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Sample records for multiple myeloma correlate

  1. Multiple myeloma

    MedlinePlus

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

  2. Multiple myeloma.

    PubMed

    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.

  3. Multiple myeloma

    PubMed Central

    Rajkumar, S. Vincent

    2008-01-01

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

  4. 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

  5. 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 ...

  6. 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.

  7. Multiple Myeloma

    MedlinePlus

    ... a type of white blood cell called a plasma cell. Plasma cells help you fight infections by making antibodies ... Doctors know that myeloma begins with one abnormal plasma cell in your bone marrow — the soft, blood- ...

  8. What Happens After Treatment for Multiple Myeloma?

    MedlinePlus

    ... After Treatment What Happens After Treatment for Multiple Myeloma? For most people, multiple myeloma never goes away ... for Multiple Myeloma Stops Working More In Multiple Myeloma About Multiple Myeloma Causes, Risk Factors, and Prevention ...

  9. Can Multiple Myeloma Be Found Early?

    MedlinePlus

    ... Myeloma Early Detection, Diagnosis, and Staging Can Multiple Myeloma Be Found Early? It’s difficult to diagnose multiple ... Your Doctor About Multiple Myeloma? More In Multiple Myeloma About Multiple Myeloma Causes, Risk Factors, and Prevention ...

  10. 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.

  11. 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

  12. 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.

  13. What Is Multiple Myeloma?

    MedlinePlus

    ... Multiple myeloma is a cancer formed by malignant plasma cells. Normal plasma cells are found in the bone marrow and ... to an infection, they mature and change into plasma cells. Plasma cells make the antibodies (also called ...

  14. Multiple Myeloma Symptoms

    MedlinePlus

    ... Investors Our Model Testimonials Investor Resources Investor Spotlight Financials Estate Planning Investor Services MMRF EVENTS MMRF Events Team for Cures Signature Events Independent Events Featured Supporters Spirit of Hope Honorees Education ... Partners Careers ABOUT MULTIPLE MYELOMA What ...

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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

  20. Smoldering multiple myeloma.

    PubMed

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

    2015-05-14

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

  1. 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

  2. [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.

  3. Genetics Home Reference: multiple myeloma

    MedlinePlus

    ... in these genes may interfere with proper control (regulation) of cell growth and division (proliferation), resulting in ... Plasma Cell Neoplasms Including Multiple Myeloma NCI Surveillance, Epidemiology, and End Results Program Educational Resources (5 links) ...

  4. 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

  5. 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.

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

    MedlinePlus

    ... What Should You Ask Your Doctor About Multiple Myeloma? As you deal with your cancer and the ... Your Doctor About Multiple Myeloma? More In Multiple Myeloma About Multiple Myeloma Causes, Risk Factors, and Prevention ...

  7. 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

  8. 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 ...

  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. Drugs Approved for Multiple Myeloma

    Cancer.gov

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

  11. 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.

  12. [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.

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

    PubMed Central

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

    2016-01-01

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

  14. 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 ...

  15. 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.

  16. [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.

  17. 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.

  18. 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

  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. 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.

  1. 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.

  2. 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

  3. 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

  4. [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.

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  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. 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.

  7. 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.

  8. 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.

  9. 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".

  10. [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.

  11. 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.

  12. 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.

  13. [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.

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. Therapy strategies for multiple myeloma: current status.

    PubMed

    Gisslinger, Heinz; Kees, Mathias

    2003-08-14

    Multiple myeloma (MM) is characterized by infiltration of bone marrow with a clone of neoplastic plasma cells. Impaired hematopoiesis and reduced production of functional immunoglobulins, as well as the induction of pathognomonic osteolytic lesions primarily contribute to the morbidity of patients with MM. Conventional chemotherapy is the treatment of choice for older patients, whereas those under 60 years benefit significantly from high-dose therapy followed by stem-cell rescue. The use of tandem transplantation, developed to further escalate the conditioning dose, has achieved additional improvement in survival. Interferon-alpha and glucocorticoids are effective as maintenance measures in MM but remain controversial because of their associated high costs and considerable toxicity. The resurrection of an old drug, thalidomide, for the therapy of MM and the development of potent immunomodulatory derivatives are highly promising new treatments that target MM cell-host interactions and the bone-marrow microenvironment, as well as the myeloma cell itself. The importance of the use of bisphosphonates for the prevention or amelioration of skeletal complications and hypercalcemia is well established. New generations of bisphosphonates show potent antitumor activity, again emphasising the importance of targeting the microenvironment of the plasma-cell clone.

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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

  14. [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.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. Stages of Plasma Cell Neoplasms (Including Multiple Myeloma)

    MedlinePlus

    ... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

  7. Treatment Options for Plasma Cell Neoplasms (Including Multiple Myeloma)

    MedlinePlus

    ... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

  8. 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.

  9. Do We Know What Causes Multiple Myeloma?

    MedlinePlus

    ... spread to other organs. Myeloma cells also show abnormalities in their chromosomes. In human cells, DNA is packaged into chromosomes. ... one chromosome has switched with part of another chromosome in the myeloma cells. ... have important abnormalities in other bone marrow cells and that these ...

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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.

  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. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. [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.

  2. 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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. Cerebral involvement in multiple myeloma: case report.

    PubMed Central

    McCarthy, J; Proctor, S J

    1978-01-01

    Cerebral myeloma in a 49-year-old white man took the form of diffuse arachnoid infiltration, intracerebral perivascular cuffing, and frank intracerebral invasion. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:417093

  9. Soluble Rank Ligand Produced by Myeloma Cells Causes Generalised Bone Loss in Multiple Myeloma

    PubMed Central

    Lawson, Michelle Anne; Yong, Kwee; Rabin, Neil; Perry, Mark; Vanderkerken, Karen; Croucher, Peter Ian

    2012-01-01

    Patients with multiple myeloma commonly develop focal osteolytic bone disease, as well as generalised osteoporosis. The mechanisms underlying the development of osteoporosis in patients with myeloma are poorly understood. Although disruption of the RANKL/OPG pathway has been shown to underlie formation of focal osteolytic lesions, its role in the development of osteoporosis in myeloma remains unclear. Increased soluble RANKL in serum from patients with myeloma raises the possibility that this molecule plays a key role. The aim of the present study was to establish whether sRANKL produced by myeloma cells contributes directly to osteoporosis. C57BL/KaLwRij mice were injected with either 5T2MM or 5T33MM murine myeloma cells. 5T2MM-bearing mice developed osteolytic bone lesions (p<0.05) with increased osteoclast surface (p<0.01) and reduced trabecular bone volume (p<0.05). Bone volume was also reduced at sites where 5T2MM cells were not present (p<0.05). In 5T2MM-bearing mice soluble mRANKL was increased (p<0.05), whereas OPG was not altered. In contrast, 5T33MM-bearing mice had no changes in osteoclast surface or trabecular bone volume and did not develop osteolytic lesions. Soluble mRANKL was undetectable in serum from 5T33MM-bearing mice. In separate experiments, RPMI-8226 human myeloma cells were transduced with an human RANKL/eGFP construct, or eGFP alone. RPMI-8226/hRANKL/eGFP cells, but not RPMI-8226/eGFP cells, stimulated osteoclastic bone resorption (p<0.05) in vitro. Sub-cutaneous injection of NOD/SCID mice with RPMI-8226/hRANKL/eGFP or RPMI-8226/eGFP cells resulted in tumour development in all mice. RPMI-8226/hRANKL/eGFP-bearing mice exhibited increased serum soluble hRANKL (p<0.05) and a three-fold increase in osteoclast number (p<0.05) compared to RPMI-8226/eGFP-bearing mice. This was associated with reduced trabecular bone volume (27%, p<0.05), decreased trabecular number (29%, p<0.05) and increased trabecular thickness (8%, p<0.05). Our findings

  10. [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.

  11. 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.

  12. [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.

  13. 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.

  14. 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

  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. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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.

  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. 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.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. [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.

  11. 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.

  12. 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.

  13. 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

  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

    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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  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. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. [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.

  10. 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.

  11. 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.

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

    PubMed

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

    2014-12-01

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

  13. 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.

  14. 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

  15. 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

  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.

  18. 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

  19. 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

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. IMWG consensus on maintenance therapy in multiple myeloma

    PubMed Central

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

    2012-01-01

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

  10. 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

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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.

  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. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

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

    PubMed Central

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

    2016-01-01

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

  10. Coexistence of chronic neutrophilic leukemia with multiple myeloma.

    PubMed

    Dinçol, Günçağ; Nalçaci, Meliha; Doğan, Oner; Aktan, Melih; Küçükkaya, Reyhan; Ağan, Mehmet; Dinçol, Koray

    2002-03-01

    A case report of simultaneous presentation of chronic neutrophilic leukemia and multiple myeloma (IgG kappa) in a 71-year-old male is described. The patient showed mature neutrophilic leukocytosis, hepatosplenomegaly, high neutrophil alkaline phosphatase score, hyperuricemia, neutrophils with toxic granulation and Döhle bodies, absence of Philadelphia chromosome and of the bcr-abl fusion gene. Moreover, a monoclonal IgG kappa paraproteinemia (36.93 g l(-1)) was detected. Bence-Jones proteinuria was 3.84 g l(-1). The bone marrow was grossly hypercellular with marked myeloid hyperplasia and aggregates of plasma cells. The patient died of severe bronchopneumonia after the transformation of chronic neutrophilic leukemia to acute myelomonocytic leukemia, 1.5 years following diagnosis.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  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. 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

  4. 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.

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

    PubMed Central

    Weisel, Katja

    2016-01-01

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

  6. Analysis of a Compartmental Model of Endogenous Immunoglobulin G Metabolism with Application to Multiple Myeloma

    PubMed Central

    Kendrick, Felicity; Evans, Neil D.; Arnulf, Bertrand; Avet-Loiseau, Hervé; Decaux, Olivier; Dejoie, Thomas; Fouquet, Guillemette; Guidez, Stéphanie; Harel, Stéphanie; Hebraud, Benjamin; Javaugue, Vincent; Richez, Valentine; Schraen, Susanna; Touzeau, Cyrille; Moreau, Philippe; Leleu, Xavier; Harding, Stephen; Chappell, Michael J.

    2017-01-01

    Immunoglobulin G (IgG) metabolism has received much attention in the literature for two reasons: (i) IgG homeostasis is regulated by the neonatal Fc receptor (FcRn), by a pH-dependent and saturable recycling process, which presents an interesting biological system; (ii) the IgG-FcRn interaction may be exploitable as a means for extending the plasma half-life of therapeutic monoclonal antibodies, which are primarily IgG-based. A less-studied problem is the importance of endogenous IgG metabolism in IgG multiple myeloma. In multiple myeloma, quantification of serum monoclonal immunoglobulin plays an important role in diagnosis, monitoring and response assessment. In order to investigate the dynamics of IgG in this setting, a mathematical model characterizing the metabolism of endogenous IgG in humans is required. A number of authors have proposed a two-compartment nonlinear model of IgG metabolism in which saturable recycling is described using Michaelis–Menten kinetics; however it may be difficult to estimate the model parameters from the limited experimental data that are available. The purpose of this study is to analyse the model alongside the available data from experiments in humans and estimate the model parameters. In order to achieve this aim we linearize the model and use several methods of model and parameter validation: stability analysis, structural identifiability analysis, and sensitivity analysis based on traditional sensitivity functions and generalized sensitivity functions. We find that all model parameters are identifiable, structurally and taking into account parameter correlations, when several types of model output are used for parameter estimation. Based on these analyses we estimate parameter values from the limited available data and compare them with previously published parameter values. Finally we show how the model can be applied in future studies of treatment effectiveness in IgG multiple myeloma with simulations of serum monoclonal

  7. Multiple Myeloma Associated Chronic Inflammatory Demyelinating Polyradiculoneuropathy: The Importance of Continued Surveillance

    PubMed Central

    Loncharich, Michael F; Gandhi, Viral; Rana, Sandeep; Balaan, Marvin

    2016-01-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease presenting with weakness and numbness in a remitting or chronic progressive course. It is known to have several clinical presentations and several associated diseases. CIDP has been associated with multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), and other paraproteinemias. We present a case of refractory CIDP in which the initial workup for multiple myeloma was negative, and multiple myeloma was then diagnosed two and half years later. Treatment of the multiple myeloma led to clinical improvement. This case is instructive in that perhaps more frequent surveillance for paraproteinemia in patients with CIPD, even after a negative initial workup, could lead to a better clinical outcome. PMID:28070468

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

    ClinicalTrials.gov

    2016-06-27

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

  9. Multiple myeloma: Development of plasma cell sarcoma during apparently successful chemotherapy

    PubMed Central

    Holt, J. M.; Robb-Smith, A. H. T.

    1973-01-01

    Three patients with multiple myeloma who developed a plasma cell sarcoma during apparently successful chemothapy are described. It is postulated that the chemotherapy induced the sarcomatous change. Images PMID:4584727

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

    PubMed Central

    Nayak, Madhurima K.

    2016-01-01

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

  11. [Infective endocarditis in a patient with multiple myeloma. A case report].

    PubMed

    Kacprzak, Aneta; Wawrzyńśka, Liliana; Szturmowicz, Monika; Wiśniewska, Joanna; Gralec, Renata; Stepińska, Janina; Szufladowicz, Marek; Biederman, Andrzej; Seferyńska, Ilona; Warzocha, Krzysztof; Torbicki, Adam

    2005-10-01

    A case of a 59 year old male with infective endocarditis is presented. Antibiotic therapy seemed effective, however, inflammation laboratory parameters increased two weeks after clinical improvement and body temperature normalisation. Subsequent extensive laboratory investigations revealed multiple myeloma. The patient underwent successful aortic valve replacement and received pharmacological therapy for multiple myeloma. Difficulties in diagnosing and treatment of patients with infective endocarditis who have other concomitant diseases, are discussed.

  12. ESRD due to Multiple Myeloma in the United States, 2001-2010.

    PubMed

    Reule, Scott; Sexton, Donal J; Solid, Craig A; Chen, Shu-Cheng; Foley, Robert N

    2016-05-01

    Although management of multiple myeloma has changed substantially in the last decade, it is unknown whether the burden of ESRD due to multiple myeloma has changed, or whether survival of patients with multiple myeloma on RRT has improved. Regarding ESRD due to multiple myeloma necessitating RRT in the United States, we evaluated temporal trends between 2001 and 2010 for demography-adjusted incidence ratios, relative to rates in 2001-2002, and mortality hazards from RRT initiation, relative to hazards in 2001-2002. In this retrospective cohort study, we used the US Renal Data System database (n=1,069,343), 2001-2010, to identify patients with ESRD due to multiple myeloma treated with RRT (n=12,703). Demography-adjusted incidence ratios of ESRD from multiple myeloma decreased between 2001-2002 and 2009-2010 in the overall population (demography-adjusted incidence ratio 0.82; 95% confidence interval, 0.79 to 0.86) and in most demographic subgroups examined. Mortality rates were 86.7, 41.4, and 34.4 per 100 person-years in the first 3 years of RRT, respectively, compared with 32.3, 20.6, and 21.3 in matched controls without multiple myeloma. Unadjusted mortality hazards ratios declined monotonically after 2004 to a value of 0.72; 95% confidence interval, 0.67 to 0.77 in 2009-2010, and declines between 2001-2002 and 2008-2009 were observed (P<0.05) in most demographic subgroups examined. Findings were similar when adjustment was made for demographic characteristics, comorbidity markers, and laboratory test values. These data suggest the incidence of RRT from multiple myeloma in the United States has decreased in the last decade, and clinically meaningful increases in survival have occurred for these patients.

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    Dingli, David

    2014-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  17. Identification of molecular vulnerabilities in human multiple myeloma cells by RNA interference lethality screening of the druggable genome.

    PubMed

    Tiedemann, Rodger E; Zhu, Yuan Xao; Schmidt, Jessica; Shi, Chang Xin; Sereduk, Chris; Yin, Hongwei; Mousses, Spyro; Stewart, A Keith

    2012-02-01

    Despite recent advances in targeted treatments for multiple myeloma, optimal molecular therapeutic targets have yet to be identified. To functionally identify critical molecular targets, we conducted a genome-scale lethality study in multiple myeloma cells using siRNAs. We validated the top 160 lethal hits with four siRNAs per gene in three multiple myeloma cell lines and two non-myeloma cell lines, cataloging a total of 57 potent multiple myeloma survival genes. We identified the Bcl2 family member MCL1 and several 26S proteasome subunits among the most important and selective multiple myeloma survival genes. These results provided biologic validation of our screening strategy. Other essential targets included genes involved in RNA splicing, ubiquitination, transcription, translation, and mitosis. Several of the multiple myeloma survival genes, especially MCL1, TNK2, CDK11, and WBSCR22, exhibited differential expression in primary plasma cells compared with other human primary somatic tissues. Overall, the most striking differential functional vulnerabilities between multiple myeloma and non-multiple myeloma cells were found to occur within the 20S proteasome subunits, MCL1, RRM1, USP8, and CKAP5. We propose that these genes should be investigated further as potential therapeutic targets in multiple myeloma.

  18. Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.

    PubMed

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

    2013-01-01

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

  19. Induction therapy alters plasma fibrin clot properties in multiple myeloma patients: association with thromboembolic complications.

    PubMed

    Undas, Anetta; Zubkiewicz-Usnarska, Lidia; Helbig, Grzegorz; Woszczyk, Dariusz; Kozińska, Justyna; Dmoszyńska, Anna; Dębski, Jakub; Podolak-Dawidziak, Maria; Kuliczkowski, Kazimierz

    2015-09-01

    Induction therapy in patients with multiple myeloma increases the risk of thromboembolism. We have recently shown that multiple myeloma patients tend to form denser fibrin clots displaying poor lysability. We investigated the effect of induction therapy on fibrin clot properties in multiple myeloma patients. Ex-vivo plasma fibrin clot permeability, turbidity, susceptibility to lysis, thrombin generation, factor VIII and fibrinolytic proteins were compared in 48 multiple myeloma patients prior to and following 3 months of induction therapy, mainly with cyclophosphamide-thalidomide-dexamethasone regimen. Patients on thromboprophylaxis with aspirin or heparins were eligible. A 3-month induction therapy resulted in improved clot properties, that is higher clot permeability, compaction, shorter lag phase and higher final turbidity, along with shorter clot lysis time and higher rate of D-dimer release from fibrin clots than the baseline values. The therapy also resulted in lower thrombin generation, antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI), but elevated factor VIII. Progressive disease was associated with lower posttreatment clot permeability and lysability. Despite thromboprophylaxis, two patients developed ischemic stroke and 10 had venous thromboembolism. They were characterized by pretreatment lower clot permeability, prolonged clot lysis time, longer lag phase, higher peak thrombin generation, TAFI and plasminogen activator inhibitor -1. Formation of denser plasma fibrin clots with reduced lysability and increased thrombin generation at baseline could predispose to thrombotic complications during induction treatment in multiple myeloma patients. We observed improved fibrin clot properties and thrombin generation in multiple myeloma patients except those with progressive disease.

  20. MTI-101 (cyclized HYD1) binds a CD44 containing complex and induces necrotic cell death in multiple myeloma.

    PubMed

    Gebhard, Anthony W; Jain, Priyesh; Nair, Rajesh R; Emmons, Michael F; Argilagos, Raul F; Koomen, John M; McLaughlin, Mark L; Hazlehurst, Lori A

    2013-11-01

    Our laboratory recently reported that treatment with the d-amino acid containing peptide HYD1 induces necrotic cell death in multiple myeloma cell lines. Because of the intriguing biological activity and promising in vivo activity of HYD1, we pursued strategies for increasing the therapeutic efficacy of the linear peptide. These efforts led to a cyclized peptidomimetic, MTI-101, with increased in vitro activity and robust in vivo activity as a single agent using two myeloma models that consider the bone marrow microenvironment. MTI-101 treatment similar to HYD1 induced reactive oxygen species, depleted ATP levels, and failed to activate caspase-3. Moreover, MTI-101 is cross-resistant in H929 cells selected for acquired resistance to HYD1. Here, we pursued an unbiased chemical biology approach using biotinylated peptide affinity purification and liquid chromatography/tandem mass spectrometry analysis to identify binding partners of MTI-101. Using this approach, CD44 was identified as a predominant binding partner. Reducing the expression of CD44 was sufficient to induce cell death in multiple myeloma cell lines, indicating that multiple myeloma cells require CD44 expression for survival. Ectopic expression of CD44s correlated with increased binding of the FAM-conjugated peptide. However, ectopic expression of CD44s was not sufficient to increase the sensitivity to MTI-101-induced cell death. Mechanistically, we show that MTI-101-induced cell death occurs via a Rip1-, Rip3-, or Drp1-dependent and -independent pathway. Finally, we show that MTI-101 has robust activity as a single agent in the SCID-Hu bone implant and 5TGM1 in vivo model of multiple myeloma.

  1. Sotatercept in patients with osteolytic lesions of multiple myeloma

    PubMed Central

    Abdulkadyrov, Kudrat M; Salogub, Galina N; Khuazheva, Nuriet K; Sherman, Matthew L; Laadem, Abderrahmane; Barger, Rachel; Knight, Robert; Srinivasan, Shankar; Terpos, Evangelos

    2014-01-01

    This phase IIa study evaluated the safety and tolerability of sotatercept, and its effects on bone metabolism and haematopoiesis in newly diagnosed and relapsed multiple myeloma (MM) patients. Patients were randomized (4:1) to receive four 28-d cycles of sotatercept (0·1, 0·3, or 0·5 mg/kg) or placebo. Patients also received six cycles of combination oral melphalan, prednisolone, and thalidomide (MPT). Thirty patients were enrolled; six received placebo and 24 received sotatercept. Overall, 25% of patients received all four sotatercept doses; 71% of sotatercept-treated patients had ≥1 dose interruption mainly due to increases in haemoglobin levels. Grade ≥3 adverse events (AEs) were reported in 17% of patients receiving placebo and 58% receiving sotatercept. Grade 4 AEs in sotatercept-treated patients were neutropenia, granulocytopenia, and atrial fibrillation (one patient each). In patients without bisphosphonate use, anabolic improvements in bone mineral density and in bone formation relative to placebo occurred, whereas bone resorption was minimally affected. Increases in haemoglobin levels, versus baseline, and the duration of the increases, were higher in the sotatercept-treated patients, with a trend suggesting a dose-related effect. Multiple doses of sotatercept plus MPT appear to be safe and generally well-tolerated in MM patients. PMID:24650009

  2. Necrobiotic Xanthogranuloma in a Patient with Multiple Myeloma

    PubMed Central

    Wruhs, Marlies; Feldmann, Robert; Sawetz, Isabelle; Breier, Friedrich; Steiner, Andreas

    2016-01-01

    An 82-year-old woman presented with a 9-month history of multiple, well-defined skin lesions on her neck and upper chest, progressively increasing in size. Histological examination of a skin biopsy showed a regular epidermis. In the dermis, granulomatous changes with central necrobiosis were found which extended focally into the subcutaneous fat. The necrobiotic areas were surrounded by Touton cells and foreign-body giant cells. Laboratory analysis revealed leucopenia. Serum electrophoresis and immunofixation disclosed the presence of an IgG-λ paraprotein. Bone marrow aspiration cytology showed 20% plasmatic cells. The skeletal X-ray revealed frontal and occipital osteolytic skull lesions as well as pubic osteolysis. Urinalysis was unremarkable without proteinuria. Based on the clinical, laboratory, and histological findings, necrobiotic xanthogranuloma in association with multiple myeloma was diagnosed. The patient was treated with bortezomib combined with oral dexamethasone. Follow-up at week 13 revealed the complete disappearance of the IgG paraproteinemia. However, the skin lesions remained unchanged. Therefore, bortezomib treatment was discontinued, and systemic corticosteroids were continued at a higher dosage. After the steroid treatment, the lesions markedly flattened. PMID:28101022

  3. Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells

    PubMed Central

    Sherbenou, Daniel W.; Aftab, Blake T.; Su, Yang; Behrens, Christopher R.; Wiita, Arun; Logan, Aaron C.; Acosta-Alvear, Diego; Hann, Byron C.; Walter, Peter; Shuman, Marc A.; Wu, Xiaobo; Atkinson, John P.; Wolf, Jeffrey L.; Martin, Thomas G.

    2016-01-01

    Multiple myeloma is incurable by standard approaches because of inevitable relapse and development of treatment resistance in all patients. In our prior work, we identified a panel of macropinocytosing human monoclonal antibodies against CD46, a negative regulator of the innate immune system, and constructed antibody-drug conjugates (ADCs). In this report, we show that an anti-CD46 ADC (CD46-ADC) potently inhibited proliferation in myeloma cell lines with little effect on normal cells. CD46-ADC also potently eliminated myeloma growth in orthometastatic xenograft models. In primary myeloma cells derived from bone marrow aspirates, CD46-ADC induced apoptosis and cell death, but did not affect the viability of nontumor mononuclear cells. It is of clinical interest that the CD46 gene resides on chromosome 1q, which undergoes genomic amplification in the majority of relapsed myeloma patients. We found that the cell surface expression level of CD46 was markedly higher in patient myeloma cells with 1q gain than in those with normal 1q copy number. Thus, genomic amplification of CD46 may serve as a surrogate for target amplification that could allow patient stratification for tailored CD46-targeted therapy. Overall, these findings indicate that CD46 is a promising target for antibody-based treatment of multiple myeloma, especially in patients with gain of chromosome 1q. PMID:27841764

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2009-12-01

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

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

    PubMed Central

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

    2010-01-01

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

  7. A virtual approach to evaluate therapies for management of multiple myeloma induced bone disease.

    PubMed

    Ji, Bing; Genever, Paul G; Fagan, Michael J

    2016-03-01

    Multiple myeloma bone disease is devastating for patients and a major cause of morbidity. The disease leads to bone destruction by inhibiting osteoblast activity while stimulating osteoclast activity. Recent advances in multiple myeloma research have improved our understanding of the pathogenesis of multiple myeloma-induced bone disease and suggest several potential therapeutic strategies. However, the effectiveness of some potential therapeutic strategies still requires further investigation and optimization. In this paper, a recently developed mathematical model is extended to mimic and then evaluate three therapies of the disease, namely: bisphosphonates, bortezomib and TGF-β inhibition. The model suggests that bisphosphonates and bortezomib treatments not only inhibit bone destruction, but also reduce the viability of myeloma cells. This contributes to the current debate as to whether bisphosphonate therapy has an anti-tumour effect. On the other hand, the analyses indicate that treatments designed to inhibit TGF-β do not reduce bone destruction, although it appears that they might reduce the viability of myeloma cells, which again contributes to the current controversy regarding the efficacy of TGF-β inhibition in multiple myeloma-induced bone disease.

  8. Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models.

    PubMed

    Punnoose, Elizabeth A; Leverson, Joel D; Peale, Franklin; Boghaert, Erwin R; Belmont, Lisa D; Tan, Nguyen; Young, Amy; Mitten, Michael; Ingalla, Ellen; Darbonne, Walter C; Oleksijew, Anatol; Tapang, Paul; Yue, Peng; Oeh, Jason; Lee, Leslie; Maiga, Sophie; Fairbrother, Wayne J; Amiot, Martine; Souers, Andrew J; Sampath, Deepak

    2016-05-01

    BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether coexpression of BCL-XL also affects antitumor responses to venetoclax in multiple myeloma. In multiple myeloma cell lines (n = 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-XL or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-XL were resistant to venetoclax but sensitive to a BCL-XL-selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-XL or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coexpressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xenografts that expressed BCL-XL, MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-XL selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies. IHC of multiple myeloma patient bone marrow biopsies and aspirates (n = 95) revealed high levels of BCL-2 and BCL-XL in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2(High)/BCL-XL (Low) In addition to MCL-1, our data suggest that BCL-XL may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib. Mol Cancer Ther; 15(5); 1132-44. ©2016 AACR.

  9. Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma

    PubMed Central

    Terpos, Evangelos; Kanellias, Nikolaos; Christoulas, Dimitrios; Kastritis, Efstathios; Dimopoulos, Meletios A

    2013-01-01

    Multiple myeloma remains an incurable disease despite the introduction of the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib that have improved the outcome of patients with both newly diagnosed and relapsed/refractory disease. However, patients who relapse after treatment with these agents or are refractory to them represent an unmet need and highlight the necessity for the development of novel anti-myeloma agents. Pomalidomide is an IMiD, structurally related to thalidomide, with enhanced antiangiogenic, antineoplastic, and anti-inflammatory properties and exhibiting potent anti-myeloma activity in vitro and in vivo. Pomalidomide has shown remarkable activity in patients who were refractory to both bortezomib and lenalidomide in Phase II and III studies. This paper reviews the chemistry and mechanisms of action of pomalidomide as well as all the available data from clinical trials on pomalidomide use in patients with refractory/relapsed multiple myeloma. PMID:23690693

  10. Assessing Heterogeneity of Osteolytic Lesions in Multiple Myeloma by 1H HR-MAS NMR Metabolomics

    PubMed Central

    Tavel, Laurette; Fontana, Francesca; Garcia Manteiga, Josè Manuel; Mari, Silvia; Mariani, Elisabetta; Caneva, Enrico; Sitia, Roberto; Camnasio, Francesco; Marcatti, Magda; Cenci, Simone; Musco, Giovanna

    2016-01-01

    Multiple myeloma (MM) is a malignancy of plasma cells characterized by multifocal osteolytic bone lesions. Macroscopic and genetic heterogeneity has been documented within MM lesions. Understanding the bases of such heterogeneity may unveil relevant features of MM pathobiology. To this aim, we deployed unbiased 1H high-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) metabolomics to analyze multiple biopsy specimens of osteolytic lesions from one case of pathological fracture caused by MM. Multivariate analyses on normalized metabolite peak integrals allowed clusterization of samples in accordance with a posteriori histological findings. We investigated the relationship between morphological and NMR features by merging morphological data and metabolite profiling into a single correlation matrix. Data-merging addressed tissue heterogeneity, and greatly facilitated the mapping of lesions and nearby healthy tissues. Our proof-of-principle study reveals integrated metabolomics and histomorphology as a promising approach for the targeted study of osteolytic lesions. PMID:27809247

  11. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: a review of the current understanding of epidemiology, biology, risk stratification, and management of myeloma precursor disease.

    PubMed

    Agarwal, Amit; Ghobrial, Irene M

    2013-03-01

    The term monoclonal gammopathy of undetermined significance (MGUS) was coined in 1978. The recent advances in our knowledge about MGUS and smoldering multiple myeloma (SMM) have helped us better understand the pathogenesis of myeloma. It seems that myeloma evolves from a precursor state in almost all cases. We do not completely understand the multistep process from the precursor state to myeloma, but studies like whole genome sequencing continue to improve our understanding of this process. The process of transformation may not be linear acquisition of changes, but rather a branched heterogeneous process. Clinical features that are prognostic of rapid transformation have been identified, but no specific molecular markers have been identified. Even with recent advances, multiple myeloma remains an incurable disease in the vast majority, and intervening at the precursor state provides a unique opportunity to alter the natural history of the disease. A limitation is that a vast majority of patients with precursor disease, especially low-risk MGUS, will never progress to myeloma in their lifetime, and treating these patients is not only unnecessary but may be potentially harmful. The challenge is to identify a subset of patients with the precursor state that would definitely progress to myeloma and in whom interventions will have a meaningful impact. As our understanding of the molecular and genetic processes improves, these studies will guide the selection of high-risk patients more appropriately and ultimately direct a tailored management strategy to either delay progression to symptomatic myeloma or even "cure" a person at this premalignant stage.

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

    PubMed

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

    2016-01-01

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

  13. Multiple myeloma in the marrow: pathogenesis and treatments

    PubMed Central

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

    2016-01-01

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

  14. New monoclonal antibodies on the horizon in multiple myeloma

    PubMed Central

    O’Donnell, Elizabeth K.; Raje, Noopur S.

    2016-01-01

    Across all cancers, monoclonal antibodies have emerged as a potential strategy for cancer therapy. Monoclonal antibodies target antigens expressed on the surface of cancer cells and accessory cells. This targeted approach uses the host’s immune system to promote the killing of cancer cells. Multiple myeloma (MM) is the second most common hematologic malignancy that remains incurable in the majority of patients. The treatment of MM has evolved dramatically over the past decade and continues to evolve with the approval of four new drugs in 2015. Most recently the United States Food and Drug Administration (US FDA) approved two monoclonal antibodies for the treatment of this disease. Monoclonal antibodies are generally well-tolerated and offer a novel method of action for treated relapsed and refractory disease and are now being studied in the upfront setting. In this article, we review the evidence for the existing approved monoclonal antibodies and discuss promising targeted therapies and innovative strategies for the treatment of MM. PMID:28203341

  15. Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma.

    PubMed

    Song, Y; Ray, A; Li, S; Das, D S; Tai, Y T; Carrasco, R D; Chauhan, D; Anderson, K C

    2016-09-01

    Proteasome inhibitor bortezomib is an effective therapy for relapsed and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance can limit its long-term utility. Recent research has focused on targeting ubiquitin receptors upstream of 20S proteasome, with the aim of generating less toxic therapies. Here we show that 19S proteasome-associated ubiquitin receptor Rpn13 is more highly expressed in MM cells than in normal plasma cells. Rpn13-siRNA (small interfering RNA) decreases MM cell viability. A novel agent RA190 targets Rpn13 and inhibits proteasome function, without blocking the proteasome activity or the 19S deubiquitylating activity. CRISPR/Cas9 Rpn13-knockout demonstrates that RA190-induced activity is dependent on Rpn13. RA190 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma and overcomes bortezomib resistance. Anti-MM activity of RA190 is associated with induction of caspase-dependent apoptosis and unfolded protein response-related apoptosis. MM xenograft model studies show that RA190 is well tolerated, inhibits tumor growth and prolongs survival. Combining RA190 with bortezomib, lenalidomide or pomalidomide induces synergistic anti-MM activity. Our preclinical data validates targeting Rpn13 to overcome bortezomib resistance, and provides the framework for clinical evaluation of Rpn13 inhibitors, alone or in combination, to improve patient outcome in MM.

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

    PubMed

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

    2014-04-03

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

  17. Multiple Myeloma in the Very Old: An IASIA Conference Report

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2016-01-01

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

  19. Silent venous thromboembolism in multiple myeloma patients treated with lenalidomide.

    PubMed

    Isoda, Atsushi; Sato, Naru; Miyazawa, Yuri; Matsumoto, Yoshinobu; Koumoto, Mina; Ookawa, Masahito; Sawamura, Morio; Matsumoto, Morio

    2015-09-01

    Lenalidomide treatment in combination with dexamethasone and/or chemotherapy is associated with a significant risk of venous thromboembolism (VTE) in patients with multiple myeloma (MM). However, the incidence of asymptomatic VTE in lenalidomide-treated MM patients remains unclear. A total of 80 relapsed and refractory MM patients treated with lenalidomide-containing regimens in a single institution between July 2010 and July 2014 were retrospectively analyzed. Of these, eight patients had asymptomatic VTE before starting lenalidomide. The remaining 72 patients received thromboprophylaxis with low-dose aspirin (100 mg daily) and monitoring of plasma D-dimer levels on each visit. During the median follow-up time of 7.3 months (range 1.0-43.5 months), 29 patients (40.3 %) showed an elevation of D-dimer (≥2.5 μg/mL), and 13 (18.1 %) showed asymptomatic VTE in a lower extremity. Median time to asymptomatic VTE events from initiation of lenalidomide treatment was 3.0 months (range 1.0-13.1 months). All patients having an asymptomatic VTE continued lenalidomide treatment on warfarinization (target international normalized ratio 1.5-2.5), and none of them developed symptomatic VTE. In conclusion, an asymptomatic VTE event occurred in 18 % of Japanese MM patients receiving lenalidomide-containing therapy despite aspirin prophylaxis. Serial monitoring of plasma D-dimer levels and early intervention may help to prevent symptomatic or lethal VTE events.

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

    PubMed Central

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

    2016-01-01

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

  1. Outcomes of multiple myeloma patients receiving bortezomib, lenalidomide, and carfilzomib.

    PubMed

    Berenson, Ariana; Vardanyan, Suzie; David, Michael; Wang, James; Harutyunyan, Nika Manik; Gottlieb, Jillian; Halleluyan, Ran; Spektor, Tanya M; Udd, Kyle A; Eshaghian, Shahrooz; Nassir, Youram; Eades, Benjamin; Swift, Regina; Berenson, James R

    2017-03-01

    New classes of drugs including the proteasome inhibitors (PI) bortezomib and, more recently, carfilzomib and the immunomodulatory agent lenalidomide have shown improved outcomes for multiple myeloma (MM) patients during the past decade. However, most of the studies reporting outcomes for patients receiving these drugs have relied on older data sets derived from large institutions that included patients not receiving their treatment at those facilities and represented only those eligible for clinical trials or were from sites where treatment options were limited. We have analyzed data from 258 MM patients who have received treatment with at least one of three agents: bortezomib, carfilzomib, and lenalidomide in a single clinic specializing in MM with respect to their responses and other outcomes to treatment regimens including these agents. Response rates were similar between these three drugs when used for the first time and again during subsequent treatment regimens. As expected, the clinical benefit rates (CBRs) were better for patients receiving their first treatment when compared to their use in subsequent treatment regimens. The CBRs were similar during their 2nd, 3rd, and 4th treatments containing these agents. Many patients refractory to these agents showed responses to regimens containing these same drugs when used in different combinations. In addition, patients refractory to one PI often responded to the other PI. The results of this study demonstrate that novel agents can be used repeatedly in novel combinations with significant clinical benefit for patients with MM.

  2. The osteoblastic niche in the context of multiple myeloma.

    PubMed

    Toscani, Denise; Bolzoni, Marina; Accardi, Fabrizio; Aversa, Franco; Giuliani, Nicola

    2015-01-01

    The osteoblastic niche has a critical role in the regulation of hemopoietic stem cell (HSC) quiescence and self-renewal and in the support of hematopoiesis. Several mechanisms are involved in the crosstalk between stem cells and osteoblasts, including soluble cytokines, adhesion molecules, and signal pathways such as the wingless-Int (Wnt), Notch, and parathyroid hormone pathways. According to the most recent evidence, there is an overlap between osteoblastic and perivascular niches that affects HSC function involving mesenchymal stromal and endothelial cells and a gradient of oxygen regulated by hypoxia inducible factor (HIF)-1α. Derived from plasma cells, multiple myeloma (MM) is a hematopoietic malignancy characterized by a peculiar dependency on the bone microenvironment. Quiescent MM cells may reside in the osteoblastic niche for protection from apoptotic stimuli; in turn, MM cells suppress osteoblast formation and function, leading to impairment of bone formation and the development of osteolytic lesions. Several recent studies have investigated the mechanisms involved in the relationship between osteoblasts and MM cells and identified potential therapeutic targets in the osteoblastic niche, including the HIF-1α, Runx2, and Wnt (both canonical and noncanonical) signaling pathways.

  3. Efficacy and safety of denosumab in multiple myeloma.

    PubMed

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

    2016-05-01

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

  4. Multiple myeloma--a case-control study.

    PubMed Central

    Cuzick, J.; De Stavola, B.

    1988-01-01

    A total of 399 patients with multiple myeloma and an equal number of match controls were interviewed about factors possibly related to the causes of their disease. Factors studied included occupation, chemical exposure, radiation exposure, prior diseases, immunizations, chronic infections and markers for defects in immune regulation. A strong risk associated with agriculture/food processing was observed (RR = 1.8, P = 0.002). The risk could not be restricted to those exposed to animals or meat products, or those exposed to pesticides. Significant excesses were also noted for reported exposures to chemicals and gases/fumes, but no specific agent or group of agents could be identified. Cases had fewer tonsillectomies above the age of 10 (P = 0.01). A large excess of shingles (herpes zoster) was observed in cases (P less than 0.001), but most of the excess cases occurred within 10 years of diagnosis, suggesting this was a preclinical manifestation of disease rather than a cause of it. PMID:3395559

  5. TRAF6 Activation in Multiple Myeloma: A Potential Therapeutic Target

    PubMed Central

    Liu, Hong; Tamashiro, Samantha; Baritaki, Stavroula; Penichet, Manuel; Yu, Youhua; Chen, Haiming; Berenson, James; Bonavida, Benjamin

    2013-01-01

    Multiple myeloma (MM) is an incurable B-lymphocyte malignancy. New therapeutic options have become available during the past several years; however nearly all patients acquire resistance to currently available therapeutic agents. Mechanisms contributing to the pathogenesis and chemoresistance of MM include genetic abnormalities, chromosomal translocations, gene mutations, the interaction between MM cells and the bone marrow microenvironment, and defects in the apoptotic signaling pathways. Survival signaling pathways associated with the pathogenesis of MM and bone marrow stromal cells play crucial roles in promoting growth, survival, adhesion, immortalization, angiogenesis, and drug resistance. The receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/tumor necrosis factor receptor-associated factor (RANK/RANKL-TRAF6) signal pathway mediates osteolytic bone lesions through the activation of the NF-κB and Janus kinase/signal transducer and activator of transcription (JNK) pathways in osteoclast precursor cells and thus contributes to the main clinical manifestations of bone disease. TRAF6 has also been identified as a ligase for Akt ubiquitination and membrane recruitment and its phosphorylation on growth factor stimulation. The inhibition of TRAF6 by silencing RNA or by decoy peptides decreases MM tumor cell proliferation and increases apoptosis as well as bone resorption. Some proteasome inhibitors and benzoxadiazole derivatives showed inhibitory effects on the activity and function of TRAF6. Overall, we propose that TRAF6 may be considered as a potential therapeutic target for the treatment of MM. PMID:22440007

  6. Ophthalmic manifestations of atypical IgD multiple myeloma.

    PubMed

    Edmunds, Matthew R; Cikatricis, Peter; Mukherji, Subhanjan; Bowyer, Jeremy D

    2012-07-19

    A previously healthy 32-year-old Caucasian female presented with sudden-onset horizontal diplopia following a paroxysm of coughing. She had recently sustained a pubic ramus fracture during an innocuous fall and had also noted a firm lump developing at the right side of her forehead. On examination, she had a right fronto-temporal mass. Visual acuities were 6/6 bilaterally. There was reduced abduction of the right eye, bilateral white, granular corneal opacities and evidence of bilateral optic disc swelling. Haematological investigations revealed normocytic anaemia, hypercalcaemia and raised erythrocyte sedimentation rate (ESR). CT showed lytic foci throughout the skull, ribs, scapulae, spine, pelvis and upper femora. Serum protein electrophoresis revealed immunoglobulin D (IgD)-kappa paraproteinaemia; urine electrophoresis showed free light chain kappa and bone marrow biopsy demonstrated 87% plasma cells. A diagnosis of IgD multiple myeloma was made, with subsequent chemotherapeutic treatment and eventual autologous stem cell transplant resulting in resolution of neuro-ophthalmic manifestations and prolonged disease remission.

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

    PubMed Central

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

    2016-01-01

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

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

    SciTech Connect

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

    2015-03-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-04-01

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

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

    PubMed Central

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

    2015-01-01

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

  13. Anti-galectin-3 therapy: a new chance for multiple myeloma and ovarian cancer?

    PubMed

    Mirandola, Leonardo; Nguyen, Diane D; Rahman, Rakhshanda L; Grizzi, Fabio; Yuefei, Yu; Figueroa, José A; Jenkins, Marjorie R; Cobos, Everardo; Chiriva-Internati, Maurizio

    2014-10-01

    Here we review the role of Galectins in the molecular pathogenesis of multiple myeloma and ovarian cancer, with a special focus on Glectin-3. Multiple myeloma is the second most common hematologic malignancy worldwide. Because the pathogenesis of multiple myeloma is still incompletely understood, there is no ultimately effective cure, and this cancer results fatal. Ovarian cancer is the most lethal gynecologic malignancy worldwide. Due to the lack of screening techniques for early detection, patients are mostly diagnosed with advanced disease, which results ultimately fatal. Multiple myeloma and ovarian cancer have different biologies, but they share a strong dependence on adhesion with extracellular matrix and other cells. Galectin-3 plays a key role in regulating such adhesive abilities of tumor cells. Here we discuss the outcomes and possible mechanism of action of a truncated, dominant negative form of Galectin-3, Galectin-3C, in these malignancies. Overall, we report that Galectin-3C is a promising new compound for effective adjuvant therapies in advanced, refractory multiple myeloma and ovarian cancer.

  14. Identifying multiple myeloma patients using data from the French health insurance databases

    PubMed Central

    Palmaro, Aurore; Gauthier, Martin; Conte, Cécile; Grosclaude, Pascale; Despas, Fabien; Lapeyre-Mestre, Maryse

    2017-01-01

    Abstract This study aimed to assess the performance of several algorithms based on hospital diagnoses and the long-term diseases scheme to identify multiple myeloma patients. Potential multiple myeloma patients in 2010 to 2013 were identified using the presence of hospital records with at least 1 main diagnosis code for multiple myeloma (ICD-10 “C90”). Alternative algorithms also considered related and associated diagnoses, combination with long-term conditions, or at least 2 diagnoses. Incident patients were those with no previous “C90” codes in the past 24 or 12 months. The sensitivity, specificity, and positive and negative predictive values (PPVs and NPVs) were computed, using a French cancer registry for the corresponding area and period as the criterion standard. Long-term conditions data extracted concerned 11,559 patients (21,846 for hospital data). The registry contained 125 cases of multiple myeloma. Sensitivity was 70% when using only main hospital diagnoses (specificity 100%, PPV 79%), 76% when also considering related diagnoses (specificity 100%, PPV 74%), and 90% with associated diagnoses included (100% specificity, 64% PPV). In relation with their good performance, selected algorithms can be used to study the benefit and risk of drugs in treated multiple myeloma patients. PMID:28328805

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

    SciTech Connect

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

    2014-05-02

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

  16. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma.

    PubMed

    Palumbo, Antonio; Ambrosini, Maria Teresa; Benevolo, Giulia; Pregno, Patrizia; Pescosta, Norbert; Callea, Vincenzo; Cangialosi, Clotilde; Caravita, Tommaso; Morabito, Fortunato; Musto, Pellegrino; Bringhen, Sara; Falco, Patrizia; Avonto, Ilaria; Cavallo, Federica; Boccadoro, Mario

    2007-04-01

    In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.

  17. Regular analgesic use and risk of multiple myeloma.

    PubMed

    Moysich, Kirsten B; Bonner, Mathew R; Beehler, Gregory P; Marshall, James R; Menezes, Ravi J; Baker, Julie A; Weiss, Joli R; Chanan-Khan, Asher

    2007-04-01

    Analgesic use has been implicated in the chemoprevention of a number of solid tumors, but to date no previous research has focused on the role of analgesics in the etiology of multiple myeloma (MM). We conducted a hospital-based case-control study of 117 patients with primary, incident MM and 483 age and residence matched controls without benign or malignant neoplasms. All participants received medical services at Roswell Park Cancer Institute in Buffalo, NY, and completed a comprehensive epidemiological questionnaire. Participants who reported analgesic use at least once a week for at least 6 months were classified as regular users; individuals who did not use analgesics regularly served as the reference group throughout the analyses. We used unconditional logistic regression analyses to compute crude and adjusted odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Compared to non-users, regular aspirin users were not at reduced risk of MM (adjusted OR=0.99; 95% CI 0.65-1.49), nor were participants with the highest frequency or duration of aspirin use. A significant risk elevation was found for participants who were regular acetaminophen users (adjusted OR=2.95; 95% CI 1.72-5.08). Further, marked increases in risk of MM were noted with both greater frequency (>7 tablets weekly; adjusted OR=4.36; 95% CI 1.70-11.2) and greater duration (>10 years; adjusted OR=3.26; 95% CI 1.52-7.02) of acetaminophen use. We observed no evidence of a chemoprotective effect of aspirin on MM risk, but observed significant risk elevations with various measures of acetaminophen use. Our results warrant further investigation in population-based case-control and cohort studies and should be interpreted with caution in light of the limited sample size and biases inherent in hospital-based studies.

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

    PubMed Central

    Yang, Hua; Du, Xingjun; Xi, Yuren

    2016-01-01

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

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

    PubMed Central

    2012-01-01

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

  20. Bruceantin inhibits multiple myeloma cancer stem cell proliferation.

    PubMed

    Issa, Mark E; Berndt, Sarah; Carpentier, Gilles; Pezzuto, John M; Cuendet, Muriel

    2016-09-01

    Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM.

  1. Treatment of multicentric Castleman's Disease accompanying multiple myeloma with bortezomib: a case report

    PubMed Central

    Yuan, Zhen-gang; Dun, Xiao-yi; Li, Yong-hua; Hou, Jian

    2009-01-01

    Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder of unknown etiology and characterized by various clinical manifestations and multiple organ involvement. It has been reported in association with POEMS syndrome and can progress to Kaposi's sarcoma or malignant lymphoma. The disease runs a more aggressive course and a poor prognosis. Optimal therapies have not been well established up to now. We here reported a case of rare MCD complicated with multiple myeloma who received bortezomib and achieved very good remission. To our knowledge, this is the first report on MCD in the setting of multiple myeloma with good response to bortezomib. PMID:19400935

  2. Circulating clonotypic B cells in multiple myeloma and monoclonal gammopathy of undetermined significance

    PubMed Central

    Thiago, Leandro S.; Perez-Andres, Martin; Balanzategui, Ana; Sarasquete, Maria E.; Paiva, Bruno; Jara-Acevedo, Maria; Barcena, Paloma; Sanchez, Maria Luz; Almeida, Julia; González, Marcos; San Miguel, Jesus F.; Garcia-Sanz, Ramón; Orfao, Alberto

    2014-01-01

    The B-cell compartment in which multiple myeloma stem cells reside remains unclear. We investigated the potential presence of mature, surface-membrane immunoglobulin-positive B lymphocytes clonally related to the tumor bone marrow plasma cells among different subsets of peripheral blood B cells from ten patients (7 with multiple myeloma and 3 with monoclonal gammopathies of undetermined significance). The presence of clonotypic immunoglobulin heavy chain gene rearrangements was determined in multiple highly-purified fractions of peripheral blood B-lymphocytes including surface-membrane IgM+ CD27− naïve B-lymphocytes, plus surface-membrane IgG+, IgA+ and IgM+ memory CD27+ B cells, and normal circulating plasma cells, in addition to (mono)clonal plasma cells, by a highly-specific and sensitive allele-specific oligonucleotide polymerase chain reaction directed to the CDR3 sequence of the rearranged IGH gene of tumor plasma cells from individual patients. Our results showed systematic absence of clonotypic rearrangements in all the different B-cell subsets analyzed, including M-component isotype-matched memory B-lymphocytes, at frequencies <0.03 cells/μL (range: 0.0003–0.08 cells/μL); the only exception were the myeloma plasma cells detected and purified from the peripheral blood of four of the seven myeloma patients. These results indicate that circulating B cells from patients with multiple myeloma and monoclonal gammopathies of undetermined significance are usually devoid of clonotypic B cells while the presence of immunophenotypically aberrant myeloma plasma cells in peripheral blood of myeloma patients is a relatively frequent finding. PMID:23872308

  3. [Cereblon -  a new target of therapy in the treatment of multiple myeloma].

    PubMed

    Staňková, M; Bešše, L; Sedlaříková, L; Vrábel, D; Hájek, R; Sevčíková, S

    2014-01-01

    Treatment of multiple myeloma (MM), currently an incurable disease, aims to achieve complete remission. Immunomodulatory drugs (IMiDs), represented by thalidomide, are one class of very effective drugs. However, the mechanism of IMiDs action is not yet completely understood. Recent research suggests that cereblon (CRBN) plays an important role in mediating anti-tumor effects of IMiDs; therefore, our review focuses on this protein. CRBN is a substrate receptor of Cul4- E3 ubiquitin ligase complex, and thus recognizes proteins destined for degradation. Bind-ing of CRBN and IMiDs inhibits function of the entire ubiquitin proteasome complex which partly explains their anti-tumor effects. In addition, a correlation between CRBN gene expression and effectiveness of treatment in MM patients treated with IMiDs was confirmed. These findings suggest that CRBN expression could possibly serve as a bio-marker to predict response to IMiD in MM patients.

  4. Novel treatment strategy with autologous activated and expanded natural killer cells plus anti-myeloma drugs for multiple myeloma

    PubMed Central

    Leivas, Alejandra; Perez-Martinez, Antonio; Blanchard, María Jesús; Martín-Clavero, Estela; Fernández, Lucía; Lahuerta, Juan José; Martinez-Lopez, Joaquín

    2016-01-01

    ABSTRACT This proof-of-concept single-arm open-label phase I clinical trial (NCT02481934) studied the safety and efficacy of multiple infusions of activated and expanded natural killer (NKAE) cells in combination with anti-myeloma drugs in multiple myeloma patients. It included five patients with relapsed or refractory MM who had received two to seven prior lines of therapy; NK cells were expanded for 3 weeks with K562-mb15-41BBL cells. Patients received four cycles of pharmacological treatment with two infusions of 7.5 × 106 NKAEs/kg per cycle. NKAE generation, expansion, and NK monitoring was assessed using flow cytometry. Eighteen clinical-grade NKAE cell GMP-grade products were generated to obtain 627 × 106 NKAEs (range: 315–919 × 106) for the first infusion and 943 × 106 (range: 471–1481 × 106) for the second infusion with 90% (±7%) purity. Neutropenia grade II occurred in two patients and was related to chemotherapy. Of the five patients, four showed disease stabilization before the end of NKAE treatment, and two showed a 50% reduction in bone marrow infiltration and a long-term (>1 y) response. The NKAE cells had a highly cytotoxic phenotype and high cytotoxicity in vitro. Infused NKAE cells were detected in bone marrow and peripheral blood after infusions. Ex vivo expansion of autologous NK cells is feasible, NKAE cells are clinically active and the multiple infusions are well tolerated in patients with relapsed or refractory myeloma. PMID:28123890

  5. Proteasome inhibition correlates with intracellular bortezomib concentrations but not with antiproliferative effects after bolus treatment in myeloma cell lines.

    PubMed

    Dettmer, Susan; Theile, Dirk; Schäfer, Julia; Seckinger, Anja; Burhenne, Jürgen; Weiss, Johanna

    2016-10-01

    Although bortezomib is successfully used against multiple myeloma, the pharmacodynamics of proteasome inhibition and its association with efficacy or resistance is poorly understood. Using ultra performance liquid chromatography coupled to tandem mass spectrometry, site-specific luminogenic substrate assays and 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide (MTT) assays, effects of bortezomib on cellular drug concentrations, chymotrypsin- , caspase- , and trypsin-like activities, and cytotoxic efficacy were evaluated in eight myeloma cell lines directly after 1 h of exposure and additionally after a 23-h washout phase. Bortezomib accumulated in myeloma cells by up to 100-fold and concentration-dependently inhibited the proteasomal activities with the chymotrypsin-like activity being the most sensitive. Whereas intracellular concentrations correlated with the inhibition of the chymotrypsin- and the caspase-like activities of the proteasome, the cytotoxic efficacy of bortezomib did not correlate with either intracellular concentrations or proteasomal inhibition. However, the ratio of concentrations measured directly after the exposure and after the washout phase (indicating drug disposition) correlated with efficacy, suggesting that the cell's ability to dispose bortezomib at least in part influences bortezomib's cytotoxicity. In conclusion, this data argues against a direct association of intracellular concentration or proteasomal inhibition with cytotoxic efficacy but advocates for an important role of cellular drug disposition. Moreover, this study underlines the pleiotropic mode of action of bortezomib going beyond proteasome inhibition.

  6. Acquired von Willebrand disease and multiple myeloma: a case report of a breast cancer survivor.

    PubMed

    Jin, Ning; Salahuddin, Farah F; Nesbitt, John A

    2014-12-01

    Acquired von Willebrand disease (aVWD) is rare disease and is associated with a variety of underlying diseases. We report a case of aVWD in the setting of multiple myeloma. The patient was a 63-year-old female with breast cancer in remission who was admitted for symptomatic anemia. She was diagnosed with multiple myeloma. She also had subcutaneous bleeding before admission. Laboratory studies revealed isolated prolongation of the activated partial thromboplastin time, which corrected in a mixing study. Her factor VIII activity, von Willebrand factor (VWF) Ag, and VWF activity were low. VWF multimer study confirmed the patient had aVWD. The treatment of aVWD is discussed in this article, including the treatment of underlying diseases, and acute management in emergent situations. An intriguing question in this case is whether the patient's multiple myeloma is a chemotherapy-induced hematological malignancy or a second primary malignancy.

  7. UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression

    PubMed Central

    Hussain, Sajjad; Bedekovics, Tibor; Chesi, Marta; Bergsagel, P. Leif; Galardy, Paul J.

    2015-01-01

    The success of proteasome inhibition in multiple myeloma highlights the critical role for the ubiquitin-proteasome system (UPS) in this disease. However, there has been little progress in finding more specific targets within the UPS involved in myeloma pathogenesis. We previously found the ubiquitin hydrolase UCH-L1 to be frequently over-expressed in B-cell malignancies, including myeloma, and showed it to be a potent oncogene in mice. Here we show that UCH-L1 is a poor prognostic factor that is essential for the progression of myeloma. We found high levels of UCHL1 to predict early progression in newly diagnosed patients; a finding reversed by the inclusion of bortezomib. We also found high UCHL1 levels to be a critical factor in the superiority of bortezomib over high-dose dexamethasone in relapsed patients. High UCHL1 partially overlaps with, but is distinct from, known genetic risks including 4p16 rearrangement and 1q21 amplification. Using an orthotopic mouse model, we found UCH-L1 depletion delays myeloma dissemination and causes regression of established disease. We conclude that UCH-L1 is a biomarker of aggressive myeloma that may be an important marker of bortezomib response, and may itself be an effective target in disseminated disease. PMID:26513019

  8. Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma.

    PubMed

    Yarde, Danielle N; Oliveira, Vasco; Mathews, Linda; Wang, Xingyu; Villagra, Alejandro; Boulware, David; Shain, Kenneth H; Hazlehurst, Lori A; Alsina, Melissa; Chen, Dung-Tsa; Beg, Amer A; Dalton, William S

    2009-12-15

    The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to replicative stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA genes are overexpressed and causative for drug resistance in human melphalan-resistant multiple myeloma cell lines. However, the transcriptional regulation of the FA/BRCA pathway is not understood. In this report, we describe for the first time a novel function of the NF-kappaB subunits, RelB/p50, as transcriptional activators of the FA/BRCA pathway. Specifically, our findings point to constitutive phosphorylation of IkappaB kinase alpha and subsequent alterations in FANCD2 expression and function as underlying events leading to melphalan resistance in repeatedly exposed multiple myeloma cells. Inhibiting NF-kappaB by small interfering RNA, blocking the IkappaB kinase complex with BMS-345541, or using the proteasome inhibitor bortezomib drastically reduced FA/BRCA gene expression and FANCD2 protein expression in myeloma cells, resulting in diminished DNA damage repair and enhanced melphalan sensitivity. Importantly, we also found that bortezomib decreases FA/BRCA gene expression in multiple myeloma patients. These results show for the first time that NF-kappaB transcriptionally regulates the FA/BRCA pathway and provide evidence for targeting Fanconi anemia-mediated DNA repair to enhance chemotherapeutic response and circumvent drug resistance in myeloma patients.

  9. The proteasome: mechanisms of biology and markers of activity and response to treatment in multiple myeloma.

    PubMed

    Manasanch, Elisabet E; Korde, Neha; Zingone, Adriana; Tageja, Nishant; Fernandez de Larrea, Carlos; Bhutani, Manisha; Wu, Peter; Roschewski, Mark; Landgren, Ola

    2014-08-01

    Since the early 1990s, the synthesis and subsequent clinical application of small molecule inhibitors of the ubiquitin proteasome pathway (UPP) has revolutionized the treatment and prognosis of multiple myeloma. In this review, we summarize important aspects of the biology of the UPP with a focus on its structure and key upstream/downstream regulatory components. We then review current knowledge of plasma cell sensitivity to proteasome inhibition and highlight new proteasome inhibitors that have recently entered clinical development. Lastly, we address the putative role of circulating proteasomes as a novel biomarker in multiple myeloma and provide guidance for future clinical trials using proteasome inhibitors.

  10. Carfilzomib for the treatment of patients with relapsed and/or refractory multiple myeloma.

    PubMed

    Stewart, A Keith

    2015-01-01

    Carfilzomib is a proteasome inhibitor that irreversibly binds to its target, resulting in sustained proteasomal inhibition with minimal off-target effects. As a single agent, carfilzomib has demonstrated durable antimyeloma activity with manageable toxicities, which has resulted in its approval in Argentina, Israel, Mexico and the USA for the treatment of patients with relapsed and refractory multiple myeloma. Data from ongoing Phase III studies that are evaluating carfilzomib in earlier lines of therapy may facilitate an expanded indication for this agent, as well as for regulatory approval in the EU. This article summarizes the chemistry, pharmacokinetics, pharmacodynamics and available clinical data for carfilzomib in the treatment of patients with multiple myeloma.

  11. Heart failure secondary to carfilzomib-induced heart block in multiple myeloma patients.

    PubMed

    Tjionas, Harisios; Gupta, Amit K

    2017-03-01

    Carfilzomib is a proteasome inhibitor and immunomodulator used to treat patients with multiple myeloma who have disease progression refractory to bortezomib. The difference in agents is that carfilzomib is an irreversible inhibitor of 20 s proteasome. The most common side effects of carfilzomib are fatigue, nausea, diarrhea, anemia, thrombocytopenia, dyspnea, and pyrexia. Less frequent side effects include cardiac manifestations for which we will explore with more detail. In this case report, we describe a 70-year-old female with multiple myeloma presenting to the emergency department with complaint of dyspnea. Patient was discovered to be in heart failure with atrioventricular block necessitating placement of a pacemaker.

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

    PubMed Central

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

    2016-01-01

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

  13. Time trend of multiple myeloma and associated secondary primary malignancies in Asian patients: a Taiwan population-based study.

    PubMed

    Tzeng, Huey-En; Lin, Cheng-Li; Tsai, Chun-Hao; Tang, Chih-Hsin; Hwang, Wen-Li; Cheng, Ya-Wen; Sung, Fung-Chang; Chung, Chi-Jung

    2013-01-01

    Studies involving second malignancies in patients with multiple myeloma are limited for the Asian population. Using data from population-based insurance claims, we assessed the risk of developing secondary malignancies after multiple myeloma, in particular hematologic malignancies. A retrospective cohort study was conducted in 3970 patients with newly diagnosed multiple myeloma from the registry of catastrophic illnesses between 1997 and 2009. A total of 15880 subjects without multiple myeloma were randomly selected as comparisons from the insured population, frequency-matched based on gender, age, and the date of diagnosis. The incidence of secondary malignancies was ascertained through cross-referencing with the National Cancer Registry System. The Cox proportional hazards model was used for analyses. The incidence of multiple myeloma in the insured population increased annually. The overall incidence of secondary malignancy was lower in the multiple myeloma cohort than in the comparison cohort (93.6 vs. 104.5 per 10,000 person-years, IRR = 0.90, 95% CI = 0.78-1.04). The incidence of hematologic malignancies was 11-fold greater for multiple myeloma patients (47.2 vs. 4.09 per 10,000 person-years) with an adjusted HR of 13.0 (95% CI = 7.79-21.6) compared with the comparison cohort. The relative risk of secondary malignancy was also strong for myeloid leukemia (21.2 vs. 1.36 per 10,000 person-years). Gender- and age-specific analysis for secondary hematologic malignancies showed that males and patients with multiple myeloma <60 years of age had a higher risk of secondary malignancy than females and patients with multiple myeloma >60 years of age. In conclusion, patients with multiple myeloma, especially younger patients, are at a high risk of hematologic malignancies.

  14. [Reseach Advances on Cancer-Testis Antigens in Multiple Myeloma -Review].

    PubMed

    Yang, Zhi-Rui; Yu, Li; Zhu, Hai-Yan

    2017-02-01

    Cancer-testis antigens (CTA) are a class of tumor-associated antigens, which are mainly located in X chromosome. CTA restrictively expressed in normal testis, ovary, placenta and so on. Their expression in other normal tissues is much lower, even can not be detected. However, their expressions are aberrantly high in human cancers. Based on CTA encoding immunogenic proteins, they can be regulated by epigentics, CTA provides very attractive targets for cancer immunotherapy. Multiple myeloma (MM) is incurable and has a low cureative rate and a high relapse rate. CTA have been detected in many MM cell lines and primary MM cells, they may be relaled to clinical prognosis. This reviews briefly summarized the research advances of CTA in the immune therapy of multiple myeloma, so as to provide a valuable therapeutic idea for myeloma.

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

    PubMed

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

    2014-11-01

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

  16. Comparative effectiveness on survival of zoledronic acid versus pamidronate in multiple myeloma.

    PubMed

    Sanfilippo, K M; Gage, B; Luo, S; Weilbaecher, K; Tomasson, M; Vij, R; Colditz, G; Carson, K

    2015-03-01

    Zoledronic acid and pamidronate are the two bisphosphonates approved in the United States to reduce multiple myeloma skeletal complications. Little prior evidence exists comparing survival outcomes between the two. We evaluated the incidence of skeletal-related events and overall survival in patients with myeloma treated with zoledronic acid versus pamidronate using a cohort of 1018 United States veterans. At a median follow-up of 26.9 months, patients receiving zoledronic acid had a 22% reduction in risk of death compared to pamidronate (hazard ratio 0.78; 95% confidence interval, 0.67-0.92). The benefit persisted after controlling for potential confounders. Adjusted Cox modeling with inverse probability weighting and propensity score matching supported these findings. Zoledronic acid was also associated with a 25% decrease in skeletal-related events. Zoledronic acid is associated with increased overall survival and decreased skeletal-related events compared to pamidronate in patients with multiple myeloma and should become the preferred bisphosphonate.

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

    PubMed Central

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

    2016-01-01

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

  18. A Next-Generation Sequencing Strategy for Evaluating the Most Common Genetic Abnormalities in Multiple Myeloma.

    PubMed

    Jiménez, Cristina; Jara-Acevedo, María; Corchete, Luis A; Castillo, David; Ordóñez, Gonzalo R; Sarasquete, María E; Puig, Noemí; Martínez-López, Joaquín; Prieto-Conde, María I; García-Álvarez, María; Chillón, María C; Balanzategui, Ana; Alcoceba, Miguel; Oriol, Albert; Rosiñol, Laura; Palomera, Luis; Teruel, Ana I; Lahuerta, Juan J; Bladé, Joan; Mateos, María V; Orfão, Alberto; San Miguel, Jesús F; González, Marcos; Gutiérrez, Norma C; García-Sanz, Ramón

    2017-01-01

    Identification and characterization of genetic alterations are essential for diagnosis of multiple myeloma and may guide therapeutic decisions. Currently, genomic analysis of myeloma to cover the diverse range of alterations with prognostic impact requires fluorescence in situ hybridization (FISH), single nucleotide polymorphism arrays, and sequencing techniques, which are costly and labor intensive and require large numbers of plasma cells. To overcome these limitations, we designed a targeted-capture next-generation sequencing approach for one-step identification of IGH translocations, V(D)J clonal rearrangements, the IgH isotype, and somatic mutations to rapidly identify risk groups and specific targetable molecular lesions. Forty-eight newly diagnosed myeloma patients were tested with the panel, which included IGH and six genes that are recurrently mutated in myeloma: NRAS, KRAS, HRAS, TP53, MYC, and BRAF. We identified 14 of 17 IGH translocations previously detected by FISH and three confirmed translocations not detected by FISH, with the additional advantage of breakpoint identification, which can be used as a target for evaluating minimal residual disease. IgH subclass and V(D)J rearrangements were identified in 77% and 65% of patients, respectively. Mutation analysis revealed the presence of missense protein-coding alterations in at least one of the evaluating genes in 16 of 48 patients (33%). This method may represent a time- and cost-effective diagnostic method for the molecular characterization of multiple myeloma.

  19. Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma.

    PubMed

    Palumbo, Antonio; Sonneveld, Pieter

    2015-08-01

    Although multiple myeloma has historically been treated with chemotherapy, prolonged survival has only been possible since the introduction of thalidomide, lenalidomide and bortezomib. However, multiple myeloma remains largely incurable, and new treatments are needed to improve long-term outcome. Elotuzumab is a humanized IgG1 monoclonal antibody that targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7) to activate NK cells, enabling selective killing of myeloma cells with minimal effects on normal tissue. The combination of elotuzumab with antimyeloma therapies that stimulate host immunity may be an attractive treatment option for patients with newly diagnosed or relapsed/refractory multiple myeloma. Here, we review the role of SLAMF7 in the pathogenesis of multiple myeloma and the preclinical and clinical development of elotuzumab.

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

    PubMed

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

    2016-01-01

    In recent years, several studies on large series of multiple myeloma (MM) patients have demonstrated the clinical utility of flow cytometry monitoring of minimal residual disease (flow-MRD) in bone marrow (BM), for improved assessment of response to therapy and prognostication. However, disturbing levels of variability exist regarding the specific protocols and antibody panels used in individual laboratories. Overall, consensus exists about the utility of combined assessment of CD38 and CD138 for the identification of BM plasma cells (PC); in contrast, more heterogeneous lists of markers are used to further distinguish between normal/reactive PCs and myeloma PCs in the MRD settings. Among the later markers, CD19, CD45, CD27, and CD81, together with CD56, CD117, CD200, and CD307, have emerged as particularly informative; however, no single marker provides enough specificity for clear discrimination between clonal PCs and normal PCs. Accordingly, multivariate analyses of single PCs from large series of normal/reactive vs. myeloma BM samples have shown that combined assessment of CD138 and CD38, together with CD45, CD19, CD56, CD27, CD81, and CD117 would be ideally suited for MRD monitoring in virtually every MM patient. However, the specific antibody clones, fluorochrome conjugates and sources of the individual markers determines its optimal (vs. suboptimal or poor) performance in an eight-color staining. Assessment of clonality, via additional cytoplasmic immunoglobulin (CyIg) κ vs. CyIgλ evaluation, may contribute to further establish the normal/reactive vs. clonal nature of small suspicious PC populations at high sensitivity levels, provided that enough cells are evaluated.

  1. Spinal focal lesion detection in multiple myeloma using multimodal image features

    NASA Astrophysics Data System (ADS)

    Fränzle, Andrea; Hillengass, Jens; Bendl, Rolf

    2015-03-01

    Multiple myeloma is a tumor disease in the bone marrow that affects the skeleton systemically, i.e. multiple lesions can occur in different sites in the skeleton. To quantify overall tumor mass for determining degree of disease and for analysis of therapy response, volumetry of all lesions is needed. Since the large amount of lesions in one patient impedes manual segmentation of all lesions, quantification of overall tumor volume is not possible until now. Therefore development of automatic lesion detection and segmentation methods is necessary. Since focal tumors in multiple myeloma show different characteristics in different modalities (changes in bone structure in CT images, hypointensity in T1 weighted MR images and hyperintensity in T2 weighted MR images), multimodal image analysis is necessary for the detection of focal tumors. In this paper a pattern recognition approach is presented that identifies focal lesions in lumbar vertebrae based on features from T1 and T2 weighted MR images. Image voxels within bone are classified using random forests based on plain intensities and intensity value derived features (maximum, minimum, mean, median) in a 5 x 5 neighborhood around a voxel from both T1 and T2 weighted MR images. A test data sample of lesions in 8 lumbar vertebrae from 4 multiple myeloma patients can be classified at an accuracy of 95% (using a leave-one-patient-out test). The approach provides a reasonable delineation of the example lesions. This is an important step towards automatic tumor volume quantification in multiple myeloma.

  2. Synergistic combination therapy with cotylenin A and vincristine in multiple myeloma models.

    PubMed

    Takahashi, Tsutomu; Honma, Yoshio; Miyake, Takaaki; Adachi, Koji; Takami, Saki; Okada, Masahiro; Kumanomidou, Satoshi; Ikejiri, Fumiyoshi; Jo, Yumi; Onishi, Chie; Kawakami, Koshi; Moriyama, Ichiro; Inoue, Masaya; Tanaka, Junko; Suzumiya, Junji

    2015-04-01

    Multiple myeloma is a malignant proliferative disease of plasma cells in the bone marrow and remains largely incurable. Cotylenin A, a fusicoccane diterpene glycoside with a complex sugar moiety, was isolated as a plant-growth regulator. Cotylenin A has been shown to inhibit the growth of various cancer cells. Herein, we examined the anti-myeloma effects of cotylenin A using five human myeloma cell lines (RPMI-8226, KMS-11, KMS-26, KMS-12 PE and KMS-12 BM) and xenografts in immunodeficient mice. Cotylenin A and vincristine synergistically inhibited the growth and induced apoptosis in myeloma cells. While other microtubule-disturbing agents also showed co-operative effects with cotylenin A, other anticancer agents, such as doxorubicin, cisplatin, camptothecin, methotrexate, gemcitabine and 5-fluorouracil, did not show such co-operation with cotylenin A. These differences might be attributed to the effects on autophagic responses. Combined treatment with cotylenin A and vincristine induced autophagy (formation of LC3-II and degradation of p62 protein). However, doxorubicin did not enhance the autophagy induced by cotylenin A. A colony-forming assay indicated that the combined treatment with cotylenin A and vincristine more effectively suppressed the formation of large colonies, which have higher self-renewal activity than vincristine alone. Expression of pluripotency-associated transcription factor Sox2 mRNA in RPMI-8226 myeloma cells was significantly suppressed by treatment with cotylenin A. Combined treatment with cotylenin A and vincristine significantly inhibited the growth of KMS-26 myeloma cells as xenografts. Our results suggest that the combination of cotylenin A and vincristine may have therapeutic value. Recently, it was reported that cotylenin A modulates the 14-3-3 intracellular signaling pathway. The 14-3-3 proteins may be novel targets in treating myeloma. However, our study could not explain how the sensitization to vincristine is related to the

  3. Cord Blood Transplantation for Multiple Myeloma: A Study from the Multiple Myeloma Working Group of the Japan Society for Hematopoietic Cell Transplantation.

    PubMed

    Kawamura, Koji; Takamatsu, Hiroyuki; Ikeda, Takashi; Komatsu, Tsunehiko; Aotsuka, Nobuyuki; Amano, Itsuto; Yamamoto, Go; Watanabe, Kentaro; Ohno, Yuju; Matsue, Kosei; Kouzai, Yasuji; Tsukada, Nobuhiro; Ishiyama, Ken; Anzai, Naoyuki; Kato, Koji; Suzuki, Ritsuro; Sunami, Kazutaka; Kanda, Yoshinobu

    2015-07-01

    Cord blood has been investigated as an alternative source for hematopoietic stem cell transplantation, but information about its use for multiple myeloma is limited. The purpose of this study was to evaluate the feasibility of cord blood transplantation (CBT) for patients with multiple myeloma. Eighty-six patients with multiple myeloma who underwent a first CBT between 2001 and 2011 were included in this retrospective study. Sixty-two of them had received other types of stem cell transplantation before CBT. The cumulative incidences of neutrophil engraftment at day 50, grade II to IV acute graft-versus-host disease (GVHD), and chronic GVHD were 81.4%, 39.0%, and 19.5%, respectively. The incidence of nonrelapse mortality at 2 years was 39.0%, but it was only 6.2% in patients who underwent planned tandem autologous/reduced-intensity conditioning CBT (auto/RIC-CBT). Progression-free survival (PFS) and overall survival (OS) at 6 years were 13.0% and 15.2%, respectively. Less than a partial response before CBT and lack of prior transplantation were independent significant adverse factors for PFS, whereas the presence of prior transplantation and planned tandem transplantation were associated with better OS. OS at 6 years in patients who underwent auto/RIC-CBT was 45.9%. In addition, the development of chronic GVHD was associated with superior PFS. In conclusion, we demonstrated that cord blood is feasible as an alternative graft source for myeloma patients. Although CBT provided long-term survival for a fraction of patients, optimal use of this graft requires further clinical studies.

  4. Expression Profiles of the Individual Genes Corresponding to the Genes Generated by Cytotoxicity Experiments with Bortezomib in Multiple Myeloma

    PubMed Central

    Ghasemi, Mehdi; Alpsoy, Semih; Türk, Seyhan; Malkan, Ümit Y.; Atakan, Şükrü; Haznedaroğlu, İbrahim C.; Güneş, Gürsel; Gündüz, Mehmet; Yılmaz, Burak; Etgül, Sezgin; Aydın, Seda; Aslan, Tuncay; Sayınalp, Nilgün; Aksu, Salih; Demiroğlu, Haluk; Özcebe, Osman İ.; Büyükaşık, Yahya; Göker, Hakan

    2016-01-01

    Objective: Multiple myeloma (MM) is currently incurable due to refractory disease relapse even under novel anti-myeloma treatment. In silico studies are effective for key decision making during clinicopathological battles against the chronic course of MM. The aim of this present in silico study was to identify individual genes whose expression profiles match that of the one generated by cytotoxicity experiments for bortezomib. Materials and Methods: We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of metadata derived from relevant information. The E-MTAB-783 dataset containing expression data from 789 cancer cell lines including 8 myeloma cell lines with drug screening data from the Wellcome Trust Sanger Institute database obtained from ArrayExpress was “Robust Multi-array analysis” normalized using GeneSpring v.12.5. Drug toxicity data were obtained from the Genomics of Drug Sensitivity in Cancer project. In order to identify individual genes whose expression profiles matched that of the one generated by cytotoxicity experiments for bortezomib, we used a linear regression-based approach, where we searched for statistically significant correlations between gene expression values and IC50 data. The intersections of the genes were identified in 8 cell lines and used for further analysis. Results: Our linear regression model identified 73 genes and some genes expression levels were found to very closely correlated with bortezomib IC50 values. When all 73 genes were used in a hierarchical cluster analysis, two major clusters of cells representing relatively sensitive and resistant cells could be identified. Pathway and molecular function analysis of all the significant genes was also investigated, as well as the genes involved in pathways. Conclusion: The findings of our present in silico study could be important not only for the understanding of the genomics of MM but also for the better arrangement of

  5. C3 glomerulopathy associated to multiple myeloma successfully treated by autologous stem cell transplant

    PubMed Central

    Hamzi, M. A.; Zniber, A.; Badaoui, G. E.; Mahtat, E.; Alhamany, Z.; Bayahia, R.; Ouzeddoun, N.

    2017-01-01

    A 32-year-old male presented with advanced renal failure and nephrotic proteinuria due to lambda light chain multiple myeloma. Renal biopsy showed a proliferative glomerulonephritis with isolated C3 deposits. Renal recovery was obtained after chemotherapy and autologous stem cell transplant. We review previously described cases of C3 glomerulopathy associated with monoclonal gammopathy. PMID:28356669

  6. Pathogenesis of Renal Failure in Multiple Myeloma: Any Role of Contrast Media?

    PubMed Central

    Mussap, Michele; Merlini, Giampaolo

    2014-01-01

    The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function. PMID:24877060

  7. The simultaneous occurrence of multiple myeloma and JAK2 positive myeloproliferative neoplasms - Report on two cases

    PubMed Central

    Badelita, S; Dobrea, C; Colita, A; Dogaru, M; Dragomir, M; Jardan, C; Coriu, D

    2015-01-01

    Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis. Abbreviations:JAK2 = Janus kinase 2 gene, PMF = primary myelofibrosis, MPNs = myeloproliferative neoplasms, ET = essential thrombocythemia, PV = polycythemia vera, MM = multiple myeloma, WBC = white blood cells, Hb = haemoglobin, Ht = haematocrit, Plt = platelets, BMB = bone marrow biopsy, CBC = blood cell count, CT = computerized tomography, LAP = leukocyte alkaline phosphatase, MGUS = monoclonal gammopathy of undetermined significance. PMID:25914740

  8. Appropriateness of applying the response criteria for multiple myeloma to Waldenstrom's macroglobulinemia?

    PubMed

    Bladé, Joan; Montoto, Silvia; Rosiñol, Laura; Montserrat, Emili

    2003-04-01

    Since the presence of an M-component is an essential disease feature in both multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM), the decrease in the M-protein size applied for response in MM is also a crucial criteria for assessing response in WM. However, WM frequently displays lymphoma-like features that should be included in the response criteria.

  9. Bone marrow lambda-type light chain crystalline structures associated with multiple myeloma.

    PubMed

    Schvartz, H; Bonhomme, P; Caulet, S; Beorchia, A; Patey, M; Caulet, T

    1985-01-01

    A 58-year-old man showed bone marrow crystalline structures associated with a lambda light chain producing multiple myeloma. Analysis and processing of electron images clearly displayed the periodic structure of the crystals. Immunochemistry suggested that they contained the whole or a fragmented constant portion of immunoglobulin.

  10. Discovery – Velcade®: A New Tool in the Fight against Multiple Myeloma

    Cancer.gov

    Velcade® represents a new type of anticancer drug called proteasome inhibitors. It has shown promise in the treatment of multiple myeloma, a cancer of the white blood cells. Velcade® is being studied for use in a variety of blood cancers and solid tumors.

  11. [Association between multiple myeloma and acute myeloid leukemia secondary to myelodysplastic syndrome].

    PubMed

    Jennane, Selim; Eddou, Hicham; Mahtat, El Mehdi; Konopacki, Johanna; Souleau, Bertrand; Malfuson, Jean Valère; Foissaud, Vincent; de Revel, Thierry

    2013-01-01

    We report a rare case of association of two distinct hematologic malignancies: refractory cytopenia with multilineage dysplasia associated with del(5q) and symptomatic multiple myeloma associated with del(17p) and del(13q). After 16 months, the patient presented an acute leukemic transformation of the myelodysplasic syndrome.

  12. Novel Agents for the Treatment of Multiple Myeloma: Proteasome Inhibitors and Immunomodulatory Agents

    PubMed Central

    Kurtin, Sandra E.; Bilotti, Elizabeth

    2013-01-01

    The integration of novel agents into the treatment of multiple myeloma (MM) has shifted the focus from an incurable disease to one that is chronic, with a realistic hope of someday achieving a cure. Proteasome inhibitors and immunomodulatory agents are the backbone of novel therapies for MM. These agents are particularly important for patients with relapsed or refractory disease, a fate faced by the majority of myeloma patients over the course of their disease. Review of recent clinical trial data for the proteasome inhibitors and immunomodulatory agents, including clinical efficacy and safety information, will assist the advanced practitioner in oncology with integrating these data into the current treatment guidelines for MM. PMID:25032010

  13. Is there a role for 'modified VAD' in the treatment of multiple myeloma?

    PubMed

    Agazzi, A; Sammassimo, S; Laszlo, D; Liptrott, Sj; Cascio, R; Alietti, A; Rabascio, C; Mancuso, P; Pruneri, G; Martinelli, G

    2009-01-01

    VAD, (Vincristine, Doxorubicin and Dexamethasone) was initially proposed as a salvage therapy for myeloma patients in whom prior alkylating agent therapy failed, although in recent years VAD has been surpassed by novel combination therapies with new biological agents such as thalidomide (and its derivative, lenalidomide) and bortezomib. After the excellent results obtained by the novel agents, VAD can no longer be proposed in preparation to autologous transplantation, although there are still indications that VAD remains useful and clinically relevant in the initial treatment of symptomatic multiple myeloma.

  14. Is there a role for ‘modified VAD’ in the treatment of multiple myeloma?

    PubMed Central

    Agazzi, A; Sammassimo, S; Laszlo, D; Liptrott, SJ; Cascio, R; Alietti, A; Rabascio, C; Mancuso, P; Pruneri, G; Martinelli, G

    2009-01-01

    VAD, (Vincristine, Doxorubicin and Dexamethasone) was initially proposed as a salvage therapy for myeloma patients in whom prior alkylating agent therapy failed, although in recent years VAD has been surpassed by novel combination therapies with new biological agents such as thalidomide (and its derivative, lenalidomide) and bortezomib. After the excellent results obtained by the novel agents, VAD can no longer be proposed in preparation to autologous transplantation, although there are still indications that VAD remains useful and clinically relevant in the initial treatment of symptomatic multiple myeloma. PMID:22276003

  15. [Bone marrow immunophenotyping for the diagnosis of multiple myeloma: practical aspects].

    PubMed

    Kurtova, A V; Sivachenko, E B; Utkina, L A; Slobodniuk, K Iu; Stepanova, N V; Iakubovich, M A; Moiseev, S I; Zueva, E E

    2008-01-01

    Multiple myeloma is a malignant proliferative disease of plasma cells. Flow cytometric immunophenotyping makes it possible to identify a malignant clone of myeloma cells in the shortest possible time, to determine its phenotype, and differentiate transformed and preserved plasma cells. The article presents an immunophenotyping strategy using three-color monoclonal antibodies (CD35, CD14, CD38, CD138, and CD19) and an algorithm of verification of transformed plasma cells. Particular emphasis is placed on both the practical aspects of performing this assay and on the clinical application of the obtained results.

  16. Complete remission of multiple myeloma after autoimmune hemolytic anemia: possible association with interferon-alpha.

    PubMed

    Gesundheit, Benjamin; Zelig, Orly; Shapira, Michael Y; Ackerstein, Aliza; Avgil, Meytal; Or, Reuven

    2007-06-01

    A patient with multiple myeloma (MM) was being maintained on human recombinant interferon-alpha (INF-alpha) after VAD and autologous bone marrow transplantation (pretreated with melphalan). An episode of immune thrombocytopenia and (Coombs positive) autoimmune hemolytic anemia (AIHA) was noted while on maintenance INF-alpha, which remitted when it was withdrawn. Following this event, he achieved a state of stable disease that persists (more than 3 years) with no specific myeloma treatment. This sequence of events suggests a relationship between an immunological reaction induced by INF-alpha and the prolonged phase of stable disease.

  17. Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma.

    PubMed

    Sanchez, Larysa; Wang, Yucai; Siegel, David S; Wang, Michael L

    2016-06-30

    Daratumumab is a human monoclonal antibody that targets CD38, a cell surface protein that is overexpressed on multiple myeloma (MM) cells. Preclinical studies have shown that daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and apoptosis. Given the encouraging efficacy and acceptable safety profile of daratumumab demonstrated in clinical trials, daratumumab has emerged as a novel treatment option for myeloma and became the first monoclonal antibody approved by the FDA for the treatment of MM.

  18. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.

    PubMed

    Nelson, Erik A; Walker, Sarah R; Kepich, Alicia; Gashin, Laurie B; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C; Frank, David A

    2008-12-15

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival.

  19. [Current approaches in multiple myeloma and other cancer-related bone diseases].

    PubMed

    Engelhardt, M; Kleber, M; Udi, J; Wäsch, R

    2012-05-01

    Multiple myeloma (MM) ranges second of all hematological malignancies and occurs most commonly in elderly patients. Almost all MM patients develop bone lesions in the course of their disease or have evidence of bone loss at initial diagnosis. Whole-body conventional radiography remains the gold standard in the diagnostic evaluation, albeit computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly used as complementary techniques in the more sensitive detection of osteolytic processes. Bisphosphonates like zoledronate or pamidronate represent the cornerstone therapeutics in osteolytic disease, and are effective supportives to potent anti-myeloma therapies, including novel agents such as the proteasome inhibitor bortezomib or immunomodulatory drugs (IMIDs, e. g. thalidomide or lenalidomide). Several studies are ongoing to investigate the effects of alternative bone-seeking agents and their therapeutic potential for the management of myeloma bone disease, such as denosumab (RANKL-neutralizing antibody), anti-sclerostin (monoclonal antibody, generated against sclerostin) or sotatercept (potent activin-A inhibitor). This review summarizes the most prominent data on myeloma bone disease pathogenesis, the role of imaging techniques as well as therapy and prevention of lytic complications in myeloma which may similarly or equally be true for other bone metastases-inducing solid tumors.

  20. High incidence of intact or fragmented immunoglobulin in urine of patients with multiple myeloma.

    PubMed

    Kraj, Maria; Kruk, Barbara; Lech-Marańda, Ewa; Warzocha, Krzysztof; Prochorec-Sobieszek, Monika

    2015-01-01

    In this prospective study we determined the incidence of intact/fragmented immunoglobulin and Bence Jones protein in urine immunofixation using Sebia reagents and HydrasysTM 2 apparatus and compared the results to concentrations of serum free light chains (FLC) assessed using Siemens BNTM II nephelometer and the immunoassay Freelite (Binding Site) in 289 patients with multiple myeloma at diagnosis. It was found that in one third of IgG, IgA and IgD myeloma patients, intact/fragmented immunoglobulin can be detected in urine and is connected with impaired renal function and reduced survival. Urine immunofixation detects monoclonal protein (FLC and intact/fragmented immunoglobulin) in 66-79% of IgG and IgA myeloma patients while serum FLC immunoassay detect it in 82-94% of IgG and IgA myeloma patients. However, the latter method is inadequate for detection of intact/fragmented immunoglobulin in urine. Serum FLC immunoassay and urine immunofixation are complementary methods in diagnosing and monitoring monoclonal protein in patients with myeloma.

  1. The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis.

    PubMed

    Dinner, Shira; Witteles, Wesley; Witteles, Ronald; Lam, Anthony; Arai, Sally; Lafayette, Richard; George, Tracy I; Schrier, Stanley L; Liedtke, Michaela

    2013-05-01

    The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.

  2. Systemic therapy with oncolytic myxoma virus cures established residual multiple myeloma in mice

    PubMed Central

    Bartee, Eric; Bartee, Mee Y; Bogen, Bjarne; Yu, Xue-Zhong

    2016-01-01

    Multiple myeloma is an incurable malignancy of plasma B-cells. Traditional chemotherapeutic regimes often induce initial tumor regression; however, virtually all patients eventually succumb to relapse caused by either reintroduction of disease during autologous transplant or expansion of chemotherapy resistant minimal residual disease. It has been previously demonstrated that an oncolytic virus known as myxoma can completely prevent myeloma relapse caused by reintroduction of malignant cells during autologous transplant. The ability of this virus to treat established residual disease in vivo, however, remained unknown. Here we demonstrate that intravenous administration of myxoma virus into mice bearing disseminated myeloma results in the elimination of 70–90% of malignant cells within 24 hours. This rapid debulking was dependent on direct contact of myxoma virus with residual myeloma and did not occur through destruction of the hematopoietic bone marrow niche. Importantly, systemic myxoma therapy also induced potent antimyeloma CD8+ T cell responses which localized to the bone marrow and were capable of completely eradicating established myeloma in some animals. These results demonstrate that oncolytic myxoma virus is not only effective at preventing relapse caused by reinfusion of tumor cells during stem cell transplant, but is also potentially curative for patients bearing established minimal residual disease. PMID:27933316

  3. Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma

    PubMed Central

    Langer, Christian; Knop, Stefan; Pischimarov, Jordan; Kull, Miriam; Stühmer, Thorsten; Steinbrunn, Torsten; Bargou, Ralf; Einsele, Hermann; Rosenwald, Andreas; Leich, Ellen

    2016-01-01

    Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the “Deutsche Studiengruppe Multiples Myelom”. Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significantly lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors. PMID:27246973

  4. Is there still a role for allogeneic stem-cell transplantation in multiple myeloma?

    PubMed Central

    Bensinger, William I.

    2007-01-01

    Despite significant improvements in survival for multiple myeloma patients through autologous stem-cell transplantation (SCT) and the introduction of novel drugs, the disease remains incurable for all but a small fraction of patients. Only allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect. High transplant-related mortality with allogeneic SCT is currently the major limitation to wider use of this potentially curative modality. Mortality can be reduced through the use of lower-intensity conditioning regimens which allow engraftment of allogeneic stem cells, but this comes at a cost of higher rates of disease progression and relapse. Promising studies to improve outcomes of allogeneic transplants include the use of more intensive non-myeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering to improve the graft-versus-myeloma activity while reducing graft-versus-host disease (GVHD), post-transplant maintenance, and targeted conditioning therapies such as bone-seeking radioisotopes. PMID:18070719

  5. Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma.

    PubMed

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

    2016-07-01

    Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1α expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma.

  6. Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry.

    PubMed

    Pessoa de Magalhães, Roberto J; Vidriales, María-Belén; Paiva, Bruno; Fernandez-Gimenez, Carlos; García-Sanz, Ramón; Mateos, Maria-Victoria; Gutierrez, Norma C; Lecrevisse, Quentin; Blanco, Juan F; Hernández, Jose; de las Heras, Natalia; Martinez-Lopez, Joaquin; Roig, Monica; Costa, Elaine Sobral; Ocio, Enrique M; Perez-Andres, Martin; Maiolino, Angelo; Nucci, Marcio; De La Rubia, Javier; Lahuerta, Juan-Jose; San-Miguel, Jesús F; Orfao, Alberto

    2013-01-01

    Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8(+) T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes

  7. Elevated Red Blood Cell Distribution Width as a Simple Prognostic Factor in Patients with Symptomatic Multiple Myeloma

    PubMed Central

    Lee, Hyewon; Kong, Sun-Young; Sohn, Ji Yeon; Shim, Hyoeun; Youn, Hye Sun; Lee, Sangeun; Kim, Hyun Ju; Eom, Hyeon-Seok

    2014-01-01

    Red blood cell distribution width (RDW) is a parameter reported in complete blood cell count tests, and has been reported as an inflammatory biomarker. Multiple myeloma (MM) is known to be associated with inflammatory microenvironments. However, the importance of RDW has been seldom studied in MM. For this study, 146 symptomatic myeloma patients with available RDW at diagnosis were retrospectively reviewed, and their characteristics were compared between two groups, those with high (>14.5%) and normal (≤14.5%) RDW. RDW was correlated to hemoglobin, MM stage, β2-microglobulin, M-protein, bone marrow plasma cells, and cellularity (P < 0.001). During induction, overall response rates of the two groups were similar (P = 0.195); however, complete response rate was higher in the normal-RDW group than it was in the high-RDW group (P = 0.005). With a median follow-up of 47 months, the normal-RDW group showed better progression-free survival (PFS) (24.2 versus 17.0 months, P = 0.029) compared to the high-RDW group. Overall survival was not different according to the RDW level (P = 0.236). In multivariate analysis, elevated RDW at diagnosis was a poor prognostic factor for PFS (HR 3.21, 95% CI 1.24–8.32) after adjustment with other myeloma-related prognostic factors. RDW would be a simple and immediately available biomarker of symptomatic MM, reflecting the systemic inflammation. PMID:24963470

  8. In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma.

    PubMed

    Pozzi, Samantha; Fulciniti, Mariateresa; Yan, Hua; Vallet, Sonia; Eda, Homare; Patel, Kishan; Santo, Loredana; Cirstea, Diana; Hideshima, Teru; Schirtzinge, Linda; Kuhstoss, Stuart; Anderson, Kenneth C; Munshi, Nikhil; Scadden, David; Kronenberg, Henry M; Raje, Noopur

    2013-04-01

    Over-expression of the protein Dickkopf-1 (Dkk1) has been associated with multiple myeloma bone disease. Previous reports with the use of anti-Dkk1 neutralizing Ab directed strategies have demonstrated a pro-anabolic effect with associated anti-myeloma activity in 2 in vivo mouse models. However new insights on the role of the wnt pathway in osteoclasts (OC) are emerging and the potential effect of a neutralizing Ab to Dkk1 in osteoclastogenesis remains to be elucidated. In order to better define the effect of an anti-Dkk1 neutralizing Ab on osteoclastogenesis and myeloma, we studied a novel anti-Dkk1 monoclonal Ab in our preclinical models. In vivo data confirmed the pro-anabolic and anti-MM effect. In vitro data in part confirmed the in vivo observation, suggesting an indirect anti-MM effect secondary to inhibition of osteoclastogenesis and thus the interaction between MM and bone microenvironment. However, when studies on osteoclastogenesis were extended to samples derived from MM patients, we observed a variable response to anti-Dkk1 treatment without correlation to expression of surface receptors for Dkk1 in OCs suggesting potential heterogeneity in the efficacy of such a strategy. In conclusion, Dkk1 is a promising target for the treatment of both MM and bone disease, and ongoing clinical studies will help elucidate its efficacy.

  9. The influence of protein fractions and electrolyte imbalance on refractive index of serum in patients with multiple myeloma

    NASA Astrophysics Data System (ADS)

    Plotnikova, L.; Polyanichko, A.; Kobeleva, M.; Uspenskaya, M.; Garifullin, A.; Voloshin, S.

    2017-01-01

    Refractometric analysis is very rapid, accurate and simple method of analysis measuring refractive index of biological liquids such as serum, plasma, spinal fluid, urine. This method can be used for definition total protein and solids concentrations in serum. The value of refractive index depends on all substances in serum including proteins, lipids as well as low molecular weight compounds, for example ions of different metals. Refractometric analysis shows strong correlations between protein concentrations in serum of patients with multiple myeloma and its(serum) refractive index which depends on protein concentration and doesn’t depends on electrolyte disbalance.

  10. Multiple myeloma and glyphosate use: a re-analysis of US Agricultural Health Study (AHS) data.

    PubMed

    Sorahan, Tom

    2015-01-28

    A previous publication of 57,311 pesticide applicators enrolled in the US Agricultural Health Study (AHS) produced disparate findings in relation to multiple myeloma risks in the period 1993-2001 and ever-use of glyphosate (32 cases of multiple myeloma in the full dataset of 54,315 applicators without adjustment for other variables: rate ratio (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.4; 22 cases of multiple myeloma in restricted dataset of 40,719 applicators with adjustment for other variables: RR 2.6, 95% CI 0.7 to 9.4). It seemed important to determine which result should be preferred. RRs for exposed and non-exposed subjects were calculated using Poisson regression; subjects with missing data were not excluded from the main analyses. Using the full dataset adjusted for age and gender the analysis produced a RR of 1.12 (95% CI 0.50 to 2.49) for ever-use of glyphosate. Additional adjustment for lifestyle factors and use of ten other pesticides had little effect (RR 1.24, 95% CI 0.52 to 2.94). There were no statistically significant trends for multiple myeloma risks in relation to reported cumulative days (or intensity weighted days) of glyphosate use. The doubling of risk reported previously arose from the use of an unrepresentative restricted dataset and analyses of the full dataset provides no convincing evidence in the AHS for a link between multiple myeloma risk and glyphosate use.

  11. The Low Expression of IL-37 Involved in Multiple Myeloma – Associated Angiogenesis

    PubMed Central

    Li, Zun-chang; Sun, Ming-dong; Zheng, Yong-qing; Fu, Hong-jie

    2016-01-01

    Background Angiogenesis plays a significant role in complex inflammatory and angiogenic processes and is also involved in multiple myeloma (MM) pathogenesis. IL-37 is a proinflammatory cytokine in antitumor activity. Our purpose was to evaluate the IL-37 clinical significance on MM. Material/Methods We measured serum levels of IL-37 in 45 patients with different stages of MM and 30 healthy control subjects and correlated IL-37 with numerous cytokines, such as angiogenesis factors including vascular endothelial growth factor (VEGF) and angiotensin-2 (Ang-2). We also measured the tube formation of human umbilical vein endothelial cells (HUVECs) after pretreatment with recombinant human IL-37 (rhIL-37). Results Serum IL-37 level was lower in the patients with MM than in the healthy control subjects, whereas VEGF and Ang-2 levels were higher, depending on International Staging System stage. Serum IL-37 level had a negative correlation to VEGF and Ang-2 levels, and VEGF had a positive correlation to Ang-2 level. The tube formation of HUVECs was suppressed by the rhIL-37 pretreatment. Conclusions Our results indicate that serum level of IL-37 plays a part in the pathophysiology of MM progression. Therefore, IL-37 serum level may be a biomarker for disease stage and angiogenesis processes. PMID:27807338

  12. PRIMA-1Met/APR-246 displays high antitumor activity in multiple myeloma by induction of p73 and Noxa.

    PubMed

    Saha, Manujendra N; Jiang, Hua; Yang, Yijun; Reece, Donna; Chang, Hong

    2013-11-01

    Targeting p53 by the small-molecule PRIMA-1(Met)/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1(Met)-induced apoptosis is not completely understood and its effect on multiple myeloma cells is unknown. In this study, we evaluated antitumor effect of PRIMA-1(Met) alone or its combination with current antimyeloma agents in multiple myeloma cell lines, patient samples, and a mouse xenograft model. Results of our study showed that PRIMA-1(Met) decreased the viability of multiple myeloma cells irrespective of p53 status, with limited cytotoxicity toward normal hematopoietic cells. Treatment of multiple myeloma cells with PRIMA-1(Met) resulted in induction of apoptosis, inhibition of colony formation, and migration. PRIMA-1(Met) restored wild-type conformation of mutant p53 and induced activation of p73 upregulating Noxa and downregulating Mcl-1 without significant modulation of p53 level. siRNA-mediated silencing of p53 showed a little effect on apoptotic response of PRIMA-1(Met), whereas knockdown of p73 led to substantial attenuation of apoptotic activity in multiple myeloma cells, indicating that PRIMA-1(Met)-induced apoptosis is, at least in part, p73-dependent. Importantly, PRIMA-1(Met) delayed tumor growth and prolonged survival of mice bearing multiple myeloma tumor. Furthermore, combined treatment of PRIMA-1(Met) with dexamethasone or doxorubicin displayed synergistic effects in both multiple myeloma cell lines and primary multiple myeloma samples. Consistent with our in vitro observations, cotreatment with PRIMA-1(Met) and dexamethasone resulted in enhanced antitumor activity in vivo. Our study for the first time shows antimyeloma activity of PRIMA-1(Met) and provides the rationale for its clinical evaluation in patients with multiple myeloma, including the high-risk group with p53 mutation/deletion.

  13. Potential prognostic long non-coding RNA identification and their validation in predicting survival of patients with multiple myeloma.

    PubMed

    Hu, Ai-Xin; Huang, Zhi-Yong; Zhang, Lin; Shen, Jian

    2017-04-01

    Multiple myeloma, a typical hematological malignancy, is characterized by malignant proliferation of plasma cells. This study was to identify differently expressed long non-coding RNAs to predict the survival of patients with multiple myeloma efficiently. Gene expressing profiles of diagnosed patients with multiple myeloma, GSE24080 (559 samples) and GSE57317 (55 samples), were downloaded from Gene Expression Omnibus database. After processing, survival-related long non-coding RNAs were identified by Cox regression analysis. The prognosis of multiple myeloma patients with differently expressed long non-coding RNAs was predicted by Kaplan-Meier analysis. Meanwhile, stratified analysis was performed based on the concentrations of serum beta 2-microglobulin (S-beta 2m), albumin, and lactate dehydrogenase of multiple myeloma patients. Gene set enrichment analysis was performed to further explore the functions of identified long non-coding RNAs. A total of 176 long non-coding RNAs significantly related to the survival of multiple myeloma patients (p < 0.05) were identified. In dataset GSE24080 and GSE57317, there were 558 and 55 patients being clustered into two groups with significant differences, respectively. Stratified analysis indicated that prediction of the prognoses with these long non-coding RNAs was independent from other clinical phenotype of multiple myeloma. Gene set enrichment analysis-identified pathways of cell cycle, focal adhesion, and G2-M checkpoint were associated with these long non-coding RNAs. A total of 176 long non-coding RNAs, especially RP1-286D6.1, AC008875.2, MTMR9L, AC069360.2, and AL512791.1, were potential biomarkers to evaluate the prognosis of multiple myeloma patients. These long non-coding RNAs participated indispensably in many pathways associated to the development of multiple myeloma; however, the molecular mechanisms need to be further studied.

  14. Incidence and clinical background of hepatitis B virus reactivation in multiple myeloma in novel agents' era.

    PubMed

    Tsukune, Yutaka; Sasaki, Makoto; Odajima, Takeshi; Isoda, Atsushi; Matsumoto, Morio; Koike, Michiaki; Tamura, Hideto; Moriya, Keiichi; Ito, Shigeki; Asahi, Maki; Imai, Yoichi; Tanaka, Junji; Handa, Hiroshi; Koiso, Hiromi; Tanosaki, Sakae; Hua, Jian; Hagihara, Masao; Yahata, Yuriko; Suzuki, Satoko; Watanabe, Sumio; Sugimori, Hiroki; Komatsu, Norio

    2016-09-01

    There are some reports regarding hepatitis B virus (HBV) reactivation in patients with myeloma who are HBV carriers or who have had a resolved HBV infection, and there is no standard prophylaxis strategy for these patients. We performed a retrospective multicenter study to determine the incidence and characteristics of HBV reactivation in patients with multiple myeloma. We identified 641 patients with multiple myeloma who had been treated using novel agents and/or autologous stem cell transplantation with high-dose chemotherapy between January 2006 and June 2014 at nine Japanese hospitals. The patients' characteristics, laboratory data, and clinical courses were retrieved and statistically analyzed. During a median follow-up of 101 weeks, one of eight (12.5 %) HBV carriers developed hepatitis and 9 of 99 (9.1 %) patients with resolved HBV infection experienced HBV reactivation; the cumulative incidences of HBV reactivation at 2 years (104 weeks) and 5 years (260 weeks) were 8 and 14 %, respectively. The nine cases of reactivation after resolved HBV infection had received entecavir as preemptive therapy or were carefully observed by monitoring their HBV DNA levels, and none of these cases developed hepatitis. Among patients with multiple myeloma, HBV reactivation was not rare. Therefore, long-term monitoring of HBV DNA levels is needed to prevent hepatitis that is related to HBV reactivation in these patients.

  15. Kidney Transplantation for Kidney Failure Due to Multiple Myeloma: Case Reports.

    PubMed

    Le, Thuy X; Wolf, Jeffrey L; Peralta, Carmen A; Webber, Allison B

    2017-03-17

    Transplantation centers have historically considered a history of multiple myeloma as a contraindication to kidney transplantation due to high recurrence rates and poor transplant survival. However, there have been significant advances in the treatment of multiple myeloma, with improved patient survival, which may allow for successful kidney transplantation in these patients. We report on 4 patients who underwent kidney transplantation at our institution between 2009 and 2015 after having achieved a very good partial response or better with chemotherapy and autologous stem cell transplantation. All 4 patients received kidneys from living donors; 2 underwent induction therapy with basiliximab, and 2, with thymoglobulin. One patient had progression of myeloma, which responded well to therapy. All had functioning transplants at 1 year after kidney transplantation. No patients experienced a rejection episode or infections with BK polyomavirus or cytomegalovirus, with follow-up ranging from 16 to 58 months after kidney transplantation. Our experience suggests that kidney transplantation is feasible in a subset of patients with multiple myeloma. Future studies are necessary to compare outcomes in these patients with other high-risk patients undergoing kidney transplantation.

  16. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells.

    PubMed

    Carbone, Ennio; Neri, Paola; Mesuraca, Maria; Fulciniti, Mariateresa T; Otsuki, Takemi; Pende, Daniela; Groh, Veronika; Spies, Thomas; Pollio, Giuditta; Cosman, David; Catalano, Lucio; Tassone, Pierfrancesco; Rotoli, Bruno; Venuta, Salvatore

    2005-01-01

    The role of natural killer (NK) cells in multiple myeloma is not fully understood. Here, NK susceptibility of myeloma cells derived from distinct disease stages was evaluated in relation to major histocompatibility complex (MHC) class I, MHC class I chain-related protein A (MICA), MHC class I chain-related protein B (MICB), and UL16 binding protein (ULBP) expression. MHC class I molecules were hardly detectable on bone marrow cells of early-stage myeloma, while late-stage pleural effusion-derived cell lines showed a strong MHC class I expression. Conversely, a high MICA level was found on bone marrow myeloma cells, while it was low or not measurable on pleural effusion myeloma cells. The reciprocal surface expression of these molecules on bone marrow- and pleural effusion-derived cell was confirmed at mRNA levels. While bone marrow-derived myeloma cells were readily recognized by NK cells, pleural effusion-derived lines were resistant. NK protection of pleural effusion cells was MHC class I dependent. Receptor blocking experiments demonstrated that natural cytotoxicity receptor (NCR) and NK receptor member D of the lectin-like receptor family (NKG2D) were the key NK activating receptors for bone marrow-derived myeloma cell recognition. In ex vivo experiments patient's autologous fresh NK cells recognized bone marrow-derived myeloma cells. Our data support the hypothesis that NK cell cytotoxicity could sculpture myeloma and represents an important immune effector mechanism in controlling its intramedullary stages.

  17. Anaesthesia of the right lower hemilip as a first manifestation of multiple myeloma. Presentation of a clinical case.

    PubMed

    Reboiras López, M D; García García, A; Antúnez López, J; Blanco Carrión, A; Gándara Vila, P; Gándara Rey, J M

    2001-01-01

    Multiple myeloma is a malignant proliferation of plasma cells. It may affect any of various bones, causing osteolytic lesions with a characteristic "punched out" radiographic appearance. The commonest symptom is bone pain. One of the most frequent locations is the mandible. Symptoms of multiple myeloma of the mandible include tumefaction, non-specific pain, tooth mobility and sometimes loss, and paraesthesia of the dental nerve. Here we report a case of multiple myeloma of the mandible which was unusual in that the presenting complaint was anaesthesia of the right lower hemilip.

  18. [Excision of a left atrial myxoma through right minithoracotomy in a patient with multiple myeloma; report of a case].

    PubMed

    Koyama, Yutaka; Goto, Yoshihiro; Ogawa, Shinji; Baba, Hiroshi; Okawa, Yasuhide

    2014-12-01

    We present a case of a 63-year-old female who underwent an excision of a left atrial myxoma. Previously, she had been diagnosed with multiple myelomas and received radiation therapy and chemotherapy. A left atrial myxoma was found at an annual medical check-up. The myxoma was removed via a right minithoracotomy with peripheral cannulation to minimize bleeding complications and surgical site infection. She was transferred to the referring hospital on postoperative day 7 due to recurrence of multiple myelomas. She was doing well 14 months after the operation. Right minithoracotomy is a useful approach to minimizing the risks of bleeding and infection in patients with multiple myelomas.

  19. Sorafenib in patients with refractory or recurrent multiple myeloma.

    PubMed

    Yordanova, Anna; Hose, Dirk; Neben, Kai; Witzens-Harig, Mathias; Gütgemann, Ines; Raab, Marc-Steffen; Moehler, Thomas; Goldschmidt, Hartmut; Schmidt-Wolf, Ingo G H

    2013-12-01

    Sorafenib is a small molecular inhibitor of several tyrosine protein kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and rapidly accelerated fibrosarcoma kinases, targeting signal transduction and angiogenic pathways. It is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. The objectives of this prospective phase II trial were to assess the activity and tolerability of sorafenib in patients with recurrent or refractory myeloma. In total, 11 patients were enrolled. Patients received 2 × 200 mg of sorafenib orally twice daily until completing 13 full cycles or disease progression. Of the side effects, 8.8% grade 3 and 1.1% grade 4 occurred. Sorafenib treatment was effective in two patients who achieved a partial response and a continuous stable disease with duration of 24.4 months and 6.9 month, respectively. Further clinical investigations are recommended to investigate sorafenib single agent activity in myeloma subgroups with ras-/BRAF-/vascular endothelial growth factor receptor pathway activation and combination therapy approaches.

  20. Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma.

    PubMed

    Abe, Masahiro; Hiura, Kenji; Wilde, Javier; Moriyama, Keiji; Hashimoto, Toshihiro; Ozaki, Shuji; Wakatsuki, Shingo; Kosaka, Masaaki; Kido, Shinsuke; Inoue, Daisuke; Matsumoto, Toshio

    2002-09-15

    Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1alpha and MIP-1beta correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1alpha and MIP-1beta. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1alpha and MIP-1beta, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1alpha and MIP-1beta induce expression of receptor activator of nuclear factor-kappaB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1alpha and MIP-1beta may be major osteoclast-activating factors produced by MM cells.

  1. Rupture of an extended mycotic aneurysm of the descending thoracic aorta in a multiple myeloma patient undergoing anti-myeloma therapy.

    PubMed

    Marumoto, Akira; Iwata, Keiji

    2016-03-01

    Infectious complications in patients with multiple myeloma remain the main cause of mortality because of disease-related immunodeficiency. A mycotic aortic aneurysm caused by Burkhoderia cepacia, which has been recognized as nosocomial pathogen in immunocompromised populations, is very rare and only few cases have been reported in the literature. We describe an unusual case of a ruptured mycotic aneurysm of the descending thoracic aorta with a DeBakey IIIb aortic dissection caused by Burkhoderia cepacia in a patient with active multiple myeloma during chemotherapy with anti-myeloma agents. Successful treatment of this mycotic aneurysm included appropriate antibiotic therapy and replacement of the aortic arch and the descending aorta for the extensive debridement of all infected aortas. This was followed by the wrapping of a prosthetic graft with a well-vascularized tissue flap of the greater omentum and of the latissimus dorsi muscle.

  2. New drugs in multiple myeloma – role of carfilzomib and pomalidomide

    PubMed Central

    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. PMID:24876816

  3. [Association of CRBN Gene with Immunomodulatory Drug Resis- tance in Multiple Myeloma].

    PubMed

    Cai, Qian-Qian; Li, Jian

    2015-06-01

    Human CRBN (cereblon) gene is located on chromosome 3 at 3p26 and its encoding protein is a member of E3 ubiquitin ligase complex (composed of CRBN, DDB1, CUL4A and ROC1). The E3 ubiquitin ligase complex functions in the ubiquitin-proteasome protein degradation pathway and attaches polyubiquitin chains to substrate proteins for degradation via the protease complex. Currently, there are no standardized assays for CRBN gene and protein measurement although quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry and Western blot are widely used. CRBN has been identified as a direct target for immunomodulatory drugs (IMiD) and plays a significant role in anti-proliferation, pro-apoptotic effects, anti-angiogenic activities, immunomodulatory activities and intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells. Recently, clinical data show that majority of the multiple myeloma patients treated with IMiD develop drug-resistance over time by unknown mechanisms. Fortunately, various in vivo and in vitro studies have revealed that the decreased CRBN expression or CRBN deletion is associated with resistance to IMiD in treating multiple myeloma, and CRBN expression levels may have a prognostic significance. Furthermore, the most recently discovered protein IKZF1, IKZF3, IRF4, C/EBPβ and Wnt/catenin signaling pathways may also be closely related to IMiD resistance in myeloma.

  4. [Infectious pleurisy as first sign of multiple myeloma in a young 28 years old].

    PubMed

    Benali, A; Kahouli, S; El Ouazzani, H; Souhi, H; Abderrahmani Rhorfi, I; Abid, A; Yahyaoui, A; Zahid, H; Messaoudi, N

    2015-10-01

    Multiple myeloma is a malignant proliferation of plasma cells, mainly affecting the bone marrow. It rarely occurs in young patients. The medical observation study reveals multiple myeloma discovered through a purulent pleurisy in a 28-year-old subject. This patient was admitted to the pneumology service of the Mohamed V military hospital in Rabat for a fever and dyspnea evolving into a context of poor general condition. Clinical examination found a right pleural fluid effusion syndrome. The pleural puncture reveals a germ-free exudative purulent fluid without plasma cells. The myeloma diagnosis was suspected due to the combination of an aplastic normochromic normocytic anemia at 4.5g/dL of hemoglobin, an accelerated erythrocyte sedimentation rate, hypercalcemia, renal failure and osteolytic lesions located mainly in the skull and pelvis area, oriented by electrophoresis and serum protein immunosubstraction revealing a narrow peak in monoclonal beta-2 globulin at 70.56g/L with a lambda monoclonal gammopathy with immunoglobulin G, and confirmed by the myelogram showing a 74% rate of bone marrow plasma cells. The occurrence of myeloma at a young age is rare and the purulent pleurisy without plasma cells is a rare form of presentation and represents a poor prognosis.

  5. Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bortezomib and dexamethasone.

    PubMed

    López-Iglesias, Ana-Alicia; González-Méndez, Lorena; San-Segundo, Laura; Herrero, Ana B; Hernández-García, Susana; Martín-Sánchez, Montserrat; Gutiérrez, Norma C; Paíno, Teresa; Avilés, Pablo; Mateos, María-Victoria; San-Miguel, Jesús F; Garayoa, Mercedes; Ocio, Enrique M

    2017-01-01

    Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients.

  6. Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bortezomib and dexamethasone

    PubMed Central

    López-Iglesias, Ana-Alicia; González-Méndez, Lorena; San-Segundo, Laura; Herrero, Ana B.; Hernández-García, Susana; Martín-Sánchez, Montserrat; Gutiérrez, Norma C.; Paíno, Teresa; Avilés, Pablo; Mateos, María-Victoria; San-Miguel, Jesús F.; Garayoa, Mercedes; Ocio, Enrique M.

    2017-01-01

    Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients. PMID:27540138

  7. Targeting the Fanconi Anemia/BRCA Pathway Circumvents Drug Resistance in Multiple Myeloma

    PubMed Central

    Yarde, Danielle N.; Oliveira, Vasco; Mathews, Linda; Wang, Xingyu; Villagra, Alejandro; Boulware, David; Shain, Kenneth H.; Hazlehurst, Lori A.; Alsina, Melissa; Chen, Dung-Tsa; Beg, Amer A.; Dalton, William S.

    2015-01-01

    The Fanconi Anemia (FA)/BRCA DNA damage repair pathway plays a pivotal role in the cellular response to replicative stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA genes are overexpressed and causative for drug resistance in human melphalan-resistant multiple myeloma (MM) cell lines. However, the transcriptional regulation of the FA/BRCA pathway is not understood. In this report, we describe for the first time a novel function of the NF-κB subunits, RelB/p50, as transcriptional activators of the FA/BRCA pathway. Specifically, our findings point to constitutive phosphorylation of IκB Kinase IKKα and subsequent alterations in FANCD2 expression and function as underlying events leading to melphalan resistance in repeatedly exposed MM cells. Inhibiting NF-κB by siRNA, blocking the IKK complex with BMS-345541, or using the proteasome inhibitor bortezomib drastically reduced FA/BRCA gene expression and FANCD2 protein expression in myeloma cells, resulting in diminished DNA damage repair and enhanced melphalan sensitivity. Importantly, we also found that bortezomib decreases FA/BRCA gene expression in multiple myeloma patients. These results show for the first time that NF-κB transcriptionally regulates the FA/BRCA pathway, and provide evidence for targeting FA-mediated DNA repair to enhance chemotherapeutic response and circumvent drug resistance in myeloma patients. PMID:19934314

  8. Time-dependent endpoints as predictors of overall survival in multiple myeloma

    PubMed Central

    2013-01-01

    Background Supporting health care sector decisions using time-dependent endpoints (TDEs) such as time to progression (TTP), progression-free survival (PFS), and event-free survival (EFS) remains controversial. This study estimated the quantitative relationship between median TDE and median overall survival (OS) in multiple myeloma (MM) patients. Methods Studies (excluding allogeneic transplantation) published from 1970 to 2011 were systematically searched (PubMed). The nonparametric Spearman’s rank correlation coefficient measured the association between median TDE and OS. The quantitative relationship between TDEs and OS was estimated with a two-step approach to a simultaneous Tobit model. Results We identified 153 studies: 230 treatment arms, 22,696 patients and mean study duration of 3.8 years. Mean of median TDEs was 22.5 months and median OS was 39.1 months. Correlation coefficients of median TTP, PFS, and EFS with median OS were 0.51 (P = 0.003), 0.75 (P < 0.0001), and 0.84 (P < 0.0001), respectively. We estimate a 2.5 month (95% confidence interval, 1.7–3.2) increase in median OS for each additional month reported for median TDEs. There was no evidence that this relationship differed by type of surrogate. Conclusion TDEs predict OS in MM patients; this relationship may be valuable in clinical trial design, drug comparisons, and economic evaluation. PMID:23497363

  9. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board.

    PubMed

    Miceli, Teresa; Colson, Kathleen; Gavino, Maria; Lilleby, Kathy

    2008-06-01

    Novel therapies for multiple myeloma include the immunomodulatory drugs lenalidomide and thalidomide and the proteasome inhibitor bortezomib, which have increased response rates and survival times. However, the agents can cause myelosuppression, which, if not managed effectively, can be life threatening and interfere with optimal therapy and quality of life. The International Myeloma Foundation's Nurse Leadership Board developed a consensus statement that includes toxicity grading, strategies for monitoring and managing myelosuppression associated with novel therapies, and educational recommendations for patients and their caregivers. Although anemia, neutropenia, and thrombocytopenia are expected side effects of novel therapies for multiple myeloma, they are manageable with appropriate interventions and education.

  10. Delineating the mTOR kinase pathway using a dual TORC1/2 inhibitor, AZD8055, in multiple myeloma.

    PubMed

    Cirstea, Diana; Santo, Loredana; Hideshima, Teru; Eda, Homare; Mishima, Yuko; Nemani, Neeharika; Mahindra, Anuj; Yee, Andrew; Gorgun, Gullu; Hu, Yiguo; Ohguchi, Hiroto; Suzuki, Rikio; Cottini, Francesca; Guichard, Sylvie M; Anderson, Kenneth C; Raje, Noopur

    2014-11-01

    Despite promising preclinical results with mTOR kinase inhibitors in multiple myeloma, resistance to these drugs may arise via feedback activation loops. This concern is especially true for insulin-like growth factor 1 receptor (IGF1R), because IGF1R signaling is downregulated by multiple AKT and mTOR feedback mechanisms. We have tested this hypothesis in multiple myeloma using the novel selective mTOR kinase inhibitor AZD8055. We evaluated p-mTOR S(2481) as the readout for mTORC2/Akt activity in multiple myeloma cells in the context of mTOR inhibition via AZD8055 or rapamycin. We next validated AZD8055 inhibition of mTORC1 and mTORC2 functions in multiple myeloma cells alone or in culture with bone marrow stroma cells and growth factors. Unlike rapamycin, AZD8055 resulted in apoptosis of multiple myeloma cells. AZD8055 treatment, however, induced upregulation of IGF1R phosphorylation in p-Akt S(473)-expressing multiple myeloma cell lines. Furthermore, exposure of AZD8055-treated cells to IGF1 induced p-Akt S(473) and rescued multiple myeloma cells from apoptosis despite mTOR kinase inhibition and TORC2/Akt blockage. The addition of blocking IGF1R antibody resulted in reversing this effect and increased AZD8055-induced apoptosis. Our study suggests that combination treatment with AZD8055 and IGF1R-blocking agents is a promising strategy in multiple myeloma with potential IGF1R/Akt signaling-mediated survival.

  11. Monoclonal gammopathy of undetermined significance and Smoldering Multiple Myeloma: A review of the current understanding of epidemiology, biology, risk stratification and management of myeloma precursor disease

    PubMed Central

    Agarwal, Amit; Ghobrial, Irene

    2012-01-01

    The term monoclonal gammopathy of undetermined significance (MGUS) was coined in 1978. The recent advances in our knowledge about MGUS and smoldering MM (SMM) have helped us better understand the pathogenesis of myeloma. It appears that myeloma evolves from a precursor state in almost all cases. We do not completely understand the multistep process from the precursor state to myeloma but studies including whole genome sequencing will continue to help in improving our understanding of this process. The process of transformation may not be linear acquisition of changes but rather a branched heterogeneous process. Clinical features that are prognostic of rapid transformation have been identified but no specific molecular markers have been identified. Even with recent advances, multiple myeloma remains an incurable disease in the vast majority and intervening at the precursor state provides a unique opportunity to alter the natural history of the disease. A limitation is that a vast majority of patients with precursor disease especially low risk MGUS will never progress to myeloma in their lifetime and treating these patients is not only unnecessary but may be potentially harmful. The challenge is to identify a subset of patients with the precursor state that would definitely progress to myeloma and in whom interventions will have a meaningful impact. As our understanding of the molecular and genetic processes improves, these studies will guide the selection of high-risk patients more appropriately and ultimately direct a tailored management strategy to either delay progression to symptomatic myeloma or even “cure” a person at this premalignant stage. PMID:23224402

  12. Therapy-related myelodysplastic syndrome/acute leukemia after multiple myeloma in the era of novel agents.

    PubMed

    Gertz, Morie A; Terpos, Evangelos; Dispenzieri, Angela; Kumar, Shaji; Shah, Rupin A; Orlowski, Robert; Kastritis, Efstathios; Dimopoulos, Meletios A; Shah, Jatin

    2015-06-01

    Survival for patients with multiple myeloma has increased. Both melphalan and lenalidomide are associated with subsequent development of myelodysplasia. We reviewed the cases of all patients with multiple myeloma who had subsequent development of myelodysplastic syndrome (MDS) or acute non-lymphoblastic leukemia (ANLL) during a 12-year period in three centers. Of 55 patients identified, two received only lenalidomide before myelodysplasia developed. The median time between the diagnoses of multiple myeloma and MDS/ANLL was 52.7 months. Median survival after the diagnosis of MDS or ANLL was 6.7 months. Treatment of MDS comprised allogeneic stem cell transplant in eight patients (median survival, 219 days; one patient alive at 624 days) and a hypomethylating agent in 21 patients (response of stable or better in five patients). Myelodysplasia remains a devastating complication of therapy for multiple myeloma, with short survival and poor response rates to available modalities.

  13. TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition.

    PubMed

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

    2016-01-01

    Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxic-myeloma cells to bortezomib. Hypoxia increased NF-кβ subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-кβ p65 protein levels in the nucleus and reduced the expression of NF-кβ-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the naïve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-кβ-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-кβ signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomib-resistance and improve survival outcomes of MM patients.

  14. ABCG2 expression, function, and promoter methylation in human multiple myeloma

    PubMed Central

    Turner, Joel G.; Gump, Jana L.; Zhang, Chunchun; Cook, James M.; Marchion, Douglas; Hazlehurst, Lori; Munster, Pamela; Schell, Michael J.; Dalton, William S.; Sullivan, Daniel M.

    2006-01-01

    We investigated the role of the breast cancer resistance protein (BCRP/ABCG2) in drug resistance in multiple myeloma (MM). Human MM cell lines, and MM patient plasma cells isolated from bone marrow, were evaluated for ABCG2 mRNA expression by quantitative polymerase chain reaction (PCR) and ABCG2 protein, by Western blot analysis, immunofluorescence microscopy, and flow cytometry. ABCG2 function was determined by measuring topotecan and doxorubicin efflux using flow cytometry, in the presence and absence of the specific ABCG2 inhibitor, tryprostatin A. The methylation of the ABCG2 promoter was determined using bisulfite sequencing. We found that ABCG2 expression in myeloma cell lines increased after exposure to topotecan and doxorubicin, and was greater in logphase cells when compared with quiescent cells. Myeloma patients treated with topotecan had an increase in ABCG2 mRNA and protein expression after treatment with topotecan, and at relapse. Expression of ABCG2 is regulated, at least in part, by promoter methylation both in cell lines and in patient plasma cells. Demethylation of the promoter increased ABCG2 mRNA and protein expression. These findings suggest that ABCG2 is expressed and functional in human myeloma cells, regulated by promoter methylation, affected by cell density, up-regulated in response to chemotherapy, and may contribute to intrinsic drug resistance. PMID:16917002

  15. [The role of the bone marrow microenvironment in the pathogenesis of multiple myeloma].

    PubMed

    Jurczyszyn, Artur; Gdula-Argasińska, Joanna; Kosmaczewska, Agata; Skotnicki, Aleksander B

    2015-04-22

    Multiple myeloma (MM) is one of the most common hematologic malignancies. It remains an incurable disease, so far. The mainstay of treatment for decades was pointless therapy with cytostatic agents and immunosuppressant's. Because myeloma is most common in the elderly population, vulnerable to aggressive therapy, non-specific treatment approaches led to poor patient survival. Intensive study of MM, allowed identification of the molecular interactions between myeloma cells and bone marrow tumour microenvironment, responsible for the development of the disease and associated complications, such as osteolytic bone lesions. Understanding the molecular mechanisms of action of adhesion molecules, cytokines and signalling pathways involved in the development of myeloma, has led to develop of novel, targeted therapies to improve the quality of patients life and significantly prolong the median survival time. This paper discusses the current state of knowledge of signalling pathways involved in the progression of cancer and the destruction of bone tissue, with particular emphasis on interactions with the bone marrow microenvironment of the tumour.

  16. Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway

    PubMed Central

    Roy, P; Mukherjee, T; Chatterjee, B; Vijayaragavan, B; Banoth, B; Basak, S

    2017-01-01

    Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma. Tumor-promoting cytokines, such as tumor necrosis factor (TNF), induce nuclear factor-κB (NFκB)- driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TNF-related apoptosis-inducing ligand (TRAIL) and other chemotherapeutic drugs. It is thought that RelA:p50 dimer, activated from IκBα-inhibited complex in response to TNF-induced canonical NFκB signal, mediates the pro-survival NFκB function in cancerous cells. Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NFκB module, which induces partial proteolysis of p100 into p52 to promote RelB:p52/NFκB activation from p100-inhibited complex during immune cell differentiation. However, role of non-canonical NFκB signaling in the drug resistance in multiple myeloma remains unclear. Here we report that myeloma-associated non-canonical aberrations reinforce pro-survival TNF signaling in producing a protracted TRAIL-refractory state. These mutations did not act through a typical p52 NFκB complex, but completely degraded p100 to reposition RelB under IκBα control, whose degradation during TNF signaling induced an early RelB:p50 containing NFκB activity. More so, autoregulatory RelB synthesis prolonged this TNF-induced RelB:p50 activity in myeloma cells harboring non-canonical mutations. Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NFκB-dependent pro-survival gene expressions and suppression of apoptosis. Indeed, high RelB mRNA expressions in myeloma patients correlated with the augmented level of pro-survival factors and resistance to therapeutic intervention. In sum, we provide evidence that cancer-associated mutations perpetuate TNF-induced pro-survival NFκB activity through autoregulatory RelB control and thereby exacerbate environmental drug

  17. [The patient complains of spinal pain or fatigue and weakness. How do I recognize whether their cause is spondylarthrosis, the patients age or multiple myeloma?].

    PubMed

    Adam, Zdeněk; Pourová, Eva; Pour, Luděk; Michalková, Eva; Krejčí, Marta; Koukalová, Renata; Řehák, Zdeněk; Vaníček, Jíří; Nebeský, Tomáš; Petrášová, Hana; Ševčíková, Sabina; Mašek, Michal; Král, Zdeněk; Čermák, Aleš

    2016-02-01

    Multiple myeloma has varied manifestations which resemble common patient complaints and that is why this disease is typically not diagnosed until it reaches an advanced stage. Spinal pains can be an expression of deformative and discogenous changes, but also a symptom of multiple myeloma. Pains in the long bones may result from the pain radiating from an arthrotic joint, but also from a large myelomatic osteolytic lesion which makes the bone prone to a spontaneous fracture. Pathological weariness may have many causes, multiple myeloma being one of them. Anemia may have a large number of causes and multiple myeloma is one of them. Raised creatinine levels and renal failure can also be due to many causes and again, multiple myeloma is one of them. Weakened immunity and frequent infections can also have many causes, among them multiple myeloma. Confusion and sleepiness may be due to psychiatric diagnosis, but also may result from hypercalcemia associated with multiple myeloma. The following text which is designed for non-hematology physicians therefore describes in detail the symptoms of multiple myeloma and diagnostic steps leading to establishing the diagnosis and it only briefly outlines the treatment related information. You can also visit www.myeloma.cz for details. This text aims to summarize the symptoms of multiple myeloma for physicians not specializing in hematology in order to facilitate earlier diagnosing of the disease.

  18. A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition.

    PubMed

    Alagpulinsa, David A; Ayyadevara, Srinivas; Yaccoby, Shmuel; Shmookler Reis, Robert J

    2016-02-01

    PARP1/2 are required for single-strand break repair, and their inhibition causes DNA replication fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end-joining mechanisms, or may persist, ultimately resulting in cell death. The combined disruption of PARP and HR activities thus produces synthetic lethality. Multiple myeloma cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDK), upstream modulators of HR, are dysregulated in multiple myeloma. Here, we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes multiple myeloma cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888-induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased γH2AX foci. Dinaciclib treatment reduces expression of HR repair genes, including Rad51, and blocks BRCA1 phosphorylation, a modification required for HR repair, thus inhibiting HR repair of chromosome DSBs. Cotreatment with dinaciclib and ABT-888 in vitro resulted in synthetic lethality of multiple myeloma cells, but not normal CD19(+) B cells, and slowed growth of multiple myeloma xenografts in SCID mice almost two-fold. These findings support combining dinaciclib with PARP inhibitors for multiple myeloma therapy. Mol Cancer Ther; 15(2); 241-50. ©2015 AACR.

  19. [68Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - Comparison to [18F]FDG and laboratory values

    PubMed Central

    Lapa, Constantin; Schreder, Martin; Schirbel, Andreas; Samnick, Samuel; Kortüm, Klaus Martin; Herrmann, Ken; Kropf, Saskia; Einsele, Herrmann; Buck, Andreas K.; Wester, Hans-Jürgen; Knop, Stefan; Lückerath, Katharina

    2017-01-01

    Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [68Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent [68Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [18F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity. [68Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [18F]FDG was available, [68Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [18F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [18F]FDG-PET positivity correlated with [68Ga]Pentixafor-PET positivity (p=0.018). [68Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma. PMID:28042328

  20. Lenalidomide affect expression level of cereblon protein in multiple myeloma cell line RPMI8226.

    PubMed

    Yang, D Y; Ren, J H; Guo, X N; Guo, X L; Cai, X Y; Guo, X F; Zhang, J N

    2015-10-29

    We investigated the mechanisms of action of immuno-modulatory drug (lenalidomide) on the protein expression of cereblon (CRBN) and their therapeutic targets in the multiple myeloma cell line RPMI8226. The multiple myeloma cell line RPMI8226 was cultured and treated with different concentrations of lenalidomide and bortezomib to determine the proliferation inhibition rate, apoptosis rate, and protein expression of CRBN. The results revealed that both lenalidomide and bortezomib inhibited the proliferation of RPMI8226 and promoted cell apoptosis. However, the protein expression of CRBN decreased signifi-cantly after treatment with lenalidomide, while bortezomib had no effect on the expression of CRBN. We confirmed that CRBN may be a target of lenalidomide.

  1. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.

    PubMed

    Krönke, Jan; Udeshi, Namrata D; Narla, Anupama; Grauman, Peter; Hurst, Slater N; McConkey, Marie; Svinkina, Tanya; Heckl, Dirk; Comer, Eamon; Li, Xiaoyu; Ciarlo, Christie; Hartman, Emily; Munshi, Nikhil; Schenone, Monica; Schreiber, Stuart L; Carr, Steven A; Ebert, Benjamin L

    2014-01-17

    Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.

  2. Multiple Myeloma Relapse Following Autologous Stem Cell Transplant Presenting With Diffuse Pulmonary Nodules

    PubMed Central

    Sumrall, Bradley; Diethelm, Lisa; Brown, Archie

    2013-01-01

    Background Multiple myeloma is a common disease, accounting for about 10% of hematologic malignancies in the United States. For eligible patients, the treatment of choice includes induction therapy (usually involving newer biologic agents) followed by autologous stem cell transplant; however, this treatment is generally not considered curative, and relapses usually occur. However, extramedullary relapse is an uncommon presentation, and relapses that involve the lungs have only rarely been described. Case Report We report the case of a patient who underwent an autologous stem cell transplant for multiple myeloma and subsequently relapsed with diffuse pulmonary nodules. She then had a rapid clinical and serologic response following initiation of salvage therapy. Conclusion This case is remarkable for both the radiographic appearance of the pulmonary involvement, as well as the rapid resolution of these findings after 2 cycles of treatment with bortezomib, dexamethasone, and lenalidomide. PMID:24358007

  3. [Diagnosis of multiple myeloma in primary care. Suspicion with an appropriate clinical history].

    PubMed

    Alvarez-Cordovés, M M; Mirpuri-Mirpuri, P G; Pérez-Monje, A

    2013-09-01

    Monoclonal gammopathies are a group of disorders characterized by stable or progressive clonal proliferation of plasma cells producing similar immunoglobulins. Multiple myeloma is characteristic of the presence of bone marrow infiltration by plasma cells, osteolytic lesions, and M component in serum or urine. As cancer cells multiply, they can cause pain and destruction of bone, and if affecting the spine, they can press on nerves causing pain and paresthesias. In patients of advanced age (average 69 years) with bone pain not associated with trauma, and which does not improve with treatment, a differential diagnosis should be performed with multiple myeloma. This should include, at least, a full blood count, biochemistry, total protein, protein electrophoresis, immunofixation, and radiographs of painful areas.

  4. Promiscuous Mutations Activate the Non-Canonical NF-kB Pathway in Multiple Myeloma

    PubMed Central

    Keats, Jonathan J.; Fonseca, Rafael; Chesi, Marta; Schop, Roelandt; Baker, Angela; Chng, Wee-Joo; Van Wier, Scott; Tiedemann, Rodger; Shi, Chang-Xin; Sebag, Michael; Braggio, Esteban; Henry, Travis; Zhu, Yuan-Xiao; Fogle, Homer; Price-Troska, Tammy; Ahmann, Gregory; Mancini, Catherine; Brents, Leslie A.; Kumar, Shaji; Greipp, Philip; Dispenzieri, Angela; Bryant, Barb; Mulligan, George; Bruhn, Laurakay; Barrett, Michael; Valdez, Riccardo; Trent, Jeff; Stewart, A. Keith; Carpten, John; Bergsagel, P. Leif

    2007-01-01

    Summary Activation of NF-kB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2, and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the non-canonical NF-kB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kB pathway in the pathogenesis of multiple myeloma. PMID:17692805

  5. Lung Postmortem Autopsy Revealing Extramedullary Involvement in Multiple Myeloma Causing Acute Respiratory Distress Syndrome

    PubMed Central

    Ravinet, Aurélie; Perbet, Sébastien; Guièze, Romain; Guérin, Renaud; Gayraud, Guillaume; Aliane, Jugurtha; Tremblay, Aymeric; Pascal, Julien; Ledoux, Albane; Chaleteix, Carine; Dechelotte, Pierre; Bay, Jacques-Olivier; Bazin, Jean-Etienne; Constantin, Jean-Michel

    2014-01-01

    Pulmonary involvement with multiple myeloma is rare. We report the case of a 61-year-old man with past medical history of chronic respiratory failure with emphysema, and a known multiple myeloma (Durie and Salmon stage III B and t(4;14) translocation). Six months after diagnosis and first line of treatment, he presented acute dyspnea with interstitial lung disease. Computed tomography showed severe bullous emphysema and diffuse, patchy, multifocal infiltrations bilaterally with nodular character, small bilateral pleural effusions, mediastinal lymphadenopathy, and a known lytic lesion of the 12th vertebra. He was treated with piperacillin-tazobactam, amikacin, oseltamivir, and methylprednisolone. Finally, outcome was unfavourable. Postmortem analysis revealed diffuse and nodular infracentimetric infiltration of the lung parenchyma by neoplastic plasma cells. Physicians should be aware that acute respiratory distress syndrome not responding to treatment of common causes could be a manifestation of the disease, even with negative BAL or biopsy and could be promptly treated with salvage therapy. PMID:25165587

  6. Donor-Derived Smoldering Multiple Myeloma following a Hematopoietic Cell Transplantation for AML

    PubMed Central

    Fiala, Mark; Slade, Michael; Westervelt, Peter

    2017-01-01

    Posttransplant Lymphoproliferative Disorder (PTLD) is one of the most common malignancies complicating solid organ transplantation. In contrast, PTLD accounts for a minority of secondary cancers following allogeneic hematopoietic cell transplantation (HCT). Here we report on a 61-year-old woman who received an ABO-mismatched, HLA-matched unrelated donor hematopoietic cell transplantation from a presumably healthy donor for a diagnosis of acute myeloid leukemia (AML). Eighteen months following her transplant, she developed a monoclonal gammopathy. Bone marrow studies revealed 10% plasma cells, but the patient lacked clinical defining features of multiple myeloma (MM); thus a diagnosis of smoldering multiple myeloma (SMM) was established. Cytogenetic and molecular studies of the bone marrow confirmed the plasma cells were donor-derived. The donor lacks a diagnosis of monoclonal gammopathy of undetermined significance, SMM, or MM. PMID:28316846

  7. Multiple myeloma and treatment-related thromboembolism: oncology nurses' role in prevention, assessment, and diagnosis.

    PubMed

    Wiley, Kathleen E

    2007-12-01

    Immunomodulating agents such as thalidomide and its newly emerged derivative, lenalidomide, are becoming increasingly popular in the treatment of multiple myeloma because of their ability to combat drug resistance. Clinical trials suggest that thalidomide and lenalidomide are effective in all stages of multiple myeloma treatment-new diagnoses, stem cell transplantations, maintenance therapy, and relapsed or refractory disease. The drugs are most efficacious when combined with additional chemotherapeutic agents and/or corticosteroids. However, deep vein thrombosis and other thromboembolic events are associated with the treatment regimens. Oncology nurses must understand the pharmacologic properties of the drugs and the potentially life-threatening complications associated with them. To provide the highest standard of care, oncology nurses must play a vital role in the prevention, diagnosis, and management of thromboembolic events through awareness of the clinical problem, assessment tools, and thromboembolic prophylactic regimens.

  8. The Addition of Low-dose Thalidomide to Bortezomib and Dexamethasone for Refractory Multiple Myeloma

    PubMed Central

    Hashimoto, Shigeo; Kuroha, Takashi; Yano, Toshio; Sato, Naoko; Furukawa, Tatsuo

    2016-01-01

    Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted. Peripheral neuropathy did not increase after thalidomide addition. Adding low-dose thalidomide may safely improve the responses for multiple myeloma refractory to bortezomib and dexamethasone. PMID:27746443

  9. Hair repigmentation associated with thalidomide use for the treatment of multiple myeloma.

    PubMed

    Lovering, Stephanie; Miao, Wenya; Bailie, Toni; Amato, Dominick

    2016-07-21

    A 75-year-old woman diagnosed with multiple myeloma in 2007 began treatment with monthly melphalan and prednisone for a total of 9 cycles in combination with thalidomide in 2009. The patient subsequently continued on thalidomide for long-term maintenance therapy. 3 years following initiation of thalidomide, the patient mentioned to her oncologist that her hair had become darker over the years. She attributed the change to thalidomide given the temporal relationship and progressive darkening over the course of therapy. The patient denies ever using any hair colouring treatments and had longstanding grey/white hair before beginning thalidomide in 2009. A case of hair repigmentation associated with the use of lenalidomide, a 4-amino-glutamyl analogue of thalidomide, in a patient with multiple myeloma was previously reported in the literature. We report herein the first case of hair repigmentation associated with the use of thalidomide, a related immunomodulatory drug.

  10. The Addition of Low-dose Thalidomide to Bortezomib and Dexamethasone for Refractory Multiple Myeloma.

    PubMed

    Hashimoto, Shigeo; Kuroha, Takashi; Yano, Toshio; Sato, Naoko; Furukawa, Tatsuo

    Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted. Peripheral neuropathy did not increase after thalidomide addition. Adding low-dose thalidomide may safely improve the responses for multiple myeloma refractory to bortezomib and dexamethasone.

  11. The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

    PubMed Central

    Bieghs, Liesbeth; Johnsen, Hans E.; Maes, Ken; Menu, Eline; Van Valckenborgh, Els; Overgaard, Michael T.; Nyegaard, Mette; Conover, Cheryl A.; Vanderkerken, Karin; De Bruyne, Elke

    2016-01-01

    Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, proliferation, and drug resistance. As in most cancers, the insulin-like growth factor (IGF) system has been demonstrated to play a key role in the pathogenesis of MM. The IGF system consists of IGF ligands, IGF receptors, IGF binding proteins (IGFBPs), and IGFBP proteases and contributes not only to the survival, proliferation, and homing of MM cells, but also MM-associated angiogenesis and osteolysis. Furthermore, increased IGF-I receptor (IGF-IR) expression on MM cells correlates with a poor prognosis in MM patients. Despite the prominent role of the IGF system in MM, strategies targeting the IGF-IR using blocking antibodies or small molecule inhibitors have failed to translate into the clinic. However, increasing preclinical evidence indicates that IGF-I is also involved in the development of drug resistance against current standard-of-care agents against MM, including proteasome inhibitors, immunomodulatory agents, and corticoids. IGF-IR targeting has been able to overcome or revert this drug resistance in animal models, enhancing the efficacy of standard-of-care agents. This finding has generated renewed interest in the therapeutic potential of IGF-I targeting in MM. The present review provides an update of the impact of the different IGF system components in MM and discusses the diagnostic and therapeutic potentials. PMID:27129151

  12. Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma

    PubMed Central

    Salem, Kelley; McCormick, Michael L.; Wendlandt, Erik; Zhan, Fenghuang; Goel, Apollina

    2014-01-01

    Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper–zinc superoxide dismutase (CuZnSOD or SOD1) correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266) and the BTZ-resistant (BR) lines (MM.1SBR, 8226BR) were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1), and glutathione (GSH) were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF) augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity. PMID:25485927

  13. Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma.

    PubMed

    Xu, Yinyin; Chen, Bingda; George, Suraj K; Liu, Beizhong

    2015-01-01

    Multiple myeloma (MM) induced bone lesion is one of the most crippling characteristics, and the MM secreted Dickkopf-1 (DKK1) has been reported to play important role in this pathologic process. However, the underlying regulation mechanisms involved in DKK1 expression are still unclear. In this study, we validated the expression patterns of microRNA (miR) 15a, 34a, 152, and 223 in MM cells and identified that miR-152 was significantly downregulated in the MM group compared with the non-MM group, and that miR-152 level was negatively correlated with the expression of DKK1 in the MM cells. Mechanistic studies showed that manipulating miR-152 artificially in MM cells led to changes in DKK-1 expression, and miR-152 blocked DKK1 transcriptional activity by binding to the 3'UTR of DKK1 mRNA. Importantly, we revealed that MM cells stably expressing miR-152 improved the chemotherapy sensitivity, and counteracted the bone disruption in an intrabone-MM mouse model. Our study contributes better understanding of the regulation mechanism of DKK-1 in MM, and opens up the potential for developing newer therapeutic strategies in the MM treatment.

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

    PubMed Central

    Maes, Ken; Nemeth, Elizabeta; Roodman, G. David; Huston, Alissa; Esteve, Flavia; Freytes, Cesar; Callander, Natalie; Katodritou, Eirini; Tussing-Humphreys, Lisa; Rivera, Seth; Vanderkerken, Karin; Lichtenstein, Alan

    2010-01-01

    Hepcidin is the principal iron-regulatory hormone and a 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 contributes to MM-related anemia. Searching for hepcidin-inducing cytokines in MM, we quantified the stimulation of hepcidin promoter-luciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6–responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti–BMP-2/4 or noggin-Fc blocked the promoter induction with all MM sera, anti–IL-6 blocked it with a minority of sera, whereas anti–BMP-4, -6, or -9 antibodies had no effect. BMP-2–immunodepleted MM sera had decreased promoter stimulatory capacity, and BMP-2 concentrations in MM sera were significantly higher than in normal sera. Our results demonstrate that BMP-2 is a major mediator of the hepcidin stimulatory activity of MM sera. PMID:20679527

  15. [Aberrant micro RNA and epigenetic network are associated with progression from MGUS to multiple myeloma].

    PubMed

    Handa, Hiroshi

    2015-08-01

    In recent years, attention has been drawn to aberrant epigenetics as well as coding gene mutations in cancers. DNA methylation, histone acetylation and methylation, and micro RNA (miRNA) are included in the field of epigenetics. miRNAs are small RNAs of only 19-25 bases in length which do not encode protein but do they control gene expression by destroying mRNA or inhibiting translation. In multiple myeloma (MM), several miRNA expressions were markedly decreased, while in contrast their target genes, associated with apoptosis, the cell cycle and DNA methylation, were markedly increased. Negative correlations were found between miRNA and target genes expressions. The miR-34 family in itself was methylated, and expression was epigenetically controlled. miRNA and other epigenetic mechanisms underlie network formation, thought to be associated with MM progression. Thus, examining miRNA of MM is currently an important issue in terms of predicting patient outcomes and developing novel therapies.

  16. Degrasyn-like Symmetrical Compounds: Possible Therapeutic Agents for Multiple Myeloma (MM-I)

    PubMed Central

    Peng, Zhenghong; Maxwell, David; Sun, Duoli; Bhanu Prasad, Basvoju A.; Schuber, Paul T.; Pal, Ashutosh; Ying, Yunming; Han, Dongmei; Gao, Liwei; Wang, Shimei; Levitzki, Alexander; Kapuria, Vaibhav; Talpaz, Moshe; Young, Matthew; Showalter, Hollis D.; Donato, Nicholas J.; Bornmann, William. G.

    2014-01-01

    A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents PMID:24457091

  17. Degrasyn-like symmetrical compounds: possible therapeutic agents for multiple myeloma (MM-I).

    PubMed

    Peng, Zhenghong; Maxwell, David S; Sun, Duoli; Bhanu Prasad, Basvoju A; Schuber, Paul T; Pal, Ashutosh; Ying, Yunming; Han, Dongmei; Gao, Liwei; Wang, Shimei; Levitzki, Alexander; Kapuria, Vaibhav; Talpaz, Moshe; Young, Matthew; Showalter, Hollis D; Donato, Nicholas J; Bornmann, William G

    2014-02-15

    A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.

  18. OUTCOME OF INTERNAL HEMIPELVECTOMY IN A PATIENT WITH MULTIPLE MYELOMA--CASE REPORT.

    PubMed

    Andronic, O; Alexa, O; Veficeasa, B

    2016-01-01

    A patient treated for thyroid cancer was diagnosed with multiple myeloma in the context of trauma. After the pelvic tumor devascularization she underwent internal hemipelvectomy Type I + IIA Enneking Classification using polymerizing bioneutral gel embolization, "Glubran 2". The purpose of this case report is to demonstrate the importance of careful selection of treatment methods, together with adequate physical therapy in order to obtain favorable long-term results.

  19. Clinical application of a rapid technique for urinary electrophoresis in multiple myeloma

    PubMed Central

    Pelletier, Micheline; Montplaisir, Serge; Rabin, Bruce S.

    1974-01-01

    Proteinuria in three cases of multiple myeloma was studied without prior concentration of the urine, using a simple technique of urinary protein electrophoresis. In each case a free light chain spike was observed in association with a glomerular, tubular or normal urine protein electrophoresis pattem. The suggestion is made that this simple procedure may become a screening test for investigation of renal diseases. PMID:4442015

  20. Diagnostic x-ray procedures and risk of leukemia, lymphoma, and multiple myeloma

    SciTech Connect

    Boice, J.D. Jr.; Morin, M.M.; Glass, A.G.; Friedman, G.D.; Stovall, M.; Hoover, R.N.; Fraumeni, J.F. Jr. )

    1991-03-13

    Exposure to diagnostic x-rays and the risk of leukemia, non-Hodgkin's lymphoma (NHL), and multiple myeloma were studied within two prepaid health plans. Adult patients with leukemia (n = 565), NHL (n = 318), and multiple myeloma (n = 208) were matched to controls (n = 1390), and over 25,000 x-ray procedures were abstracted from medical records. Dose response was evaluated by assigning each x-ray procedure a score based on estimated bone marrow dose. X-ray exposure was not associated with chronic lymphocytic leukemia, one of the few malignant conditions never linked to radiation (relative risk (RR), 0.66). For all other forms of leukemia combined (n = 358), there was a slight elevation in risk (RR, 1.17) but no evidence of a dose-response relationship when x-ray procedures near the time of diagnosis were excluded. Similarly, patients with NHL were exposed to diagnostic x-ray procedures more often than controls (RR, 1.32), but the RR fell to 0.99 when the exposure to diagnostic x-ray procedures within 2 years of diagnosis was ignored. For multiple myeloma, overall risk was not significantly high (RR, 1.14), but there was consistent evidence of increasing risk with increasing numbers of diagnostic x-ray procedures. These data suggest that persons with leukemia and NHL undergo x-ray procedures frequently just prior to diagnosis for conditions related to the development or natural history of their disease. There was little evidence that diagnostic x-ray procedures were causally associated with leukemia or NHL. The risk for multiple myeloma, however, was increased among those patients who were frequently exposed to x-rays.

  1. Combination regimens using doxorubicin and pegylated liposomal doxorubicin prior to autologous transplantation in multiple myeloma.

    PubMed

    Moreau, Philippe

    2009-07-01

    Doxorubicin and pegylated liposomal doxorubicin are key compounds of several induction regimens used prior to autologous stem cell transplantation in patients with de novo multiple myeloma, such as vincristine, doxorubicin, dexamethasone (VAD), vincristine, pegylated liposomal doxorubicin/Doxil, dexamethasone (DVd) or PS-341/bortezomib, doxorubicin, dexamethasone (PAD). The aim of this article is to summarize the more recent data available on the efficacy of these combinations and to discuss their role as part of initial therapy.

  2. Cerebrospinal Fluid Cytological Diagnosis in Multiple Myeloma With Leptomeningeal Involvement: A Report of Two Cases.

    PubMed

    Ren, Haitao; Zou, Yueli; Zhao, Yanhuan; Li, Jian; Han, Xiao; He, Junying; Guan, Hongzhi

    2017-01-01

    Multiple myeloma (MM) with central nervous system (CNS) infiltration is uncommon and the diagnosis is more complicated than that of MM. Here we report two cases of CNS MM that was diagnosed by cerebrospinal fluid cytology examination. Cerebrospinal fluid cytology examination can help to detect malignant cells and immunocytochemistry stain is of great value in identifying an unknown tumor. Diagn. Cytopathol. 2017;45:66-68. © 2016 Wiley Periodicals, Inc.

  3. Clinical potential of SLAMF7 antibodies – focus on elotuzumab in multiple myeloma

    PubMed Central

    Friend, Reed; Bhutani, Manisha; Voorhees, Peter M; Usmani, Saad Z

    2017-01-01

    Elotuzumab is one of the first monoclonal antibodies to be approved for the treatment of multiple myeloma. It is a humanized immunoglobulin G kappa (IgGκ) antibody that targets signaling lymphocytic activation molecule family member 7 (SLAMF7), a surface marker that is highly expressed on normal and malignant plasma cells. This review summarizes the preclinical and clinical data that led to the approval of elotuzumab, along with a discussion on the ongoing and future clinical investigations. PMID:28356715

  4. Stem cell transplantation for multiple myeloma: current status and future directions.

    PubMed

    Caldera, Humberto; Giralt, Sergio

    2004-07-01

    High-dose chemotherapy or chemoradiation therapy supported with autologous stem cell transplantation is now recognized as a valid therapeutic option for patients with multiple myeloma. Results of randomized trials have established autografting as the treatment of choice for patients younger than 65 years, as part of their initial therapy. In this review, the issues of who benefits from transplant, what is the optimal procedure, and whether there is a potential role for allografting are addressed.

  5. MTI-101 (cyclized HYD1) binds a CD44 containing complex and induces necrotic cell death in multiple myeloma

    PubMed Central

    Gebhard, Anthony W.; Jain, Priyesh; Nair, Rajesh R.; Emmons, Michael F.; Argilagos, Raul F.; Koomen, John M.; McLaughlin, Mark L.; Hazlehurst, Lori A.

    2013-01-01

    Our laboratory recently reported that treatment with the d-amino acid containing peptide HYD1 induces necrotic cell death in multiple myeloma (MM) cell lines. Due to the intriguing biological activity and promising in vivo activity of HYD1, we pursued strategies for increasing the therapeutic efficacy of the linear peptide. These efforts led to a cyclized peptidomimetic, MTI-101, with increased in vitro activity and robust in vivo activity as single agent using two myeloma models that consider the bone marrow microenvironment. MTI-101 treatment similar to HYD1 induced reactive oxygen species, depleted ATP levels and failed to activate caspase 3. Moreover, MTI-101 is cross-resistant in H929 cells selected for acquired resistance to HYD1. Here, we pursued an unbiased chemical biology approach using biotinylated peptide affinity purification and LC-MS/MS analysis to identify binding partners of MTI-101. Using this approach CD44 was identified as a predominant binding partner. Reducing the expression of CD44 was sufficient to induce cell death in MM cell lines, indicating that MM cells require CD44 expression for survival. Ectopic expression of CD44s correlated with increased binding of the FAM-conjugated peptide. However ectopic expression of CD44s was not sufficient to increase the sensitivity to MTI-101 induced cell death. Mechanistically, we show that MTI-101 induced cell death occurs via a Rip1, Rip3 or Drp1 dependent and independent pathway. Finally, we show that MTI-101 has robust activity as a single agent in the SCID-Hu bone implant and 5TGM1 in vivo model of multiple myeloma. PMID:24048737

  6. [CAR Technology and Its Application in Treatment of Multiple Myeloma--Review].

    PubMed

    Li, Tong; Wang, Hong-Tao; Liu, Zhuo-Gang

    2016-02-01

    Multiple myeloma (MM) is a hematologic malignancy resulted from genetic mutations in the process of B lymphocyte differentiating into plasma cells, the chemotherapy is the main treatment method, especially with the development of proteasome inhibitors and other drugs, the overall survival rate of MM patients has improved greatly, but the chemoresistance is still an important reason for treatment failure. Chimeric antigen receptor (CAR)-modified T lymphocyte therapy is a new method for tumor adoptive immunotherapy. By means of genetic modification, T cells are able to identify the target antigen specifically, and to kill target cells without major histocompatibility complex (MHC) restriction, therefore the specific killing activity is conspicuous, which has got considerable attention by the public, and has made remarkable achievements particularly in the treatment of B-lineage leukemia and lymphoma, but no systematic literatures were reported in the field of multiple myeloma using CAR therapy. Therefore, this review summarizes the research results of different CAR target in vivo and in vitro experiments for multiple myeloma.

  7. Nonspecific Interstitial Pneumonitis after Bortezomib and Thalidomide Treatment in a Multiple Myeloma Patient

    PubMed Central

    Kang, Wonseok; Kim, Jin Seok; Cho, Sang Ho; Kim, Sung Kyu; Chang, Joon

    2010-01-01

    Bortezomib, an inhibitor of 26S proteosome, is recently approved treatment option for multiple myeloma. Thalidomide, a drug with immunomodulating and antiangiogenic effects, has also shown promise as an effective treatment in multiple myeloma. Pulmonary complications are believed to be rare, especially interstitial lung disease. Here, we describe a patient with dyspnea and diffuse pulmonary infiltrates while receiving bortezomib and thalidomide in combination with dexamethasone for treatment-naïve multiple myeloma. Bronchoalveolar lavage demonstrated a significant decrease in the ratio of CD4 : CD8 T lymphocytes (CD4/8 ratio, 0.54). Extensive workup for other causes, including infections, was negative. A lung biopsy under video-assisted thorascopic surgery revealed a diagnosis of nonspecific interstitial pneumonitis. The symptoms and imaging study findings improved after initiating steroid treatment. Physicians should be aware of this potential complication in patients receiving the novel molecular-targeted antineoplastic agents, bortezomib and thalidomide, who present with dyspnea and new pulmonary infiltrates and fail to improve despite treatment with broad-spectrum antibiotics. PMID:20376900

  8. Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma

    PubMed Central

    2014-01-01

    Background Multiple myeloma is characterized by clonal expansion of B cells producing monoclonal immunoglobulins or fragments thereof, which can be detected in the serum and/or urine and are ideal target antigens for patient-specific immunotherapies. Methods Using phage particles as immunological carriers, we employed a novel chemically linked idiotype vaccine in a clinical phase I/II trial including 15 patients with advanced multiple myeloma. Vaccines composed of purified paraproteins linked to phage were manufactured successfully for each patient. Patients received six intradermal immunizations with phage idiotype vaccines in three different dose groups. Results Phage idiotype was well tolerated by all study participants. A subset of patients (80% in the middle dose group) displayed a clinical response indicated by decrease or stabilization of paraprotein levels. Patients exhibiting a clinical response to phage vaccines also raised idiotype-specific immunoglobulins. Induction of a cellular immune response was demonstrated by a cytotoxicity assay and delayed type hypersensitivity tests. Conclusion We present a simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible patient-specific therapy for patients with advanced multiple myeloma and produced promising anti-tumor activity in a subset of patients. PMID:24885819

  9. Multiple myeloma treatment at relapse after autologous stem cell transplantation: A practical analysis.

    PubMed

    Malard, F; Harousseau, J L; Mohty, M

    2017-01-01

    Over the past decade, significant advances have been made in the field of multiple myeloma. Introduction of the so-called novel agents, proteasome inhibitors (PI) and immunomodulatory drugs (IMiD), and improved supportive care have resulted in significantly better outcome. Standard first line treatment in fit patients include PI and IMiD based induction, high dose melphalan with autologous hematopoietic stem cell transplantation (ASCT) and consolidation/maintenance. However, despite these progresses MM remains incurable for the majority of patients and most patients will relapse. Next generation PI (carfilzomib, ixazomib) and IMiD (pomalidomide) and new therapeutic classes: monoclonal antibody (elotuzumab, daratumumab) and pan-deacetylase inhibitors (panobinostat) have been successfully evaluated in relapse multiple myeloma. Some of these new agents are now approved for multiple myeloma treatment at relapse. However choosing the most appropriate treatment at relapse may be difficult. This review sum up the most important studies and provide evidence to choose the most relevant therapeutic strategy for relapse after ASCT, based on disease, patient and previous treatment related parameters.

  10. Smoldering multiple myeloma risk factors for progression: a Danish population-based cohort study.

    PubMed

    Sørrig, Rasmus; Klausen, Tobias W; Salomo, Morten; Vangsted, Annette J; Østergaard, Brian; Gregersen, Henrik; Frølund, Ulf Christian; Andersen, Niels F; Helleberg, Carsten; Andersen, Kristian T; Pedersen, Robert S; Pedersen, Per; Abildgaard, Niels; Gimsing, Peter

    2016-09-01

    Several risk scores for disease progression in patients with smoldering multiple myeloma (SMM) have been proposed; however, all have been developed using single-center registries. To examine risk factors for time to progression (TTP) to multiple myeloma (MM) for SMM, we analyzed a nationwide population-based cohort of 321 patients with newly diagnosed SMM registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M-protein ≥30 g/L and immunoparesis significantly influenced TTP (HR 2.7, 95%CI (1.5;4.7), P = 0.001, and HR 3.3, 95%CI (1.4;7.8), P = 0.002, respectively). High free light chain (FLC) ratio did not significantly influence TTP in our cohort. Therefore, our data do not support recent IMWG proposal of identifying patients with FLC ratio above 100 as having ultra high-risk of transformation to MM. Using only immunoparesis and M-protein ≥30 g/L, we created a scoring system to identify low-, intermediate-, and high-risk SMM. This first population-based study of patients with SMM confirms that an M-protein ≥30 g/L and immunoparesis remain important risk factors for progression to MM.

  11. Prediction of patients with multiple myeloma eligible for second- or third-line treatment in France.

    PubMed

    Rondeau, Virginie; Cornet, Edouard; Moreau, Philippe; Troussard, Xavier

    2016-08-01

    Multiple myeloma (MM) is one of the most common hematological malignancies, with an estimated 4888 incident cases in France in 2012. The management of patients with MM has changed considerably in recent years. We proposed an approach to predict the number of patients with multiple myeloma eligible for second- and third-line treatment for the period 2012-2020. The input parameters of this model were incident cases of multiple myeloma from the Basse-Normandie French Regional Registry of Hematological Malignancies (RRHMBN) for the period 2000-2012 and survival rates among patients under and over age 65 from the French National Institute of Statistics and Economic Studies (INSEE). In addition, data on mortality rates and progression-free survival (PFS) were extracted from the literature. Our analyses showed that the total incidence of MM in France is predicted to increase by 29 % between 2012 and 2020. We used the proposed approach to predict that at least 47.8 % of first-line MM patients will be eligible for second-line treatment (and 45.6 % will be eligible for third-line treatment). Predicting the number of patients with MM eligible for a new treatment is a prerequisite to planning healthcare and calculating treatment costs.

  12. Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies

    PubMed Central

    Caltagirone, Simona; Ruggeri, Marina; Aschero, Simona; Gilestro, Milena; Oddolo, Daniela; Gay, Francesca; Bringhen, Sara; Musolino, Caterina; Baldini, Luca; Musto, Pellegrino; Petrucci, Maria T.; Gaidano, Gianluca; Passera, Roberto; Bruno, Benedetto; Palumbo, Antonio; Boccadoro, Mario; Omedè, Paola

    2014-01-01

    Multiple myeloma is a plasma cell disorder characterized by malignant plasma cell infiltration in the bone marrow, serum and/or urine monoclonal protein and organ damage. The aim of this study was to investigate the impact of chromosome 1 abnormalities in a group of elderly patients (>65 years) with newly diagnosed multiple myeloma enrolled in the GIMEMA-MM-03-05 trial and treated with bortezomib, melphalan and prednisone or bortezomib, melphalan, prednisone and thalidomide followed by bortezomib and thalidomide maintenance. We also evaluated the link between chromosome 1 abnormalities and other clinical, genetic and immunophenotypic features by a multivariate logistic regression model. Interphase fluorescence in situ hybridization on immunomagnetically purified plasma cells and bone marrow multiparameter flow cytometry were employed. A multivariate Cox model showed that chromosome 1 abnormalities, age >75 years and a CD19+/CD117− immunophenotype of bone marrow plasma cells were independent risk factors for overall survival in elderly patients with newly diagnosed multiple myeloma. Moreover, a detrimental effect of thalidomide, even when administered in association with bortezomib, was observed in patients with abnormal chromosome 1 as well as in those with 17p deletion, while the benefit of adding thalidomide to the bortezomib-melphalan-prednisone regimen was noted in patients carrying an aggressive CD19+/CD117− bone marrow plasma cell immunophenotype. This trial was registered at www.clinicaltri-als.gov as #NCT01063179. PMID:25015938

  13. Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy.

    PubMed

    Kleber, Martina; Udi, Josefina; Metzke, Barbara; Terpos, Evangelos; Roodmann, G David; Morgan, Gareth; Dispenzieri, Angela; Einsele, Hermann; Wäsch, Ralph; Engelhardt, Monika

    2012-06-01

    An international myeloma meeting entitled "Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy" was held in Freiburg, Germany in July 2011 to discuss novel insights into and approaches to myeloma bone disease and other bone-seeking tumors. This review briefly summarizes the most prominent data of the meeting and current literature on our understanding of bone disease, the role of imaging techniques, operative interventions and systemic bone-seeking treatment, all of which should further improve our future therapeutic choices.

  14. U.s. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma.

    PubMed

    Herndon, Thomas M; Deisseroth, Albert; Kaminskas, Edvardas; Kane, Robert C; Koti, Kallappa M; Rothmann, Mark D; Habtemariam, Bahru; Bullock, Julie; Bray, Jeffrey D; Hawes, Jessica; Palmby, Todd R; Jee, Josephine; Adams, William; Mahayni, Houda; Brown, Janice; Dorantes, Angelica; Sridhara, Rajeshwari; Farrell, Ann T; Pazdur, Richard

    2013-09-01

    The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described. A single-arm trial enrolled 266 patients with multiple myeloma refractory to the most recent therapy who had received prior treatment with bortezomib and an immunomodulatory agent (IMID). Patients received carfilzomib by intravenous infusion over 2 to 10 minutes at a dose of 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of the 28 days of cycle 1, and at a dose of 27 mg/m2 on the same schedule in cycle 2 and subsequent cycles. The primary efficacy endpoint was overall response rate (ORR) as determined by an independent review committee using International Myeloma Working Group Uniform Response Criteria. The safety of carfilzomib was evaluated in 526 patients with multiple myeloma treated with various dosing regimens. The ORR was 23%. The median duration of response was 7.8 months. The most common adverse reactions associated with carfilzomib infusion were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and fever. The most common serious adverse events were pneumonia, acute renal failure, fever, and congestive heart failure. Infusion reactions to carfilzomib could be reduced by pretreatment with dexamethasone and intravenous fluids. On July 20, 2012, the FDA granted accelerated approval of carfilzomib for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an IMID and who have shown disease progression while on therapy or within 60 days of completion of the last therapy.

  15. Multiple pesticide exposures and the risk of multiple myeloma in Canadian men.

    PubMed

    Kachuri, Linda; Demers, Paul A; Blair, Aaron; Spinelli, John J; Pahwa, Manisha; McLaughlin, John R; Pahwa, Punam; Dosman, James A; Harris, Shelley A

    2013-10-15

    Multiple myeloma (MM) has been linked to certain agricultural exposures, including pesticides. This analysis aimed to investigate the association between lifetime use of multiple pesticides and MM risk using two exposure metrics: number of pesticides used and days per year of pesticide use. A frequency-matched, population-based case-control study was conducted among men in six Canadian provinces between 1991 and 1994. Data from 342 MM cases and 1,357 controls were analyzed using logistic regression to calculate odds ratios (OR) and 95% confidence intervals. Pesticides were grouped by type, chemical class and carcinogenic potential, using a composite carcinogenic probability score. Selected individual pesticides were also examined. Regression models were adjusted for age, province of residence, use of proxy respondents, smoking and selected medical history variables. The overall pattern of results was complex. Positive trends in risk were observed for fungicides (ptrend=0.04) and pesticides classified as probably carcinogenic or higher (ptrend=0.03). Excess risks of MM were observed among men who reported using at least one carbamate pesticide (OR=1.94, 1.16-3.25), one phenoxy herbicide (OR=1.56, 1.09-2.25) and ≥3 organochlorines (OR=2.21, 1.05-4.66). Significantly higher odds of MM were seen for exposure to carbaryl (OR=2.71, 1.47-5.00) and captan (OR=2.96, 1.40-6.24). Use of mecoprop for >2 days per year was also significantly associated with MM (OR=2.15, 1.03-4.48). Focusing on multiple pesticide exposures is important because this more accurately reflects how exposures occur in occupational settings. Significant associations observed for certain chemical classes and individual pesticides suggest that these may be MM risk factors.

  16. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

    PubMed Central

    Mitchell, Jonathan S.; Li, Ni; Weinhold, Niels; Försti, Asta; Ali, Mina; van Duin, Mark; Thorleifsson, Gudmar; Johnson, David C.; Chen, Bowang; Halvarsson, Britt-Marie; Gudbjartsson, Daniel F.; Kuiper, Rowan; Stephens, Owen W.; Bertsch, Uta; Broderick, Peter; Campo, Chiara; Einsele, Hermann; Gregory, Walter A.; Gullberg, Urban; Henrion, Marc; Hillengass, Jens; Hoffmann, Per; Jackson, Graham H.; Johnsson, Ellinor; Jöud, Magnus; Kristinsson, Sigurður Y.; Lenhoff, Stig; Lenive, Oleg; Mellqvist, Ulf-Henrik; Migliorini, Gabriele; Nahi, Hareth; Nelander, Sven; Nickel, Jolanta; Nöthen, Markus M.; Rafnar, Thorunn; Ross, Fiona M.; da Silva Filho, Miguel Inacio; Swaminathan, Bhairavi; Thomsen, Hauke; Turesson, Ingemar; Vangsted, Annette; Vogel, Ulla; Waage, Anders; Walker, Brian A.; Wihlborg, Anna-Karin; Broyl, Annemiek; Davies, Faith E.; Thorsteinsdottir, Unnur; Langer, Christian; Hansson, Markus; Kaiser, Martin; Sonneveld, Pieter; Stefansson, Kari; Morgan, Gareth J.; Goldschmidt, Hartmut; Hemminki, Kari; Nilsson, Björn; Houlston, Richard S.

    2016-01-01

    Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10−8), 6q21 (rs9372120, P=9.09 × 10−15), 7q36.1 (rs7781265, P=9.71 × 10−9), 8q24.21 (rs1948915, P=4.20 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development. PMID:27363682

  17. Circulating serum microRNAs as novel diagnostic and prognostic biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance.

    PubMed

    Kubiczkova, Lenka; Kryukov, Fedor; Slaby, Ondrej; Dementyeva, Elena; Jarkovsky, Jiri; Nekvindova, Jana; Radova, Lenka; Greslikova, Henrieta; Kuglik, Petr; Vetesnikova, Eva; Pour, Ludek; Adam, Zdenek; Sevcikova, Sabina; Hajek, Roman

    2014-03-01

    Multiple myeloma still remains incurable in the majority of cases prompting a further search for new and better prognostic markers. Emerging evidence has suggested that circulating microRNAs can serve as minimally invasive biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance. In this study, a global analysis of serum microRNAs by TaqMan Low Density Arrays was performed, followed by quantitative real-time PCR. The analyses revealed five deregulated microRNAs: miR-744, miR-130a, miR-34a, let-7d and let-7e in monoclonal gammopathy of undetermined significance, newly diagnosed and relapsed multiple myeloma when compared to healthy donors. Multivariate logistical regression analysis showed that a combination of miR-34a and let-7e can distinguish multiple myeloma from healthy donors with a sensitivity of 80.6% and a specificity of 86.7%, and monoclonal gammopathy of undetermined significance from healthy donors with a sensitivity of 91.1% and a specificity of 96.7%. Furthermore, lower levels of miR-744 and let-7e were associated with shorter overall survival and remission of myeloma patients. One-year mortality rates for miR-744 and let-7e were 41.9% and 34.6% for the 'low' expression and 3.3% and 3.9% for the 'high' expression groups, respectively. Median time of remission for both miR-744 and let-7e was approximately 11 months for the 'low' expression and approximately 47 months for the 'high' expression groups of myeloma patients These data demonstrate that expression patterns of circulating microRNAs are altered in multiple myeloma and monoclonal gammopathy of undetermined significance and miR-744 with let-7e are associated with survival of myeloma patients.

  18. High-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with multiple myeloma and renal insufficiency.

    PubMed

    Ballester, O F; Tummala, R; Janssen, W E; Fields, K K; Hiemenz, J W; Goldstein, S C; Perkins, J B; Sullivan, D M; Rosen, R; Sackstein, R; Zorsky, P; Saez, R; Elfenbein, G J

    1997-10-01

    Six patients with multiple myeloma and chronic renal insufficiency (serum creatinine >3.0 mg/dl), including four on dialysis, received high-dose busulfan and cyclophosphamide (BUCY) followed by autologous peripheral stem cell transplantation. Peripheral blood stem cells were collected after priming with cyclophosphamide, etoposide and G-CSF. Patterns of engraftment and toxicities were not apparently different from those seen in myeloma patients with normal renal function. There was one toxicity-related death, resulting from a massive spontaneous subdural hematoma. One patient died of disease progression 6 months after transplant, while the remaining four patients are alive and free of myeloma progression 6 to 39 months after high-dose therapy. Two of these patients have remained in complete remission for 28 and 39 months. Our experience suggests that high-dose therapy with BUCY and autologous peripheral blood stem cell rescue is feasible in patients with multiple myeloma and renal failure.

  19. Identification of four potential predicting miRNA biomarkers for multiple myeloma from published datasets

    PubMed Central

    Sun, Peng; Liu, Gao

    2017-01-01

    Background Multiple myeloma is a cancer which has a high occurrence rate and causes great injury to people worldwide. In recent years, many studies reported the effects of miRNA on the appearance of multiple myeloma. However, due to the differences of samples and sequencing platforms, a large number of inconsistent results have been generated among these studies, which limited the cure of multiple myeloma at the miRNA level. Methods We performed meta-analyses to identify the key miRNA biomarkers which could be applied on the treatment of multiple myeloma. The key miRNAs were determined by overlap comparisons of seven datasets in multiple myeloma. Then, the target genes for key miRNAs were predicted by the software TargetScan. Additionally, functional enrichments and binding TFs were investigated by DAVID database and Tfacts database, respectively. Results Firstly, comparing the normal tissues, 13 miRNAs were differently expressed miRNAs (DEMs) for at least three datasets. They were considered as key miRNAs, with 12 up-regulated (hsa-miR-106b, hsa-miR-125b, hsa-miR-130b, hsa-miR-138, hsa-miR-15b, hsa-miR-181a, hsa-miR-183, hsa-miR-191, hsa-miR-19a, hsa-miR-20a, hsa-miR-221 and hsa-miR-25) and one down-regulated (hsa-miR-223). Secondly, functional enrichment analyses indicated that target genes of the upregulated miRNAs were mainly transcript factors and enriched in transcription regulation. Besides, these genes were enriched in multiple pathways: the cancer signal pathway, insulin signal metabolic pathway, cell binding molecules, melanin generation, long-term regression and P53 signaling pathway. However, no significant enrichment was found for target genes of the down-regulated genes. Due to the distinct regulation function, four miRNAs (hsa-miR-19a has-miR-221 has-miR25 and has-miR223) were ascertained as the potential prognostic and diagnostic markers in MM. Thirdly, transcript factors analysis unveiled that there were 148 TFs and 60 TFs which bind target genes

  20. Mass cytometry analysis shows that a novel memory phenotype B cell is expanded in multiple myeloma

    PubMed Central

    Hansmann, Leo; Blum, Lisa; Ju, Chia-Hsin; Liedtke, Michaela; Robinson, William H.; Davis, Mark M.

    2015-01-01

    It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals and thus high resolution technologies are likely required. We used cytometry by time-of-flight (CyTOF) and next generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related pre-cancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 pre-cancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T, B, and natural killer cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0±0.7% (mean±SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27+) and naïve (CD24loCD38+) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells. PMID:25711758

  1. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma

    PubMed Central

    Hutchison, Colin A.; Batuman, Vecihi; Behrens, Judith; Bridoux, Frank; Sirac, Christophe; Dispenzieri, Angela; Herrera, Guillermo A.; Lachmann, Helen; Sanders, Paul W.

    2012-01-01

    Renal failure remains a principal cause of morbidity for patients with multiple myeloma. Once reversible factors such as hypercalcemia have been corrected, the most common cause of severe renal failure in these patients is a tubulointerstitial pathology that results from the very high circulating concentrations of monoclonal immunoglobulin free light chains. These endogenous proteins can result in isolated proximal tubule cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (myeloma kidney). Less frequently, high levels of free light chains can lead to immunoglobulin light chain amyloidosis and light chain deposition disease, although these conditions are usually associated with insidious progression of renal failure rather than acute kidney injury. Unless there is rapid intervention, progressive and irreversible damage occurs, particularly interstitial fibrosis and tubular atrophy. Despite advances in our understanding of the pathogenesis of these processes there has been a gap in translating these achievements into improved patient outcomes. The International Kidney and Monoclonal Gammopathy Research Group was formed to address this need. In this Review, we discuss the mechanisms of disease and diagnostic approaches to patients with acute kidney injury complicating multiple myeloma. PMID:22045243

  2. Understanding biology to tackle the disease: Multiple myeloma from bench to bedside, and back.

    PubMed

    Bianchi, Giada; Anderson, Kenneth C

    2014-01-01

    Multiple myeloma (MM) is a cancer of antibody-producing plasma cells. The pathognomonic laboratory finding is a monoclonal immunoglobulin or free light chain in the serum and/or urine in association with bone marrow infiltration by malignant plasma cells. MM develops from a premalignant condition, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage termed smoldering multiple myeloma (SMM), which differs from active myeloma by the absence of disease-related end-organ damage. Unlike MGUS and SMM, active MM requires therapy. Over the past 6 decades, major advancements in the care of MM patients have occurred, in particular, the introduction of novel agents (ie, proteasome inhibitors, immunomodulatory agents) and the implementation of hematopoietic stem cell transplantation in suitable candidates. The effectiveness and good tolerability of novel agents allowed for their combined use in induction, consolidation, and maintenance therapy, resulting in deeper and more sustained clinical response and extended progression-free and overall survival. Previously a rapidly lethal cancer with few therapeutic options, MM is the hematologic cancer with the most novel US Food and Drug Administration-approved drugs in the past 15 years. These advances have resulted in more frequent long-term remissions, transforming MM into a chronic illness for many patients.

  3. Atypical IgM multiple myeloma with deletion of c-MAF.

    PubMed

    Juárez Salcedo, L M; López Rubio, M; Gil Fernández, J J; Garcia-Suarez, J; Magro, E; Arranz, E; Gutiérrez Jomarrón, I; Marcellini Antonio, S; Blasco, A; Burgaleta, C

    2015-10-01

    IgM multiple myeloma (MM) is a rare subtype of myeloma that shares clinical and pathological features with Waldenström's macroglobulinaemia. These are two separate entities that differ both in therapy and prognosis. We report a 57-year-old male, who presented with anaemia, hypercalcaemia, acute renal failure and several vertebral fractures that clinically suggested a multiple myeloma. Further investigations revealed a serum monoclonal component of IgM lambda type and a bone marrow infiltrated by small, lymphoplasmocytic cells. IgM MM was finally diagnosed by means of both inmunophenotypic and immunohistochemistry techniques, stressing the importance of inmunophenotypic evaluation when clinical and morphological features are discordant. Fluorescence in situ hybridization (FISH) studies disclosed a particular combination of deletion 13q14, t(11;14) and monoallelic deletion C-MAF without t(14;16). The clinical evolution after a Bortezomib-containing polychemotherapy and autologous stem cell transplantation (ASCT) conditioned with busulphan and melphalan is also presented. This very uncommon case highlights the impact of immunophenotyping on the differential diagnosis between IgM MM and WM, to choose the best treatment and establish an appropriate outcome.

  4. Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation.

    PubMed

    Weinstock, Mathew; Aljawai, Yosra; Morgan, Elizabeth A; Laubach, Jacob; Gannon, Muriel; Roccaro, Aldo M; Varga, Cindy; Mitsiades, Constantine S; Paba-Prada, Claudia; Schlossman, Robert; Munshi, Nikhil; Anderson, Kenneth C; Richardson, Paul P; Weller, Edie; Ghobrial, Irene M

    2015-06-01

    Extramedullary disease (EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty-three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy-proven EMD was identified, comprising 8·3% of the total study population. EMD was present at the time of diagnosis in 14·5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4·1 years (95% CI: 3·1, 5·1) and the median overall survival from time of EMD diagnosis was 1·3 years (95% CI: 0·8, 2·3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation.

  5. New Insights into the Treatment of Multiple Myeloma with Histone Deacetylase Inhibitors

    PubMed Central

    Cea, Michele; Cagnetta, Antonia; Gobbi, Marco; Patrone, Franco; Richardson, Paul G.; Hideshima, Teru; Anderson, Kenneth C.

    2014-01-01

    Multiple Myeloma (MM) is a common hematologic malignancy of plasma cells representing an excellent model of epigenomics dysregulation in human disease. Importantly, these findings, in addition to provide a better understanding of the underlying molecular changes leading to this malignance, furnish the basis for an innovative therapeutic approach. Histone deacetylase inhibitors (HDACIs), including Vorinostat and Panobinostat, represent a novel class of drugs targeting enzymes involved in epigenetic regulation of gene expression, which have been evaluated also for the treatment of multiple myeloma. Although the clinical role in this setting is evolving and their precise utility remains to be determined, to date that single-agent anti-MM activity is modest. More importantly, HDACIs appear to be synergistic both in vitro and in vivo when combined with other anti-MM agents, mainly proteasome inhibitors including bortezomib. The molecular basis underlying this synergism seems to be multifactorial and involves interference with protein degradation as well as the interaction of myeloma cells with microenvironment. Here we review molecular events underling antitumor effects of HDACIs and the most recent results of clinical trials in relapsed and refractory MM. PMID:23016853

  6. Thalidomide in multiple myeloma: lack of response of soft-tissue plasmacytomas.

    PubMed

    Bladé, J; Perales, M; Rosiñol, L; Tuset, M; Montoto, S; Esteve, J; Cobo, F; Villela, L; Rafel, M; Nomdedeu, B; Montserrat, E

    2001-05-01

    Thalidomide is active in patients with refractory myeloma. Seventeen patients (nine men/eight women, median age 73 years) with multiple myeloma (MM) were treated with thalidomide. Fifteen patients had refractory disease and two untested relapse. The median dose of thalidomide was 500 mg (range, 200-800 mg). Nine of the 17 patients (53%) responded. The response rate was significantly higher in patients with no extramedullary disease than in those with soft tissue masses (75% CI: 43-95% versus 0%; P = 0.01)). Of note, no decrease in the size of soft tissue plasmacytomas was observed in all the five patients who had extramedullary involvement. This data suggests that the mechanism of action and effectiveness of thalidomide might depend on the site of the tumour cells.

  7. Chetomin, targeting HIF-1α/p300 complex, exhibits antitumour activity in multiple myeloma

    PubMed Central

    Viziteu, Elena; Grandmougin, Camille; Goldschmidt, Hartmut; Seckinger, Anja; Hose, Dirk; Klein, Bernard; Moreaux, Jerome

    2016-01-01

    Background: Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. The constitutive expression of HIF-1α in MM suggests that inhibition of HIF-1α-mediated transcription represents an interesting target in MM. Methods: As p300 is a crucial co-activator of hypoxia-inducible transcription, disrupting the complex HIF-1α/p300 to target HIF activity appears to be an attractive strategy. Results: We reported that chetomin, an inhibitor of HIF-1α/p300 interaction, exhibits antitumour activity in human myeloma cell lines and primary MM cells from patients. Conclusions: Our data suggest that chetomin may be of clinical value in MM and especially for patients characterised by a high EP300/HIF-1α expression and a poor prognosis. PMID:26867162

  8. Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma

    PubMed Central

    Chang, Xiubao; Zhu, Yuanxiao; Shi, Changxin; Stewart, A. Keith

    2014-01-01

    Although immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, are widely used in the treatment of multiple myeloma (MM), the molecular mechanism of IMiDs' action is largely unknown. In this review, we will summarize recent advances in the application of IMiDs in MM cancer treatment as well as their effects on immunomodulatory activities, anti-angiogenic activities, intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells, anti-inflammatory activities, anti-proliferation, pro-apoptotic effects, cell cycle arrest, and inhibition of cell migration and metastasis. In addition, the potential IMiDs' target protein, IMiDs' target protein's functional role, and the potential molecular mechanisms of IMiDs resistance will be discussed. We wish, by presentation of our naive discussion, that this review article will facilitate further investigation in these fields. PMID:24374776

  9. Can leptomeningeal myelomatosis be predicted in patients with IgD multiple myeloma?

    PubMed

    Velasco, R; Petit, J; Llatjós, R; Juan, A; Bruna, J

    2010-08-01

    Involvement of the central nervous system (CNS) by multiple myeloma (MM) is rare. Immunoglobulin D (IgD) MM represents only 1% to 2% of all MM patients. Previous reports show a disproportionate number of patients with IgD MM with leptomeningeal myelomatosis (LMM). Several biological markers have been associated with LMM. The development of LMM in a woman with IgD MM is reported. Our patient should be considered as having a high-risk of CNS disease based on: (i) presence of IgD-lambda MM; (ii) high myeloma burden (stage III); (iii) additional extramedullary disease; (iv) presence of circulating plasma cells, some with plasmablastic morphology; and (v) CD56-negative immunophenotype. The association between these features of MM reported previously and a high risk of LMM is reviewed. Studies including patients with these features are warranted to confirm their attributed LMM risk and to investigate the role of prophylactic chemoradiotherapy in this clinical setting.

  10. Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics.

    PubMed

    Greenberg, Alexandra J; Rajkumar, S Vincent; Vachon, Celine M

    2012-06-07

    Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), is one of the most common premalignant conditions in the general population. The cause of MGUS is largely unknown. Recent studies show that there is an increased prevalence of MGUS in blood relatives of persons with lymphoproliferative and plasma cell proliferative disorders, suggesting presence of shared underlying genetic influences. In the past few years, additional studies have examined risk factors and biologic characteristics that may contribute to the increased prevalence of MGUS among relatives of probands with MGUS, MM, and other blood malignancies. This article reviews the known epidemiology and risk factors for familial MGUS and myeloma, the risk of lymphoproliferative disorders and other malignancies among blood-relatives of patients with MGUS and MM, and discusses future directions for research.

  11. MET/HGF pathway in multiple myeloma: from diagnosis to targeted therapy?

    PubMed

    Gambella, Manuela; Palumbo, Antonio; Rocci, Alberto

    2015-01-01

    The interaction between neoplastic cells and the microenvironment is critical in several cancers and plays a central role in multiple myeloma. Microenvironmental stimuli support plasma cell proliferation, survival, motility and can determine drug resistance. The network between plasma cells and surrounding cells is also responsible for increasing angiogenesis, unbalancing bone formation and bony lesions. The MET/HGF pathway is a key player in this interaction and has been found to be abnormally active in both malignant plasma cells and surrounding cells. Patients with abnormal MET and/or HGF levels usually have a poor outcome even when treated with novel drugs. This review addresses the role of MET/HGF in the pathogenesis of myeloma and describes the role of MET/HGF signaling as a prognostic factor. The different techniques to detect MET/HGF abnormalities are examined and a description of compounds targeting MET/HGF is also provided.

  12. Selective purging of human multiple myeloma cells from autologous stem cell transplant grafts using oncolytic myxoma virus

    PubMed Central

    Bartee, Eric; Chan, Winnie S.; Moreb, Jan S.; Cogle, Christopher R.; McFadden, Grant

    2012-01-01

    Autologous stem cell transplantation (ASCT) and novel therapies have improved overall survival of patients with multiple myeloma; however, most patients relapse and eventually succumb to their disease. Evidence indicates that residual cancer cells contaminate autologous grafts and may contribute to early relapses after ASCT. Here, we demonstrate that ex vivo treatment with an oncolytic poxvirus called myxoma virus results in specific elimination of human myeloma cells by inducing rapid cellular apoptosis while fully sparing normal hematopoietic stem and progenitor cells (HSPCs). The specificity of this elimination is based on strong binding of the virus to myeloma cells coupled with an inability of the virus to bind or infect CD34+ HSPCs. These two features allow myxoma to readily identify and distinguish even low levels of myeloma cells in complex mixtures. This ex vivo MYXV treatment also effectively inhibits systemic in vivo engraftment of human myeloma cells into immunodeficient mice and results in efficient elimination of primary CD138+ myeloma cells contaminating patient hematopoietic cell products. We conclude that ex vivo myxoma treatment represents a safe and effective method to selectively eliminate myeloma cells from hematopoietic autografts prior to reinfusion. PMID:22516053

  13. The DAC system and associations with multiple myeloma.

    PubMed

    Ocio, Enrique M; San Miguel, Jesús F

    2010-12-01

    Despite the clear progress achieved in recent years in the treatment of MM, most patients eventually relapse and therefore novel therapeutic options are still necessary for these patients. In this regard, several drugs that target specific mechanisms of the tumor cells are currently being explored in the preclinical and clinical setting. This manuscripts offers a review of the rationale and current status of the antimyeloma activity of one of the most relevant examples of these targeted drugs: deacetylase inhibitors (DACi). Several studies have demonstrated the prooncogenic activity of deacetylases (DACs) through the targeting not only of histones but also of non histone proteins relevant to tumor progression, such as p53, E2F family members, Bcl-6, Hsp90, HIF-1α or Nur77. This fact together with the DACs overexpression present in several tumors, has prompted the development of some DACi with potential antitumor effect. This situation is also evident in the case of MM as two mechanisms of DACi, the inhibition of the epigenetic inactivation of p53 and the blockade of the unfolded protein response, through the inhibition of the aggressome formation (by targeting DAC6) and the inactivation of the chaperone system (by acetylating HSP-90), provides the rationale for the exploration of the potential antimyeloma activity of these compounds. Several DACi with different chemical structure and different selectivity for targeting the DAC families have been tested in MM. Their preclinical activity in monotherapy has been quite exciting and has been described to be mediated by various mechanisms: the induction of apoptosis and cell cycle arrest mainly by the upregulation of p21; the interferece with the interaction between plasma cells and the microenvironment, by reducing the expression and signalling of several cytokines or by inhibiting angiogenesis. Finally they also have a role in protecting murine models from myeloma bone disease. Neverteless, the clinical activity in

  14. Identification of the key genes connected with plasma cells of multiple myeloma using expression profiles

    PubMed Central

    Zhang, Kefeng; Xu, Zhongyang; Sun, Zhaoyun

    2015-01-01

    Objective To uncover the potential regulatory mechanisms of the relevant genes that contribute to the prognosis and prevention of multiple myeloma (MM). Methods Microarray data (GSE13591) were downloaded, including five plasma cell samples from normal donors and 133 plasma cell samples from MM patients. Differentially expressed genes (DEGs) were identified by Student’s t-test. Functional enrichment analysis was performed for DEGs using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Transcription factors and tumor-associated genes were also explored by mapping genes in the TRANSFAC, the tumor suppressor gene (TSGene), and tumor-associated gene (TAG) databases. A protein–protein interaction (PPI) network and PPI subnetworks were constructed by Cytoscape software using the Search Tool for the Retrieval of Interacting Genes (STRING) database. Results A total of 63 DEGs (42 downregulated, 21 upregulated) were identified. Functional enrichment analysis showed that HLA-DRB1 and VCAM1 might be involved in the positive regulation of immune system processes, and HLA-DRB1 might be related to the intestinal immune network for IgA production pathway. The genes CEBPD, JUND, and ATF3 were identified as transcription factors. The top ten nodal genes in the PPI network were revealed including HLA-DRB1, VCAM1, and TFRC. In addition, genes in the PPI subnetwork, such as HLA-DRB1 and VCAM1, were enriched in the cell adhesion molecules pathway, whereas CD4 and TFRC were both enriched in the hematopoietic cell pathway. Conclusion Several crucial genes correlated to MM were identified, including CD4, HLA-DRB1, TFRC, and VCAM1, which might exert their roles in MM progression via immune-mediated pathways. There might be certain regulatory correlations between HLA-DRB1, CD4, and TFRC. PMID:26229487

  15. Cytogenetic Alterations in Multiple Myeloma: Prognostic Significance and the Choice of Frontline Therapy.

    PubMed

    Stella, Flavia; Pedrazzini, Estela; Agazzoni, Mara; Ballester, Oscar; Slavutsky, Irma

    2015-01-01

    Multiple myeloma tumor cells demonstrate multiple and often complex genetic lesions as evaluated by standard cytogenetic/FISH studies. Over the past decade, specific abnormalities have been associated with standard or high-risk clinical behavior and they have become strong prognostic indicators. Further, as evidenced by recent randomized clinical trials, the choice of front-line therapy (transplant vs. no transplant, inclusion of novel drugs such as bortezomib, thalidomide, and lenalidomide) may be able to overcome the adverse effect of high-risk genetic lesions.

  16. Fatal Rhabdomyolysis Caused by Morganella morganii in a Patient with Multiple Myeloma

    PubMed Central

    Imataki, Osamu; Uemura, Makiko

    2017-01-01

    A 64-year-old Japanese man with multiple myeloma was admitted to our institute due to fever and hypotension. He had received multiple courses of chemotherapy just before his febrile episode. Blood culturing detected Morganella morganii. At the time of the diagnosis, his laboratory findings revealed massive rhabdomyolysis with a significantly increased creatinine kinase level (CK; 3,582 U/L); 98.8% of which corresponded to the CK-MB isotype. We diagnosed the patient with sepsis caused by M. morganii, complicated with severe rhabdomyolysis. He died of multi-organ failure 2 days later. Clinicians should closely observe patients with possible systemic infection-associated rhabdomyolysis. PMID:28154285

  17. Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-κB activity in myeloma cells

    PubMed Central

    2010-01-01

    Background Components of the microenvironment such as bone marrow stromal cells (BMSCs) are well known to support multiple myeloma (MM) disease progression and resistance to chemotherapy including the proteasome inhibitor bortezomib. However, functional distinctions between BMSCs in MM patients and those in disease-free marrow are not completely understood. We and other investigators have recently reported that NF-κB activity in primary MM cells is largely resistant to the proteasome inhibitor bortezomib, and that further enhancement of NF-κB by BMSCs is similarly resistant to bortezomib and may mediate resistance to this therapy. The mediating factor(s) of this bortezomib-resistant NF-κB activity is induced by BMSCs is not currently understood. Results Here we report that BMSCs specifically derived from MM patients are capable of further activating bortezomib-resistant NF-κB activity in MM cells. This induced activity is mediated by soluble proteinaceous factors secreted by MM BMSCs. Among the multiple factors evaluated, interleukin-8 was secreted by BMSCs from MM patients at significantly higher levels compared to those from non-MM sources, and we found that IL-8 contributes to BMSC-induced NF-κB activity. Conclusions BMSCs from MM patients uniquely enhance constitutive NF-κB activity in MM cells via a proteinaceous secreted factor in part in conjunction with IL-8. Since NF-κB is known to potentiate MM cell survival and confer resistance to drugs including bortezomib, further identification of the NF-κB activating factors produced specifically by MM-derived BMSCs may provide a novel biomarker and/or drug target for the treatment of this commonly fatal disease. PMID:20604947

  18. The emergence of non-secretory multiple myeloma during the non-cytotoxic treatment of essential thrombocythemia: a case report

    PubMed Central

    2013-01-01

    Introduction The emergence of multiple myeloma as a second malignancy in patients with essential thrombocythemia is extremely rare. Several cases have been published so far, pointing out the impact of a cytotoxic effect during treatment of essential thrombocythemia on the development of multiple myeloma. Case presentation We report the case of a 52-year-old Caucasian man who presented to our hospital because of leukocytosis, a slightly decreased hemoglobin level and thrombocytosis. After a complete hematological work-up, essential thrombocythemia was diagnosed. The patient was included in a multicenter clinical study, treated with anagrelide and his platelet counts were maintained in the normal range for more than 3 years. A sudden drop in his hemoglobin level with normal leukocyte and platelet count occurred at the same time as a back pain. Magnetic resonance imaging of his spine revealed the existence of a pathological fracture of Th4, the collapse of the upper edge of Th7 and osteolytic lesions of multiple thoracic vertebrae. Repeated hematological examinations, including bone biopsy with immunohistochemistry, disclosed diagnosis of multiple myeloma of the non-secretory type. Conclusions To the best of our knowledge this is the first published case in which multiple myeloma developed during the treatment of essential thrombocythemia with the non-cytotoxic drug anagrelide. Our attempts to find a common origin for the coexistence of multiple myeloma and essential thrombocythemia have not confirmed the genetic basis of their appearance. Further studies are needed to determine the biological impact of this coexistence. PMID:24025541

  19. Overcoming inherent resistance to histone deacetylase inhibitors in multiple myeloma cells by targeting pathways integral to the actin cytoskeleton.

    PubMed

    Mithraprabhu, S; Khong, T; Spencer, A

    2014-03-20

    Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with multiple myeloma (MM). Although HDACi have demonstrable synergy when combined with proteasome inhibitors (PIs), recent evidence indicates that combination of HDACi and PI is beneficial only in a subset of patients with advanced MM, clearly indicating that other rational combinations should be explored. In this context we hypothesized that understanding the molecular signature associated with inherent resistance to HDACi would provide a basis for the identification of therapeutic combinations with improved clinical efficacy. Using human myeloma cell lines (HMCL) categorized as sensitive, intermediate or resistant to HDACi, gene expression profiling (GEP) and gene ontology enrichment analyses were performed to determine if a genetic signature associated with inherent resistance to HDACi-resistance could be identified. Correlation of GEP to increasing or decreasing sensitivity to HDACi indicated a unique 35-gene signature that was significantly enriched for two pathways - regulation of actin cytoskeleton and protein processing in endoplasmic reticulum. When HMCL and primary MM samples were treated with a combination of HDACi and agents targeting the signaling pathways integral to the actin cytoskeleton, synergistic cell death was observed in all instances, thus providing a rationale for combining these agents with HDACi for the treatment of MM to overcome resistance. This report validates a molecular approach for the identification of HDACi partner drugs and provides an experimental framework for the identification of novel therapeutic combinations for anti-MM treatment.

  20. Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma

    PubMed Central

    Kasparu, Hedwig; Leitgeb, Clemens; Rauch, Elisabeth; Linkesch, Werner; Zojer, Niklas; Greil, Richard; Seebacher, Adelheid; Pour, Ludek; Weißmann, Adalbert; Adam, Zdeněk

    2014-01-01

    Bendamustine with bortezomib and dexamethasone was evaluated in 79 patients with relapsed/refractory multiple myeloma. Median age was 64 years, and patients had a median of 2 prior treatment lines (range, 1 to 6 lines). Bendamustine 70 mg/m2 days 1 and 4; bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, and 11; and dexamethasone 20 mg days 1, 4, 8, and 11 once every 28 days was given for up to 8 cycles. Primary end point was overall response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival, time to response, and toxicity. ORR was 60.8%, and when minor responses were included, 75.9%. Median time to response was 31 days. ORR rate was similar in patients previously exposed to bortezomib, lenalidomide, and bortezomib plus lenalidomide. PFS was 9.7 and OS was 25.6 months. Multivariate analysis showed high lactate dehydrogenase, ≥3 prior treatment lines, and low platelet counts correlating with short survival. Grade 3/4 thrombocytopenia was noted in 38%, and grade 3/4/5 infections were noted in 23%. Grade ≤2 polyneuropathy increased from 19% at baseline to 52% at cycle 8 and grade 4, from 0% to 7%. Bendamustine-bortezomib-dexamethasone is active and well tolerated in patients with relapsed/refractory myeloma. This trial was registered in the EudraCT database as No. 2008-006421-13. PMID:24227817

  1. Clinical significance of CD81 expression by clonal plasma cells in high-risk smoldering and symptomatic multiple myeloma patients.

    PubMed

    Paiva, B; Gutiérrez, N-C; Chen, X; Vídriales, M-B; Montalbán, M-Á; Rosiñol, L; Oriol, A; Martínez-López, J; Mateos, M-V; López-Corral, L; Díaz-Rodríguez, E; Pérez, J-J; Fernández-Redondo, E; de Arriba, F; Palomera, L; Bengoechea, E; Terol, M-J; de Paz, R; Martin, A; Hernández, J; Orfao, A; Lahuerta, J-J; Bladé, J; Pandiella, A; Miguel, J-F San

    2012-08-01

    The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81(+) SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma.

  2. Pomalidomide: the new immunomodulatory agent for the treatment of multiple myeloma

    PubMed Central

    Chanan-Khan, A A; Swaika, A; Paulus, A; Kumar, S K; Mikhael, J R; Rajkumar, S V; Dispenzieri, A; Lacy, M Q

    2013-01-01

    In this report, we provide a comprehensive review on the preclinical and clinical investigations conducted in development of the next-generation immunomodulatory drug (IMiD) pomalidomide for the treatment of relapsed/refractory multiple myeloma (MM). We consulted PubMed, MEDLINE, ASH, ASCO annual symposium abstracts and http://clinicaltrials.gov/ for the purpose of this literature review. Twenty-six preclinical and 11 clinical studies were examined. These studies delineate the mechanisms of action of pomalidomide and attest to the robust clinical activity in relapsed/refractory MM. MM is the second most common hematological malignancy in the US. Despite availability of several therapeutic agents, MM remains incurable. Thus, the development of new therapies remains a priority. Pomalidomide is the newest member of the IMiDs class of drugs, and in preclinical and clinical investigations, it has demonstrated an improved efficacy and toxicity profile in comparison to its sister compounds, lenalidomide and thalidomide. Importantly, recent clinical studies have demonstrated its activity in relapsed or refractory myeloma, particularly in lenalidomide and bortezomib-refractory patients. Thus, the addition of pomalidomide to the anti-myeloma armamentarium is widely anticipated to have a significant impact on the overall clinical outcome of advanced stage relapsed and refractory MM patients. PMID:24013664

  3. Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma.

    PubMed

    Hunsucker, Sally A; Magarotto, Valeria; Kuhn, Deborah J; Kornblau, Steven M; Wang, Michael; Weber, Donna M; Thomas, Sheeba K; Shah, Jatin J; Voorhees, Peter M; Xie, Hong; Cornfeld, Mark; Nemeth, Jeffrey A; Orlowski, Robert Z

    2011-03-01

    Signalling through the interleukin (IL)-6 pathway induces proliferation and drug resistance of multiple myeloma cells. We therefore sought to determine whether the IL-6-neutralizing monoclonal antibody siltuximab, formerly CNTO 328, could enhance the activity of melphalan, and to examine some of the mechanisms underlying this interaction. Siltuximab increased the cytotoxicity of melphalan in KAS-6/1, INA-6, ANBL-6, and RPMI 8226 human myeloma cell lines (HMCLs) in an additive-to-synergistic manner, and sensitized resistant RPMI 8226.LR5 cells to melphalan. These anti-proliferative effects were accompanied by enhanced activation of drug-specific apoptosis in HMCLs grown in suspension, and in HMCLs co-cultured with a human-derived stromal cell line. Siltuximab with melphalan enhanced activation of caspase-8, caspase-9, and the downstream effector caspase-3 compared with either of the single agents. This increased induction of cell death occurred in association with enhanced Bak activation. Neutralization of IL-6 also suppressed signalling through the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased phosphorylation of Akt, p70 S6 kinase and 4E-BP1. Importantly, the siltuximab/melphalan regimen demonstrated enhanced anti-proliferative effects against primary plasma cells derived from patients with myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis. These studies provide a rationale for translation of siltuximab into the clinic in combination with melphalan-based therapies.

  4. Deazaneplanocin A Is a Promising Drug to Kill Multiple Myeloma Cells in Their Niche

    PubMed Central

    Gaudichon, Jérémie; Milano, Francesco; Cahu, Julie; DaCosta, Lætitia; Martens, Anton C.; Renoir, Jack-Michel; Sola, Brigitte

    2014-01-01

    Tumoral plasma cells has retained stemness features and in particular, a polycomb-silenced gene expression signature. Therefore, epigenetic therapy could be a mean to fight for multiple myeloma (MM), still an incurable pathology. Deazaneplanocin A (DZNep), a S-adenosyl-L-homocysteine hydrolase inhibitor, targets enhancer of zest homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2) and is capable to induce the death of cancer cells. We show here that, in some MM cell lines, DZNep induced both caspase-dependent and -independent apoptosis. However, the induction of cell death was not mediated through its effect on EZH2 and the trimethylation on lysine 27 of histone H3 (H3K27me3). DZNep likely acted through non-epigenetic mechanisms in myeloma cells. In vivo, in xenograft models, and in vitro DZNep showed potent antimyeloma activity alone or in combination with bortezomib. These preclinical data let us to envisage new therapeutic strategies for myeloma. PMID:25255316

  5. Characterization of the molecular mechanism of the bone-anabolic activity of carfilzomib in multiple myeloma.

    PubMed

    Hu, Bo; Chen, Yu; Usmani, Saad Z; Ye, Shiqiao; Qiang, Wei; Papanikolaou, Xenofon; Heuck, Christoph J; Yaccoby, Shmuel; Williams, Bart O; Van Rhee, Frits; Barlogie, Bart; Epstein, Joshua; Qiang, Ya-Wei

    2013-01-01

    Carfilzomib, the next generation of proteasome inhibitor, may increase osteoblast-related markers in patients with multiple myeloma, but the molecular mechanism of its effect on mesenchymal stem cell differentiation to osteoblasts remains unknown. Herein, we demonstrated that carfilzomib significantly promoted mesenchymal stem cell differentiation into osteoblasts. In osteoprogenitor cells and primary mesenchymal stem cells from patients with myeloma, carfilzomib induced increases in alkaline phosphatase activity, matrix mineralization, and calcium deposition via Wnt-independent activation of β-catenin/TCF signaling. Using affinity pull-down assays with immunoblotting analysis and immunofluorescence, we found that carfilzomib induced stabilization of both free and active forms of β-catenin in a time- and dose-dependent manner that was not associated with β-catenin transcriptional regulation. Nuclear translocation of β-catenin protein was associated with TCF transcriptional activity that was independent of the effects of GSK3β-activation and of signaling induced by 19 Wnt ligands, 10 Frizzled receptors, and LRP5/6 co-receptors. Blocking activation of β-catenin/TCF signaling by dominant negative TCF1 or TCF4 attenuated carfilzomib-induced matrix mineralization. Thus, carfilzomib induced osteoblast differentiation via Wnt-independent activation of the β-catenin/TCF pathway. These results provide a novel molecular mechanism critical to understanding the anabolic role of carfilzomib on myeloma-induced bone disease.

  6. Risk factors for MDS and acute leukemia following total therapy 2 and 3 for multiple myeloma.

    PubMed

    Usmani, Saad Z; Sawyer, Jeffrey; Rosenthal, Adam; Cottler-Fox, Michele; Epstein, Joshua; Yaccoby, Shmuel; Sexton, Rachael; Hoering, Antje; Singh, Zeba; Heuck, Christoph J; Waheed, Sarah; Chauhan, Nabeel; Johann, Donald; Abdallah, Al-Ola; Muzaffar, Jameel; Petty, Nathan; Bailey, Clyde; Crowley, John; van Rhee, Frits; Barlogie, Bart

    2013-06-06

    Lenalidomide has been linked to myelodysplastic syndrome (MDS) after autotransplants for myeloma. Total therapy trials (TT; TT2(-/+) thalidomide) and TT3 (TT3a with bortezomib, thalidomide; TT3b with additional lenalidomide) offered the opportunity to examine the contribution of these immune-modulatory agents to MDS-associated cytogenetic abnormalities (MDS-CA) and clinical MDS or acute leukemia ("clinical MDS/AL"). Of 1080 patients with serial cytogenetic studies, MDS-CA occurred in 11% and clinical MDS/AL in 3%. Risk features of MDS-CA included TT3b, age ≥65 years, male gender, levels of β-2-microglobulin >5.5 mg/L, and multiple myeloma relapse. Clinical MDS/AL occurred less frequently in the control arm of TT2 and more often with TT3a and TT3b. Since MDS-CA often antedated clinical disease, periodic cytogenetic monitoring is recommended. Larger CD34 quantities should be collected upfront as the risk of MDS could be reduced by applying higher CD34 doses with transplant. Thus, treatment, host, and myeloma features could be linked to MDS development after therapy for this malignancy. This trial was registered at www.clinicaltrials.gov: TT3A: NCT00081939, TT3B: NCT00572169.

  7. Monoclonal antibodies - A new era in the treatment of multiple myeloma.

    PubMed

    Jelinek, Tomas; Hajek, Roman

    2016-03-01

    Monoclonal antibodies (mAbs) are currently the most investigated therapeutic compounds in oncology, but there is no monoclonal antibody approved in the treatment of multiple myeloma (MM). Nevertheless several really promising molecules are under investigation in phase III clinical trials. Dominantly daratumumab (anti-CD38) and elotuzumab (anti-CS1) showed extraordinary effectiveness in phase I/II trials. The toxicity was acceptable which is important for their addition to standard anti-myeloma agents like proteasome inhibitors or immunomodulatory drugs. Monoclonal antibodies such as denosumab (anti-RANKL) or BHQ880 (anti-DKK-1) are investigated also in the management of myeloma bone disease. This review is focused on the most promising mAbs, their mechanisms of action and the rationale of use. Practically all available results have been described. If the ongoing trials confirm the efficacy and safety of mAbs, they would become an important part of MM treatment that would be translated in the further improvement of therapeutic outcomes.

  8. Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells.

    PubMed

    Qiang, Ya-Wei; Yao, Lei; Tosato, Giovanna; Rudikoff, Stuart

    2004-01-01

    Multiple myeloma (MM) is an incurable form of cancer characterized by accumulation of malignant plasma cells in the bone marrow. During the course of this disease, tumor cells cross endothelial barriers and home to the bone marrow. In latter stages, myeloma cells extravasate through blood vessels and may seed a variety of organs. Insulin-like growth factor I (IGF-I) is one of several growth factors shown to promote the growth of MM cells. In the current study, we have assessed the ability of IGF-I to serve additionally as a chemotactic factor affecting the mobility and invasive properties of these cells. Results indicate that IGF-I promotes transmigration through vascular endothelial cells and bone marrow stromal cell lines. Analysis of endogenous signaling pathways revealed that protein kinase D/protein kinase Cmicro (PKD/PKCmicro) and RhoA were both activated in a phosphatidylinositol 3-kinase (PI-3K)-dependent manner. Inhibition of PI-3K, PKCs, or Rho-associated kinase by pharmacologic inhibitors abrogated migration, whereas mitogen-activated protein kinase (MAPK), Akt, and p70S6 kinase inhibitors had no effect. These results suggest that IGF-I promotes myeloma cell migration by activation of PI-3K/PKCmicro and PI-3K/RhoA pathways independent of Akt. The identification of IGF-I as both a proliferative and migratory factor provides a rational basis for the development of targeted therapeutic strategies directed at IGF-I in the treatment of MM.

  9. Nanoparticle delivery systems, general approaches, and their implementation in multiple myeloma.

    PubMed

    de la Puente, Pilar; Azab, Abdel Kareem

    2017-02-16

    Multiple myeloma (MM) is a hematological malignancy that remains incurable, with relapse rates >90%. The main limiting factor for the effective use of chemotherapies in MM is the serious side effects caused by these drugs. The emphasis in cancer treatment has shifted from cytotoxic, non-specific chemotherapies to molecularly targeted and rationally designed therapies showing greater efficacy and fewer side effects. Traditional chemotherapy has shown several disadvantages such as lack of targeting capabilities, systemic toxicity, and side effects; low therapeutic index, as well as most anticancer drugs, has poor water solubility. Nanoparticle delivery systems (NPs) are capable of targeting large doses of chemotherapies into the target area while sparing healthy tissues, overcoming the limitations of traditional chemotherapy. Here, we review the current state of the art in nanoparticle-based strategies designed to treat MM. Many nanoparticle delivery systems have been studied for myeloma using non-targeted NPs (liposomes, polymeric NPs, and inorganic NPs), triggered NPs, as well as targeted NPs (VLA-4, ABC drug transporters, bone microenvironment targeting). The results in preclinical and clinical studies are promising; however, there remains much to be learned in the emerging field of nanomedicine in myeloma.

  10. What Are the Risk Factors for Multiple Myeloma?

    MedlinePlus

    ... this cancer are at least 65 years old. Gender Men are slightly more likely to develop multiple ... would like to unsubscribe/opt out from our communications, please follow this link: http://www.cancer.org/ ...

  11. Cytogenetics in the management of multiple myeloma: an update by the Groupe francophone de cytogénétique hématologique (GFCH).

    PubMed

    Daudignon, Agnès; Quilichini, Benoît; Ameye, Geneviève; Poirel, Hélène; Bastard, Christian; Terré, Christine

    2016-10-01

    Cytogenetics of multiple myeloma has evolved in recent years by the emergence of Interphasic fluorescence in situ hybridization (FISH) performed on sorted plasma cells detecting abnormalities independently of a proliferative and infiltrative index. Cytogenetic analysis plays a major part in the risk stratification of myeloma diagnosis due to prognostic impact of various cytogenetic abnormalities as well as to the association between emerging therapeutic approaches in MM. Thus, practice guidelines now recommend interphasic FISH or alternative molecular technics as the initial analysis for multiple myeloma. The Groupe francophone de cytogénétique hématologique (GFCH) proposes in this issue an update of managing multiple myeloma cytogenetics.

  12. [Sorting of side population cells from multiple myeloma cell lines and analysis of their biological characteristics].

    PubMed

    Zhang, Xiao-Li; Zhang, Li-Na; Huang, Hong-Ming; Ding, Run-Sheng; Shi, Wei; Xu, Rui-Rong; Yu, Xiao-Tang; Jiang, Sheng-Hua

    2014-06-01

    This study was aimed to sort the side population (SP) cells from human multiple myeloma cell lines, then detect the biological characteristics of those SP cells. After Hoechst33342 staining, intracellular Hoechst33342 fluorescence staining differences of myeloma cell lines observed by the fluorescence microscopy. The fluorescence-activated cell sorting (FACS) technology was used to isolate SP cells and main population (MP) cells; proliferative capacity in vitro was determined by cell growth curve; the cell colony forming ability was compared by colony forming test. The CD138 expression was detected by flow cytometry. The expression of ABCG2 mRNA was detected by reverse transcription PCR; CCK-8 assay and colony forming test were used to evaluate the effect of bortezomib on the cell proliferation, vitality and colony forming ability of the two populations. The results showed that the myeloma cell lines had a small proportion of SP cells, especially, RPMI 8226 cells accounted for the highest proportion of SP cells (7.10 ± 2.69)%, which have also been confirmed under the fluorescence microscope; the proliferative activity and cell colony forming ability of SP cells were significantly higher than those of MP cells (P < 0.05). The expression levels of CD138 in SP and MP cells were not significantly different (P > 0.05). RT-PCR results showed that SP cells expressed the drug-resistance gene ABCG2, but MP cells hardly express these genes. The inhibition rate of bortezomib on SP cells was significantly lower than that on MP cells (P < 0.05), however, the difference was not significant (P > 0.05) at bortezomib 40 nmol/L. Bortezomib could reduce colony formation in the both two cell populations, but more severe reduction appeared in the MP cells. It is concluded that the myeloma cell line contain a small amount of SP cells with the cancer stem cell characteristics.

  13. Dilemma: Correlation Between Serum Level of Hepcidin and IL-6 in Anemic Myeloma Patients

    PubMed Central

    Ibricevic-Balic, Lejla; Icindic-Nakas, Emina; Hasic, Sabaheta; Kiseljakovic, Emina; Sofo-Hafizovic, Alma; Balic, Sefkija

    2016-01-01

    Introduction: Anemia occurs in 60% to 80 % of patients with newly diagnosed myeloma multiplex (MM). The cause of anemia in MM is probably multi factorial and involved among the others hepcidin and some cytokines, especially interleukine-6. Anemia in MM is one of the risk factor used in Durie-Salmon classification for staging and prognostic score. Treatment options are set according to this score with most significant impact on survival. Aim: To estimate baseline level of serum hepcidin, IL-6 and iron metabolism markers in anemic MM patients, possible role of hepcidin and its interaction with IL-6. Methods: 27 patients with newly diagnosed MM were enrolled in this observational, prospective study and age, gender matched 60 healthy controls. Erythrocyte count, hemoglobin, serum hepcidin, interleukin-6, iron, ferritin and transferrin were measured. Results: Anemia was diagnosed in 70% of MM patients. Serum hepcidin was significantly higher in MM group (55.5 ng/mL) than in control 5.9 ng/mL (p=0000). In myeloma patients serum IL-6 was 3.59 pg/mL, anemic 3.80 pg/mL, non-anemic 0.33 pg/mL, without significant difference. It was not found significant correlation between hepcidin and IL-6 in anemic myeloma patients. Conclusion: High level of hepcidin probably causes anemia in MM but its high expression is not due only to IL-6. PMID:28210014

  14. Increased effect of IMiDs by addition of cytokine-induced killer cells in multiple myeloma.

    PubMed

    Bullok, Katharina F; Sippel, Christoph; Schmidt-Wolf, Ingo G H

    2016-12-01

    Immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide and pomalidomide, represent the basic principle of multiple myeloma treatment. However, the development of resistance is a limiting factor. Over the last years, the efficient application of cytokine-induced killer (CIK) cells has been reported as an alternative strategy to treat hematological neoplasms. In this study, we tested for a potential synergistic effect by combining the IMiDs thalidomide, lenalidomide and pomalidomide with CIK cells in different myeloma cell lines in vitro. Myeloma cells tested with CIK cells were significantly reduced. In the combination, myeloma cells were significantly reduced compared with cells only tested with IMiDs but not to the cells tested with CIK cells. Otherwise, the number of CIK cells was significantly reduced when treated with IMiDs. Because IMiDs are active in patients with myeloma, these results lead to the expectation that combination of IMiDs and CIK cells achieve better results in the treatment of multiple myeloma compared with the single use of IMiDs. Therefore, further examinations in an in vivo setting are necessary to have a closer look on the cellular interactions. Copyright © 2015 John Wiley & Sons, Ltd.

  15. Identifying multiple myeloma patients using data from the French health insurance databases: Validation using a cancer registry.

    PubMed

    Palmaro, Aurore; Gauthier, Martin; Conte, Cécile; Grosclaude, Pascale; Despas, Fabien; Lapeyre-Mestre, Maryse

    2017-03-01

    This study aimed to assess the performance of several algorithms based on hospital diagnoses and the long-term diseases scheme to identify multiple myeloma patients.Potential multiple myeloma patients in 2010 to 2013 were identified using the presence of hospital records with at least 1 main diagnosis code for multiple myeloma (ICD-10 "C90"). Alternative algorithms also considered related and associated diagnoses, combination with long-term conditions, or at least 2 diagnoses. Incident patients were those with no previous "C90" codes in the past 24 or 12 months. The sensitivity, specificity, and positive and negative predictive values (PPVs and NPVs) were computed, using a French cancer registry for the corresponding area and period as the criterion standard.Long-term conditions data extracted concerned 11,559 patients (21,846 for hospital data). The registry contained 125 cases of multiple myeloma. Sensitivity was 70% when using only main hospital diagnoses (specificity 100%, PPV 79%), 76% when also considering related diagnoses (specificity 100%, PPV 74%), and 90% with associated diagnoses included (100% specificity, 64% PPV).In relation with their good performance, selected algorithms can be used to study the benefit and risk of drugs in treated multiple myeloma patients.

  16. Adverse Prognostic Impact of Bone Marrow Microvessel Density in Multiple Myeloma

    PubMed Central

    Lee, Nuri; Lee, Hyewon; Moon, Soo Young; Sohn, Ji Yeon; Hwang, Sang Mee; Yoon, Ok Jin; Youn, Hye Sun

    2015-01-01

    Background Angiogenesis is important for the proliferation and survival of multiple myeloma (MM) cells. Bone marrow (BM) microvessel density (MVD) is a useful marker of angiogenesis and is determined by immunohistochemical staining with anti-CD34 antibody. This study investigated the prognostic impact of MVD and demonstrated the relationship between MVD and previously mentioned prognostic factors in patients with MM. Methods The study included 107 patients with MM. MVD was assessed at initial diagnosis in a blinded manner by two hematopathologists who examined three CD34-positive hot spots per patient and counted the number of vessels in BM samples. Patients were divided into three groups according to MVD tertiles. Cumulative progression-free survival (PFS) and overall survival (OS) curves, calculated by using Kaplan-Meier method, were compared among the three groups. Prognostic impact of MVD was assessed by calculating Cox proportional hazard ratio (HR). Results Median MVDs in the three groups were 16.8, 33.9, and 54.7. MVDs were correlated with other prognostic factors, including β2-microglobulin concentration, plasma cell percentage in the BM, and cancer stage according to the International Staging System. Multivariate Cox regression analysis showed that high MVD was an independent predictor of PFS (HR=2.57; 95% confidence interval, 1.22-5.42; P=0.013). PFS was significantly lower in the high MVD group than in the low MVD group (P=0.025). However, no difference was observed in the OS (P=0.428). Conclusions Increased BM MVD is a marker of poor prognosis in patients newly diagnosed with MM. BM MVD should be assessed at the initial diagnosis of MM. PMID:26354343

  17. A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival

    PubMed Central

    Botta, C; Di Martino, M T; Ciliberto, D; Cucè, M; Correale, P; Rossi, M; Tagliaferri, P; Tassone, P

    2016-01-01

    Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment. PMID:27983725

  18. HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment

    SciTech Connect

    Borsi, Enrica; Perrone, Giulia; Terragna, Carolina; Martello, Marina; Zamagni, Elena; Tacchetti, Paola; Pantani, Lucia; Brioli, Annamaria; Dico, Angela Flores; Zannetti, Beatrice Anna; Rocchi, Serena; Cavo, Michele

    2014-11-01

    Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma. - Highlights: • HIF-1α inhibition induces a mild apoptotic cell death. • Down-modulation of cytokine-induced signaling cascades upon HIF-1α inhibition. • Reduced interaction between MM cells and BMSCs upon HIF-1α down-modulation. • Reduced PCs adhesion to the extracellular matrix protein induced by EZN-2968. • HIF-1α inhibition may be an attractive therapeutic strategy for Multiple Myeloma.

  19. PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation

    PubMed Central

    Teoh, Phaik Ju; Bi, Chonglei; Sintosebastian, Chirackal; Tay, Liang Seah; Fonseca, Rafael; Chng, Wee Joo

    2016-01-01

    Despite therapeutic advancement, multiple myeloma (MM) remains incurable with drug resistance being one of the main challenges in the clinic. Myeloma cells possess high protein secretory load, leading to increased intracellular endoplasmic reticulum (ER) stress. Hence, they are vulnerable to further perturbation to its protein homeostasis. In studying the therapeutic mechanism of PRIMA-1 (mutant-p53-reactivating-agent), we uncovered its novel p53-independent-mechanism that can be exploited for myeloma. Despite its inability in restoring the wild type-p53 protein conformation and transcriptional function in the mutant-p53-human-myeloma-cells, PRIMA-1 was efficacious against myeloma cells with differential p53 genotypes. Strikingly, cells without p53 expression demonstrated highest drug sensitivity. Genome-wide gene-expression analysis revealed the involvement of ER stress/UPR-pathway in inducing PRIMA-1-toxicity. UPR markers, HSP70, CHOP and GADD34, were significantly up-regulated, concomitantly with the induction of apoptosis. Furthermore, there was a global attenuation of protein synthesis, correlated with phospho-eIF2a up-regulation. Mechanistically, we identified that PRIMA-1 could cause the demethylation of TP73, through DNMT1 depletion, to subsequently enhance UPR. Of clinical significance, we observed that PRIMA-1 had additive therapeutic effects with another UPR-inducing-agent, bortezomib. Importantly, it can partially re-sensitize bortezomib-resistant cells to bortezomib. Given that MM is already stressed at the baseline in the ER, our results implicated that PRIMA-1 is a potential therapeutic option in MM by targeting its Achilles heel. PMID:27533450

  20. Retreatment with Bendamustine-Bortezomib-Dexamethasone in a Patient with Relapsed/Refractory Multiple Myeloma

    PubMed Central

    Nappi, Davide; Di Perna, Maria; Zacheo, Irene; Pareto, Anna Emanuele; Picardi, Marco; Pane, Fabrizio

    2016-01-01

    The clinical management of relapsed/refractory multiple myeloma and the correct choice of the most suitable therapy in heavily pretreated and fragile patients are tough clinical issues for clinicians. In advanced phases of disease, the choice of available therapies becomes very poor, and the retreatment with previously adopted and effective therapy, although unpredictable, could be an effective option. In this report, we describe the clinical history of a patient, previously treated with 9 lines of therapy, refractory to bortezomib and IMIDs, for whom the retreatment with bendamustine resulted in a stable disease with good quality of life. PMID:27867671

  1. Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma in Older Adults.

    PubMed

    Guerard, Emily J; Tuchman, Sascha A

    2016-02-01

    Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are plasma cell disorders of aging. The landscape of the diagnosis and management of MM and MGUS are rapidly changing. This article provides an updated understanding of the clinical presentation, evaluation, diagnosis, and management of older adults with MM and MGUS. Because most oncology providers are not formally trained in geriatric medicine, geriatricians play a key role in providing oncologists with a broader understanding of patient health status in the hope of improving outcomes for older adults with MM.

  2. Assessment of bortezomib induced peripheral neuropathy in multiple myeloma by the reduced Total Neuropathy Score.

    PubMed

    Zaroulis, Chrysothea K; Chairopoulos, Konstantinos; Sachanas, Sotirios P; Maltezas, Dimitris; Tzenou, Tatiana; Pessach, Ilias; Koulieris, Efstathios; Koutra, Eleni; Kilindireas, Konstantinos; Pangalis, Gerasimos A; Kyrtsonis, Marie-Christine

    2014-10-01

    We evaluated bortezomib induced peripheral neuropathy (BIPN) characteristics in an attempt to better clarify the type, grade, duration and reversibility of neuropathy as well as investigate possible peripheral neuropathy (PN) risk factors and detect the best way to manage it. We calculated the grading of neuropathy using the Total Neuropathy Score reduced version (TNSr) in a series of 51 patients with relapsed/refractory multiple myeloma treated with bortezomib. Seventy percent developed clinical PN. BIPN, although manageable, is frequently underestimated in patients treated with bortezomib intravenously. Continuous follow-up and management of PN are needed to avoid quality of life impairment.

  3. Multiple Myeloma Treatment Strategies with Novel Agents in 2011: A European Perspective

    PubMed Central

    Beksac, Meral; Bladé, Joan; Cavenagh, Jamie; Cavo, Michele; Delforge, Michel; Dimopoulos, Meletios; Drach, Johannes; Einsele, Hermann; Facon, Thierry; Goldschmidt, Hartmut; Harousseau, Jean-Luc; Hess, Urs; Kropff, Martin; Leal da Costa, Fernando; Louw, Vernon; Magen-Nativ, Hila; Mendeleeva, Larisa; Nahi, Hareth; Plesner, Torben; San-Miguel, Jesús; Sonneveld, Pieter; Udvardy, Miklos; Sondergeld, Pia; Palumbo, Antonio

    2011-01-01

    The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices. PMID:21441574

  4. 68Ga-PSMA PET/CT Imaging in Multiple Myeloma.

    PubMed

    Sasikumar, Arun; Joy, Ajith; Pillai, M R A; Nanabala, Raviteja; Thomas, Boben

    2017-02-01

    The potential applications of Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT in the imaging of prostate cancer are now well established. A few case reports regarding the potential use of Ga-PSMA PET/CT in nonprostate cancer malignancies are also published. Apparently, the tumor neoangiogenesis is the mechanism attributed to increased Ga-PSMA uptake in the tumor sites in nonprostatic malignancies. We describe the use of Ga-PSMA PET/CT in imaging multiple myeloma. The intense Ga-PSMA avidity of the lesions also opens up the possibility of theranostics with Lu-PSMA.

  5. [Research progress on multiple myeloma immunophenotyping and minimal residual disease detected by flow cytometry].

    PubMed

    Li, Han-Qing; Zhai, Yong-Ping

    2015-02-01

    Multiple myeloma (MM) is a haematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow and remained incurable. Flow cytometry has been widely used in the detection of immunophenotype and minimal residual disease, diagnosis, monitoring and prognosis of MM. Normal plasma cells and malignant plasma cells can be distinguished according to different cell surface antigen expression. The clinical significane of many immune markes has been elucidated. However, the clinical significance of some phenotype remains controversial, the detection scheme and gating strategy are not unified. This review discusses the recent research progress on detection of MM immunophenotype and minimal residual disease by flow cytovetry.

  6. Multiple myeloma and engine exhausts, fresh wood, and creosote: a case-referent study

    SciTech Connect

    Flodin, U.; Fredriksson, M.; Persson, B.

    1987-01-01

    The effect of potential risk factors for multiple myeloma was evaluated in a case-referent study encompassing 131 cases and 431 randomized referents, all alive. Information on exposure was obtained with questionnaires mailed to the subjects. An analysis of the material by means of the Miettinen confounder score technique resulted in a few rate ratios significantly exceeding unity--namely, occupational exposure to engine exhausts, creosote, and fresh wood. In view of other studies that suggest ionizing radiation as a risk factor, it was somewhat surprising that low-level gamma radiation from background exposure was less common among the cases than the referents.

  7. Multiple myeloma and engine exhausts, fresh wood, and creosote: a case-referent study.

    PubMed

    Flodin, U; Fredriksson, M; Persson, B

    1987-01-01

    The effect of potential risk factors for multiple myeloma was evaluated in a case-referent study encompassing 131 cases and 431 randomized referents, all alive. Information on exposure was obtained with questionnaires mailed to the subjects. An analysis of the material by means of the Miettinen confounder score technique resulted in a few rate ratios significantly exceeding unity--namely, occupational exposure to engine exhausts, creosote, and fresh wood. In view of other studies that suggest ionizing radiation as a risk factor, it was somewhat surprising that low-level gamma radiation from background exposure was less common among the cases than the referents.

  8. A patient with progressive multiple myeloma treated successfully with arsenic trioxide after allogeneic bone marrow transplantation.

    PubMed

    Gesundheit, B; Shapira, M Y; Ackerstein, A; Resnik, I B; Bitan, M; Or, R

    2007-01-01

    Multiple myeloma (MM) is an incurable progressive disease. Many therapeutic options are available to delay progression, including autologous and allogeneic bone marrow transplantation. At advanced stages, MM is often refractory to treatment. We report a heavily pretreated patient with graft-versus-host disease after bone marrow transplantations, treated at a terminal stage with a modified protocol for arsenic trioxide (ATO). This patient with poor clinical status tolerated the treatment very well. He had a remarkable clinical response and achieved complete remission. The mechanisms of ATO are presented and the potential role of ATO for MM is discussed.

  9. Crescentic Glomerulonephritis in IgA Multiple Myeloma: A Case Report

    PubMed Central

    Moscoso-Solorzano, Grace T.; Madureira-Silva, Marcus V.; Balda, Carlos; Franco, Marcello F.; Mastroianni-Kirsztajn, Gianna

    2011-01-01

    Background There are few reports of glomerulonephritis (GN) with crescents and a rapidly progressive course that lead to a diagnosis of a previously unsuspected B-cell dyscrasia. Case Presentation: We report a case of rapidly progressive GN: the patient showed no evidence of etiology at the time of biopsy and was diagnosed as IgA multiple myeloma (MM) during investigation based on a renal biopsy. He presented diffuse proliferative and exudative GN and marked plasma cell infiltration of the kidney. Conclusion The present case raises the possibility that proliferative GN with crescents may be a rare mode of presentation of MM. PMID:22470380

  10. Prognostic value of unrelated atypical serum immunofixation patterns during multiple myeloma therapy.

    PubMed

    Guimarães, Cristina; Bergantim, Rui; Ramalho, Renata; Couto, Nuno; Guimarães, João T; Trigo, Fernanda

    2012-06-26

    Autologous stem cell transplantation (ASCT) is the gold standard therapy for suitable multiple myeloma (MM) patients after induction with high dose therapy. To date, the evidence of a reliable marker of prognosis in these cases remains scarce. Our aim was to evaluate appearance of unrelated atypical serum immunofixation patterns (ASIPs) as a marker of prognosis in MM patients submitted to ASCT. We retrospectively analysed data from 65 patients. Interestingly, we observed that presence of ASIPs was associated with longer progression-free survival and longer overall survival. Our results suggested that presence of ASIPs could be a novel marker of good prognosis in MM patients submitted to ASCT.

  11. Disease-specific survival for patients with multiple myeloma: significant improvements over time in all age groups.

    PubMed

    Libby, Edward; Garcia, David; Quintana, Dulcinea; Fekrazad, M Houman; Bauman, Julie; Ebaid, Ala; Hromas, Robert; Rabinowitz, Ian; Wiggins, Charles

    2014-12-01

    This study analyzed the survival of patients with multiple myeloma. Surveillance, Epidemiology, and End Results (SEER) and Centers for Disease Control and Prevention (CDC) databases were queried to calculate myeloma cause-specific survival curves by the Kaplan and Meier product-limit method. The Cox proportional hazards model was used to assess univariate and multivariate predictors of myeloma cause-specific survival. The outcome of interest was death due to myeloma. Results from a Cox proportional hazards model restricted to age and time period at diagnosis demonstrated that the magnitude of improvement in survival by time period varied by age at diagnosis. Among patients under 60 years at diagnosis, hazard ratios for myeloma cause-specific death decreased by more 50% from the first interval of observation to the last. Hazard ratios decreased during the study period by 39% among patients 60-69 years of age and by 27% among patients who were 70 years of age and older. Survival is improving in patients with myeloma of all ages.

  12. Targeting executioner procaspase-3 with the procaspase-activating compound B-PAC-1 induces apoptosis in multiple myeloma cells.

    PubMed

    Zaman, Shadia; Wang, Rui; Gandhi, Varsha

    2015-11-01

    Multiple myeloma (MM) is a plasma cell neoplasm that has a low apoptotic index. We investigated a new class of small molecules that target the terminal apoptosis pathway, called procaspase activating compounds (PACs), in myeloma cells. PAC agents (PAC-1 and B-PAC-1) convert executioner procaspases (procaspase 3, 6, and 7) to active caspases 3, 6, and 7, which cleave target substrates to induce cellular apoptosis cascade. We hypothesized that targeting this terminal step could overcome survival and drug-resistance signals in myeloma cells and induce programmed cell death. Myeloma cells expressed executioner caspases. Additionally, our studies demonstrated that B-PAC-1 is cytotoxic to chemotherapy-resistant or sensitive myeloma cell lines (n = 7) and primary patient cells (n = 11). Exogenous zinc abrogated B-PAC-1-induced cell demise. Apoptosis induced by B-PAC-1 treatment was similar in the presence or absence of growth-promoting cytokines such as interleukin 6 and hepatocyte growth factor. Presence or absence of antiapoptotic proteins such as BCL-2, BCL-XL, or MCL-1 did not impact B-PAC-1-mediated programmed cell death. Collectively, our data demonstrate the proapoptotic effect of B-PAC-1 in MM and suggest that activating terminal executioner procaspases 3, 6, and 7 bypasses survival and drug-resistance signals in myeloma cells. This novel strategy has the potential to become an effective antimyeloma therapy.

  13. Adenosine Generated in the Bone Marrow Niche Through a CD38-Mediated Pathway Correlates With Progression of Human Myeloma

    PubMed Central

    Horenstein, Alberto L; Quarona, Valeria; Toscani, Denise; Costa, Federica; Chillemi, Antonella; Pistoia, Vito; Giuliani, Nicola; Malavasi, Fabio

    2016-01-01

    Human myeloma cells express CD38 at high levels and grow in hypoxic niches inside the bone marrow. Myeloma cells respond to hypoxia with metabolic changes leading to aerobic glycolysis, thus reducing adenosine triphosphate (ATP) and increasing NAD+. Our hypothesis is that these conditions favor the enzymatic pathways involved in the production of adenosine in the niche. Within the niche, NAD+ is able to activate a discontinuous adenosinergic pathway that relies upon CD38, CD203a and CD73 or TRACP, according to the environmental pH. The observed variability in adenosine concentrations in bone marrow aspirates is a result of the interactions taking place among myeloma and other cells in the bone marrow niche. A pilot study showed that adenosine profiles differ during disease progression. Adenosine levels were significantly higher in the bone marrow plasma of patients with symptomatic myeloma and correlated with ISS staging, suggesting that adenosine is produced in the myeloma niche at micromolar levels by an ectoenzymatic network centered on CD38. Adenosine levels increase with disease aggressiveness, a finding that supports adenosine as a potential marker of myeloma progression. PMID:27761584

  14. Oligodendroglioma metastasis to the bone marrow mimicking multiple myeloma: A case report

    PubMed Central

    JIAN, YUAN; GAO, WEN; WU, YIN; LI, YANCHEN; ZHANG, YONG; YANG, GUANGZHONG; CHEN, WENMING

    2016-01-01

    The present study reports a case of a 59-year-old male suffering from oligodendroglioma that metastasized to the bone marrow (BM). The metastasis was detected 5 years after craniotomy was performed for the resection of the primary tumor; however, it manifested as multiple myeloma (MM)-like bone lesions, a small M component and myeloma cell-like morphology in the BM. A brain magnetic resonance imaging scan was performed; evidence from the previously performed oligodendroglioma resection was observed on the scan, but there were no significant findings, which made the diagnosis particularly challenging. The patient exhibited no response to the multiple combination therapies administered targeting MM and oligodendroglioma, and subsequently developed epilepsy and pneumonia, prior to succumbing to multiple organ failure. Among the various tumor types involving the central nervous system, oligodendroglioma is the least likely to metastasize; thus, distant metastases from brain oligodendrogliomas are extremely rare. To the best of our knowledge, this is the first case of metastatic oligodendroglioma presenting with typical MM-like symptoms and without any recurrence in the brain. PMID:27347150

  15. Cost-Effectiveness of Autologous Stem Cell Treatment as Compared to Conventional Chemotherapy for Treatment of Multiple Myeloma in India.

    PubMed

    Prinja, Shankar; Kaur, Gunjeet; Malhotra, Pankaj; Jyani, Gaurav; Ramachandran, Raja; Bahuguna, Pankaj; Varma, Subhash

    2017-03-01

    Recent innovations in treatment of multiple myeloma include autologous stem cell transplantation (ASCT) along with high dose chemotherapy (HDC). We undertook this study to estimate incremental cost per quality adjusted life year gained (QALY) with use of ASCT along with HDC as compared to conventional chemotherapy (CC) alone in treatment of multiple myeloma. A combination of decision tree and markov model was used to undertake the analysis. Incremental costs and effects of ASCT were compared against the baseline scenario of CC (based on Melphalan and Prednisolone regimen) in the patients of multiple myeloma. A lifetime study horizon was used and future costs and consequences were discounted at 5%. Consequences were valued in terms of QALYs. Incremental cost per QALY gained using ASCT as against CC for treatment of multiple myeloma was estimated using both a health system and societal perspective. The cost of providing ASCT (with HDC) for multiple myeloma patients was INR 500,631, while the cost of CC alone was INR 159,775. In the long run, cost per patient per year for ASCT and CC arms was estimated to be INR 119,740 and INR 111,565 respectively. The number of QALYs lived per patient in case of ASCT and HDC alone were found to be 4.1 and 3.5 years respectively. From a societal perspective, ASCT was found to incur an incremental cost of INR 334,433 per QALY gained. If the ASCT is initiated early to patients, the incremental cost for ASCT was found to be INR 180,434 per QALY gained. With current mix of patients, stem cell treatment for multiple myeloma is not cost effective at a threshold of GDP per capita. It becomes marginally cost-effective at 3-times the GDP per capita threshold. However, accounting for the model uncertainties, the probability of ASCT to be cost effective is 59%. Cost effectiveness of ASCT can be improved with early detection and initiation of treatment.

  16. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma.

    PubMed

    Hurt, Elaine M; Wiestner, Adrian; Rosenwald, Andreas; Shaffer, A L; Campo, Elias; Grogan, Tom; Bergsagel, P Leif; Kuehl, W Michael; Staudt, Louis M

    2004-02-01

    The oncogene c-maf is translocated in approximately 5%-10% of multiple myelomas. Unexpectedly, we observed c-maf expression in myeloma cell lines lacking c-maf translocations and in 50% of multiple myeloma bone marrow samples. By gene expression profiling, we identified three c-maf target genes: cyclin D2, integrin beta7, and CCR1. c-maf transactivated the cyclin D2 promoter and enhanced myeloma proliferation, whereas dominant inhibition of c-maf blocked tumor formation in immunodeficient mice. c-maf-driven expression of integrin beta7 enhanced myeloma adhesion to bone marrow stroma and increased production of VEGF. We propose that c-maf transforms plasma cells by stimulating cell cycle progression and by altering bone marrow stromal interactions. The frequent overexpression of c-maf in myeloma makes it an attractive target for therapeutic intervention.

  17. Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance, Allogeneic Transplant, and Immune Therapy.

    PubMed

    Krishnan, Amrita; Vij, Ravi; Keller, Jesse; Dhakal, Binod; Hari, Parameswaran

    2016-01-01

    For multiple myeloma, introduction of novel agents as part of the front-line treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) induces deep responses in a majority of patients with this disease. However, disease relapse is inevitable, and, with each relapse, the remission duration becomes shorter, ultimately leading to a refractory disease. Consolidation and maintenance strategy after ASCT is one route to provide sustained disease control and prevent repeated relapses. Though the consolidation strategy remains largely confined to clinical trials, significant data support the efficacy of consolidation in improving the depth of response and outcomes. There are also increasing rates of minimal residual disease-negativity with additional consolidation therapy. On the other hand, maintenance with novel agents post-transplant is well established and has been shown to improve both progression-free and overall survival. Evolving paradigms in maintenance include the use of newer proteasome inhibitors, immunotherapy maintenance, and patient-specific maintenance-a concept that utilizes minimal residual disease as the primary driver of decisions regarding starting or continuing maintenance therapy. The other approach to overcome residual disease is immune therapeutic strategies. The demonstration of myeloma-specific alloimmunity from allogeneic transplantation is well established. More sophisticated and promising immune approaches include adoptive cellular therapies, tumor vaccines, and immune checkpoint manipulations. In the future, personalized minimal residual disease-driven treatment strategies following ASCT will help overcome the residual disease, restore multiple myeloma-specific immunity, and achieve sustained disease control while minimizing the risk of overtreatment.

  18. Interleukin-6-related genotypes, body mass index, and risk of multiple myeloma and plasmacytoma.

    PubMed

    Cozen, Wendy; Gebregziabher, Mulugeta; Conti, David V; Van Den Berg, David J; Coetzee, Gerhard A; Wang, Sophia S; Rothman, Nathaniel; Bernstein, Leslie; Hartge, Patricia; Morhbacher, Ann; Coetzee, Simon G; Salam, Muhammad T; Wang, Wei; Zadnick, John; Ingles, Sue A

    2006-11-01

    Interleukin-6 (IL-6) promotes normal plasma cell development and proliferation of myeloma cells in culture. We evaluated IL-6 genotypes and body mass index (BMI) in a case-control study of multiple myeloma and plasmacytoma. DNA samples and questionnaires were obtained from incident cases of multiple myeloma (n = 134) and plasmacytoma (n = 16; plasma cell neoplasms) ascertained from the Los Angeles County population-based cancer registry and from siblings or cousins of cases (family controls, n = 112) and population controls (n = 126). Genotypes evaluated included IL-6 promoter gene single nucleotide polymorphisms (SNP) at positions -174, -572, and -597; one variable number of tandem repeats (-373 A(n)T(n)); and one SNP in the IL-6 receptor (IL-6ralpha) gene at position -358. The variant allele of the IL-6 promoter SNP -572 was associated with a roughly 2-fold increased risk of plasma cell neoplasms when cases were compared with family [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 0.7-4.7] or population controls (OR, 2.4; 95% CI, 1.2-4.7). The -373 9A/9A genotype was associated with a decreased risk compared with the most common genotype (OR for cases versus family controls, 0.4; 95% CI, 0.1-1.7; OR for cases versus population controls, 0.3; 95% CI, 0.1-0.9). No other SNPs were associated with risk. Obesity (BMI >or= 30 kg/m(2)) increased risk nonsignificantly by 40% and 80% when cases were compared with family controls or population controls, respectively, relative to persons with a BMI of <25 kg/m(2). These results suggest that IL-6 promoter genotypes may be associated with increased risk of plasma cell neoplasms.

  19. Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma.

    PubMed

    Delgado-Calle, Jesus; Anderson, Judith; Cregor, Meloney D; Hiasa, Masahiro; Chirgwin, John M; Carlesso, Nadia; Yoneda, Toshiyuki; Mohammad, Khalid S; Plotkin, Lilian I; Roodman, G David; Bellido, Teresita

    2016-03-01

    In multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3-dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma.

  20. Monitoring a Nuclear Factor-κB Signature of Drug Resistance in Multiple Myeloma*

    PubMed Central

    Xiang, Yun; Remily-Wood, Elizabeth R.; Oliveira, Vasco; Yarde, Danielle; He, Lili; Cheng, Jin Q.; Mathews, Linda; Boucher, Kelly; Cubitt, Christopher; Perez, Lia; Gauthier, Ted J.; Eschrich, Steven A.; Shain, Kenneth H.; Dalton, William S.; Hazlehurst, Lori; Koomen, John M.

    2011-01-01

    The emergence of acquired drug resistance results from multiple compensatory mechanisms acting to prevent cell death. Simultaneous monitoring of proteins involved in drug resistance is a major challenge for both elucidation of the underlying biology and development of candidate biomarkers for assessment of personalized cancer therapy. Here, we have utilized an integrated analytical platform based on SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring mass spectrometry, a versatile and powerful tool for targeted quantification of proteins in complex matrices, to evaluate a well-characterized model system of melphalan resistance in multiple myeloma (MM). Quantitative assays were developed to measure protein expression related to signaling events and biological processes relevant to melphalan resistance in multiple myeloma, specifically: nuclear factor-κB subunits, members of the Bcl-2 family of apoptosis-regulating proteins, and Fanconi Anemia DNA repair components. SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring methods were developed for quantification of these selected target proteins in amounts of material compatible with direct translation to clinical specimens (i.e. less than 50,000 cells). As proof of principle, both relative and absolute quantification were performed on cell line models of MM to compare protein expression before and after drug treatment in naïve cells and in drug resistant cells; these liquid chromatography-multiple reaction monitoring results are compared with existing literature and Western blots. The initial stage of a systems biology platform for examining drug resistance in MM has been implemented in cell line models and has been translated to MM cells isolated from a patient. The ultimate application of this platform could assist in clinical decision-making for individualized patient treatment. Although these specific assays have

  1. A rare case of nasopharyngeal carcinoma in a patient with multiple myeloma after treatment by lenalidomide

    PubMed Central

    Xu, Gaixiang; Wang, Bo; Yang, Min; Qian, Wenbin

    2015-01-01

    Multiple myeloma (MM) is a plasma-cell malignancy leading to a significant life-expectancy shortening. Lenalidomide is an oral immunomodulatory drug (IMiD) approved in the United States for patients with MM. Although the introduction of lenalidomide combined with dexamethasone (Len/Dex) has improved the outcome of patients with relapsed/refractory multiple myeloma (RRMM), it is a common knowledge that lenalidomide has been linked to the development of secondary primary malignancies in the MM patients, especially in those who use lenalidomide as a maintenance therapy. In the published literature, these are also many cases reported by clinicians in different secondary primary malignancies after the diagnosis of MM treated with lenalidomide. In this present article, we provided our patient who was identified nasopharyngeal carcinoma (NPC) 46 months after the diagnosis of MM and 21 months after lenalidomide treatment. To the best of our knowledge, this is the first case report related to the occurrence of NPC in a patient with MM after treatment by lenalidomide. Although it is not very sure that the incidence of NPC was associated with the use of lenalidomide, we clinicians should pay adequate attention to this phenomenon in the clinical processing. And much more cooperative studies of large numbers of MM patients are needed to evaluate a possible association between lenalidomide and NPC. PMID:26823839

  2. Management of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM)

    PubMed Central

    KYLE, ROBERT A.; BUADI, FRANC IS; RAJKUMAR, S. VINC ENT

    2014-01-01

    Monoclonal gammopathy of undetermined significance (MGUS) is defined as a serum M protein level of less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of end-organ damage. The prevalence of MGUS is 3.2% in the white population but is approximately twice that high in the black population. MGUS may progress to multiple myeloma, AL amyloidosis, Waldenström macroglobulinemia, or lymphoma. The risk of progression is approximately 1% per year, but the risk continues even after more than 25 years of observation. Risk factors for progression include the size of the serum M protein, the type of serum M protein, the number of plasma cells in the bone marrow, and the serum free light chain ratio. Smoldering (asymptomatic) multiple myeloma (SMM) is characterized by the presence of an M protein level of 3 g/dL or higher and/or 10% or more monoclonal plasma cells in the bone marrow but no evidence of end-organ damage. The overall risk of progression to a malignant condition is 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% to 2% per year for the following 10 years. Patients with both MGUS and SMM must be followed up for their lifetime. PMID:21888255

  3. Severe hypernatremia and hyperchloremia in an elderly patient with IgG-kappa-type multiple myeloma

    PubMed Central

    Imashuku, Shinsaku; Kudo, Naoko; Kubo, Kagekatsu

    2013-01-01

    A 77-year-old male was admitted to hospital after suffering a pelvic bone fracture in a road traffic accident and was incidentally found to have IgG-kappa-type multiple myeloma with hypercalcemia. The patient was also noted to be hypokalemic and had low HCO3−, with possible damage to the distal tubules in the kidneys. When the treatment was begun with bortezomib/dexamethasone/elcatonin and sodium bicarbonate (NaHCO3) in normal saline (equivalent to a daily sodium dose of 200 millimoles per liter [mmol/L]), the patient was in a state of poor oral fluid intake. The patient developed hypernatremia and hyperchloremia, with a peak serum sodium and chloride levels of 183 mmol/L and 153 mmol/L, respectively, at the sixth day after the start of treatment. Following the switch of the intravenous infusions from normal saline to soldem 1 and soldem 3 solutions, these high-electrolyte levels gradually returned to normal over the next 7 days. Although the patient showed disturbed consciousness (Japan Coma Scale = JCS-I-3) during the period of electrolyte abnormality, he eventually fully recovered without sequelae. In this patient, we successfully managed the severe hypernatremia/hyperchloremia, caused by the combined effects of intravenous saline burden in a state of poor oral fluid intake, during the treatment for IgG-kappa type multiple myeloma. PMID:23700375

  4. Dendritic cell immunotherapy for cancer: application to low-grade lymphoma and multiple myeloma.

    PubMed

    Hart, D N; Hill, G R

    1999-10-01

    The confirmation that most cancers express one or more molecular changes, which may act as tumour-associated antigens (TAA), combined with the knowledge that T lymphocytes recognize even single amino acid differences in MHC presented peptides has stimulated renewed clinical interest in immunotherapeutic strategies. Dendritic cells (DC) are now recognized as specialist antigen-presenting cells, which initiate, direct and regulate immune responses. Recent data suggest that DC are not recruited into, or activated by, cancers and that other abnormalities in DC function are associated with malignancy, including multiple myeloma. This provides a rationale for designing immunotherapeutic strategies, which exploit DC as nature's adjuvant either in vivo or in vitro. Low-grade lymphoma and multiple myeloma are slowly progressive malignancies, which generally express a unique immunoglobulin idiotype as a potential TAA. Data from animal models and clinical studies suggest that DC-based immunotherapy strategies, applied when the patient has minimal residual disease, may improve the long-term prognosis in these diseases.

  5. Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity

    PubMed Central

    Cornell, R F; Kassim, A A

    2016-01-01

    The use of modern therapies such as thalidomide, bortezomib and lenalidomide coupled with upfront high-dose therapy and autologous stem cell transplant (ASCT) has resulted in improved survival in patients with newly diagnosed multiple myeloma (MM). However, patients with relapsed/refractory multiple myeloma (RRMM) often have poorer clinical outcomes and might benefit from novel therapeutic strategies. Emerging therapies, such as deacetylase inhibitors, monoclonal antibodies and new proteasome inhibitors, appear promising and may change the therapeutic landscape in RRMM. A limited number of studies has shown a benefit with salvage ASCT in patients with RRMM, although there remains ongoing debate about its timing and effectiveness. Improvement in transplant outcomes has re-ignited a debate on the timing and possible role for salvage ASCT and allogeneic stem cell transplant in RRMM. As the treatment options for management of patients with RRMM become increasingly complex, physicians must consider both disease- and patient-related factors in choosing the appropriate therapeutic approach, with the goal of improving efficacy while minimizing toxicity. PMID:26726946

  6. [Treatment of multiple myeloma with intravenous pamidronate. Pain prevention and suppression of hypercalcemia risk].

    PubMed

    Díaz, Carlos; Soutelo, María J; Quiroga, Luis; Palmer, Luis; Lutfi, Rubén

    2004-01-01

    In a prospective clinical study, with the patient as its own control, we selected patients with stage III multiple myeloma. We treated them monthly with intravenous (i.v.) Disodic Pamidronate: 90 mg