, 9.1%, respectively; the expression of other antigens was negative. cκ or cλ monoclonal restriction was detected in 27 cases (81.8%) of MM, both cκ and cλ in the remaining cases of MM was negative. It is concluded that detecting the immunophenotype of MM patients by flow cytometry with CD38/SSC gating method and basing on the heterogeneity of cell antigens can discriminate myeloma cells from normal plasma cells, which provides evidence for targeted therapy and prognosis evaluation.

  9. Stem cell marker nestin is expressed in plasma cells of multiple myeloma patients.

    PubMed

    Svachova, H; Pour, L; Sana, J; Kovarova, L; Raja, K R Muthu; Hajek, R

    2011-08-01

    Nestin is considered to be a characteristic marker of multipotent proliferative precursors found in some embryonic and fetal tissues. Its expression might be a suitable diagnostic and prognostic indicator of malignancy and a potential marker of cancer stem cells in solid tumors. Unexpectedly, nestin protein was detected in mature CD138(+)CD38(+) plasma cells of multiple myeloma patients and statistical analysis confirmed significant differences between myeloma patients and control group without hematological malignancy. Our results represent the first evidence of nestin expression in multiple myeloma. Further studies are required to elucidate the role of this protein in multiple myeloma. Copyright © 2011 Elsevier Ltd. All rights reserved.

  10. New insights into role of microenvironment in multiple myeloma.

    PubMed

    Tricot, Guido J

    2002-08-01

    Multiple Myeloma (MM) is a malignant disease of terminally differentiated B cells. It most likely originates in a B cell which has traversed the germinal center and has been exposed there extensively to antigens based on the high number of somatic mutations in the complementarity determining regions. The cell of origin is either a plasmablast, or more likely, a memory B-cell. Typically MM goes through different phases from indolent (MGUS, smoldering myeloma) to overt myeloma and then to a fulminant phase, characterized by extramedullary manifestations, high LDH, immature morphology and increased proliferation rate. In the indolent phase, the disease already has acquired major cytogenetic abnormalities as demonstrated by FISH and DNA flow cytometry. It has a gene pattern very similar to myeloma cells on gene array analysis. In the early stages of overt MM, the myeloma cells are completely dependent upon the micro-environment for their growth and survival. The interaction between myeloma cells and micro-environment causes bone disease, genetic instability and more importantly, drug-resistance, which is caused by upregulation of anti-apoptotic factors, resistance to apoptosis induced by FAS and TRAIL activation, and by cell adhesion-induced growth arrest. In this phase of the disease, MM is susceptible to chemotherapy, if delivered with adequate intensity. In the fulminant phase of MM, myeloma cells have acquired sufficient genetic alternations to become completely independent of the micro-environment which allows them to grow at extramedullary sites. Because of the many DNA breaks necessary for immature B cells to become mature plasma cells, B cells already have inherent genetic instability. DNA breaks are necessary for VDJ recombinations, somatic mutations and isotype switching and it is therefore not surprising that genetic alternations frequently occur at the Ig heavy chain site at 14q32, which is abnormal in three quarters of myeloma patients. Some of the

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

    PubMed Central

    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

  12. Renal status of multiple myeloma patients in ibadan, Nigeria.

    PubMed

    Fasola, F A; Eteng, K I I; Shokunbi, W A; Akinyemi, J O; Salako, B L

    2012-12-01

    The spectrum of clinical manifestation in multiple myeloma (MM) ranges from asymptomatic disease to severely debilitative state. Unexplained renal disease is an indication for the investigation of patients for MM. This study is a retrospective analysis of the renal profile of patients with multiple myeloma in relation to management strategy in our institution. Medical records of 64 patients with multiple myeloma seen between 2000 and 2008 were retrospectively reviewed at an 850-bed tertiary hospital in South-Western Nigeria. The Mahn-Whitney test was used to compare laboratory features between patient with renal failure and those without renal failure. Subjects with serum creatinine ≥2mg/dL were regarded to have renal failure. Overall survival was calculated from diagnosis to death or lost to follow-up. A total of forty three patients were eligible. The renal status was categorized into three according to serum creatinine level; those with normal serum creatinine level (0.5-1.5mg/dl) were 26 (60.5%), serum creatinine level (>1.6-1.9mg/dl), and creatinine level ≥2mg/ dl were 3(7%) and 14(32.5%) respectively. Hyperuricaemia was observed in 6(42.9%) of MM patients with renal failure compared with 7(26.9%) of patient without renal failure (p<0.05). Twenty-one percent of those with renal failure had hypercalceamia. Thirty-six percent of the renal failure patients had haemodialysis. The average survival for all patients with renal failure was 18 months after diagnosis. The outcome in patients with renal failure remained poor with early mortality despite supportive management. Hyperuricaemia and dehydration, given the hot climate might have worked in concert with other factors to worsen the renal status in these patients.

  13. RENAL STATUS OF MULTIPLE MYELOMA PATIENTS IN IBADAN, NIGERIA

    PubMed Central

    Fasola, F.A; Eteng, K.I.I; Shokunbi, W.A; Akinyemi, J.O; Salako, B.L

    2012-01-01

    Introduction: The spectrum of clinical manifestation in multiple myeloma (MM) ranges from asymptomatic disease to severely debilitative state. Unexplained renal disease is an indication for the investigation of patients for MM. This study is a retrospective analysis of the renal profile of patients with multiple myeloma in relation to management strategy in our institution. Methods: Medical records of 64 patients with multiple myeloma seen between 2000 and 2008 were retrospectively reviewed at an 850–bed tertiary hospital in South-Western Nigeria. The Mahn-Whitney test was used to compare laboratory features between patient with renal failure and those without renal failure. Subjects with serum creatinine ≥2mg/dL were regarded to have renal failure. Overall survival was calculated from diagnosis to death or lost to follow-up Results: A total of forty three patients were eligible. The renal status was categorized into three according to serum creatinine level; those with normal serum creatinine level (0.5-1.5mg/dl) were 26 (60.5%), serum creatinine level (>1.6-1.9mg/dl), and creatinine level ≥2mg/ dl were 3(7%) and 14(32.5%) respectively. Hyperuricaemia was observed in 6(42.9%) of MM patients with renal failure compared with 7(26.9%) of patient without renal failure (p<0.05). Twenty–one percent of those with renal failure had hypercalceamia. Thirty–six percent of the renal failure patients had haemodialysis. The average survival for all patients with renal failure was 18 months after diagnosis. Conclusion: The outcome in patients with renal failure remained poor with early mortality despite supportive management. Hyperuricaemia and dehydration, given the hot climate might have worked in concert with other factors to worsen the renal status in these patients. PMID:25161410

  14. Treatment for patients with newly diagnosed multiple myeloma in 2015.

    PubMed

    Mateos, María-Victoria; Ocio, Enrique M; Paiva, Bruno; Rosiñol, Laura; Martínez-López, Joaquín; Bladé, Joan; Lahuerta, Juan-José; García-Sanz, Ramón; San Miguel, Jesús F

    2015-11-01

    Multiple myeloma is the second most frequent haematological disease. The introduction of high-dose melphalan followed by autologous haematopoietic cell transplant (HDT/ASCT) for young patients and the availability of novel agents for young and elderly patients with multiple myeloma have dramatically changed the perspective of treatment. However, further research is necessary if we want to definitively cure the disease. Treatment goals for transplant-eligible and non-transplant-eligible patients should be to prolong survival by achieving the best possible response, while ensuring quality of life. The treatment should be individualized on the basis of host and disease features and better monitoring of the response upon use of high-sensitivity techniques for evaluating residual disease. For young patients, HDT/ASCT is a standard of care for treatment and its efficacy has been enhanced and challenged by the new drugs. For elderly patients, treatment options were limited to alkylators, but new upfront treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) combined or not with alkylators have significantly improved outcomes.Extended treatment for young and elderly patients improves the quality and duration of clinical responses; however,the optimal scheme, appropriate doses and duration of long-term therapy have not yet been fully determined.This review summarises the progress in the treatment of patients with newly diagnosed multiple myeloma, addressing critical questions such as the optimal induction, early versus late ASCT, consolidation and/or maintenance for young patients, and how we can choose the best option for non-transplant-eligible patients.

  15. 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.

  16. 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.

  17. 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

  18. The Evolution of Prognostic Factors in Multiple Myeloma

    PubMed Central

    Hassanein, Mona; Rasheed, Walid; Aljurf, Mahmoud; Alsharif, Fahad

    2017-01-01

    Multiple myeloma (MM) is a heterogeneous hematologic malignancy involving the proliferation of plasma cells derived by different genetic events contributing to the development, progression, and prognosis of this disease. Despite improvement in treatment strategies of MM over the last decade, the disease remains incurable. All efforts are currently focused on understanding the prognostic markers of the disease hoping to incorporate the new therapeutic modalities to convert the disease into curable one. We present this comprehensive review to summarize the current standard prognostic markers used in MM along with novel techniques that are still in development and highlight their implications in current clinical practice. PMID:28321258

  19. Bortezomib-induced painful neuropathy in patients with multiple myeloma

    PubMed Central

    Usnarska-Zubkiewicz, Lidia; Pokryszko-Dragan, Anna

    2013-01-01

    Neurotoxicity towards the peripheral nervous system which appears clinically in the form of painful neuropathy is an essential dose-limiting factor during the treatment of multiple myeloma. In this review article different forms of this painful neuropathy are presented together with currently available diagnostic tools which are usually applied to confirm the diagnosis. Also, the most often used neurological scales estimating neurological deficit are presented. Special attention is paid to the management of the reversibility of bortezomib-induced neuropathic pain. PMID:24596530

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

    PubMed

    Kyle, Robert A; San-Miguel, Jesus F; Mateos, Maria-Victoria; Rajkumar, S Vincent

    2014-10-01

    Monoclonal gammopathy of undetermined significance (MGUS) is characterized by an M spike less than 3 g/dL and a bone marrow containing fewer than 10% plasma cells without evidence of CRAB (hypercalcemia, renal insufficiency, anemia, or bone lesions). Light chain MGUS has an abnormal free light chain (FLC) ratio, increased level of the involved FLC, no monoclonal heavy chain, and fewer than 10% monoclonal plasma cells in the bone marrow. Smoldering multiple myeloma has an M protein of at least 3 g/dL and/or at least 10% monoclonal plasma cells in the bone marrow without CRAB features.

  1. Central Neurotoxicity of Immunomodulatory Drugs in Multiple Myeloma

    PubMed Central

    Patel, Urmeel H.; Mir, Muhammad A.; Sivik, Jeffrey K.; Raheja, Divisha; Pandey, Manoj K.; Talamo, Giampaolo

    2015-01-01

    Immunomodulatory drugs (IMiDs) currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient), lenalidomide (4 patients), and pomalidomide (1 patient) was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy. PMID:25852850

  2. 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.

  3. [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. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  4. Extramedullary plasmacytomas in the context of multiple myeloma.

    PubMed

    Aguado, Beatriz; Iñigo, Belen; Sastre, Jose L; Oriol, Albert

    2011-11-01

    Plasmacytoma is a frequent complication of multiple myeloma, either at diagnosis or within disease progression. The extramedullary disease confers a poorer prognosis and is biologically distinct with high-risk molecular and histological features, being resistant to conventional treatments. Radiation therapy remains the most effective treatment for extramedullary lesions to achieve local control. There are very limited data from randomized trials regarding the most appropriate systemic treatment. Case reports such as those presented here, as well as retrospective analysis of series, suggest that lenalidomide is an effective agent, in combination with dexamethasone, in this setting. Additional studies are needed to define the proper management of this condition.

  5. Differential Activities of Thalidomide and Isoprenoid Biosynthetic Pathway Inhibitors in Multiple Myeloma Cells

    PubMed Central

    Holstein, Sarah A.; Tong, Huaxiang; Hohl, Raymond J.

    2013-01-01

    Thalidomide has emerged as an effective agent for treating multiple myeloma, however the precise mechanism of action remains unknown. Agents known to target the isoprenoid biosynthetic pathway (IBP) can have cytotoxic effects in myeloma cells. The interactions between thalidomide and IBP inhibitors in human multiple myeloma cells were evaluated. Enhanced cytotoxicity and induction of apoptosis was observed in RPMI-8226 cells. Examination of intracellular levels of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) revealed a wide variance in basal levels and response to IBP inhibitors. These findings provide a mechanism for the differential sensitivity of myeloma cells to pharmacologic manipulation of the IBP. PMID:19646757

  6. Multiple myeloma patients have a specific serum metabolomic profile that changes after achieving complete remission.

    PubMed

    Puchades-Carrasco, Leonor; Lecumberri, Ramón; Martínez-López, Joaquín; Lahuerta, Juan-José; Mateos, María-Victoria; Prósper, Felipe; San-Miguel, Jesús F; Pineda-Lucena, Antonio

    2013-09-01

    Multiple myeloma remains an incurable disease. New approaches to develop better tools for improving patient prognostication and monitoring treatment efficacy are very much needed. In this study, we aimed to evaluate the potential of metabolomics by (1)H-NMR to provide information on metabolic profiles that could be useful in the management of multiple myeloma. Serum samples were collected from multiple myeloma patients at the time of diagnosis and after achieving complete remission. A matched control set of samples was also included in the study. The (1)H-NMR measurements used to obtain the metabolic profile for each patient were followed by the application of univariate and multivariate statistical analyses to determine significant differences. Metabolic profiles of multiple myeloma patients at diagnosis exhibited higher levels of isoleucine, arginine, acetate, phenylalanine, and tyrosine, and decreased levels of 3-hydroxybutyrate, lysine, glutamine, and some lipids compared with the control set. A similar analysis conducted in multiple myeloma patients after achieving complete remission indicated that some of the metabolic changes (i.e., glutamine, cholesterol, lysine) observed at diagnosis displayed a variation in the opposite direction upon responding to treatment, thus contributing to multiple myeloma patients having a closer metabolic profile to those of healthy individuals after the disappearance of major disease manifestations. The results highlight the potential of metabolic profiles obtained by 1H-NMR in identifying multiple myeloma biomarkers that may be useful to objectively discriminate individuals with and without multiple myeloma, and monitor response to treatment. ©2013 AACR.

  7. Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma.

    PubMed

    Stiff, Andrew; Caserta, Enrico; Sborov, Douglas W; Nuovo, Gerard J; Mo, Xiaokui; Schlotter, Sarah Y; Canella, Alessandro; Smith, Emily; Badway, Joseph; Old, Matthew; Jaime-Ramirez, Alena Cristina; Yan, Pearlly; Benson, Don M; Byrd, John C; Baiocchi, Robert; Kaur, Balveen; Hofmeister, Craig C; Pichiorri, Flavia

    2016-05-01

    Multiple myeloma remains incurable and the majority of patients die within 5 years of diagnosis. Reolysin, the infusible form of human reovirus (RV), is a novel viral oncolytic therapy associated with antitumor activity likely resulting from direct oncolysis and a virus-mediated antitumor immune response. Results from our phase I clinical trial investigating single agent Reolysin in patients with relapsed multiple myeloma confirmed tolerability, but no objective responses were evident, likely because the virus selectively entered the multiple myeloma cells but did not actively replicate. To date, the precise mechanisms underlying the RV infectious life cycle and its ability to induce oncolysis in patients with multiple myeloma remain unknown. Here, we report that junctional adhesion molecule 1 (JAM-1), the cellular receptor for RV, is epigenetically regulated in multiple myeloma cells. Treatment of multiple myeloma cells with clinically relevant histone deacetylase inhibitors (HDACi) results in increased JAM-1 expression as well as increased histone acetylation and RNA polymerase II recruitment to its promoter. Furthermore, our data indicate that the combination of Reolysin with HDACi, potentiates RV killing activity of multiple myeloma cells in vitro and in vivo This study provides the molecular basis to use these agents as therapeutic tools to increase the efficacy of RV therapy in multiple myeloma. Mol Cancer Ther; 15(5); 830-41. ©2016 AACR. ©2016 American Association for Cancer Research.

  8. EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes.

    PubMed

    Hernando, Henar; Gelato, Kathy A; Lesche, Ralf; Beckmann, Georg; Koehr, Silke; Otto, Saskia; Steigemann, Patrick; Stresemann, Carlo

    2016-02-01

    Multiple myeloma is a plasma cell malignancy characterized by marked heterogeneous genomic instability including frequent genetic alterations in epigenetic enzymes. In particular, the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in multiple myeloma. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a master transcriptional regulator of differentiation. EZH2 catalyzes methylation of lysine 27 on histone H3 and its deregulation in cancer has been reported to contribute to silencing of tumor suppressor genes, resulting in a more undifferentiated state, and thereby contributing to the multiple myeloma phenotype. In this study, we propose the use of EZH2 inhibitors as a new therapeutic approach for the treatment of multiple myeloma. We demonstrate that EZH2 inhibition causes a global reduction of H3K27me3 in multiple myeloma cells, promoting reexpression of EZH2-repressed tumor suppressor genes in a subset of cell lines. As a result of this transcriptional activation, multiple myeloma cells treated with EZH2 inhibitors become more adherent and less proliferative compared with untreated cells. The antitumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together, our data suggest that EZH2 inhibition may provide a new therapy for multiple myeloma treatment and a promising addition to current treatment options. Mol Cancer Ther; 15(2); 287-98. ©2015 AACR.

  9. Thalidomide thromboprophylaxis in multiple myeloma: a review of current evidence.

    PubMed

    Alexander, Marliese; Kirsa, Sue; Mellor, James D

    2012-12-01

    Currently multiple antithrombotic agents are used for thalidomide thromboprophylaxis in multiple myeloma patients. Agents used include low-dose aspirin, fixed low-dose and therapeutic warfarin and prophylactic low molecular weight heparin. To evaluate the evidence for the efficacy and safety of aspirin, warfarin and low molecular weight heparin thromboprophylaxis in multiple myeloma patients on thalidomide a literature search was conducted in May and June 2011. Databases searched included the Cochrane Database of Systemic Reviews and the Database of Abstracts of Reviews of Effects, Evidence Based Medicine Reviews and Ovid MEDLINE. The search was restricted to English language articles and limited to articles published from 2005 to 2011. Most studies consisted of small prospective cohort studies not originally designed to assess thromboprophylaxis as an outcome. A single comparative randomized trial, several retrospective review articles, two meta-analyses and two clinical practice guidelines were also identified. Current evidence fails to demonstrate a clear advantage of any particular thromboprophylaxis strategy. Results from the only prospective comparative randomized trial found no significant differences among aspirin, warfarin and low molecular weight heparin. More studies are required that consider not only efficacy and safety, but also costs, lifestyle burden and patient preference. © 2012 Wiley Publishing Asia Pty Ltd.

  10. The impact of comorbidity on mortality in multiple myeloma: a Danish nationwide population-based study.

    PubMed

    Gregersen, Henrik; Vangsted, Annette Juul; Abildgaard, Niels; Andersen, Niels Frost; Pedersen, Robert Schou; Frølund, Ulf Christian; Helleberg, Carsten; Broch, Bettina; Pedersen, Per Trøllund; Gimsing, Peter; Klausen, Tobias Wirenfeldt

    2017-07-01

    To describe the prevalence of comorbidity and its impact on survival in newly diagnosed multiple myeloma patients compared with population controls. Cases of newly diagnosed symptomatic multiple myeloma during the 2005-2012 period were identified in the Danish National Multiple Myeloma Registry. For each myeloma patient, 10 members of the general population matched by age and sex were chosen from the national Civil Registration System. Data on comorbidity in the myeloma patients and the general population comparison cohort were collected by linkage to the Danish National Patient Registry (DNPR). Cox proportional hazards regression models were used to evaluate the prognostic significance of comorbidity. The study included 2190 cases of multiple myeloma and 21,900 population controls. The comorbidity was increased in multiple myeloma patients compared with population controls, odds ratio (OR) 1.4 (1.1-1.7). The registration of comorbidity was highly increased within the year preceding diagnosis of multiple myeloma (OR 3.0 [2.5-3.5]), which was attributable to an increased registration of various diseases, in particular, renal disease with OR 11.0 (8.1-14.9). The median follow-up time from diagnosis of multiple myeloma for patients alive was 4.3 years (interquartile range 2.4-6.3). Patients with registered comorbidity had increased mortality compared with patients without comorbidity, hazard ratio 1.6 (1.5-1.8). Multiple myeloma patients have increased comorbidity compared with the background population, in particular during the year preceding the diagnosis of myeloma. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  11. Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma.

    PubMed

    Atanackovic, Djordje; Panse, Jens; Hildebrandt, York; Jadczak, Adam; Kobold, Sebastian; Cao, Yanran; Templin, Julia; Meyer, Sabrina; Reinhard, Henrike; Bartels, Katrin; Lajmi, Nesrine; Zander, Axel R; Marx, Andreas H; Bokemeyer, Carsten; Kröger, Nicolaus

    2011-10-01

    To date, multiple myeloma remains an incurable malignancy due to the persistence of minimal residual disease in the bone marrow. In this setting, monoclonal antibodies against myeloma-specific cell surface antigens represent a promising therapeutic approach, which is however hampered by a lack of appropriate target structures expressed across all pathogenic myeloma cell populations. We, therefore, investigated functionally relevant immunoreceptors specifically associated with myeloma cells as well as their clonogenic precursors. Potential target proteins were identified using antibody arrays against phosphorylated immunoreceptors with lysates from myeloma cell lines. CD229 expression was confirmed in primary myeloma cells by reverse transcriptase polymerase chain reaction, western blot, fluorescence-activated cell sorting, and immunohistochemistry. Apoptosis, clonogenic growth, and sensitivity to chemotherapy were determined following short-interfering RNA-mediated downregulation of CD229. Antibody-dependent cellular and complement-dependent cytotoxicity were analyzed using a monoclonal antibody against CD229 to demonstrate the antigen's immunotherapeutic potential. Our screening assay identified CD229 as the most strongly over-expressed/phosphorylated immunoreceptor in myeloma cell lines. Over-expression was further demonstrated in the CD138-negative population, which has been suggested to represent myeloma precursors, as well as on primary tumor cells from myeloma patients. Accordingly, CD229 staining of patients' bone marrow samples enabled the identification of myeloma cells by flow cytometry and immunohistochemistry. Down-regulation of CD229 led to a decreased number of viable myeloma cells and clonal myeloma colonies, and enhanced the anti-tumor activity of conventional chemotherapeutics. Targeting CD229 with a monoclonal antibody resulted in complement- and cell-mediated lysis of myeloma cells. Our results demonstrate that the immunoreceptor CD229 is

  12. Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

    PubMed Central

    Atanackovic, Djordje; Panse, Jens; Hildebrandt, York; Jadczak, Adam; Kobold, Sebastian; Cao, Yanran; Templin, Julia; Meyer, Sabrina; Reinhard, Henrike; Bartels, Katrin; Lajmi, Nesrine; Zander, Axel R.; Marx, Andreas H.; Bokemeyer, Carsten; Kröger, Nicolaus

    2011-01-01

    Background To date, multiple myeloma remains an incurable malignancy due to the persistence of minimal residual disease in the bone marrow. In this setting, monoclonal antibodies against myeloma-specific cell surface antigens represent a promising therapeutic approach, which is however hampered by a lack of appropriate target structures expressed across all pathogenic myeloma cell populations. We, therefore, investigated functionally relevant immunoreceptors specifically associated with myeloma cells as well as their clonogenic precursors. Design and Methods Potential target proteins were identified using antibody arrays against phosphorylated immunoreceptors with lysates from myeloma cell lines. CD229 expression was confirmed in primary myeloma cells by reverse transcriptase polymerase chain reaction, western blot, fluorescence-activated cell sorting, and immunohistochemistry. Apoptosis, clonogenic growth, and sensitivity to chemotherapy were determined following short-interfering RNA-mediated downregulation of CD229. Antibody-dependent cellular and complement-dependent cytotoxicity were analyzed using a monoclonal antibody against CD229 to demonstrate the antigen’s immunotherapeutic potential. Results Our screening assay identified CD229 as the most strongly over-expressed/phosphorylated immunoreceptor in myeloma cell lines. Over-expression was further demonstrated in the CD138-negative population, which has been suggested to represent myeloma precursors, as well as on primary tumor cells from myeloma patients. Accordingly, CD229 staining of patients’ bone marrow samples enabled the identification of myeloma cells by flow cytometry and immunohistochemistry. Down-regulation of CD229 led to a decreased number of viable myeloma cells and clonal myeloma colonies, and enhanced the anti-tumor activity of conventional chemotherapeutics. Targeting CD229 with a monoclonal antibody resulted in complement- and cell-mediated lysis of myeloma cells. Conclusions Our

  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. Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication.

    PubMed

    An, Gang; Acharya, Chirag; Feng, Xiaoyan; Wen, Kenneth; Zhong, Mike; Zhang, Li; Munshi, Nikhil C; Qiu, Lugui; Tai, Yu-Tzu; Anderson, Kenneth C

    2016-09-22

    The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesions in patients with multiple myeloma (MM). Mechanisms remain elusive as to whether myeloma-supporting OCs also induce suppressive immune bone marrow (BM) microenvironment. Here, we first show that OCs significantly protect MM cells against T-cell-mediated cytotoxicity via direct inhibition of proliferating CD4(+) and CD8(+) T cells. The immune checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), and CD200, as well as T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), and CD38 are significantly upregulated during osteoclastogenesis. Importantly, the levels of these molecules, except CD38, are higher in OCs than in MM cells. Anti-PD-L1 monoclonal antibody (mAb) and IDO inhibitor partly overcome OC-inhibited T-cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells. In addition, Galectin-9 and a proliferation-induced ligand (APRIL), secreted by OCs, are significantly upregulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells. APRIL induces PD-L1 expression in MM cells, providing additional immune inhibition by OCs. Moreover, CD38 is significantly upregulated during osteoclastogenesis. When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO. Taken together, these results define the expression of multiple immune proteins and cytokines in OCs essential for suppressive MM BM milieu. These results further support the combination of targeting these molecules to improve anti-MM immunity. © 2016 by The American Society of Hematology.

  15. Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

    PubMed Central

    An, Gang; Acharya, Chirag; Feng, Xiaoyan; Wen, Kenneth; Zhong, Mike; Zhang, Li; Munshi, Nikhil C.; Qiu, Lugui; Tai, Yu-Tzu

    2016-01-01

    The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesions in patients with multiple myeloma (MM). Mechanisms remain elusive as to whether myeloma-supporting OCs also induce suppressive immune bone marrow (BM) microenvironment. Here, we first show that OCs significantly protect MM cells against T-cell–mediated cytotoxicity via direct inhibition of proliferating CD4+ and CD8+ T cells. The immune checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), and CD200, as well as T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), and CD38 are significantly upregulated during osteoclastogenesis. Importantly, the levels of these molecules, except CD38, are higher in OCs than in MM cells. Anti–PD-L1 monoclonal antibody (mAb) and IDO inhibitor partly overcome OC-inhibited T-cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells. In addition, Galectin-9 and a proliferation-induced ligand (APRIL), secreted by OCs, are significantly upregulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells. APRIL induces PD-L1 expression in MM cells, providing additional immune inhibition by OCs. Moreover, CD38 is significantly upregulated during osteoclastogenesis. When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO. Taken together, these results define the expression of multiple immune proteins and cytokines in OCs essential for suppressive MM BM milieu. These results further support the combination of targeting these molecules to improve anti-MM immunity. PMID:27418644

  16. Monoclonal antibody therapy in multiple myeloma: where do we stand and where are we going?

    PubMed

    Thanendrarajan, Sharmilan; Davies, Faith E; Morgan, Gareth J; Schinke, Carolina; Mathur, Pankaj; Heuck, Christoph J; Zangari, Maurizio; Epstein, Joshua; Yaccoby, Shmuel; Weinhold, Niels; Barlogie, Bart; van Rhee, Frits

    2016-01-01

    Multiple myeloma is a plasma cell malignancy that is characterized by refractory and relapsing course of disease. Despite the introduction of high-dose chemotherapy in combination with autologous stem cell transplantation and innovative agents such as proteasome inhibitors and immunomodulatory drugs, achieving cure in multiple myeloma is a challenging endeavor. In the last couple of years, enormous advances were made in implementing monoclonal antibody therapy in multiple myeloma. A large number of preclinical and clinical studies have been introduced successfully, demonstrating a safe and efficient administration of monoclonal antibodies in multiple myeloma. In particular, the application of monoclonal antibodies in combination with immunomodulatory drugs, proteasome inhibitors, corticosteroids or conventional chemotherapy seem to be promising and will expand the treatment arsenal for patients with multiple myeloma.

  17. The effects of proteasome inhibitors on bone remodeling in multiple myeloma.

    PubMed

    Zangari, Maurizio; Suva, Larry J

    2016-05-01

    Bone disease is a characteristic feature of multiple myeloma, a malignant plasma cell dyscrasia. In patients with multiple myeloma, the normal process of bone remodeling is dysregulated by aberrant bone marrow plasma cells, resulting in increased bone resorption, prevention of new bone formation, and consequent bone destruction. The ubiquitin-proteasome system, which is hyperactive in patients with multiple myeloma, controls the catabolism of several proteins that regulate bone remodeling. Clinical studies have reported that treatment with the first-in-class proteasome inhibitor bortezomib reduces bone resorption and increases bone formation and bone mineral density in patients with multiple myeloma. Since the introduction of bortezomib in 2003, several next-generation proteasome inhibitors have also been used clinically, including carfilzomib, oprozomib, ixazomib, and delanzomib. This review summarizes the available preclinical and clinical evidence regarding the effect of proteasome inhibitors on bone remodeling in multiple myeloma. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

    PubMed Central

    Shay, Gemma; Tauro, Marilena; Loiodice, Fulvio; Tortorella, Paolo; Sullivan, Daniel M.; Hazlehurst, Lori A.; Lynch, Conor C.

    2017-01-01

    Multiple myeloma is a plasma cell malignancy that homes aberrantly to bone causing extensive skeletal destruction. Despite the development of novel therapeutic agents that have significantly improved overall survival, multiple myeloma remains an incurable disease. Matrix metalloproteinase-2 (MMP-2) is associated with cancer and is significantly overexpressed in the bone marrow of myeloma patients. These data provide rationale for selectively inhibiting MMP-2 activity as a multiple myeloma treatment strategy. Given that MMP-2 is systemically expressed, we used novel “bone-seeking” bisphosphonate based MMP-2 specific inhibitors (BMMPIs) to target the skeletal tissue thereby circumventing potential off-target effects of MMP-2 inhibition outside the bone marrow-tumor microenvironment. Using in vivo models of multiple myeloma (5TGM1, U266), we examined the impact of MMP-2 inhibition on disease progression using BMMPIs. Our data demonstrate that BMMPIs can decrease multiple myeloma burden and protect against cancer-induced osteolysis. Additionally, we have shown that MMP-2 can be specifically inhibited in the multiple myeloma-bone microenvironment, underscoring the feasibility of developing targeted and tissue selective MMP inhibitors. Given the well-tolerated nature of bisphosphonates in humans, we anticipate that BMMPIs could be rapidly translated to the clinical setting for the treatment of multiple myeloma. PMID:28611279

  19. Distinct and shared three‐dimensional chromosome organization patterns in lymphocytes, monoclonal gammopathy of undetermined significance and multiple myeloma

    PubMed Central

    Sathitruangsak, Chirawadee; Righolt, Christiaan H.; Klewes, Ludger; Tung Chang, Doris; Kotb, Rami

    2016-01-01

    The consistent appearance of specific chromosomal translocations in multiple myeloma has suggested that the positioning of chromosomes in the interphase nucleus might play a role in the occurrence of particular chromosomal rearrangements associated with malignant transformation. Using fluorescence in situ hybridization, we have determined the positions of selected chromosome pairs (18 and 19, 9 and 22, 4 and 14, 14 and 16, 11 and 14) in interphase nuclei of myeloma cells compared to normal lymphocytes of treatment‐naïve patients. All chromosome pairs were arranged in a nonrandom pattern. Chromosomes commonly involved in myeloma‐associated translocations (4 and 14, 14 and 16, 11 and 14) were found in close spatial proximity, and this is correlated with the occurrence of overlapping chromosome territories. The spatial distribution of chromosomes may increase the possibility of chromosomal translocations in multiple myeloma. PMID:27711972

  20. The Singapore Myeloma Study Group Consensus Guidelines for the management of patients with multiple myeloma.

    PubMed

    de Mel, Sanjay; Chen, Yunxin; Gopalakrishnan, Sathish Kumar; Ooi, Melissa; Teo, Constance; Tan, Daryl; Teo, Min Li Claire; Tso, Allison Cy; Lee, Lian King; Nagarajan, Chandramouli; Goh, Yeow Tee; Chng, Wee Joo

    2017-02-01

    Multiple myeloma (MM) is an incurable plasma cell neoplasm with an incidence of 100 patients per year in Singapore. Major advances have been made in the diagnosis, risk stratification and treatment of MM in the recent past. The reclassification of a subset of patients with smouldering MM, based on high-risk biomarkers, and the development of the revised international staging system are among the key new developments in diagnosis and staging. The use of novel agent-based treatment has resulted in significant improvements in the survival and quality of life of many patients with MM. Determining the optimal use of proteasome inhibitors, immunomodulators and, more recently, monoclonal antibodies is an area of ongoing investigation. In this guideline, we aim to provide an overview of the management of MM, incorporating the latest developments in diagnosis and treatment. Copyright: © Singapore Medical Association.

  1. The Singapore Myeloma Study Group Consensus Guidelines for the management of patients with multiple myeloma

    PubMed Central

    de Mel, Sanjay; Chen, Yunxin; Gopalakrishnan, Sathish Kumar; Ooi, Melissa; Teo, Constance; Tan, Daryl; Teo, Min Li Claire; Tso, Allison CY; Lee, Lian King; Nagarajan, Chandramouli; Goh, Yeow Tee; Chng, Wee Joo

    2017-01-01

    Multiple myeloma (MM) is an incurable plasma cell neoplasm with an incidence of 100 patients per year in Singapore. Major advances have been made in the diagnosis, risk stratification and treatment of MM in the recent past. The reclassification of a subset of patients with smouldering MM, based on high-risk biomarkers, and the development of the revised international staging system are among the key new developments in diagnosis and staging. The use of novel agent-based treatment has resulted in significant improvements in the survival and quality of life of many patients with MM. Determining the optimal use of proteasome inhibitors, immunomodulators and, more recently, monoclonal antibodies is an area of ongoing investigation. In this guideline, we aim to provide an overview of the management of MM, incorporating the latest developments in diagnosis and treatment. PMID:27609508

  2. New Treatment Approaches for Older Adults with Multiple Myeloma

    PubMed Central

    Wildes, Tanya M; Vij, Ravi; Petersdorf, Stephen H.; Medeiros, Bruno C.; Hurria, Arti

    2012-01-01

    The incidence of multiple myeloma (MM) increases with age, and with the aging of the population, the number of adults with MM is expected to double in the next 20 years. Novel agents, including the immunomodulatory agents thalidomide and lenalidomide, and the proteosome inhibitor bortezomib have dramatically changed the treatment of multiple myeloma in the past decade. The purpose of this review was to examine the recent clinical therapeutic trials in older adults with MM. A number of trials have evaluated the addition of novel agents to the traditional backbone of melphalan and prednisone. The combination of thalidomide with melphalan and prednisone has been evaluated in 7 randomized trials. The combination improves response rates and, in meta-analyses, survival, but at the expense of increased toxicity. Other combination regimens which include lenalidomide or bortezomib likewise are associated with higher response rates, but at the expense of greater toxicity. High dose dexamethasone is excessively toxic in older adults and should be avoided. The roles for high-dose therapy with autologous stem cell transplant or intermediate-dose melphalan with autologous stem cell transplant in older adults with MM in the era of modern therapy remain to be defined. In summary, there are a number of new therapeutic options for older adults with MM, allowing an individualized treatment strategy based on the patient's comorbidities and goals of care. PMID:23024730

  3. Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma.

    PubMed

    Issa, Mark E; Takhsha, Farnaz Sedigheh; Chirumamilla, Chandra Sekhar; Perez-Novo, Claudina; Vanden Berghe, Wim; Cuendet, Muriel

    2017-01-01

    Multiple myeloma (MM) is a hematological malignancy, which remains incurable because most patients eventually relapse or become refractory to current treatments. Due to heterogeneity within the cancer cell microenvironment, cancer cell populations employ a dynamic survival strategy to chemotherapeutic treatments, which frequently results in a rapid acquisition of therapy resistance. Besides resistance-conferring genetic alterations within a tumor cell population selected during drug treatment, recent findings also reveal non-mutational mechanisms of drug resistance, involving a small population of "cancer stem cells" (CSCs) which are intrinsically more refractory to the effects of a variety of anticancer drugs. Other studies have implicated epigenetic mechanisms in reversible drug tolerance to protect the population from eradication by potentially lethal exposures, suggesting that acquired drug resistance does not necessarily require a stable heritable genetic alteration. Clonal evolution of MM cells and the bone marrow microenvironment changes contribute to drug resistance. MM-CSCs may not be a static population and survive as phenotypically and functionally different cell types via the transition between stem-like and non-stem-like states in local microenvironments, as observed in other types of cancers. Targeting MM-CSCs is clinically relevant, and different approaches have been suggested to target molecular, metabolic and epigenetic signatures, and the self-renewal signaling characteristic of MM CSC-like cells. Here, we summarize epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma.

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

    PubMed Central

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

    2015-01-01

    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

  5. UNCEMENTED ARTHROPLASTY AFTER HIP METASTATIC DISEASE AND MULTIPLE MYELOMA

    PubMed Central

    Baptista, André Mathias; Meirelles, Sergio Pinheiro de Souza; Rebolledo, Daniel César Seguel; Correia, Luiz Filipe Marques; de Camargo, Olavo Pires

    2016-01-01

    ABSTRACT Objective: To describe a case series using a combination of narrative, graphical exploratory analysis and Bayesian Network modeling. Methods: Case series with 34 patients undergoing uncemented and hybrid arthroplasty procedures secondary to hip pain or fracture secondary to metastatic disease or multiple myeloma. Results: The most common tumors included gastrointestinal, multiple myeloma and breast cancer. Most devices were total arthroplasty (n = 16, 84.2%) rather than partial and uncemented arthroplasty (n = 12, 63.2%) rather than hybrid. The average time between surgery and deambulation was 20 days, the average length of hospital stay was 13 days, and the average patient survival was 589 days. Only one infection was reported. Uncemented and hybrid arthroplasty devices did not differ regarding time to walk, as well as the length of hospital stay in this sample. Conclusion: Our model may be used as a prior for the addition of subsequent patient samples, personalizing, thus, its recommendations to other patient populations. Level of Evidence IV, Case series. PMID:28243172

  6. Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma.

    PubMed

    Hoy, Sheridan M

    2016-04-01

    Carfilzomib (Kyprolis®) is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome (the proteolytic core particle within the 26S proteasome), inducing growth arrest and apoptosis. This intravenous drug is approved in the EU and the USA as combination therapy with oral lenalidomide and intravenous or oral dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. In the multinational, phase III ASPIRE study in this patient population, carfilzomib triple combination therapy significantly prolonged progression-free survival (PFS), reflecting a clinically relevant gain in PFS of 8.7 months, compared with lenalidomide plus dexamethasone. Improvements in overall response rate and patients' global health status were also observed with carfilzomib triple combination therapy. A significant improvement in overall survival (OS) is yet to be demonstrated, with the prespecified stopping boundary not crossed at the time of the prespecified interim analysis, although OS data were not mature by the cut-off date. Carfilzomib triple combination therapy had a manageable tolerability profile. The incidences of the most frequently reported grade 3 or higher adverse events of special interest (with the exception of neutropenia, anaemia and thrombocytopenia) were low in both the carfilzomib triple combination therapy and lenalidomide plus dexamethasone groups. Although final OS data are awaited, current evidence suggests carfilzomib in combination with lenalidomide and dexamethasone is a welcome addition to the treatment options currently available for patients with relapsed multiple myeloma.

  7. Multiple myeloma: patient outcomes in real-world practice.

    PubMed

    Yong, Kwee; Delforge, Michel; Driessen, Christoph; Fink, Leah; Flinois, Alain; Gonzalez-McQuire, Sebastian; Safaei, Reza; Karlin, Lionel; Mateos, Maria-Victoria; Raab, Marc S; Schoen, Paul; Cavo, Michele

    2016-10-01

    With increasing number of therapies available for the treatment of multiple myeloma, it is timely to examine the course of patients' journeys. We investigated patient characteristics, treatment durations and outcomes, and symptom burden across the treatment pathway in Belgium, France, Germany, Italy, Spain, Switzerland and the UK. In total, 435 physicians retrospectively reviewed 4997 patient charts. Profiles of patients diagnosed with multiple myeloma during the last 12 months were similar across countries; bone pain was the most common presentation. Median duration of first-line therapy was 6 months, followed by a median treatment-free interval of 10 months; both these decreased with increasing lines of therapy, as did time to progression. Depth of response, as assessed by the treating physician, also decreased with each additional line of therapy: 74% of patients achieved at least a very good partial response at first line, compared with only 11% at fifth line. Deeper responses were associated with longer time to progression, although these were physician-judged. Toxicities and co-morbidities increased with later treatment lines, and were more likely to have led to discontinuation of treatment. These real-world data provide an insight into patient outcomes and treatment decisions being made in clinical practice. © 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

  8. 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

  9. Epidemiology of Multiple Myeloma in the Czech Republic.

    PubMed

    Maluskova, D; Svobodová, I; Kucerova, M; Brozova, L; Muzik, J; Jarkovský, J; Hájek, R; Maisnar, V; Dusek, L

    2017-01-01

    Multiple myeloma (MM) is a cancer of plasma cells with an incidence of 4.8 cases per 100,000 population in the Czech Republic in 2014; the burden of MM in the Czech Republic is moderate when compared to other European countries. This work brings the latest information on MM epidemiology in the Czech population. The Czech National Cancer Registry is the basic source of data for the population-based evaluation of MM epidemiology. This database also makes it possible to assess patient survival and to predict probable short-term as well as long-term trends in the treatment burden of the entire population. According to the latest Czech National Cancer Registry data, there were 504 new cases of MM and 376 deaths from MM in 2014. Since 2004, there has been a 26.9% increase in MM incidence and an 8.3% increase in MM mortality. In 2014, there were 1,982 persons living with MM or a history of MM, corresponding to a 74.4% increase when compared to MM prevalence in 2004. The 5-year survival of patients treated in the period 2010-2014 was nearly 40%. The available data make it possible to analyse long-term trends in MM epidemiology and to predict the future treatment burden as well as treatment results.Key words: multiple myeloma - epidemiology - Czech National Cancer Registry - Registry of Monoclonal Gammopathies - Czech Republic.

  10. 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.

  11. New Strategies in the Treatment of Multiple Myeloma

    PubMed Central

    Munshi, Nikhil C.; Anderson, Kenneth C.

    2014-01-01

    Multiple myeloma (MM) is the second most common hematologic malignancy affecting terminally differentiated plasma cells. Although high-dose chemotherapy and autologous stem cell transplantation improved survival in younger patients, the natural history of MM has been changed with the availability of five new agents approved in last 10 years (thalidomide, bortezomib, lenalidomide, liposomal doxorubicin and carfilzomib). Despite this significant improvement in overall outcome, MM remains incurable in majority of patients prompting continued search for additional therapeutic options. Extensive molecular and genomic characterization of MM cells in its bone marrow milieu, which affects myeloma cell growth and survival, has provided number of novel drugable targets and pathways. Perturbation of protein catabolism at multiple levels has become an important target in MM. Similarly with improvements in monoclonal antibody generation and vaccine development along with identification of number of cell surface and cellular targets have led to development of various strategies including antibodies and antibody-drug conjugates which are under investigation both preclinically as well as in early clinical studies. We propose that eventually, molecularly-informed multi-agent combination therapies will be required to eliminate the MM cell clone for a long-term disease control. PMID:23515406

  12. 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.

  13. Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

    PubMed Central

    Rajkumar, S. Vincent

    2014-01-01

    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

  14. Human heat shock protein-specific cytotoxic T lymphocytes display potent antitumour immunity in multiple myeloma

    PubMed Central

    Li, Rong; Qian, Jianfei; Zhang, Wenhao; Fu, Weijun; Du, Juan; Jiang, Hua; Zhang, Hui; Zhang, Chunyang; Xi, Hao; Yi, Qing; Hou, Jian

    2014-01-01

    Tumour cell–derived heat shock proteins (HSPs) are used as vaccines for immunotherapy of cancer patients. However, it is proposed that the peptide chaperoned on HSPs, not HSPs themselves, elicited a potent immune response. Given that HSPs are highly expressed by most myeloma cells and vital to myeloma cell survival, we reasoned that HSPs themselves might be an ideal myeloma antigen. In the present study, we explored the feasibility of targeting HSPs themselves for treating multiple myeloma. We identified and chose HLA-A*0201-binding peptides from human HSPB1 (HSP27) and HSP90AA1 (HSP90), and confirmed their immunogenicity in HLA-A*0201 transgenic mice. Dendritic cells pulsed with HSPB1 and HSP90AA1 peptides were used to stimulate peripheral blood mononuclear cells from healthy volunteers and myeloma patients to generate HSP peptide-specific cytotoxic T lymphocytes (CTLs). HSP peptide-specific CTLs efficiently lysed HLA-A*0201+ myeloma cells (established cell lines and primary plasma cells) but not HLA-A*0201− myeloma cells in vitro, indicating that myeloma cells naturally express HSP peptides in the context of major histocompatibility complex class I molecules. More importantly, HSP peptide-specific CTLs effectively reduced tumour burden in the xenograft mouse model of myeloma. Our study clearly demonstrated that HSPs might be novel tumour antigens for immunotherapy of myeloma. PMID:24824351

  15. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.

    PubMed

    Mateos, María-Victoria; Hernández, Miguel-Teodoro; Giraldo, Pilar; de la Rubia, Javier; de Arriba, Felipe; López Corral, Lucía; Rosiñol, Laura; Paiva, Bruno; Palomera, Luis; Bargay, Joan; Oriol, Albert; Prosper, Felipe; López, Javier; Olavarría, Eduardo; Quintana, Nuria; García, José-Luis; Bladé, Joan; Lahuerta, Juan-José; San Miguel, Jesús-F

    2013-08-01

    For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention. In this randomized, open-label, phase 3 trial, we randomly assigned 119 patients with high-risk smoldering myeloma to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety. After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower. Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00480363.).

  16. Immunoglobulin D Multiple Myeloma With Rapidly Progressing Renal Failure

    PubMed Central

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

    2015-01-01

    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

  17. 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.

  18. Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms

    PubMed Central

    Abdi, Jahangir; Chen, Guoan; Chang, Hong

    2013-01-01

    In the era of new and mostly effective therapeutic protocols, multiple myeloma still tends to be a hard-to-treat hematologic cancer. This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment. Furthermore, the heterogeneous nature of multiple myeloma makes treating patients with the same drug challenging because finding a drugable oncogenic process common to all patients is not yet feasible, while our current knowledge of genetic/epigenetic basis of multiple myeloma pathogenesis is outstanding. Nonetheless, bone marrow microenvironment components are well known as playing critical roles in myeloma tumor cell survival and environment-mediated drug resistance happening most possibly in all myeloma patients. Generally speaking, however; real mechanisms underlying drug resistance in multiple myeloma are not completely understood. The present review will discuss the latest findings and concepts in this regard. It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations. It will also highlight how bone marrow microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could contribute to drug resistance in multiple myeloma. PMID:24327604

  19. Input of DNA microarrays to identify novel mechanisms in multiple myeloma biology and therapeutic applications

    PubMed Central

    Mahtouk, Karène; Hose, Dirk; De Vos, John; Moreaux, Jérôme; Jourdan, Michel; Rossi, Jean François; Rème, Thierry; Goldschmidt, Harmut; Klein, Bernard

    2007-01-01

    Multiple myeloma (MM) is a B cell neoplasia characterized by the proliferation of a clone of malignant plasma cells in the bone marrow. We review here the input of gene expression profiling (GEP) of myeloma cells and of their tumor microenvironment to develop new tumor classifiers, to better understand the biology of myeloma cells, to identify some mechanisms of drug sensitivity and resistance, to identify new myeloma growth factors, and to depict the complex interactions between tumor cells and their microenvironment. We discuss how these findings may improve the clinical outcome of this still incurable disease. PMID:18094409

  20. Simplified response monitoring criteria for multiple myeloma in patients undergoing therapy with novel agents using computed tomography.

    PubMed

    Schabel, Christoph; Horger, Marius; Kum, Sara; Weisel, Katja; Fritz, Jan; Ioanoviciu, Sorin D; Bier, Georg

    2016-12-01

    Multiple myeloma is a malignant hematological disorder of the mature B-cell lymphocytes originating in the bone marrow. While therapy monitoring is still mainly based on laboratory biomarkers, the additional use of imaging has been advocated due to inaccuracies of serological biomarkers or in a-secretory myelomas. Non-enhanced CT and MRI have similar sensitivities for lesions in yellow marrow-rich bone marrow cavities with a favourable risk and cost-effectiveness profile of CT. Nevertheless, these methods are still limited by frequently high numbers of medullary lesions and its time consumption for proper evaluation. To establish simplified response criteria by correlating size and CT attenuation changes of medullary multiple myeloma lesions in the appendicular skeleton with the course of lytic bone lesions in the entire skeleton. Furthermore to evaluate these criteria with respect to established hematological myeloma-specific parameters for the prediction of treatment response to bortezomib or lenalidomide. Non-enhanced reduced-dose whole-body CT examinations of 78 consecutive patients (43 male, 35 female, mean age 63.69±9.2years) with stage III multiple myeloma were retrospectively re-evaluated. On per patient basis, size and mean CT attenuation of 2-4 representative lesions in the limbs were measured at baseline and at a follow-up after a mean of 8 months. Results were compared with the course of lytical bone lesions as well with that of specific hematological biomarkers. Myeloma response was assessed according to the International Myeloma Working Group (IMWG) uniform response criteria. Testing for correlation between response of medullary lesions (Respmed) and response of all myeloma manifestations including osteolyses (Resptotal) was performed using the corrected contingency coefficient (Ccorr). The correlation between Respmed based on length diameter and transverse diameter and Resptotal was perfect (Ccorr=1.0; p<0.0001) whereas the correlation based on

  1. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.

    PubMed

    Lokhorst, Henk M; Plesner, Torben; Laubach, Jacob P; Nahi, Hareth; Gimsing, Peter; Hansson, Markus; Minnema, Monique C; Lassen, Ulrik; Krejcik, Jakub; Palumbo, Antonio; van de Donk, Niels W C J; Ahmadi, Tahamtan; Khan, Imran; Uhlar, Clarissa M; Wang, Jianping; Sasser, A Kate; Losic, Nedjad; Lisby, Steen; Basse, Linda; Brun, Nikolai; Richardson, Paul G

    2015-09-24

    Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥ 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. Daratumumab monotherapy had a favorable safety profile and encouraging

  2. Bence Jones proteinuria in smoldering multiple myeloma as a predictor marker of progression to symptomatic multiple myeloma.

    PubMed

    González-Calle, V; Dávila, J; Escalante, F; de Coca, A G; Aguilera, C; López, R; Bárez, A; Alonso, J M; Hernández, R; Hernández, J M; de la Fuente, P; Puig, N; Ocio, E M; Gutiérrez, N C; García-Sanz, R; Mateos, M V

    2016-10-01

    The diagnosis of smoldering multiple myeloma (SMM) includes patients with a heterogeneous risk of progression to active multiple myeloma (MM): some patients will never progress, whereas others will have a high risk of progression within the first 2 years. Therefore, it is important to improve risk assessment at diagnosis. We conducted a retrospective study in a large cohort of SMM patients, in order to investigate the role of Bence Jones (BJ) proteinuria at diagnosis in the progression to active MM. We found that SMM patients presenting with BJ proteinuria had a significantly shorter median time to progression (TTP) to MM compared with patients without BJ proteinuria (22 vs 88 months, respectively; hazard ratio=2.3, 95% confidence interval=1.4-3.9, P=0.002). We also identified risk subgroups based on the amount of BJ proteinuria: ⩾500 mg/24 h, <500 mg/24 h and without it, with a significantly different median TTP (13, 37 and 88 months, P<0.001). Thus, BJ proteinuria at diagnosis is an independent variable of progression to MM that identifies a subgroup of high-risk SMM patients (51% risk of progression at 2 years) and ⩾500 mg of BJ proteinuria may allow, if validated in another series, to reclassify these patients to MM requiring therapy before the end-organ damage development.

  3. 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

  4. A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

    PubMed

    Rand, Kristin A; Song, Chi; Dean, Eric; Serie, Daniel J; Curtin, Karen; Sheng, Xin; Hu, Donglei; Huff, Carol Ann; Bernal-Mizrachi, Leon; Tomasson, Michael H; Ailawadhi, Sikander; Singhal, Seema; Pawlish, Karen; Peters, Edward S; Bock, Cathryn H; Stram, Alex; Van Den Berg, David J; Edlund, Christopher K; Conti, David V; Zimmerman, Todd; Hwang, Amie E; Huntsman, Scott; Graff, John; Nooka, Ajay; Kong, Yinfei; Pregja, Silvana L; Berndt, Sonja I; Blot, William J; Carpten, John; Casey, Graham; Chu, Lisa; Diver, W Ryan; Stevens, Victoria L; Lieber, Michael R; Goodman, Phyllis J; Hennis, Anselm J M; Hsing, Ann W; Mehta, Jayesh; Kittles, Rick A; Kolb, Suzanne; Klein, Eric A; Leske, Cristina; Murphy, Adam B; Nemesure, Barbara; Neslund-Dudas, Christine; Strom, Sara S; Vij, Ravi; Rybicki, Benjamin A; Stanford, Janet L; Signorello, Lisa B; Witte, John S; Ambrosone, Christine B; Bhatti, Parveen; John, Esther M; Bernstein, Leslie; Zheng, Wei; Olshan, Andrew F; Hu, Jennifer J; Ziegler, Regina G; Nyante, Sarah J; Bandera, Elisa V; Birmann, Brenda M; Ingles, Sue A; Press, Michael F; Atanackovic, Djordje; Glenn, Martha J; Cannon-Albright, Lisa A; Jones, Brandt; Tricot, Guido; Martin, Thomas G; Kumar, Shaji K; Wolf, Jeffrey L; Deming Halverson, Sandra L; Rothman, Nathaniel; Brooks-Wilson, Angela R; Rajkumar, S Vincent; Kolonel, Laurence N; Chanock, Stephen J; Slager, Susan L; Severson, Richard K; Janakiraman, Nalini; Terebelo, Howard R; Brown, Elizabeth E; De Roos, Anneclaire J; Mohrbacher, Ann F; Colditz, Graham A; Giles, Graham G; Spinelli, John J; Chiu, Brian C; Munshi, Nikhil C; Anderson, Kenneth C; Levy, Joan; Zonder, Jeffrey A; Orlowski, Robert Z; Lonial, Sagar; Camp, Nicola J; Vachon, Celine M; Ziv, Elad; Stram, Daniel O; Hazelett, Dennis J; Haiman, Christopher A; Cozen, Wendy

    2016-12-01

    Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10(-7)) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR. ©2016 American Association for Cancer Research.

  5. Minor clone provides a reservoir for relapse in multiple myeloma.

    PubMed

    Magrangeas, F; Avet-Loiseau, H; Gouraud, W; Lodé, L; Decaux, O; Godmer, P; Garderet, L; Voillat, L; Facon, T; Stoppa, A M; Marit, G; Hulin, C; Casassus, P; Tiab, M; Voog, E; Randriamalala, E; Anderson, K C; Moreau, P; Munshi, N C; Minvielle, S

    2013-02-01

    Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations' control to eradicate all myeloma subclones in order to obtain long-term remission.

  6. 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

  7. Novel treatment approaches for patients with multiple myeloma.

    PubMed

    Sinha, Rajni; Kaufman, Jonathan L; Lonial, Sagar

    2006-01-01

    Treatment options for patients with multiple myeloma are a rapidly progressing area of clinical and scientific development. The discovery of key signaling pathways needed for myeloma cell growth and proliferation has resulted in a plethora of new and different treatment options. Chief among these new agents are the proteasome inhibitor bortezomib and the immunomodulatory agents thalidomide and lenalidomide. Efficacy for these agents has been extensively studied in the relapsed and refractory states, and more recently in induction therapy. Impressive responses have been observed in the induction and relapsed disease states, completely changing the disease treatment paradigms. Building on these successes and strong preclinical work, other signal transduction inhibitors are being tested in phase I and phase II clinical trials. These include agents that target histone acetylation, farnesylation, heat shock proteins, and direct AKT-targeting agents. Additionally, monoclonal antibody targets are being developed in an effort to target the tumor cells extracellularly. Clinical trial development based on preclinically designed rational combinations and targets have the potential to rapidly translate these findings into meaningful clinical responses.

  8. Cytotherapies in multiple myeloma: a complementary approach to current treatments?

    PubMed

    Ciavarella, Sabino; Caselli, Anna; Savonarola, Annalisa; Tamma, Antonella Valentina; Tucci, Marco; Silvestris, Franco

    2013-06-01

    Based on their tumor tropism, mesenchymal stem cells (MSCs) have been proposed as carriers of cytotoxic molecules in pioneering strategies of anti-cancer gene therapy. Similar to solid tumors, MSCs, genetically modified to stably express the TNF-related apoptosis-inducing ligand (TRAIL), have been applied to counter-attack multiple myeloma (MM) in vitro and envisioned as a promising strategy for future anti-MM treatments. Accumulating evidence based on the detection of genetic and functional abnormalities in MSCs from MM patients points to the supportive function of MSCs in both the development and progression of MM, driven by chronic interplays with malignant cells within the marrow milieu. In this review, we revisit the function of MSCs in the pathophysiology of MM and explore the pivotal mechanisms of their interaction with myeloma cells. We also discuss the therapeutic significance of novel strategies using TRAIL-engineered MSCs in this cancer model, dissecting their role as new tools for future treatments against MM. A cytotherapy based on TRAIL-engineered MSCs against MM may be successfully combined with either conventional approaches of autologous stem cell transplantation or with novel anti-MM drugs. Intensive preclinical investigations are required to identify the best sources as well as modalities of MSC administration, thus defining the translational suitability of this strategy in the clinical setting.

  9. Immunosurveillance and therapy of multiple myeloma are CD226 dependent

    PubMed Central

    Guillerey, Camille; Ferrari de Andrade, Lucas; Vuckovic, Slavica; Miles, Kim; Ngiow, Shin Foong; Yong, Michelle C.R.; Teng, Michele W.L.; Colonna, Marco; Ritchie, David S.; Chesi, Martha; Bergsagel, P. Leif; Hill, Geoffrey R.; Smyth, Mark J.; Martinet, Ludovic

    2015-01-01

    Multiple myeloma (MM) is an age-dependent hematological malignancy. Evaluation of immune interactions that drive MM relies on in vitro experiments that do not reflect the complex cellular stroma involved in MM pathogenesis. Here we used Vk*MYC transgenic mice, which spontaneously develop MM, and demonstrated that the immune system plays a critical role in the control of MM progression and the response to treatment. We monitored Vk*MYC mice that had been crossed with Cd226 mutant mice over a period of 3 years and found that CD226 limits spontaneous MM development. The CD226-dependent anti-myeloma immune response against transplanted Vk*MYC MM cells was mediated both by NK and CD8+ T cells through perforin and IFN-γ pathways. Moreover, CD226 expression was required for optimal antimyeloma efficacy of cyclophosphamide (CTX) and bortezomib (Btz), which are both standardly used to manage MM in patients. Activation of costimulatory receptor CD137 with mAb (4-1BB) exerted strong antimyeloma activity, while inhibition of coinhibitory receptors PD-1 and CTLA-4 had no effect. Taken together, the results of this study provide in vivo evidence that CD226 is important for MM immunosurveillance and indicate that specific immune components should be targeted for optimal MM treatment efficacy. As progressive immunosuppression associates with MM development, strategies aimed to increase immune functions may have important therapeutic implications in MM. PMID:25893601

  10. Many Multiple Myelomas: Making More of the Molecular Mayhem

    PubMed Central

    Chesi, Marta; Bergsagel, P. Leif

    2014-01-01

    Multiple myeloma (MM) is malignancy of isotype-switched, BM-localized plasma cells that frequently results in bone destruction, BM failure, and death. Important molecular subgroups are identified by three classes of recurrent immunoglobulin gene translocations and hyperdiploidy, both of which affect disease course. From a clinical standpoint, it is critical to identify MM patients carrying the t(4;14) translocation, which is present in 15% of myelomas and is associated with dysregulation of WHSC1/MMSET and often FGFR3. These patients should all receive bortezomib as part of their initial induction treatment because this has been shown to significantly prolong survival. In contrast, patients with translocations affecting the MAF family of transcription factors, del17p, or gene-expression profiling (GEP)–defined high-risk disease appear to have a worse prognosis that is not dramatically improved by any intervention. These patients should be enrolled in innovative clinical trials. The remaining patients with cyclin D translocations or hyperdiploidy do well with most therapies, and the goal should be to control disease while minimizing toxicity. PMID:22160056

  11. Evaluation of immunomodulatory drugs in multiple myeloma: single center experience

    PubMed Central

    Ozkan, Melda Comert; Tombuloglu, Murat; Sahin, Fahri; Saydam, Guray

    2015-01-01

    Objective: Multiple myeloma (MM) comprises 1% of all cancers and 10% of hematologic malignancies and known as an incurable disease. The introduction of immunomodulatory drugs (IMiDs) has brought a major shift in therapeutic paradigm in the treatment of newly diagnosed and relapsed/refractory MM patients. The aim of this study was to evaluate the relationship between response status and hematological parameters in patients with MM treated with thalidomide or lenalidomide. Methods: Sixty-eight patients who were treated with IMiDs in Ege University, School of Medicine, Department of Hematology, between 2005 and 2012, were evaluated, retrospectively. Results and Conclusion: We could not find any difference between the hematological parameters before and after the treatment neither with thalidomide nor lenalidomide. However, the heterogenity of our groups, the difference in treatment strategies and potential side effects would have an impact on this result. It is needed to perform prospective clinical trials to prove that whether correction of hematological parameters would reflect the response status in patients with myeloma that treated with IMiDs. PMID:27069758

  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.

  13. Targeting vasculogenesis to prevent progression in multiple myeloma.

    PubMed

    Moschetta, M; Mishima, Y; Kawano, Y; Manier, S; Paiva, B; Palomera, L; Aljawai, Y; Calcinotto, A; Unitt, C; Sahin, I; Sacco, A; Glavey, S; Shi, J; Reagan, M R; Prosper, F; Bellone, M; Chesi, M; Bergsagel, L P; Vacca, A; Roccaro, A M; Ghobrial, I M

    2016-05-01

    The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.

  14. Multiple myeloma epidemiology and survival: A unique malignancy.

    PubMed

    Kazandjian, Dickran

    2016-12-01

    Multiple myeloma (MM), although a rare disease, is the second most common hematologic malignancy. It is found in the spectrum of plasma cell dyscrasias, which begins with monoclonal gammopathy of unknown significance (MGUS) to overt plasma cell leukemia and extramedullary myeloma. MM is associated with significant morbidity due to its end-organ destruction. It is a disease of the older population and its incidence in the African American population is twice that of the European American population. Improvements in the treatment of MM in the past couple of decades, beginning with the use of autologous stem cell transplantation followed by availability of novel treatments such as immunomodulatory drugs (ImIDs) and proteasome inhibitors (PIs) has transformed the natural history of the disease leading to longer survival times. Advancements in the diagnosis, monitoring, and treatment of MM are of the utmost importance as the general population lives longer due to other improvements in health care. The recent introduction of novel therapies has been paralleled by advancements in the monitoring of MM, namely, by the availability exquisitely sensitive techniques in detecting minimal residual disease. As drug development and technology continues to improve, it will be important to design rationale clinical trials enrolling patient populations that represent the overall population, including racial minorities and the elderly, so that trial results can be appropriately extrapolated. Herein, the changing epidemiology, improvements in survival, and the health disparity observed in important subgroups of MM are reviewed. Published by Elsevier Inc.

  15. Minor clone provides a reservoir for relapse in multiple myeloma

    PubMed Central

    Magrangeas, Florence; Avet-Loiseau, Hervé; Gouraud, Wilfried; Lodé, Laurence; Decaux, Olivier; Godmer, Pascal; Garderet, Laurent; Voillat, Laurent; Facon, Thierry; Stoppa, Anne Marie; Marit, Gerald; Hulin, Cyrille; Casassus, Philippe; Tiab, Mourad; Voog, Eric; Randriamalala, Edouard; Anderson, Kenneth C; Moreau, Philippe; Munshi, Nikhil C; Minvielle, Stéphane

    2014-01-01

    Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. Because MM is a highly heterogeneous disease associated to a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression: 1q21 gain, NF-κB activating mutations, RB1 and TP53 deletions was examined. By using high resolution SNP arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population, but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations’ control to eradicate all myeloma subclones in order to obtain long-term remission. PMID:22874878

  16. Multistep tumorigenesis of multiple myeloma: its molecular delineation.

    PubMed

    Iida, Shinsuke; Ueda, Ryuzo

    2003-04-01

    Multiple myeloma (MM) is an incurable malignant neoplasm affecting terminally differentiated B-cells. It derives from post-germinal center B-cells and develops as a result of multistep tumorigenic events, because approximately one third of all MM cases have a history of preceding monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma. MM terminates in the formation of extramedullary invasion or in secondary plasma cell leukemia. To account for this clinical experience, investigators have found that intrinsic chromosomal instability followed by complex chromosomal translocations/deletions plays a crucial role in the development from MGUS to MM. Representative aberrations include chromosomal rearrangements involving 14q32 loci and deletion at the long arm of chromosome 13. Contributing to the progression of MM itself are genomic instability and altered methylation of the specific gene promoters. The former results in activation of specific oncogenes such as RAS and FGFR3 or in inactivation of p53, and the latter results in inactivation of tumor suppressor genes, including p16. An accurate understanding of each of these molecular events should help clarify the development of specific molecular targeting therapies based on the differences in dysfunctional signaling pathways found in the cells of all MM patients.

  17. Clonal competition with alternating dominance in multiple myeloma

    PubMed Central

    Keats, Jonathan J.; Chesi, Marta; Egan, Jan B.; Garbitt, Victoria M.; Palmer, Stephen E.; Braggio, Esteban; Van Wier, Scott; Blackburn, Patrick R.; Baker, Angela S.; Dispenzieri, Angela; Kumar, Shaji; Rajkumar, S. Vincent; Carpten, John D.; Barrett, Michael; Fonseca, Rafael; Stewart, A. Keith

    2012-01-01

    Emerging evidence indicates that tumors can follow several evolutionary paths over a patient's disease course. With the use of serial genomic analysis of samples collected at different points during the disease course of 28 patients with multiple myeloma, we found that the genomes of standard-risk patients show few changes over time, whereas those of cytogenetically high-risk patients show significantly more changes over time. The results indicate the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. A detailed analysis of one high-risk patient sampled at 7 time points over the entire disease course identified 2 competing subclones that alternate in a back and forth manner for dominance with therapy until one clone underwent a dramatic linear evolution. With the use of the Vk*MYC genetically engineered mouse model of myeloma we modeled this competition between subclones for predominance occurring spontaneously and with therapeutic selection. PMID:22498740

  18. Renal, hematologic and infectious complications in multiple myeloma.

    PubMed

    Bladé, Joan; Rosiñol, Laura

    2005-01-01

    Renal failure is a common complication in patients with multiple myeloma. It is generally due to tubular light-chain damage, and it is reversible in about 50% of patients. The reversibility rate depends on the degree of light-chain nephropathy. The initial therapy should consist of dexamethasone- or cyclophosphamide-based regimens. High-dose therapy/autologous transplant may be of benefit in selected patients. Early plasma exchange may be useful in patients who have severe renal failure but do not yet require dialysis. Renal replacement with dialysis is a worthwhile measure in patients with end-stage renal failure. Anemia is the most common hematologic complication. About 70% of anemic patients respond to recombinant human erythropoietin (rHuEPO), resulting not only in an increase in the hemoglobin level but also in an improvement in the quality of life. The hemoglobin level should ideally be maintained at around 12 g/dL. Infection is the main cause of morbidity and mortality in patients with myeloma. The highest risk of infection is within the first 2 months of initiation of therapy as well as in patients with renal failure and in those with relapsed and refractory disease.

  19. 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

  20. Risk and impact of tuberculosis in patients with multiple myeloma.

    PubMed

    Tsai, Chun-Kuang; Huon, Leh-Kiong; Ou, Shuo-Ming; Kuan, Ai-Seon; Yeh, Chiu-Mei; Lee, Yu-Ting; Liu, Yao-Chung; Chen, Tzeng-Ji; Liu, Jin-Hwang; Liu, Chia-Jen

    2017-11-01

    We investigated the risk and impact of mycobacterium tuberculosis (TB) infection in patients with multiple myeloma (MM). We identified 3979 MM patients from Taiwan's National Health Insurance database between 2000 and 2011 and compared the incidence rates of TB infection in these patients with 15,916 randomly selected age-, sex-, and comorbidity-matched subjects without MM. The risk of TB was higher in the myeloma cohort (adjusted hazard ratio [HR] 3.11, 95% confidence interval [CI] 2.41-4.02). Risk factors for MM patients contracting TB were age ≥65 (adjusted HR 1.93, 95% CI 1.19-3.15), alcohol use disorder (adjusted HR 2.86, 95% CI 1.24-6.62), and steroid daily dose equivalent to prednisone 5 mg or more (adjusted HR 2.38, 95% CI 1.50-3.77). MM patients with TB had a higher mortality risk than those without (adjusted HR 2.03, 95% CI 1.54-2.67). The incidence of TB is significantly higher in MM patients.

  1. 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

  2. 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

  3. 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

  4. Magnetic resonance appearance of monoclonal gammopathies of unknown significance and multiple myeloma. The GRI Study Group.

    PubMed

    Bellaïche, L; Laredo, J D; Lioté, F; Koeger, A C; Hamze, B; Ziza, J M; Pertuiset, E; Bardin, T; Tubiana, J M

    1997-11-01

    A prospective multicenter study. To evaluate the use of magnetic resonance imaging, in the differentiation between monoclonal gammopathies of unknown significance and multiple myeloma. Although multiple myeloma has been studied extensively with magnetic resonance imaging, to the authors' knowledge, no study has evaluated the clinical interest of magnetic resonance imaging in the differentiation between monoclonal gammopathies of unknown significance and multiple myeloma. The magnetic resonance examinations of the thoracolumbar spine in 24 patients with newly diagnosed monoclonal gammopathies of unknown significance were compared with those performed in 44 patients with newly diagnosed nontreated multiple myeloma. All findings on magnetic resonance examination performed in patients with monoclonal gammopathies of unknown significance were normal, whereas findings on 38 (86%) of the 44 magnetic resonance examinations performed in patients with multiple myeloma were abnormal. Magnetic resonance imaging can be considered as an additional diagnostic tool in differentiating between monoclonal gammopathies of unknown significance and multiple myeloma, which may be helpful when routine criteria are not sufficient. An abnormal finding on magnetic resonance examination in a patient with monoclonal gammopathies of unknown significance should suggest the diagnosis of multiple myeloma after other causes of marrow signal abnormalities are excluded. Magnetic resonance imaging also may be proposed in the long-term follow-up of monoclonal gammopathies of unknown significance when a new biologic or clinical event suggests the diagnosis of malignant monoclonal gammopathy.

  5. 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.

  6. Rapid Progression of Solitary Plasmacytoma to Multiple Myeloma in Lumbar Vertebra

    PubMed Central

    Yang, Jin Seo; Kang, Suk Hyung; Choi, Hyuk Jai

    2013-01-01

    The prognosis of solitary plasmacytoma varies greatly, with some patients recovering after surgical removal or local fractional radiation therapy, and others progressing to multiple myeloma years later. Primary detection of progression to multiple myeloma is important in the treatment of solitary plasmacytoma. There have been several analyses of the risk factors involved in the early progression to multiple myeloma. We describe one case of solitary plasmacytoma of the lumbar vertebra that was treated with surgical decompression with stabilization and additional radiotherapy. The patient had no factors associated with rapid progression to multiple myeloma such as age, size, immunologic results, pathological findings, and serum free light chain ratio at the time of diagnosis. However, his condition progressed to multiple myeloma less than two months after the initial diagnosis of solitary plasmacytoma. We suggest that surgeons should be vigilant in watching for rapid progression to multiple myeloma even in case that the patient with solitary plasmacytoma has no risk factors for rapid progression to multiple myeloma. PMID:24379952

  7. TRIP13 impairs mitotic checkpoint surveillance and is associated with poor prognosis in multiple myeloma.

    PubMed

    Tao, Yi; Yang, Guang; Yang, Hongxing; Song, Dongliang; Hu, Liangning; Xie, Bingqian; Wang, Houcai; Gao, Lu; Gao, Minjie; Xu, Hongwei; Xu, Zhijian; Wu, Xiaosong; Zhang, Yiwen; Zhu, Weiliang; Zhan, Fenghuang; Shi, Jumei

    2017-02-01

    AAA-ATPase TRIP13 is one of the chromosome instability gene recently established in multiple myeloma (MM), the second most common and incurable hematological malignancy. However, the specific function of TRIP13 in MM is largely unknown. Using sequential gene expression profiling, we demonstrated that high TRIP13 expression levels were positively correlated with progression, disease relapse, and poor prognosis in MM patients. Overexpressing human TRIP13 in myeloma cells prompted cell growth and drug resistance, and overexpressing murine TRIP13, which shares 93% sequence identity with human TRIP13, led to colony formation of NIH/3T3 fibroblasts in vitro and tumor formation in vivo. Meanwhile, the knockdown of TRIP13 inhibited myeloma cell growth, induced cell apoptosis, and reduced tumor burden in xenograft MM mice. Mechanistically, we observed that the overexpression of TRIP13 abrogated the spindle checkpoint and induced proteasome-mediated degradation of MAD2 primarily through the Akt pathway. Thus, our results demonstrate that TRIP13 may serve as a biomarker for MM disease development and prognosis, making it a potential target for future therapies.

  8. Lycorine Downregulates HMGB1 to Inhibit Autophagy and Enhances Bortezomib Activity in Multiple Myeloma

    PubMed Central

    Roy, Mridul; Liang, Long; Xiao, Xiaojuan; Peng, Yuanliang; Luo, Yuhao; Zhou, Weihua; Zhang, Ji; Qiu, Lugui; Zhang, Shuaishuai; Liu, Feng; Ye, Mao; Zhou, Wen; Liu, Jing

    2016-01-01

    Multiple myeloma (MM) is largely incurable and drug-resistant. Novel therapeutic approaches such as inhibiting autophagy or rational drug combinations are aimed to overcome this issue. In this study, we found that lycorine exhibits a promising anti-proliferative activity against MM in vitro and in vivo by inhibiting autophagy. We identified High mobility group box 1 (HMGB1), an important regulator of autophagy, as the most aberrantly expressed protein after lycorine treatment and as a critical mediator of lycorine activity. Gene expression profiling (GEP) analysis showed that higher expression of HMGB1 is linked with the poor prognosis of MM. This correlation was further confirmed in human bone marrow CD138+ primary myeloma cells and MM cell lines. Mechanistically, proteasomal degradation of HMGB1 by lycorine inhibits the activation of MEK-ERK thereby decreases phosphorylation of Bcl-2 resulting in constitutive association of Bcl-2 with Beclin-1. In addition, we observed higher HMGB1 expression in bortezomib resistant cells and the combination of bortezomib plus lycorine was highly efficient in vitro and in vivo myeloma models as well as in re-sensitizing resistant cells to bortezomib. These observations indicate lycorine as an effective autophagy inhibitor and reveal that lycorine alone or in combination with bortezomib is a potential therapeutic strategy. PMID:27924158

  9. Vertebroplasty for pain relief and spinal stabilization in multiple myeloma.

    PubMed

    Tancioni, Flavio; Lorenzetti, Martin; Navarria, Pierina; Nozza, Andrea; Castagna, Luca; Gaetani, Paolo; Aimar, Enrico; Levi, Daniel; Di Ieva, Antonio; Pisano, Patrizia; Santoro, Armando; Scorsetti, Marta; Rodriguez y Baena, Riccardo

    2010-04-01

    Mechanical stabilization of oncological vertebral fractures with cement augmentation is the first mechanism of pain relief, with or without restoration of vertebral body height. The aim of this study was to assess the safety and efficacy of vertebroplasty for painful vertebral body fractures in patients with multiple myeloma, in each phase of the disease. The authors reviewed a consecutive group of patients with multiple myeloma who underwent vertebroplasty at our Institute between November 2003 and December 2005. Twenty-eight levels were performed on 11 patients during 14 treatment sessions. All patients suffered from intractable back pain, and presented various lesion types (with and without fractures of posterior wall, and with and without epidural disease). The preoperative median visual analog scale (VAS) score was 7. The median duration of symptoms was 1.1 months. Eight patients were ambulating with orthopaedic devices (57%) in the pre-treatment period. Improvement or complete pain relief was observed in all patients (immediately in 8 cases, and after 2 days in 6 cases). The median VAS pain score decreased to 2. There was no symptomatic procedure-related complication. There were three cases (21%) of PMMA leakage: in the disc space in one case (7%), and in the anterior spinal canal in two cases (14%). Complete removal of orthopaedic devices was obtained in five patients (36%). No new deformation or collapse of the treated vertebrae was observed during the follow-up (range 1 day-25 months). In conclusion, vertebroplasty is a safe and efficient procedure in the treatment of painful vertebral body fractures in patients with multiple myeloma, without potential contraindications, such as fractures of the posterior wall or epidural disease. We also treated three and more levels in 28% of cases in a single session without complications. Due to the early pain relief and the low complication rate, it is possible to expand the indication to vertebroplasty for the

  10. 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

  11. Relapse of Multiple Myeloma Presenting as Extramedullary Plasmacytomas in Multiple Organs

    PubMed Central

    Köse, Murat; Buraniqi, Ersida; Akpinar, Timur Selçuk; Kayacan, Seyit Mehmet; Tükek, Tufan

    2015-01-01

    Multiple myeloma is a neoplastic plasma cell disorder. It is characterized by collections of abnormal plasma cells accumulating in the bone marrow, where they interfere with the production of normal blood cells. It usually presents as a multisystemic involvement, whose symptoms and signs vary greatly. Some patients have slowly progressive disease while others have aggressive clinical behavior by extramedullary involvement. In addition to renal failure, anemia, hypercalcemia, lytic bone lesions, and immunodeficiency, it also affects multiple organ system, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, lymph nodes, and bone. To raise awareness of the variable presentations of this disease, we report a 53-year-old male patient, with multiple myeloma in his first remission who relapsed with extramedullary plasmacytomas (EMPs) involving multiple organs, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, and lymph nodes. PMID:25694834

  12. An interesting cause of esophageal ulcer etiology: Multiple myeloma of IgG kappa subtype

    PubMed Central

    Pehlivan, Yavuz; Sevinc, Alper; Sari, Ibrahim; Gulsen, Murat T; Buyukberber, Mehmet; Kalender, Mehmet E; Camci, Celalettin

    2006-01-01

    Multiple myeloma is a neoplasm of mature and immature plasma cells. A 50-year-old woman with lumbago, dysphagia, and left arm pain was presented. Upper endoscopical examination was performed. There was an exudate-covered ulcer in the distal esophagus, located at 30-32 cm from the incisors, covering the whole mucosa. Histopathological examination of the specimens obtained from the lesion showed the involvement of plasma cells consistent with multiple myeloma of IgG kappa subtype. Esophageal involvement of multiple myeloma should be kept in mind in patients presenting with dysphagia. PMID:16610044

  13. Multiple myeloma cells promote migration of bone marrow mesenchymal stem cells by altering their translation initiation.

    PubMed

    Dabbah, Mahmoud; Attar-Schneider, Oshrat; Zismanov, Victoria; Tartakover Matalon, Shelly; Lishner, Michael; Drucker, Liat

    2016-10-01

    The role of the bone marrow microenvironment in multiple myeloma pathogenesis and progression is well recognized. Indeed, we have shown that coculture of bone marrow mesenchymal stem cells from normal donors and multiple myeloma cells comodulated translation initiation. Here, we characterized the timeline of mesenchymal stem cells conditioning by multiple myeloma cells, the persistence of this effect, and the consequences on cell phenotype. Normal donor mesenchymal stem cells were cocultured with multiple myeloma cell lines (U266, ARP1) (multiple myeloma-conditioned mesenchymal stem cells) (1.5 h,12 h, 24 h, 48 h, and 3 d) and were assayed for translation initiation status (eukaryotic translation initiation factor 4E; eukaryotic translation initiation factor 4G; regulators: mechanistic target of rapamycin, MNK, 4EBP; targets: SMAD family 5, nuclear factor κB, cyclin D1, hypoxia inducible factor 1, c-Myc) (immunoblotting) and migration (scratch assay, inhibitors). Involvement of mitogen-activated protein kinases in mesenchymal stem cell conditioning and altered migration was also tested (immunoblotting, inhibitors). Multiple myeloma-conditioned mesenchymal stem cells were recultured alone (1-7 d) and were assayed for translation initiation (immunoblotting). Quantitative polymerase chain reaction of extracted ribonucleic acid was tested for microRNAs levels. Mitogen-activated protein kinases were activated within 1.5 h of coculture and were responsible for multiple myeloma-conditioned mesenchymal stem cell translation initiation status (an increase of >200%, P < 0.05) and elevated migration (16 h, an increase of >400%, P < 0.05). The bone marrow mesenchymal stem cells conditioned by multiple myeloma cells were reversible after only 1 d of multiple myeloma-conditioned mesenchymal stem cell culture alone. Decreased expression of microRNA-199b and microRNA-125a (an increase of <140%, P < 0.05) in multiple myeloma-conditioned mesenchymal stem cells supported elevated

  14. 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

  15. 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.

  16. A Case of Multiple Myeloma Presenting with Diabetes Insipidus.

    PubMed

    Paul, Rudrajit; Ruia, Aditya V; Saha, Asim; Mondal, Jayati; Sau, T J; Thakur, Indranil; Haldar, Kunal

    2017-05-01

    Multiple myeloma (MM) can present with involvement of the central nervous system in the form of nerve palsy, plasma cell masses or, rarely, with endocrinological effects due to involvement of the pituitary gland. Usually, in such cases, the disease has a rapid progression and poor prognosis. We report a 52-year-old man who was admitted to the Kolkata Medical College, Kolkata, India, in 2016 with a prolonged low-grade fever and hypernatremia. Shortly afterwards, the patient began to complain of increased urinary frequency and drowsiness. The hypernatremia was treated with intranasal desmopressin and free water replacement. Serum protein electrophoresis and an immunofixation study revealed an immunoglobulin G-κ monoclonal band. Magnetic resonance imaging of the pituitary gland revealed the absence of a posterior bright spot and spotty infiltration of the pituitary fossa. A bone marrow biopsy confirmed a diagnosis of cranial diabetes insipidus due to posterior pituitary MM infiltration.

  17. New developments in the treatment of patients with multiple myeloma.

    PubMed

    Minnema, M C; van der Spek, E; van de Donk, N W C J; Lokhorst, H M

    2010-01-01

    Much progress has been made in the treatment of patients with multiple myeloma (MM). The introduction of new drugs such as thalidomide, bortezomib and lenalidomide has created more possibilities for patients than many years before. In addition, autologous peripheral blood stem cell transplantation after high-dose melphalan has become the standard of care for younger patients. Allogeneic stem cell transplantation is an experimental option for those younger patients with a human leucocyte antigen identical donor. Because of these rapid developments and many treatment options we need good quality clinical studies that can guide us in what to do in everyday practice. This review will focus on those studies that have changed the treatment guidelines for patients with MM.

  18. Streptococcus agalactiae Native Valve Endocarditis: Uncommon Presentation of Multiple Myeloma.

    PubMed

    Pinho Oliveira, Ana; Delgado, Anne; Martins, Cláudia; Gama, Pedro

    2016-08-01

    Adults with chronic immunosuppressive conditions are at an increased risk for Streptococcus agalactiae endocarditis, which is typically characterized by acute onset, presence of large vegetations, rapid valvular destruction and frequent complications. We report a rare case of a 74 years old man presenting with fever, renal infarction, ischemic stroke and uveitis. Infective endocarditis was diagnosed and Streptococcus agalactiae was isolated in blood cultures. A multiple myeloma Ig G-K was also diagnosed. The infective endocarditis was successfully treated with a course of benzylpenicillin and gentamicin. The authors highlight the severity of vascular embolic disease present in this case and the diagnostic challenge. They also intend to remind about the association between Streptococcus agalactiae endocarditis and chronic diseases, despite its low reported prevalence.

  19. Incidence and pathogenesis of megaloblastic erythropoiesis in multiple myeloma

    PubMed Central

    Hoffbrand, A. V.; Hobbs, J. R.; Kremenchuzky, S.; Mollin, D. L.

    1967-01-01

    Intermediate megaloblastic changes occurred in six (19%) of 32 patients with multiple myeloma and trivial megaloblastic changes in a further ten (31%). Folate deficiency was the predominant cause of these changes and in at least two patients was sufficiently severe to contribute to anaemia. Folate deficiency appeared to be due to exćess folate utilization by the tumour and was related to the amount of paraprotein produced daily. Five of the 32 patients had subnormal serum B12 levels. Reduction in the serum B12 level was related to the reduction in the normal circulating immunoglobulins and occurred despite normal B12 absorption. Possible explanations for this finding are discussed. PMID:5602978

  20. A practical review on carfilzomib in multiple myeloma.

    PubMed

    Muchtar, Eli; Gertz, Morie A; Magen, Hila

    2016-06-01

    Carfilzomib, a second-generation proteasome inhibitor, has been increasingly used in relapsed/refractory multiple myeloma (MM) since its approval by the American food and drug administration (FDA) in the summer of 2012. The drug is active as a single agent and in combination with other antimyeloma agents. As a result of its efficacy and safety in the relapsed/refractory setting, carfilzomib is being evaluated in patients with newly diagnosed MM as well as in high-risk smoldering MM. This review will give a comprehensive summary of the drug, including its mechanism of action, the evaluated doses and schedules as well as a summary of the main clinical trials in the relapsed/refractory and newly diagnosed settings. A focus will be placed upon certain subgroups of interest as well as a description of the toxicity associated with carfilzomib use and a clinical perspective on toxicity management.

  1. Spontaneous Tumour Lysis Syndrome in a Multiple Myeloma

    PubMed Central

    Eliacik, Eylem; Saglam, Mustafa; Doner, Baris

    2016-01-01

    The tumor lysis syndrome (TLS) is a collection of metabolic abnormalities that occur in consequence of the release of intracellular contents following lysis of tumor cells. TLS occurs spontaneously or after chemotherapy. Spontaneous TLS is uncommon occurrence in multiple myeloma (MM). We define a case of a 70-year-old woman patient who was found to have MM with spontaneous TLS, following a compression fracture of the T-12 vertebrae. While serum uric acid and phosphorous levels were high, low calcium levels were identified. There were also acute kidney injury and metabolic acidosis. Upon the diagnosis of TLS, she was treated with hydration, allopurinol, sodium bicarbonate, and calcium gluconate. The improvement of her laboratory data was observed. We submitted this case in order to draw attention to the presentation of MM with spontaneous TLS. PMID:27956901

  2. Targeting SDF-1 in multiple myeloma tumor microenvironment.

    PubMed

    Bouyssou, Juliette M C; Ghobrial, Irene M; Roccaro, Aldo M

    2016-09-28

    Multiple myeloma (MM) is a type of B-cell malignancy that remains incurable to date. The bone marrow (BM) microenvironment plays a crucial role in MM progression. The chemokine SDF-1 (CXCL12) is an important actor of the BM microenvironment that has the ability to regulate numerous processes related to its malignant transformation during MM development. The activity of SDF-1 is mainly mediated by its specific receptor CXCR4, which is expressed at the surface of MM cells and various other BM cell types. Current treatments available for MM patients mainly target tumor cells but have limited effects on the BM microenvironment. In this context, SDF-1 and CXCR4 represent ideal targets for the normalization of the MM-supportive BM microenvironment. The present review focuses on the activity of SDF-1 in the MM BM microenvironment and the current efforts carried out to target the SDF-1/CXCR4 axis for treatment of MM.

  3. Relapse of Multiple Myeloma Presenting as Lower Lip Numbness

    PubMed Central

    Al-Riyami, Yusra M.; Bakathir, Abdulaziz; Al-Farsi, Khalil; Al-Azri, Faisal

    2016-01-01

    Multiple myeloma (MM) is an uncommon malignancy characterised by the proliferation of clonal plasma cells. There are few published reports describing the extramedullary presentation of MM manifesting primarily in the head and neck region. In addition, the occurrence of an isolated relapse of MM in these sites is exceedingly rare. We report a 56-year-old female who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in 2010 with sudden-onset numbness of the lower lip. She had a history of MM in remission following chemotherapy and a bone marrow transplant. Clinical and radiographic examinations were indicative of a possible relapse of MM, which was subsequently confirmed by bone marrow aspiration and histopathological evaluation. This unique case highlights the unusual site of relapse of a haematolymphoid malignancy. PMID:28003900

  4. 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

  5. Targeting B-cell maturation antigen in multiple myeloma

    PubMed Central

    Tai, Yu-Tzu; Anderson, Kenneth C

    2015-01-01

    Novel effective immunotherapies are needed for patients with multiple myeloma (MM), since disease recurrence remains a major obstacle. B-cell maturation antigen (BCMA), a cell surface protein universally expressed on malignant plasma cells , has emerged as a very selective antigen to be targeted in novel treatments for MM. We here first review BCMA-related biology, and then highlight the recent clinical development of a novel afucosylated anti-BCMA monoclonal antibody conjugated with monomethyl auristatin F via noncleavable linker (GSK2857916). Chimeric antigen receptor-expressing T cells targeting BCMA may also induce specific and durable anti-MM responses by patients’ own effector cells. Clinical trials testing these two approaches (NCT02064387, NCT02215967) are currently ongoing in relapsed and refractory MM patients. PMID:26370838

  6. The clinical significance of cereblon expression in multiple myeloma.

    PubMed

    Schuster, Steven R; Kortuem, K Martin; Zhu, Yuan Xiao; Braggio, Esteban; Shi, Chang-Xin; Bruins, Laura A; Schmidt, Jessica E; Ahmann, Greg; Kumar, Shaji; Rajkumar, S Vincent; Mikhael, Joseph; Laplant, Betsy; Champion, Mia D; Laumann, Kristina; Barlogie, Bart; Fonseca, Rafael; Bergsagel, P Leif; Lacy, Martha; Stewart, A Keith

    2014-01-01

    Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). We demonstrate here that no patient with very low CRBN expression responded to IMiD plus dexamethasone therapy. In 53 refractory MM patients treated with pomalidomide and dexamethasone, CRBN levels predict for decreased response rates and significant differences in PFS (3.0 vs. 8.9 months, p<0.001) and OS (9.1 vs. 27.2 months, p=0.01) (lowest quartile vs. highest three quartiles). While higher CRBN levels can serve as a surrogate for low risk disease, our study demonstrates that low CRBN expression can predict resistance to IMiD monotherapy and is a predictive biomarker for survival outcomes.

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

    PubMed

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

    2016-05-11

    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.

  8. 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

  9. Dexamethasone-induced catatonia in a patient with multiple myeloma.

    PubMed

    Vanstechelman, Sylvie; Vantilborgh, Anna; Lemmens, Gilbert

    2016-12-01

    Catatonia is a complex neuropsychiatric syndrome, caused by different underlying metabolic, neurologic, psychiatric and toxic conditions. Although catatonia is often associated with psychiatric disorders such as schizophrenia or depression, in about 20 to 39% of the patients a somatic illness is found. Unfortunately, this diagnosis is often missed although catatonia is characterized by a specific symptom complex. We report a case of acute catatonia with psychotic features in a patient with multiple myeloma (MM), caused by systemic use of dexamethasone. Physicians should be aware of possible psychiatric side effects when prescribing high doses of dexamethasone. Further, MM patients on corticosteroids should be closely monitored for mild psychological and/or psychiatric symptoms since they may be predictive for the onset of catatonia.

  10. Posttransplant maintenance therapy in multiple myeloma: the changing landscape

    PubMed Central

    Sengsayadeth, S; Malard, F; Savani, B N; Garderet, L; Mohty, M

    2017-01-01

    Transplant-eligible patients with multiple myeloma (MM) now have extended survival after diagnosis owing to effective modern treatment strategies that include new agents in induction therapy, autologous stem cell transplant (ASCT), consolidation therapy and posttransplant maintenance therapy. Standard of care for newly diagnosed, fit patients includes ASCT and, often nowadays, posttransplant maintenance. Several large studies have shown the efficacy of maintenance with thalidomide, lenalidomide and bortezomib in the treatment scheme of MM with regards to prolonging progression-free survival and, to a lesser degree, overall survival. Herein we discuss the data currently available to support the use of maintenance therapy in patients after ASCT as well as the newer available agents that may be a part of its changing landscape in the years to come. PMID:28338672

  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. Daratumumab: monoclonal antibody therapy to treat multiple myeloma.

    PubMed

    Xia, C; Ribeiro, M; Scott, S; Lonial, S

    2016-10-01

    Daratumumab (Darzalex[TM]) is a human monoclonal antibody (MAb) that targets CD38; a surface protein highly expressed across multiple myeloma (MM) cells. Preclinical studies have shown daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC) antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis upon secondary crosslinking and immunomodulatory effects via a decrease in immune suppressive cells. Daratumumab has a favorable toxicity profile and encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) and stem cell transplant have already failed. Given the encouraging efficacy and acceptable safety profile, daratumumab has emerged as a novel treatment option for MM both as a monotherapy and in combination with conventional and novel anti-MM agents. This review will focus on preclinical pharmacology, pharmacokinetics, safety and clinical development of daratumumab in MM.

  13. Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma.

    PubMed

    Li, Yi; Zheng, Yuhuan; Li, Tianshu; Wang, Qiang; Qian, Jianfei; Lu, Yong; Zhang, Mingjun; Bi, Enguang; Yang, Maojie; Reu, Frederic; Yi, Qing; Cai, Zhen

    2015-09-15

    We previously showed that macrophages (MΦs) infiltrate the bone marrow (BM) of patients with myeloma and may play a role in drug resistance. This study analyzed chemokines expressed by myeloma BM that are responsible for recruiting monocytes to the tumor bed. We found that chemokines CCL3, CCL14, and CCL2 were highly expressed by myeloma and BM cells, and the levels of CCL14 and CCL3 in myeloma BM positively correlated with the percentage of BM-infiltrating MΦs. In vitro, these chemokines were responsible for chemoattracting human monocytes to tumor sites and in vivo for MΦ infiltration into myeloma-bearing BM in the 5TGM1 mouse model. Surprisingly, we also found that these chemokines stimulated MΦ in vitro proliferation induced by myeloma cells and in vivo in a human myeloma xenograft SCID mouse model. The chemokines also activated normal MΦ polarization and differentiation into myeloma-associated MΦs. Western blot analysis revealed that these chemokines promoted growth and survival signaling in MΦs via activating the PI3K/Akt and ERK MAPK pathways and c-myc expression. Thus, this study provides novel insight into the mechanism of MΦ infiltration of BM and also potential targets for improving the efficacy of chemotherapy in myeloma.

  14. Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis.

    PubMed

    Landgren, O; Devlin, S; Boulad, M; Mailankody, S

    2016-12-01

    Driven by access to better drugs, on average, newly diagnosed multiple myeloma patients have over 10 years overall survival. Using modern combination therapies-with or without the addition of high-dose melphalan and autologous stem cell transplantation-up to 80% of patients reach a complete response. As a logical and necessary step forward, clinical studies have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. In this context, MRD has been proposed as a regulatory end point for drug approval in newly diagnosed multiple myeloma. To better define the role of MRD negativity in relation to clinical outcomes, we undertook a meta-analysis including published clinical trials of newly diagnosed multiple myeloma patients. We applied a random effects model which weighted studies using the inverse-variance method. Studies were combined on the scale of the logarithm of the hazard ratio (HR) and the corresponding s.d. We found that MRD negativity (versus positivity) was associated with better PFS (HR=0.35; 95% confidence interval (CI) 0.27-0.46; P<0.001) and overall survival (HR=0.48; 95% CI 0.33-0.70; P<0.001). Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma.

  15. Analysis of soluble urokinase plasminogen activator receptor in multiple myeloma for predicting prognosis.

    PubMed

    Shen, Jie; Wang, Qing; Wang, Juan; Su, Guo-Hong; Wang, Juan; Guo, Sheng-Hu; Liu, Y A; Wu, Zheng; Liu, Rong-Feng; Li, Xing; Guo, Xiao-Jin; Cao, Jing; Zhang, Yue-Hua; Wang, Zhi-Yu

    2015-10-01

    Multiple myeloma is a type of malignancy, which affects the plasma cells of the bone marrow. Recent studies have found that malignant plasma cells may express urokinase plasminogen activator (uPA) and uPA receptor (uPAR), and that initiation of proteolytic events by this system contributes to the process of invasion and destruction of the bone marrow. Studies have also suggested that the level of the soluble form of uPAR (suPAR) may act as a marker for prognosis in patients with multiple myeloma, and that there is an association between uPAR/suPAR expression, and clinical characteristics, efficacy of treatment in disease control and patient survival. In order to investigate this, the present study used flow cytometry to detect the monoclonal antibodies associated with multiple myeloma, specifically, uPAR (CD87), CD56 and CD38. Patients with multiple myeloma were divided into the following groups: The effective groups (remission and stable disease) and the ineffective group (progressive disease). suPAR expression in the effective groups was 257.6±32.47 pg/ml and 331.0±99.80 pg/ml respectively, which was not significantly different from that of the normal control group (P>0.05). By contrast, the suPAR level in the invalid group was 562.2±291.0 pg/ml, which was significantly different from the levels in the normal control group (P<0.01) and the effective groups (P<0.05). suPAR levels were positively correlated with disease stage (P<0.01), renal function (P<0.05), C-reactive protein (P<0.005), β2-microglobulin (P<0.001), extramedullary involvement (P<0.001), chromosome 13 deletion (P<0.01) and survival >2 years (P<0.01). They were was negatively correlated with hemoglobin concentration. No correlation was observed between uPAR expression and suPAR levels. The present study also indicated that the stage of disease and suPAR expression were independent factors, which predicted survival of <2 years. In conclusion, high suPAR expression appears to predict disease

  16. Multiple myeloma international staging system: "staging" or simply "aging" system?

    PubMed

    Bataille, Regis; Annweiler, Cedric; Beauchet, Olivier

    2013-12-01

    Because of the wide variation in multiple myeloma (MM) survival, numerous studies have focused over the past 40 years on the biological and cytogenetic prognostic values in MM patients. Since 2005, the MM International Staging System (ISS) has recognized the combination of beta-2 microglobulin (β2M) with serum albumin (SA) concentrations as the most simple and potent combination to determine the prognosis in MM patients. Curiously, the reasons for the efficiency of the combination of β2M with SA remain not clear-cut. In 2007, Fonseca and San Miguel (Prognostic factors and staging in multiple myeloma. Hematol Oncol Clin North Am 2007; 21:1115-40) underlined that cytogenetic assessment might also be useful for evaluating MM prognosis. Furthermore, new perspectives recently appeared with the genomic approach. Here, we (1) question the specific rationale for β2M and SA as prognostic markers in MM, (2) emphasize the well-documented prognostic implications of β2M and SA as potent biomarkers of comorbidity in older adults, and (3) conclude that the current MM-ISS is rather a staging system for age-related comorbidity burden (ie, aging system) than a specific MM staging system, and should not be used alone. Thus, we suggest that: (1) cytogenetics with the superscript MM-ISS could be the standard method; (2) some factors discovered using genomics could reflect the comorbidity burden and the intrinsic malignancy of MM clone, and thus needs more investigation; and (3) while waiting for standard genomic classification. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Observational study of multiple myeloma in Latin America.

    PubMed

    Hungria, Vania T M; Maiolino, Angelo; Martinez, Gracia; Duarte, Gislaine Oliveira; Bittencourt, Rosane; Peters, Lygia; Colleoni, Gisele; Oliveira, Luciana C O; Crusoé, Edvan; Coelho, Érika O D M; Pasquini, Ricardo; Magalhães, Sílvia M M; Nunes, Renata; Neto, Jorge V Pinto; Faria, Rosa Malena O; Souza, Mair; Hamerschlak, Nelson; Flantl, Dorotea; Navarro, J R; Conte, Guillermo; Gomez-Almaguer, David; Ruiz-Argüelles, Guillermo; Durie, Brian G M

    2017-01-01

    Relatively little is known about the outcomes of multiple myeloma in Latin America, a world region where incorporation of novel agents is generally slow. In the current retrospective-prospective study, we aimed to describe the patterns of care and treatment results in five Latin American countries. Between April 2007 and October 2009, patients who had been diagnosed from January 2005 to December 2007 were registered at 23 institutions from Argentina, Brazil, Chile, Mexico, and Peru. We divided patients into two cohorts, according to transplantation eligibility, and analyzed them with regard to first-line treatment and overall survival (OS). We analyzed a total of 852 patients, 46.9 % of whom were female. The median follow-up was 62 months. Among transplantation-ineligible patients (N = 461), the mean age was 67.4 years, approximately one third of patients received a thalidomide-based treatment in the first line, and the median OS was 43.0 months. Transplantation-eligible patients (N = 391) had a mean age of 54.7 years and a median OS of 73.6 months. Autologous transplantation was performed in 58.6 % of the patients for whom this procedure was initially planned and in only 26.9 % of the overall patients. Our long-term results reflect the contemporary literature for patients with multiple myeloma treated with autologous transplantation and thalidomide-based regimens in clinical trials and observational studies. However, further efforts are needed to approve and incorporate novel agents in Latin American countries, as well as to increase access to transplantation, in order to achieve the expected improvements in patient outcomes.

  18. A preclinical assay for chemosensitivity in multiple myeloma

    PubMed Central

    Khin, Zayar P.; Ribeiro, Maria L. C.; Jacobson, Timothy; Hazlehurst, Lori; Perez, Lia; Baz, Rachid; Shain, Kenneth; Silva, Ariosto S.

    2013-01-01

    Accurate preclinical predictions of the clinical efficacy of experimental cancer drugs are highly desired but often haphazard. Such predictions might be improved by incorporating elements of the tumor microenvironment in preclinical models by providing a more physiological setting. In generating improved xenograft models, it is generally accepted that the use of primary tumors from patients are preferable to clonal tumor cell lines. Here we describe an interdisciplinary platform to study drug response in multiple myeloma (MM), an incurable cancer of the bone marrow. This platform uses microfluidic technology to minimize the number of cells per experiment, while incorporating 3D extracellular matrix and mesenchymal cells derived from the tumor microenvironment. We used sequential imaging and a novel digital imaging analysis algorithm to quantify changes in cell viability. Computational models were used convert experimental data into dose-exposure-response "surfaces" which offered predictive utility. Using this platform, we predicted chemosensitivity to bortezomib and melphalan, two clinical MM treatments, in 3 MM cell lines and 7 patient-derived primary MM cell populations. We also demonstrated how this system could be used to investigate environment-mediated drug resistance and drug combinations that target it. This interdisciplinary preclinical assay is capable of generating quantitative data that can be used in computational models of clinical response, demonstrating its utility as a tool to contribute to personalized oncology. Major Findings By designing an experimental platform with the specific intent of generating experimental parameters for a computational clinical model of personalized therapy in multiple myeloma, while taking in consideration the limitations of working with patient primary cells, and the need to incorporate elements of the tumor microenvironment, we have generated patient-individualized estimations of initial response and time to relapse

  19. 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. © 2016 John Wiley & Sons Ltd.

  20. 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

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

    PubMed

    Husnain, Muhammad; Kurtin, Sandra; Barkett, Nikki; Bin Riaz, Irbaz; Agarwal, Amit

    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.

  2. Genetic events in the pathogenesis of multiple myeloma

    PubMed Central

    Chng, W. J.; Glebov, O.; Bergsagel, P.L.; Kuehl, W. M.

    2007-01-01

    The genetics of myeloma has been increasingly elucidated in recent years. Recurrent genetic events, and also biologically distinct and clinically relevant genetic subtypes of myeloma have been defined. This has facilitated our understanding of the molecular pathogenesis of the disease. In addition, some genetic abnormalities have proved to be highly reproducible prognostic factors. With the expanding therapeutic armamentarium, it is time to include genetic assessment as part of clinical evaluation of myeloma patients to guide management. In this review we examine the role of various genetic abnormalities in the molecular pathogenesis of myeloma, and the use of such abnormalities in disease classification, prognosis and clinical management. PMID:18070707

  3. Suppression of tumor growth by a heterologous antibody directed against multiple myeloma dominant CD38 antigen in SCID mice injected with multiple myeloma cells.

    PubMed

    Barabas, Arpad Z; Cole, Chad D; Graeff, Richard M; Kovacs, Zoltan B; Lafreniere, Rene

    2016-01-01

    Employing passive immunization - using a heterologous anti-CD38 IgG antibody containing serum - in SCID mice injected subcutaneously with human multiple myeloma cells, we have shown that treatments with the antiserum - especially in the presence of complement - significantly decreased cancer growth. However, administered antibody and complement was not sufficient in amount to prevent cancer cell multiplication and cancer growth expansion to a satisfactory degree. Larger volumes of the same components more than likely would have further reduced cancer growth and prolonged the life of mice. In control mice, cancer growth progressed faster proving that lytic immune response against multiple myeloma cells is necessary for cancer cell kill.

  4. 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

  5. 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.

  6. 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

  7. European Perspective on Multiple Myeloma Treatment Strategies in 2014

    PubMed Central

    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

    2014-01-01

    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. PMID:25063227

  8. Association of response endpoints with survival outcomes in multiple myeloma

    PubMed Central

    Lonial, S; Anderson, K C

    2014-01-01

    Since the introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, more patients with multiple myeloma are achieving deep, durable responses and disease control, and are living longer. These improvements have afforded more robust analyses of the relationship between response and survival. Generally, these studies have demonstrated that improvements in the quality of response across all stages of treatment are associated with better disease control and longer survival. Thus, achievement of maximal response should be strongly considered, particularly in the frontline setting, but must also be balanced with tolerability, quality of life and patient preferences. In select patients, achievement of a lesser response may be adequate to prolong survival, and attempts to treat these patients to a deeper response may place them at unnecessary risk without significant benefit. Maintenance therapy has been shown to improve the quality of response and disease control and, in some studies, survival. Studies support maintenance therapy for high-risk patients as a standard of care, and there are emerging data supporting maintenance therapy in standard-risk patients to improve progression-free and possibly overall survival. Multidrug regimens combining a proteasome inhibitor and an IMiD have shown exceptional response outcomes with acceptable increases in toxicity in both the frontline and salvage settings, and are becoming a standard treatment approach. Moving forward, the use of immunophenotypic and molecular response criteria will be essential in better understanding the impact of highly active and continuous treatment regimens across myeloma patient populations. Future translational studies will help to develop antimyeloma agents to their fullest potential. The introduction of novel targeted therapies, including the IMiD pomalidomide and the proteasome inhibitors carfilzomib and ixazomib (MLN9708), will provide

  9. The Predictive Role of the Neutrophil/Lymphocyte Ratio in Survival with Multiple Myeloma: A Single Center Experience.

    PubMed

    Onec, Birgul; Okutan, Harika; Albayrak, Murat; Saribacak Can, Esra; Aslan, Vedat; Unver Koluman, Basak; Soyer Kosemehmetoglu, Ozge; Albayrak, Aynur; Kos, Durdu Mehmet

    2017-03-01

    Recent studies have shown a positive correlation between tumor-related immune response markers and the poor outcome in solid tumors. In this study, we aimed to investigate the neutrophil/lymphocyte ratio (NLR) in multiple myeloma. To the best of our knowledge, this would be the second report concerning this topic. We retrospectively reviewed the data for 52 multiple myeloma patients. The patients were grouped using the baseline NLR as NLR ≤ 1.72 and NLR > 1.72 using receiver operating characteristic analysis to determine a cut off. We compared the two groups in terms of both the known prognostic factors of the myeloma and the overall survival (OS). Our study showed that NLR is associated with C-reactive protein and β2 microglobulin (P = 0.02 and P = 0.001, respectively). The patients with NLR > 1.72 had significantly worse stages, performance status, and kidney functions. The whole group's OS was estimated as 35.1 months while the patients with lower NLR had better OS when compared with those with NLR > 1.72 (42.75 and 26.14 months, respectively, P: 0.04). Neutrophil/lymphocyte ratio, which is associated with stage, performance status, and kidney functions, can be used in daily practice as a predictor for survival in multiple myeloma. Simply adding NLR to the routine charts may enrich our data for larger studies. © 2016 Wiley Periodicals, Inc.

  10. [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