Myeloma
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Multiple myeloma (also known as myelomatosis or myeloma) is a cancer in which there is abnormal growth in the number of plasma cells in the bone-marrow and blood. This can suppress the normal production of blood cells, including those associated with the body's immune system. The plasma cells may collect in the bone to make small tumours known as plasmacytomas. Multiple myeloma is most common in people aged over 60, and is rare before the age of 40.

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Molecular Biology of Multiple Myeloma

Information Patients and the Public (15 links)


Information for Health Professionals / Researchers (12 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Lacy MQ
"IM iD"eally treating multiple myeloma.
Blood. 2013; 121(11):1926-8 [PubMed]
In this issue of Blood, Leleu and colleagues(1) and Richardson and colleagues(2) publish two different trials using pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (MM).


Hawley TS, Riz I, Yang W, et al.
Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1.
Am J Hematol. 2013; 88(4):265-72 [PubMed] Article available free on PMC after 01/04/2014
Multiple myeloma (MM) is characterized by the malignant expansion of differentiated plasma cells. Although many chemotherapeutic agents display cytotoxic activity toward MM cells, patients inevitably succumb to their disease because the tumor cells become resistant to the anticancer drugs. The cancer stem cell hypothesis postulates that a small subpopulation of chemotherapy-resistant cancer cells is responsible for propagation of the tumor. Herein we report that efflux of the pluripotent stem cell dye CDy1 identifies a subpopulation in MM cell lines characterized by increased expression of P-glycoprotein, a member of the ABC (ATP-binding cassette) superfamily of transporters encoded by ABCB1. We also demonstrate that ABCB1-overexpressing MM cells are resistant to the second-generation proteasome inhibitor carfilzomib that recently received accelerated approval for the treatment of therapy-refractive MM by the U.S. Food and Drug Administration. Moreover, increased resistance to carfilzomib in sensitive MM cells following drug selection was associated with upregulation of ABCB1 cell-surface expression which correlated with increased transporter activity as measured by CDy1 efflux. We further show that chemosensitization of MM cells to carfilzomib could be achieved in vitro by cotreatment with vismodegib, a hedgehog pathway antagonist which is currently in MM clinical trials. CDy1 efflux may therefore be a useful assay to determine whether high expression of ABCB1 is predictive of poor clinical responses in MM patients treated with carfilzomib. Our data also suggest that inclusion of vismodegib might be a potential strategy to reverse ABCB1-mediated drug resistance should it occur.


Klingler JH, Sircar R, Deininger MH, et al.
Vesselplasty: a new minimally invasive approach to treat pathological vertebral fractures in selected tumor patients - preliminary results.
Rofo. 2013; 185(4):340-50 [PubMed]
PURPOSE: To evaluate the effectiveness and safety of percutaneous vesselplasty in pathological vertebral fractures of the thoracolumbar spine in selected tumor patients.
MATERIALS AND METHODS: Eleven pathological vertebral fractures in nine patients were treated with vesselplasty (Vessel-X®, MAXXSPINE). Nine of eleven vertebras (81.8 %) had major posterior wall deficiency (> 30 %). Clinical and radiological (CT) measures were obtained before and 3 months after the procedure.
RESULTS: The mean VAS improved significantly from preoperative to postoperative (6.9 ± 2.2 to 3.7 ± 2.3; p < 0.05), as did the ODI (59.7 %± 19.2 % to 40.3 %± 24.0 %; p < 0.05). The physical component summary of the SF-36 was significantly improved by the operation (19.2 ± 8.0 to 31.0 ± 16.5; p < 0.05). Symptomatic cement leakage or other operation-associated complications were not observed. Three patients were primarily treated with concomitant minimally invasive stabilization via fixateur interne. One patient had to undergo minimally invasive stabilization via fixateur interne 4 months after vesselplasty due to further collapse of the treated vertebral body.
CONCLUSION: From these preliminary results, vesselplasty appears to be a treatment option worth considering in pathological vertebral fractures, even in the case of posterior wall deficiency. Selected tumor patients might benefit from vesselplasty as a minimally invasive procedure for stabilization of the fractured vertebra, pain control, and improvement in body function and quality of life. Long-term prospective studies with a larger sample size are required to validate these results.


Roccaro AM, Sacco A, Maiso P, et al.
BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression.
J Clin Invest. 2013; 123(4):1542-55 [PubMed] Article available free on PMC after 01/04/2014
BM mesenchymal stromal cells (BM-MSCs) support multiple myeloma (MM) cell growth, but little is known about the putative mechanisms by which the BM microenvironment plays an oncogenic role in this disease. Cell-cell communication is mediated by exosomes. In this study, we showed that MM BM-MSCs release exosomes that are transferred to MM cells, thereby resulting in modulation of tumor growth in vivo. Exosomal microRNA (miR) content differed between MM and normal BM-MSCs, with a lower content of the tumor suppressor miR-15a. In addition, MM BM-MSC-derived exosomes had higher levels of oncogenic proteins, cytokines, and adhesion molecules compared with exosomes from the cells of origin. Importantly, whereas MM BM-MSC-derived exosomes promoted MM tumor growth, normal BM-MSC exosomes inhibited the growth of MM cells. In summary, these in vitro and in vivo studies demonstrated that exosome transfer from BM-MSCs to clonal plasma cells represents a previously undescribed and unique mechanism that highlights the contribution of BM-MSCs to MM disease progression.


Rajkumar SV
Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management.
Am J Hematol. 2013; 88(3):226-35 [PubMed]
UNLABELLED: DISEASE OVERVIEW: Multiple myeloma accounts for approximately 10% of hematologic malignancies.
DIAGNOSIS: The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end-organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end-organ damage. RISK STRATIFICATION: In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high-risk myeloma. Patients with t(4;14) translocation are considered intermediate-risk. All others are considered as standard-risk. RISK-ADAPTED INITIAL THERAPY: Standard-risk patients can be treated with lenalidomide plus low-dose dexamethasone (Rd), or a bortezomib-containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate-risk and high-risk patients require a bortezomib-based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard-risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12-18 months. MAINTENANCE THERAPY: After initial therapy, lenalidomide maintenance is considered for standard-risk patients who are not in very good partial response or better, while maintenance with a bortezomib-based regimen should be considered in pateints with intermediate or high-risk myeloma. MANAGEMENT OF REFRACTORY DISEASE: Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents.


Nalesnik MA
Plasma cell tumors in transplant patients.
Blood. 2013; 121(8):1247-9 [PubMed]
In this issue of Blood, Perry and colleagues describe a form of plasmacytic post-transplant lymphoproliferative disorder (PTLD) that occurs in pediatric organ recipients, is not associated with Epstein-Barr virus (EBV), and is responsive to minimal therapy.(1) Might this represent a separate pathway for PTLD development?


Yyusnita, Norsiah, Zakiah I, et al.
MicroRNA (miRNA) expression profiling of peripheral blood samples in multiple myeloma patients using microarray.
Malays J Pathol. 2012; 34(2):133-43 [PubMed]
MicroRNAs (miRNAs) are mostly located at cancer-associated genomic regions or in fragile sites, suggesting their important role in the pathogenesis of human cancers. Multiple myeloma (MM) is a cancer of plasma cells, the third most common cancer of the blood after lymphoma and leukaemia. There are several published reports on miRNAs in MM, however most used bone marrow rather than peripheral blood samples. The aim of this study is to characterise miRNA expression in normal and MM patients using peripheral blood samples as it is less invasive and is readily available from patients. Blood samples from 35 MM patients were analysed using the microarray method. We identified up-regulation of 36 miRNAs (57%) and down-regulation of 27 miRNAs (43%). We also identified the CCND2, HMGA2 and IGF1R genes were among the highly predictive target genes (P(CT) > 0.80) for most of the deregulated miRNAs. These genes are known to play important roles in MM as well as other cancers. Five miRNAs (let-7c, miR-16, miR- 449, miR-181a and miR-181b) were found to exhibit similar expression patterns (p < 0.05) in peripheral blood when compared to data obtained by using bone marrow aspirates from MM patients in other studies. In conclusion, our study has demonstrated that miRNAs are also present and differentially expressed in the peripheral blood of MM patients compared to controls and may potentially serve as candidate tumour biomarkers in MM. In particular, let-7c and miR-16 have been shown to be significantly expressed in the bone marrow.


Heuck CJ, Mehta J, Bhagat T, et al.
Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis.
J Immunol. 2013; 190(6):2966-75 [PubMed]
Epigenetic changes play important roles in carcinogenesis and influence initial steps in neoplastic transformation by altering genome stability and regulating gene expression. To characterize epigenomic changes during the transformation of normal plasma cells to myeloma, we modified the HpaII tiny fragment enrichment by ligation-mediated PCR assay to work with small numbers of purified primary marrow plasma cells. The nano-HpaII tiny fragment enrichment by ligation-mediated PCR assay was used to analyze the methylome of CD138(+) cells from 56 subjects representing premalignant (monoclonal gammopathy of uncertain significance), early, and advanced stages of myeloma, as well as healthy controls. Plasma cells from premalignant and early stages of myeloma were characterized by striking, widespread hypomethylation. Gene-specific hypermethylation was seen to occur in the advanced stages, and cell lines representative of relapsed cases were found to be sensitive to decitabine. Aberrant demethylation in monoclonal gammopathy of uncertain significance occurred primarily in CpG islands, whereas differentially methylated loci in cases of myeloma occurred predominantly outside of CpG islands and affected distinct sets of gene pathways, demonstrating qualitative epigenetic differences between premalignant and malignant stages. Examination of the methylation machinery revealed that the methyltransferase, DNMT3A, was aberrantly hypermethylated and underexpressed, but not mutated in myeloma. DNMT3A underexpression was also associated with adverse overall survival in a large cohort of patients, providing insights into genesis of hypomethylation in myeloma. These results demonstrate widespread, stage-specific epigenetic changes during myelomagenesis and suggest that early demethylation can be a potential contributor to genome instability seen in myeloma. We also identify DNMT3A expression as a novel prognostic biomarker and suggest that relapsed cases can be therapeutically targeted by hypomethylating agents.


Princewill K, Kyere S, Awan O, Mulligan M
Multiple myeloma lesion detection with whole body CT versus radiographic skeletal survey.
Cancer Invest. 2013; 31(3):206-11 [PubMed]
OBJECTIVE: To compare accuracy of CT versus radiographs in detecting myeloma lesions.
MATERIALS AND METHODS: Retrospective review of patients who were simultaneously evaluated with radiographs and PET/CT scans. Two radiologists independently assessed each modality.
RESULTS: Total number of lesions detected with CT was 968 versus 248 for radiographs (p < .001). Nine patients (18%) had no lesions on either CT or radiographs. Of the remaining 42 patients, 39 had more lesions on CT. CT could have resulted in upstaging of disease in 31 cases (61%).
CONCLUSION: CT is superior for detecting myeloma lesions.


Held LA, Rizzieri D, Long GD, et al.
A Phase I study of arsenic trioxide (Trisenox), ascorbic acid, and bortezomib (Velcade) combination therapy in patients with relapsed/refractory multiple myeloma.
Cancer Invest. 2013; 31(3):172-6 [PubMed]
PURPOSE: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade™) (AAV) for patients with relapsed/refractory multiple myeloma.
EXPERIMENTAL DESIGN: ATO (0.25 mg/kg) and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m(2) or 1.3 mg/m(2) IV bolus on days 1 and 8 of a 21-day cycle). Results: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered.
CONCLUSION: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population.


Hsu WL, Preston DL, Soda M, et al.
The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950-2001.
Radiat Res. 2013; 179(3):361-82 [PubMed]
A marked increase in leukemia risks was the first and most striking late effect of radiation exposure seen among the Hiroshima and Nagasaki atomic bomb survivors. This article presents analyses of radiation effects on leukemia, lymphoma and multiple myeloma incidence in the Life Span Study cohort of atomic bomb survivors updated 14 years since the last comprehensive report on these malignancies. These analyses make use of tumor- and leukemia-registry based incidence data on 113,011 cohort members with 3.6 million person-years of follow-up from late 1950 through the end of 2001. In addition to a detailed analysis of the excess risk for all leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia (neither of which appear to be radiation-related), we present results for the major hematopoietic malignancy types: acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, Hodgkin and non-Hodgkin lymphoma and multiple myeloma. Poisson regression methods were used to characterize the shape of the radiation dose-response relationship and, to the extent the data allowed, to investigate variation in the excess risks with gender, attained age, exposure age and time since exposure. In contrast to the previous report that focused on describing excess absolute rates, we considered both excess absolute rate (EAR) and excess relative risk (ERR) models and found that ERR models can often provide equivalent and sometimes more parsimonious descriptions of the excess risk than EAR models. The leukemia results indicated that there was a nonlinear dose response for leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia, which varied markedly with time and age at exposure, with much of the evidence for this nonlinearity arising from the acute myeloid leukemia risks. Although the leukemia excess risks generally declined with attained age or time since exposure, there was evidence that the radiation-associated excess leukemia risks, especially for acute myeloid leukemia, had persisted throughout the follow-up period out to 55 years after the bombings. As in earlier analyses, there was a weak suggestion of a radiation dose response for non-Hodgkin lymphoma among men, with no indication of such an effect among women. There was no evidence of radiation-associated excess risks for either Hodgkin lymphoma or multiple myeloma.


Kortuem KM, Stewart AK
Carfilzomib.
Blood. 2013; 121(6):893-7 [PubMed]
This spotlight review focuses on the second-generation proteasome inhibitor carfilzomib, which was recently approved by the U.S. Food and Drug Administration for treatment of relapsed and refractory multiple myeloma patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. This review focuses on clinical trial data leading to drug approval and provides advice for treating physicians who are now accessing this drug for patients.


Seki R, Yamagishi S, Matsui T, et al.
Pigment epithelium-derived factor (PEDF) inhibits survival and proliferation of VEGF-exposed multiple myeloma cells through its anti-oxidative properties.
Biochem Biophys Res Commun. 2013; 431(4):693-7 [PubMed]
Vascular endothelial growth factor (VEGF) has been reported not only to induce angiogenesis within the bone marrow, but also directly stimulate the proliferation and survival of multiple myeloma cells, thus being involved in the development and progression of this second most common hematological malignancy. We, along with others, have found that pigment epithelium-derived factor (PEDF) has anti-angiogenic and anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of VEGF. However, effects of PEDF on VEGF-exposed myeloma cells remain unknown. In this study, we examined whether and how PEDF could inhibit the VEGF-induced proliferation and survival of myeloma cells. PEDF, a glutathione peroxidase mimetic, ebselen, or an inhibitor of NADPH oxidase, diphenylene iodonium significantly inhibited the VEGF-induced reactive oxygen species (ROS) generation, increase in anti-apoptotic and growth-promoting factor, myeloid cell leukemia 1 (Mcl-1) expression, and proliferation in U266 myeloma cells. VEGF blocked apoptosis of multiple myeloma cells isolated from patients, which was prevented by PEDF. PEDF also reduced p22phox levels in VEGF-exposed U266 cells. Furthermore, overexpression of dominant-negative human Rac-1 mutant mimicked the effects of PEDF on ROS generation and Mcl-1 expression in U266 cells. Our present study suggests that PEDF could block the VEGF-induced proliferation and survival of multiple myeloma U266 cells through its anti-oxidative properties via suppression of p22phox, one of the membrane components of NADPH oxidase. Suppression of VEGF signaling by PEDF may be a novel therapeutic target for multiple myeloma.


Wolniak KL, Goolsby CL, Chen YH, et al.
Expansion of a clonal CD8+CD57+ large granular lymphocyte population after autologous stem cell transplant in multiple myeloma.
Am J Clin Pathol. 2013; 139(2):231-41 [PubMed]
Clonal expansions of large granular lymphocytes (LGLs) have been identified in patients following stem cell transplants and may represent posttransplant LGL leukemias or reactive immune responses. To differentiate between these 2 possibilities, we assessed peripheral blood and bone marrow of patients with myeloma after autologous stem cell transplant. All patients examined shortly after autologous stem cell transplant had significant increases in the LGLs in the peripheral blood and bone marrow (71% of lymphocytes) as compared with controls (39%). This increase was detectable years after transplant. The LGLs had a reproducible immunophenotype of CD8+CD57+ T cells without phenotypic abnormalities in 19 of 20 patients. Sixty-five percent of the post-autologous stem cell transplant patients had clonal T-cell receptor gene rearrangements in the bone marrow, yet no patients had neutropenia or splenomegaly. Although the LGL expansions were clonal and persistent, the lack of clinical sequelae suggests the clonal LGL expansion is a reactive, potentially beneficial, immune response to autologous stem cell transplant.


Bhaskar A, Gupta R, Sreenivas V, et al.
Synergistic effect of vascular endothelial growth factor and angiopoietin-2 on progression free survival in multiple myeloma.
Leuk Res. 2013; 37(4):410-5 [PubMed]
Bone marrow neoangiogenesis plays an important role in multiple myeloma (MM) and depends on the interplay of angiogenic cytokines. We investigated the levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin (Ang)-1, Ang-2 and hypoxia inducible factor-1 alpha (HiF-1α) in MM patients and their association with treatment outcome. Serum levels and mRNA expression of VEGF, Ang-2, Ang-1, bFGF and HiF-1α were evaluated in 71 MM patients using enzyme-linked immunosorbent assay and reverse transcriptase polymerase chain reaction. In multivariate Cox regression analysis, serum levels of VEGF≥756 pg/ml (HR 2.2, 95% CI 1.02-4.91; p=0.045) and relative mRNA expression levels of Ang-2≥0.93 (HR 21.0, 95% CI 6.27-70.45; p<0.001) were predictive of inferior progression free survival (PFS) and patients with concomitant increase in VEGF and Ang-2 had poor outcome compared to the rest of the patients (HR 32.6, 95% CI 7.20-148.36; p<0.001). These results suggest that VEGF and Ang-2 act in synergy and their expression levels at presentation are predictive of PFS in MM.


Benson DM
Can NKT cells extinguish smoldering myeloma?
Blood. 2013; 121(3):418-20 [PubMed]
One of the greatest challenges in all of medicine is to improve on the life of an asymptomatic patient; however, in this issue of Blood, Richter and colleagues share provocative new data taking steps toward accomplishing this goal.


Zhou W, Yang Y, Xia J, et al.
NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers.
Cancer Cell. 2013; 23(1):48-62 [PubMed]
Using sequential gene expression profiling (GEP) samples, we defined a major functional group related to drug resistance that contains chromosomal instability (CIN) genes. One CIN gene in particular, NEK2, was highly correlated with drug resistance, rapid relapse, and poor outcome in multiple cancers. Overexpressing NEK2 in cancer cells resulted in enhanced CIN, cell proliferation and drug resistance, while targeting NEK2 by NEK2 shRNA overcame cancer cell drug resistance and induced apoptosis in vitro and in a xenograft myeloma mouse model. High expression of NEK2 induced drug resistance mainly through activation of the efflux pumps. Thus, NEK2 represents a strong predictor for drug resistance and poor prognosis in cancer and could be an important target for cancer therapy.


Tesfay MZ, Kirk AC, Hadac EM, et al.
PEGylation of vesicular stomatitis virus extends virus persistence in blood circulation of passively immunized mice.
J Virol. 2013; 87(7):3752-9 [PubMed] Article available free on PMC after 01/10/2013
We are developing oncolytic vesicular stomatitis viruses (VSVs) for systemic treatment of multiple myeloma, an incurable malignancy of antibody-secreting plasma cells that are specifically localized in the bone marrow. One of the presumed advantages for using VSV as an oncolytic virus is that human infections are rare and preexisting anti-VSV immunity is typically lacking in cancer patients, which is very important for clinical success. However, our studies show that nonimmune human and mouse serum can neutralize clinical-grade VSV, reducing the titer by up to 4 log units in 60 min. In addition, we show that neutralizing anti-VSV antibodies negate the antitumor efficacy of VSV, a concern for repeat VSV administration. We have investigated the potential use of covalent modification of VSV with polyethylene glycol (PEG) or a function-spacer-lipid (FSL)-PEG construct to inhibit serum neutralization and to limit hepatosplenic sequestration of systemically delivered VSV. We report that in mice passively immunized with neutralizing anti-VSV antibodies, PEGylation of VSV improved the persistence of VSV in the blood circulation, maintaining a more than 1-log-unit increase in VSV genome copies for up to 1 h compared to the genome copy numbers for the non-PEGylated virus, which was mostly cleared within 10 min after intravenous injection. We are currently investigating if this increase in PEGylated VSV circulating half-life can translate to increased virus delivery and better efficacy in mouse models of multiple myeloma.


Surovy AM, Pelivani N, Hegyi I, et al.
Giant cellulitis-like Sweet Syndrome, a new variant of neutrophilic dermatosis.
JAMA Dermatol. 2013; 149(1):79-83 [PubMed]
BACKGROUND: Neutrophilic dermatoses comprise a wide spectrum of inflammatory diseases with overlapping features characterized histologically by the presence of an aseptic neutrophilic infiltrate in the epidermis, dermis, and/or hypodermis and are often associated with systemic inflammatory and neoplastic disorders.
OBSERVATIONS: We describe 3 patients with an unusual neutrophilic dermatosis characterized by relapsing episodes of fever, widespread infiltrated plaques with bullous appearance, and variable involvement of the arms, legs, abdomen, and/or trunk. Light microscopy studies showed marked edema of the papillary dermis with an inflammatory infiltrate consisting mainly of mature neutrophils. All 3 patients were morbidly obese, and workup revealed underlying cancer in 2 cases: myeloma and breast carcinoma. Management of the underlying disease resulted in long-term remission of the skin disease.
CONCLUSIONS: The clinicopathologic features in our 3 cases best correspond to a widespread giant cellulitis-like form of Sweet syndrome. Knowledge of this newly observed unusual variant of Sweet syndrome within the broad spectrum of neutrophilic diseases is important for its prompt and proper management.


Fujiwara S, Kawano Y, Yuki H, et al.
PDK1 inhibition is a novel therapeutic target in multiple myeloma.
Br J Cancer. 2013; 108(1):170-8 [PubMed] Article available free on PMC after 01/10/2013
BACKGROUND: Cancer cells utilise the glycolytic pathway even when adequate oxygen is present, a phenomenon known as the Warburg effect. We examined whether this system is operative in multiple myeloma (MM) cells and whether glycolysis inhibition is a potential therapeutic modality.
METHODS: The MM cells were purified from 59 patients using CD138-immunomagnetic beads. The expression levels of genes associated with glycolysis, c-MYC, GLUT1, LDHA, HIF1A and pyruvate dehydrogenase kinase-1 (PDK1) were determined by real-time PCR. Glucose consumption and lactate production by MM cell lines were analysed. Oxamate, an LDH inhibitor, and dichloroacetate (DCA), a PDK1 inhibitor, were employed. Inhibition of PDK1 expression was achieved using a siRNA.
RESULTS: High LDHA expression was found to be an indicator of poor prognosis. It was also positively correlated with the expression of PDK1, c-MYC and GLUT1. Greater glucose consumption and lactate production in MM cells was associated with higher LDHA expression. All the glycolysis inhibitors (oxamate, DCA and PDK1 siRNA) induced apoptosis in MM cells. DCA combined with bortezomib showed additive cytotoxic effects.
CONCLUSION: The present data suggest that the Warburg effect is operative in MM cells. As PDK1 is not overexpressed in normal tissues, PDK1 inhibition could serve as a novel therapeutic approach.


Leleu X, Attal M, Arnulf B, et al.
Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02.
Blood. 2013; 121(11):1968-75 [PubMed]
The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).


Usmani SZ, Mitchell A, Waheed S, et al.
Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3.
Blood. 2013; 121(10):1819-23 [PubMed] Article available free on PMC after 07/03/2014
Prognostic implications of 3 imaging tools, metastatic bone survey, magnetic resonance imaging, and positron emission tomography (PET), were evaluated in 2 consecutive Total Therapy 3 trials for newly diagnosed myeloma. Data including PET at baseline and on day 7 of induction as well as standard prognostic factors were available in 302 patients of whom 277 also had gene expression profiling (GEP)-derived risk information. According to multivariate analysis, more than 3 focal lesions on day 7 imparted inferior overall survival and progression-free survival, overall and in the subset with GEP-risk data. GEP high-risk designation retained independent significance for all 3 end points examined. Thus, the presence of > 3 focal lesions on day 7 PET follow-up may be exploited toward early therapy change, especially for the 15% of patients with GEP-defined high-risk disease with a median overall survival expectation of 2 years. This trial was registered at www.clinicaltrials.gov as #NCT00081939 and # NCT00572169.


Sayed D, Al-Sadoon MK, Badr G
Silica nanoparticles sensitize human multiple myeloma cells to snake (Walterinnesia aegyptia) venom-induced apoptosis and growth arrest.
Oxid Med Cell Longev. 2012; 2012:386286 [PubMed] Article available free on PMC after 07/03/2014
BACKGROUND: Multiple myeloma (MM), an almost incurable disease, is the second most common blood cancer. Initial chemotherapeutic treatment could be successful; however, resistance development urges the use of higher toxic doses accompanied by hematopoietic stem cell transplantation. The establishment of more effective treatments that can overcome or circumvent chemoresistance has become a priority. We recently demonstrated that venom extracted from Walterinnesia aegyptia (WEV) either alone or in combination with silica nanoparticles (WEV+NPs) mediated the growth arrest and apoptosis of prostate cancer cells. In the present study, we evaluated the impact of WEV alone and WEV+NP on proliferation and apoptosis of MM cells.
METHODS: The impacts of WEV alone and WEV+NP were monitored in MM cells from 70 diagnosed patients. The influences of WEV and WEV+NP were assessed with flow cytometry analysis.
RESULTS: WEV alone and WEV+NP decreased the viability of MM cells. Using a CFSE proliferation assay, we found that WEV+NP strongly inhibited MM cell proliferation. Furthermore, analysis of the cell cycle using the propidium iodide (PI) staining method indicated that WEV+NP strongly altered the cell cycle of MM cells and enhanced the induction of apoptosis.
CONCLUSIONS: Our data reveal the biological effects of WEV and WEV+NP on MM cells that enable these compounds to function as effective treatments for MM.


Le Bourgeois A, Lestang E, Guillaume T, et al.
Prognostic impact of immune status and hematopoietic recovery before and after fludarabine, IV busulfan, and antithymocyte globulins (FB2 regimen) reduced-intensity conditioning regimen (RIC) allogeneic stem cell transplantation (allo-SCT).
Eur J Haematol. 2013; 90(3):177-86 [PubMed]
This retrospective analysis aimed to assess hematopoietic and immune recovery in a cohort of 53 patients [males: n = 33; median age: 59 yr (range: 22-70)] who received a FB2 (fludarabine 120-150 mg/m² + IV busulfan 6.4 mg/kg + antithymocyte globulin thymoglobulin 5 mg/kg) reduced-intensity conditioning (RIC) allo-stem cells transplantations (SCT). With a median follow-up of 19 months (range: 2-53), the 2-yr overall survival, disease-free survival (DFS), relapse incidence, and non-relapse mortality were 63%, 59.5%, 35%, and 6%, respectively. In univariate analysis, the factors correlated with a significantly higher 2-yr OS and DFS were a higher total circulating lymphocytes count at transplant (>730/mm(3) ; OS: 81% vs. 43%, P = 0.02; DFS: 73% vs. 45.5%, P = 0.03) and a higher recovery of leukocytes (>5300/mm(3) ) (2-yr OS: 81% vs. 44%, P = 0.007; 2-yr DFS: 72% vs. 46%, P = 0.08), neutrophils (>3200/mm(3) ) (2-yr OS: 76% vs. 50%, P = 0.03; 2-yr DFS: 67% vs. 52.0%, P = 0.1), and monocytes (>590/mm(3) ; 2-yr OS: 80% vs. 45%, P = 0.004; 2-yr DFS: 76% vs. 42%, P = 0.01) at day +30 post-transplant. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm(3) ) and a higher monocytes count (>590/mm(3) ) at day +30 post-transplant. These results suggest that immune status and hematopoietic recovery before and after FB2 RIC allo-SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo-SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo-SCT.


Rossi A, Mark T, Jayabalan D, et al.
BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma.
Blood. 2013; 121(11):1982-5 [PubMed] Article available free on PMC after 14/03/2014
The combination of clarithromycin, lenalidomide, and dexamethasone (BiRd) was evaluated as therapy for treatment-naive symptomatic multiple myeloma (MM), with overall response at 2 years of 90%. We reviewed the long-term follow-up of initial BiRd therapy. Seventy-two patients were given dexamethasone 40 mg weekly, clarithromycin 500 mg twice daily, and lenalidomide 25 mg daily on days 1 to 21 of a 28-day cycle. After a median follow-up of 6.6 years, overall response rates were 93%, with a very good partial response or better of 68%. Median progression-free survival was 49 months. Evaluation for the development of second primary malignancies (SPMs) was conducted, and no increase in incidence was noted in our cohort of patients who received frontline immunomodulatory therapy. BiRd remains a highly potent and safe regimen for frontline therapy in patients with MM without apparent increase in risk of SPMs. This trial was registered at www.clinicaltrials.gov as #NCT00151203.


Stewart AK, Trudel S, Bahlis NJ, et al.
A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial.
Blood. 2013; 121(9):1517-23 [PubMed] Article available free on PMC after 28/02/2014
We conducted a randomized, controlled trial comparing thalidomide-prednisone as maintenance therapy with observation in 332 patients who had undergone autologous stem cell transplantation with melphalan 200 mg/m2. The primary end point was overall survival (OS); secondary end points were myeloma-specific progression-free survival,progression-free survival, incidence of venous thromboembolism, and health-related quality of life (HRQoL). With a median follow-up of 4.1 years, no differences in OS between thalidomide-prednisone and observation were detected (respective 4-year estimates of 68% vs 60%, respectively; hazard ratio = 0.77; P = .18); thalidomide-prednisone was associated with superior myeloma-specific progression-free survival and progression-free survival (for both outcomes, the 4-year estimates were 32% vs 14%; hazard ratio = 0.56; P < .0001) and more frequent venous thromboembolism (7.3% vs none; P = .0004). Median survival after first disease recurrence was 27.7 months with thalidomide-prednisone and 34.1 months in the observation group. Nine second malignancies were observed with thalidomide-prednisone versus 6 in the observation group. Those allocated to thalidomide-prednisone reported worse HRQoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems. We conclude that maintenance therapy with thalidomide-prednisone after autologous stem cell transplantation improves the duration of disease control, but is associated with worsening of patient-reported HRQoL and no detectable OS benefit.


Petrucci MT, Giraldo P, Corradini P, et al.
A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma.
Br J Haematol. 2013; 160(5):649-59 [PubMed]
Multiple myeloma (MM) typically follows a relapsing course with many patients requiring multiple therapies. This single-arm phase 2 study prospectively evaluated the efficacy and safety of bortezomib retreatment in MM patients who had relapsed after achieving at least a partial response (≥ PR) to prior bortezomib-based therapy. Patients aged ≥ 18 years, with measurable, secretory MM, who relapsed ≥ 6 months after prior bortezomib treatment were eligible. Patients received up to eight cycles of bortezomib (± dexamethasone). The primary endpoint was best confirmed response at retreatment; secondary endpoints included duration of response (DOR), time to progression (TTP), and safety. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. A total of 130 patients (median of two prior lines of therapy) were enrolled and received retreatment. At retreatment, 28% and 72% of patients received bortezomib and bortezomib-dexamethasone, respectively. Overall response rate was 40%. In patients who achieved ≥ PR, median DOR and TTP were 6.5 and 8.4 months, respectively. Thrombocytopenia was the most common grade ≥ 3 AE (35%). Forty percent of patients experienced neuropathy events, which improved and resolved in a median of 1.5 and 8.9 months, respectively. In conclusion, bortezomib retreatment was effective and tolerable in relapsed MM patients, with no evidence of cumulative toxicities.


Suzuki K
Current therapeutic strategy for multiple myeloma.
Jpn J Clin Oncol. 2013; 43(2):116-24 [PubMed]
This is a review regarding the current therapeutic strategies in the management of multiple myeloma. Due to the introduction of several new effective therapeutic agents, multiple myeloma is one of the most active and changing fields in clinical oncology. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chain). High-dose chemotherapy supported with autologous peripheral blood stem cells is an effective treatment for the disease. However, multiple myelomas are still difficult to cure and require long-term disease control. In recent years, the introduction of novel drugs (bortezomib, lenalidomide and thalidomide) has improved treatment.


Uherková L, Vančurová I, Vyhlídalová I, et al.
Novel human multiple myeloma cell line UHKT-893.
Leuk Res. 2013; 37(3):320-6 [PubMed]
UNLABELLED: We established and characterized a new IL-6 dependent multiple myeloma (MM) cell line UHKT-893 from the bone marrow of a relapsed 57-year-old woman.
RESULTS: Using nephelometry, cells with plasma cell phenotype and morphology were found to secrete IgG and free kappa (κ)-light chain of immunoglobulin. κ-Light chain was also recognized intracellularly by flow cytometry and by mass spectrometry. VH4-39 region of IgVH genes was rearranged and somatically hypermutated. Cytogenetic analysis of cells revealed new chromosome abnormalities in all breakpoints unique in both MM patients and cell lines - t(1;6), t(1;11), t(5;15), t(5;21), +der(11;15) and der(16). IL-6 independent subline UHKT-893a was established by adaptation to descending IL-6 concentration, while the original cell line keeps on maintaining its IL-6 dependency.
CONCLUSION: The cell line provides a suitable material for cellular and molecular studies of tumor abnormalities, with potentially unique mutagenic features of myeloma disease. It may be utilized for human hybridoma construction and vaccine development. Both IL-6 dependent and independent cell clones represent an important model for studies of myeloma cell growth and resistance emerging during targeted therapy.


Dolloff NG, Talamo G
Targeted therapy of multiple myeloma.
Adv Exp Med Biol. 2013; 779:197-221 [PubMed]
Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematologic cancer. MM is characterized by the accumulation of malignant plasma cells within the bone marrow, and presents clinically with a broad range of symptoms, including hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM is a heterogeneous disease associated with genomic instability, where patients may express multiple genetic abnormalities that affect several oncogenic pathways. Commonly detected genetic aberrations are translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)]. Advances in the basic understanding of MM and the development of novel agents, such as the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib, have increased therapeutic response rates and prolonged patient survival. Despite these advances MM remains incurable in the majority of patients, and it is therefore critical to identify additional therapeutic strategies and targets for its treatment. In this chapter, we review the underlying genetic components of MM and discuss the results of recent clinical trials that demonstrate the effectiveness of targeted agents in the management of MM. In addition, we discuss experimental therapies that are currently in clinical development along with their molecular rationale in the treatment of MM.


This page last updated: 22nd May 2013
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