Myeloma
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Myeloma (also known as myelomatosis or multiple 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. Myeloma is most common in people aged over 60, and is rare before the age of 40.

In 2010, 4,672 people in the UK were diagnosed with myeloma (Source: Cancer Research UK)

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Latest Research Publications

Information Patients and the Public (8 links)


Information for Health Professionals / Researchers (4 links)

Latest Research Publications

Showing publications with corresponding authors from the UK (Source: PubMed).

Chaidos A, Barnes CP, Cowan G, et al.
Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma.
Blood. 2013; 121(2):318-28 [PubMed]
The phenotype and function of cells enriched in tumor-propagating activity and their relationship to the phenotypic architecture in multiple myeloma (MM) are controversial. Here, in a cohort of 30 patients, we show that MM composes 4 hierarchically organized, clonally related subpopulations, which, although phenotypically distinct, share the same oncogenic chromosomal abnormalities as well as immunoglobulin heavy chain complementarity region 3 area sequence. Assessed in xenograft assays, myeloma-propagating activity is the exclusive property of a population characterized by its ability for bidirectional transition between the dominant CD19(-)CD138(+) plasma cell (PC) and a low frequency CD19(-)CD138(-) subpopulation (termed Pre-PC); in addition, Pre-PCs are more quiescent and unlike PCs, are primarily localized at extramedullary sites. As shown by gene expression profiling, compared with PCs, Pre-PCs are enriched in epigenetic regulators, suggesting that epigenetic plasticity underpins the phenotypic diversification of myeloma-propagating cells. Prospective assessment in paired, pretreatment, and posttreatment bone marrow samples shows that Pre-PCs are up to 300-fold more drug-resistant than PCs. Thus, clinical drug resistance in MM is linked to reversible, bidirectional phenotypic transition of myeloma-propagating cells. These novel biologic insights have important clinical implications in relation to assessment of minimal residual disease and development of alternative therapeutic strategies in MM.
Centre for Haematology, Department of Medicine, Imperial College London, London


Buckle CH, De Leenheer E, Lawson MA, et al.
Soluble rank ligand produced by myeloma cells causes generalised bone loss in multiple myeloma.
PLoS One. 2012; 7(8):e41127 [PubMed] Free Access to Full Article
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 demonstrate that soluble RANKL produced by myeloma cells causes generalised bone loss, suggesting that targeting RANKL may prevent osteoporosis in patients with myeloma.
Department of Human Metabolism, University of Sheffield Faculty of Medicine, Dentistry and Health, Sheffield


Haynes R, Leung N, Kyle R, Winearls CG
Myeloma kidney: improving clinical outcomes?
Adv Chronic Kidney Dis. 2012; 19(5):342-51 [PubMed]
Renal impairment is a common complication of multiple myeloma, affecting 20% to 40% of new cases (depending on the definition). Most cases are mild and easily reversible, but it may manifest as severe acute renal injury requiring dialysis. Renal impairment is associated with a large tumor mass and consequently confers a poor prognosis. The prognosis of myeloma has improved with the introduction of novel agents and autologous stem cell transplantation. These improvements appear to apply equally to patients with renal impairment, although the risk of complication is usually higher in this group of patients. In addition to improved overall survival, there is some evidence that novel therapies have improved the renal prognosis. Treatment with high-dose dexamethasone and bortezomib can rapidly reduce light chain production and provide an opportunity for renal recovery. Although trials of plasma exchange (to remove the nephrotoxic light chain) have shown a disappointing lack of benefit, high cutoff dialysis removes larger quantities of light chain; therefore, trials are underway to investigate whether this can improve the renal prognosis independently of chemotherapy. Outcomes in patients with myeloma kidney do appear to be improving, but more trials are needed (some of which are in progress). There is cause for optimism for physicians and for patients suffering from this condition.
Oxford Kidney Unit, Churchill Hospital, Oxford


Stringer S, Cook M, Cockwell P
Achieving an early myeloma response in patients with kidney impairment.
Adv Chronic Kidney Dis. 2012; 19(5):303-11 [PubMed]
There is increasing evidence, particularly in severe acute kidney injury, that treatment of multiple myeloma with regimens that include dexamethasone in combination with novel chemotherapy agents are associated with an early disease response in most patients. However, the evidence to guide the optimal chemotherapy regimen in patients with kidney impairment is limited, and treatment choices are complicated by the effect of kidney function on drug dosing. Here, we summarize the current status of this field, with a particular focus on chemotherapy regimens that are based on dexamethasone and novel agents and an outline of those areas in which further work is needed to improve the evidence base.
School of Immunity and Infection, University of Birmingham, Edgbaston, and Department of Nephrology, Queen Elizabeth Hospital Birmingham, Birmingham


Lachmann HJ, Wassef NL
The role of immunological assessment in patients with acute kidney injury and possible myeloma.
Adv Chronic Kidney Dis. 2012; 19(5):287-90 [PubMed]
Acute kidney injury (AKI) in plasma cell multiple myeloma (MM) is a medical emergency requiring a rapid, accurate diagnosis because prompt commencement of therapy and supportive care are essential. Most cases of AKI in MM are caused by cast nephropathy secondary to high levels of nephrotoxic serum free light chains (FLCs). This article reviews the role and relevance of FLC as an immunological biomarker for AKI and MM. We discuss the utility of FLC measurement as a screening tool in the cast nephropathy clinical setting. We present its analytical pitfalls and evolving evidence for the integration of an FLC assay into clinical algorithms.
National Amyloidosis Centre, University College London Medical School, London


Feyler S, Scott GB, Parrish C, et al.
Tumour cell generation of inducible regulatory T-cells in multiple myeloma is contact-dependent and antigen-presenting cell-independent.
PLoS One. 2012; 7(5):e35981 [PubMed] Free Access to Full Article
Regulatory T-cells (T(Reg) cells) are increased in patients with multiple myeloma (MM). We investigated whether MM cells could generate and/or expand T(Reg) cells as a method of immuno-surveillance avoidance. In an in vitro model, CD4(+)CD25(-)FoxP3(-) T-cells co-cultured with malignant plasma cells (primary MM cells and cell lines) induced a significant generation of CD4(+)CD25(+)FoxP3(+) inducible T(Reg) cells (tT(Reg) cells; p<0.0001), in a contact-dependent manner. tT(Reg) cells were polyclonal, demonstrated a suppressive phenotype and phenotypically, demonstrated increased FoxP3 (p = 0.0001), increased GITR (p<0.0001), increased PD1 (p = 0.003) and decreased CD62L (p = 0.007) expression compared with naturally occurring T(Reg) cells. FACS-sorted tT(Reg) cells differentiated into FoxP(+)IL-17(+) and FoxP3(-)IL-17(+) CD4(+) cells upon TCR-mediated stimulation. Blocking experiments with anti-ICOS-L MoAb resulted in a significant inhibition of tT(Reg) cell generation whereas both IL-10 & TGFβ blockade did not. MM tumour cells can directly generate functional T(Reg) cells in a contact-dependent manner, mediated by ICOS/ICOS-L. These features suggest that tumour generation of T(Reg) cells may contribute to evasion of immune surveillance by the host.
Transplant Immunology Group, Academic Department of Haematology and Oncology, University of Leeds, Leeds


Vitovski S, Chantry AD, Lawson MA, Croucher PI
Targeting tumour-initiating cells with TRAIL based combination therapy ensures complete and lasting eradication of multiple myeloma tumours in vivo.
PLoS One. 2012; 7(5):e35830 [PubMed] Free Access to Full Article
Multiple myeloma (MM) remains an incurable disease despite improvements to available treatments and efforts to identify new drug targets. Consequently new approaches are urgently required. We have investigated the potential of native tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with doxorubicin, to induce apoptotic cell death in phenotypically distinct populations of myeloma cells in vitro and in vivo. The cytotoxic potential of TRAIL alone, and in combination with DOX, was assessed in vitro in purified CD138(+) and CD138(-) cells from the MM cell lines and samples from patients with MM. Mouse xenografts obtained by implanting CD138(-) MM cells were used to assess the efficacy of TRAIL, alone and in combination with DOX, in vivo. CD138(-) cells were shown to be more resistant to the cytotoxic activity of TRAIL than CD138(+) cells and have reduced expression of TRAIL death receptors. This resistance results in preferential killing of CD 138(+) cells during exposure of MM culture to TRAIL. Furthermore, prolonged exposure results in the appearance of TRAIL-resistant CD138(-) cells. However, when TRAIL is combined with doxorubicin, this results in complete eradication of MM cells in vivo. Most importantly, this treatment successfully eliminates CD138(-) cells implicated in tumour initiation and growth maintenance. These findings may explain the failure of current therapies and offer a promising new approach in the quest to cure MM and disseminated cancers.
The Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield Medical School, Sheffield


Morgan GJ, Davies FE, Gregory WM, et al.
Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial.
Blood. 2012; 119(23):5374-83 [PubMed]
The Medical Research Council Myeloma IX Trial (ISRCTNG8454111) examined traditional and thalidomide-based induction and maintenance regimens and IV zoledronic acid (ZOL) and oral clodronate (CLO) in 1960 patients with newly diagnosed multiple myeloma. Overall survival (OS) and skeletal-related event (SRE) data have been reported for the overall trial population. The present analysis investigated optimal therapy regimens for different patient populations in Myeloma IX. Patients were assigned to intensive or nonintensive treatment pathways and randomized to induction cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) versus cyclophosphamide, thalidomide, and dexamethasone (CTD; intensive) or melphalan and prednisolone versus attenuated oral CTD (CTDa; nonintensive). Patients were also randomized to ZOL or CLO. In the nonintensive pathway, CTDa produced better responses and lower SRE rates than melphalan and prednisolone. ZOL improved OS compared with CLO independently of sex, stage, or myeloma subtype, most profoundly in patients with baseline bone disease or other SREs. In patients treated for ≥ 2 years, ZOL improved OS compared with CLO from randomization (median not reached for either; P = .02) and also from first on-study disease progression (median, 34 months for ZOL vs 27 months for CLO; P = .03). Thalidomide-containing regimens had better efficacy than traditional regimens, and ZOL demonstrated greater benefits than CLO.
The Institute of Cancer Research, Royal Marsden National Health Service Foundation Trust, London
Research funded by:


Morgan GJ, Gregory WM, Davies FE, et al.
The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis.
Blood. 2012; 119(1):7-15 [PubMed]
Thalidomide maintenance has the potential to modulate residual multiple myeloma (MM) after an initial response. This trial compared the effect of thalidomide maintenance and no maintenance on progression-free survival (PFS) and overall survival (OS) in MM patients. After intensive or nonintensive induction therapy, 820 newly diagnosed MM patients were randomized to open-label thalidomide maintenance until progression, or no maintenance. Interphase FISH (iFISH) analysis was performed at study entry. Median PFS was significantly longer with thalidomide maintenance (log-rank P < .001). Median OS was similar between regimens (log-rank P = .40). Patients with favorable iFISH showed improved PFS (P = .004) and a trend toward a late survival benefit. Patients with adverse iFISH receiving thalidomide showed no significant PFS benefit and worse OS (P = .009). Effective relapse therapy enhanced survival after progression, translating into a significant OS benefit. Meta-analysis of this and other studies show a significant late OS benefit (P < .001, 7-year difference hazard ratio = 12.3; 95% confidence interval, 5.5-19.0). Thalidomide maintenance significantly improves PFS and can be associated with improved OS. iFISH testing is important in assessing the clinical impact of maintenance therapy. Overview analysis demonstrated that thalidomide maintenance was associated with a significant late OS benefit. This trial was registered at www.isrctn.org as #ISRCTN68454111.
Institute of Cancer Research, Royal Marsden Hospital, London


Boyd KD, Ross FM, Walker BA, et al.
Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival.
Clin Cancer Res. 2011; 17(24):7776-84 [PubMed]
PURPOSE: Regions on 1p with recurrent deletions in presenting myeloma patients were examined with the purpose of defining the deletions and assessing their survival impact.
EXPERIMENTAL DESIGN: Gene mapping, gene expression, FISH, and mutation analyses were conducted on patient samples from the MRC Myeloma IX trial and correlated with clinical outcome data.
RESULTS: 1p32.3 was deleted in 11% of cases, and deletion was strongly associated with impaired overall survival (OS) in patients treated with autologous stem cell transplant (ASCT). In patients treated less intensively, del(1)(p32.3) was not associated with adverse progression-free survival (PFS) or OS. The target of homozygous deletions was CDKN2C, however its role in the adverse outcome of cases with hemizygous deletion was less certain. 1p22.1-21.2 was the most frequently deleted region and contained the candidate genes MTF2 and TMED5. No mutations were identified in these genes. 1p12 was deleted in 19% of cases, and deletion was associated with impaired OS in univariate analysis. The target of homozygous deletion was FAM46C, which was mutated in 3.4% of cases. When cases with FAM46C deletion or mutation were considered together, they were strongly associated with impaired OS in the intensive treatment setting.
CONCLUSION: Deletion of 1p32.3 and 1p12 was associated with impaired OS in myeloma patients receiving ASCT. FAM46C was identified as a gene with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations.
The Institute of Cancer Research, Haemato-oncology Research Unit, Division of Molecular Pathology, London


Boyd KD, Ross FM, Tapper WJ, et al.
The clinical impact and molecular biology of del(17p) in multiple myeloma treated with conventional or thalidomide-based therapy.
Genes Chromosomes Cancer. 2011; 50(10):765-74 [PubMed]
Hemizygous deletion of 17p (del(17p)) has been identified as a variable associated with poor prognosis in myeloma, although its impact in the context of thalidomide therapy is not well described. The clinical outcome of 85 myeloma patients with del(17p) treated in a clinical trial incorporating both conventional and thalidomide-based induction therapies was examined. The clinical impact of deletion, low expression, and mutation of TP53 was also determined. Patients with del(17p) did not have inferior response rates compared to patients without del(17p), but, despite this, del(17p) was associated with impaired overall survival (OS) (median OS 26.6 vs. 48.5 months, P < 0.001). Within the del(17p) group, thalidomide induction therapy was associated with improved response rates compared to conventional therapy, but there was no impact on OS. Thalidomide maintenance was associated with impaired OS, although our analysis suggests that this effect may have been due to confounding variables. A minimally deleted region on 17p13.1 involving 17 genes was identified, of which only TP53 and SAT2 were underexpressed. TP53 was mutated in <1% in patients without del(17p) and in 27% of patients with del(17p). The higher TP53 mutation rate in samples with del(17p) suggests a role for TP53 in these clinical outcomes. In conclusion, del(17p) defined a patient group associated with short survival in myeloma, and although thalidomide induction therapy was associated with improved response rates, it did not impact OS, suggesting that alternative therapeutic strategies are required for this group.
The Institute of Cancer Research, Section of Haemato-Oncology, London
Research funded by:


Katodritou E, Terpos E, North J, et al.
Tumor-primed natural killer cells from patients with multiple myeloma lyse autologous, NK-resistant, bone marrow-derived malignant plasma cells.
Am J Hematol. 2011; 86(12):967-73 [PubMed]
Natural killer (NK) cells are cytotoxic lymphocytes able to kill tumor cells and virus-infected cells. Human-resting NK cells can be activated by co-culture with NK-resistant CTV-1a cells. These tumor-activated cells (TaNKs) are cytotoxic to a range of NK-resistant tumor cells in vitro. This potential, however, has not been explored in multiple myeloma (MM). In this study, we demonstrate that TaNK cells from 21 MM patients lyse a variety of myeloma targets, including primary isolates of autologous and allogeneic CD138+ myeloma cells whilst sparing CD138-ve bone marrow cells. Myeloma patients' TaNK-induced lysis of the U266 cell line was significantly higher compared to normal controls (median-specific lysis 79.1% vs. 69.5%) (P = 0.003). In addition, TaNKs induced substantial lysis of autologous and allogeneic CD138+ myeloma cells (median-specific lysis 52.5% and 37.4%, respectively). The percentage of specific lysis did not correlate with important disease characteristics (ISS, age, and high-risk molecular abnormalities) or with the disease status and antimyeloma treatment, including novel agents and dexamethasone. In conclusion, tumor-primed NK cells are able to induce substantial lysis of myeloma targets including autologous and allogeneic CD138+ myeloma plasma cells and could be an additional therapeutic approach in MM, particularly in the era of novel agents.
Department of Hematology, University College Medical School, London
Research funded by:


Wu P, Walker BA, Brewer D, et al.
A gene expression-based predictor for myeloma patients at high risk of developing bone disease on bisphosphonate treatment.
Clin Cancer Res. 2011; 17(19):6347-55 [PubMed]
PURPOSE: Myeloma bone disease impairs quality of life and is associated with impaired survival. Even with effective bisphosphonate treatment, a significant proportion of patients still develop skeletal-related events (SRE). Identifying such patients at presentation would allow treatment modification.
EXPERIMENTAL DESIGN: To investigate the molecular basis of bone disease at presentation and to develop a predictive signature for patients at high risk of developing SREs on bisphosphonates, 261 presenting myeloma samples were analyzed by global gene expression profiling. The derived "SRE gene signature" was complemented by the integration of associated clinical parameters to generate an optimal predictor.
RESULTS: Fifty genes were significantly associated with presenting bone disease, including the WNT signaling antagonist DKK1 and genes involved in growth factor signaling and apoptosis. Higher serum calcium level and the presence of bone disease and hyperdiploidy at presentation were associated with high risk of SRE development. A gene signature derived from the fourteen genes overexpressed in the SRE group was able to identify patients at high risk of developing an SRE on treatment. These genes either belonged to the IFN-induced family or were involved in cell signaling and mitosis. Multivariate logistic model selection yielded an optimal SRE predictor comprising seven genes and calcium level, which was validated as an effective predictor in a further set of patients.
CONCLUSIONS: The simple expression-based SRE predictor can effectively identify individuals at high risk of developing bone disease while being on bisphosphonates. This predictor could assist with developing future trials on novel therapies aimed at reducing myeloma bone disease.
Section of Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Sutton, Surrey
Research funded by:


Boyd KD, Ross FM, Chiecchio L, et al.
Gender disparities in the tumor genetics and clinical outcome of multiple myeloma.
Cancer Epidemiol Biomarkers Prev. 2011; 20(8):1703-7 [PubMed]
BACKGROUND: Several cancer types have differences in incidence and clinical outcome dependent on gender, but these are not well described in myeloma. The aim of this study was to characterize gender disparities in myeloma.
METHODS: We investigated the association of gender with the prevalence of tumor genetic lesions and the clinical outcome of 1,960 patients enrolled in the phase III clinical trial MRC Myeloma IX. Genetic lesions were characterized by FISH.
RESULTS: Disparities were found in the prevalence of primary genetic lesions with immunoglobulin heavy chain gene (IGH) translocations being more common in women (50% of female patients vs. 38% of male patients, P < 0.001) and hyperdiploidy being more common in men (50% female vs. 62% male, P < 0.001). There were also differences in secondary genetic events with del(13q) (52% female vs. 41% male, P < 0.001) and +1q (43% female vs. 36% male, P = 0.042) being found more frequently in female myeloma patients. Female gender was associated with inferior overall survival (median: 44.8 months female vs. 49.9 months male, P = 0.020).
CONCLUSIONS: We found gender-dependent differences in the prevalence of the primary genetic events of myeloma, with IGH translocations being more common in women and hyperdiploidy more common in men. This genetic background may impact subsequent genetic events such as +1q and del(13q), which were both more frequent in women. The higher prevalence of lesions associated with poor prognosis in the female myeloma population, such as t(4;14), t(14;16) and +1q, may adversely affect clinical outcome.
IMPACT: These differences suggest that gender influences the primary genetic events of myeloma.
The Institute of Cancer Research, Section of Haemato-Oncology, London
Research funded by:


Fayers PM, Palumbo A, Hulin C, et al.
Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials.
Blood. 2011; 118(5):1239-47 [PubMed]
The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.
Institute of Applied Health Sciences, University of Aberdeen, Aberdeen


Morgan GJ, Davies FE, Gregory WM, et al.
Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation.
Blood. 2011; 118(5):1231-8 [PubMed] Free Access to Full Article
As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.
Institute of Cancer Research, Royal Marsden Hospital, London
Research funded by:


Cook G, Liakopoulou E, Pearce R, et al.
Factors influencing the outcome of a second autologous stem cell transplant (ASCT) in relapsed multiple myeloma: a study from the British Society of Blood and Marrow Transplantation Registry.
Biol Blood Marrow Transplant. 2011; 17(11):1638-45 [PubMed]
Autologous stem cell transplant as primary (first ASCT) therapy in multiple myeloma (MM) is standard practice. The role of a second ASCT as management of relapsed disease remains uncertain. We conducted a retrospective case-matched control analysis on patients (n = 106) who underwent a second ASCT compared with conventional chemotherapy (CCT) as for relapsed MM. The median age was 53 years (range: 26-75) and median follow-up 48 months (range: 8, 136). The cumulative incidence of 1 and 5 years nonrelapse mortality (NRM) was 7% (95% confidence interval [CI] 3%-13%) and 12% (95% CI 7%-19%), with a second ASCT inducing a greater partial remission (PR) rate of 63%. The 4-year overall survival (OS) rate was 33% (95% CI 24%-45%). Factors associated with improved OS and progression-free survival (PFS) included younger age (<55 years), β(2)MG <2.5 mg/L at diagnosis, a remission duration of >9 months from first ASCT, and a greater PR in response to their first ASCT. In a matched-cohort analysis with patients receiving conventional chemotherapy (CCT), the same factors were associated with improved OS, with the exception of a longer remission duration (>18 months) from first ASCT. Second ASCT in relapsed MM is associated with superior OS and PFS compared with CCT, offering a potential consolidative option for selected patients.
St. James's Institute of Oncology, Leeds Teaching Hospitals Trust, Leeds


Moradi P, Bhogal M, Thaung C, Dart J
Epibulbar molluscum contagiosum lesions in multiple myeloma.
Cornea. 2011; 30(8):910-1 [PubMed]
PURPOSE: To describe the history and clinical presentation of a case of primary epibulbar molluscum contagiosum in multiple myeloma, after penetrating keratoplasty.
METHODS: A 70-year-old man, with previously diagnosed multiple myeloma and atopic dermatitis and keratoconjunctivitis, presented 6 months after right penetrating keratoplasty with white multilobular nodules of the right limbus. No skin lesions were evident. Evaluation consisted of slit-lamp examination, and an excisional biopsy of the involved conjunctival epithelium was carried out with local cryotherapy. Excised tissue was sent for histopathologic studies.
RESULTS: Slit-lamp examination revealed the presence of eight, 1-3 mm nodules of the perilimbal conjunctiva. In addition, there were opaque plaques at the level of the corneal epithelium. Mild perilesional conjunctival injection was evident, but there was no follicular conjunctival reaction. Histopathologic study of the lesions revealed eosinophilic intracytoplasmic inclusions (molluscum bodies) within the epithelial tissue.
CONCLUSIONS: There are no other reports of primary epibulbar molluscum, without previous cutaneous lesions, in immunocompromised patients without AIDS or after keratoplasty. This diagnosis should be included in the differential of focal thickening of the conjunctival epithelium, and potentially the corneal epithelium, in immunosuppressed patients.
Moorfields Eye Hospital, London


Khurram SA, McPhaden A, Hislop WS, Hunter KD
Crystal storing histiocytosis of the tongue as the initial presentation of multiple myeloma.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011; 111(4):494-6 [PubMed]
Crystal-storing histiocytosis (CSH) is a rare consequence of abnormal accumulation of immunoglobulins which may arise in a number of different clinical scenarios. In this report, we describe the case of a male patient who presented with an apparently innocuous lesion on the dorsum of tongue which showed the typical features of CSH. Subsequent investigations revealed an associated plasmacytoma, and the patient developed further systemic lesions. The rarity of such lesions presents diagnostic difficulties, yet accurate diagnosis underpins the timely implementation of appropriate therapy.
Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield


Morgan GJ
Can bisphosphonates improve outcomes in patients with newly diagnosed multiple myeloma?
Crit Rev Oncol Hematol. 2011; 77 Suppl 1:S24-30 [PubMed]
Preclinical and clinical evidence suggests that bisphosphonates have anticancer activities both within and outside bone. Early clinical trials of bisphosphonates provided evidence for antimyeloma effects in exploratory analyses in high-risk subsets, and recent trials of zoledronic acid (ZOL) have provided further support of antimyeloma activity The MRC Myeloma IX trial is an innovative 2 x 2 factorial trial comparing ZOL and clodronate (CLO) in patients with newly diagnosed multiple myeloma receiving either intensive or non-intensive therapy regimens. Results showed that ZOL significantly reduced skeletal morbidity and significantly improved both progression-free and overall survival versus CLO. Notably, the survival benefit with ZOL remained significant after adjustment for skeletal-related events, consistent with clinically meaningful antimyeloma activity. Further analyses of these data will provide greater insight into ZOL interactions with primary treatment regimens for multiple myeloma.
The Institute of Cancer Research, Royal Marsden NHS Foundation Trust, London
Research funded by:


Morgan G
Future drug developments in multiple myeloma: an overview of novel lenalidomide-based combination therapies.
Blood Rev. 2010; 24 Suppl 1:S27-32 [PubMed]
The introduction of thalidomide, lenalidomide, and bortezomib has changed the way that multiple myeloma (MM) is treated and has greatly improved survival outcomes. These novel agents are often used in combination with conventional drugs, such as dexamethasone, to optimize clinical responses; however, they are also being evaluated as part of novel treatment combinations to build upon the success of available treatment regimens. Lenalidomide-based combinations are a focus of clinical research due to the high efficacy, good tolerability, and lack of cumulative toxicity associated with lenalidomide. Lenalidomide is an IMiDs® immunomodulatory compound with a dual mechanism of action - tumoricidal effects rapidly reduce MM burden while long-term immunomodulatory actions maintain tumor suppression. Several new agents with antimyeloma effects have been identified including: epigenetic agents (e.g. histone deacetylase inhibitors); novel proteasome inhibitors; novel immunomodulatory compounds; cyclin-dependent kinase inhibitors; interleukin-6 inhibitors; and other experimental agents such as heat-shock protein 90 inhibitors and monoclonal antibodies targeting MM cell surface receptors (e.g. anti-CS1 and anti-CD40). Many of these new agents, in combination with lenalidomide, are in early phases of clinical evaluation. Early clinical results are promising, indicating that the novel lenalidomide-based drug combinations are effective and generally well tolerated in patients with MM; future research will continue to evaluate these novel combinations and help to identify the optimal setting (e.g. induction, salvage, or maintenance) in which they may provide the greatest impact on the disease course.
Institute of Cancer Research and The Royal Marsden Hospital, London


Davies F, Baz R
Lenalidomide mode of action: linking bench and clinical findings.
Blood Rev. 2010; 24 Suppl 1:S13-9 [PubMed]
New effective strategies are required that specifically address the challenges of multiple myeloma (MM) treatment, namely, disease recurrence, immunosuppression, and treatment-related toxicities. Recent preclinical and clinical findings suggest that the IMiDs® immunomodulatory compound lenalidomide has a dual mechanism of action, involving both a direct tumoricidal activity and immunomodulation, which may result in rapid and sustained control of MM, respectively. The tumoricidal effect of lenalidomide occurs through several mechanisms, including disruption of stromal support, induction of tumor suppressor genes, and activation of caspases. The immunomodulatory effects of lenalidomide, including T-cell and natural killer (NK)-cell activation, and increased expression of death effector molecules, lead to enhanced immune cell function and may explain the beneficial effects of this agent in the maintenance setting. Lenalidomide appears to be effective regardless of prior thalidomide treatment, which may reflect mechanistic differences - lenalidomide has greater immunomodulatory properties than thalidomide, whereas thalidomide has greater antiangiogenic activity. Recent studies also suggest that the concomitant use of dexamethasone may influence lenalidomide's direct and immunomodulatory effects. Lenalidomide in combination with dexamethasone synergistically inhibits proliferation and induces apoptosis; however, dexamethasone appears to antagonize the immune-enhancing effect of lenalidomide. A study has demonstrated that a regimen of lenalidomide in combination with an optimal dose and schedule of dexamethasone may increase survival by allowing synergistic antiproliferative effects, without affecting immunomodulatory activity. As preclinical and clinical research continue, additional insights into the dual mechanism of action of lenalidomide will help to further optimize the use of lenalidomide in MM.
The Institute of Cancer Research and Royal Marsden Hospital


Jiang J, Cole D, Westwood N, et al.
Crucial roles for protein kinase C isoforms in tumor-specific killing by apoptin.
Cancer Res. 2010; 70(18):7242-52 [PubMed]
The chicken anemia virus-derived protein apoptin induces apoptosis in a variety of human malignant and transformed cells but not in normal cells. However, the mechanisms through which apoptin achieves its selective killing effects are not well understood. We developed a lentiviral vector encoding a green fluorescent protein-apoptin fusion gene (LV-GFP-AP) that can efficiently deliver apoptin into hematopoietic cells. Apoptin selectively killed the human multiple myeloma cell lines MM1.R and MM1.S, and the leukemia cell lines K562, HL60, U937, KG1, and NB4. In contrast, normal CD34(+) cells were not killed and maintained their differentiation potential in multilineage colony formation assays. In addition, dexamethasone-resistant MM1.R cells were found to be more susceptible to apoptin-induced cell death than the parental matched MM1.S cells. Death susceptibility correlated with increased phosphorylation and activation of the apoptin protein in MM1.R cells. Expression array profiling identified differential kinase profiles between MM1.R and MM1.S cells. Among these kinases, protein kinase Cβ (PKCβ) was found by immunoprecipitation and in vitro kinase studies to be a candidate kinase responsible for apoptin phosphorylation. Indeed, shRNA knockdown or drug-mediated inhibition of PKCβ significantly reduced apoptin phosphorylation. Furthermore, apoptin-mediated cell death proceeded through the upregulation of PKCβ, activation of caspase-9/3, cleavage of the PKCδ catalytic domain, and downregulation of the MERTK and AKT kinases. Collectively, these results elucidate a novel pathway for apoptin activation involving PKCβ and PKCδ. Further, they highlight the potential of apoptin and its cellular regulators to purge bone marrow used in autologous transplantation for multiple myeloma.
Department of Haematological and Molecular Medicine, The Rayne Institute, King's College London
Research funded by:


Walsby EJ, Pratt G, Hewamana S, et al.
The NF-kappaB inhibitor LC-1 has single agent activity in multiple myeloma cells and synergizes with bortezomib.
Mol Cancer Ther. 2010; 9(6):1574-82 [PubMed]
Multiple myeloma remains incurable with conventional therapeutics. Thus, new treatments for this condition are clearly required. In this study we evaluated the novel NF-kappaB inhibitor LC-1 in multiple myeloma cell lines and plasma cells derived from multiple myeloma patients. LC-1 was cytotoxic to multiple myeloma cell lines H929, U266, and JJN3, and induced apoptosis in a dose-dependent manner with an overall LD(50) of 3.6 micromol/L (+/-1.8) after 48 hours in culture. Primary multiple myeloma cells, identified by CD38 and CD138 positivity, had a mean LD(50) for LC-1 of 4.9 micromol/L (+/-1.6); normal bone marrow cells were significantly less sensitive to the cytotoxic effects of LC-1 (P = 0.0002). Treatment of multiple myeloma cell lines with LC-1 resulted in decreased nuclear localization of the NF-kappaB subunit Rel A and the inhibition of NF-kappaB target genes. In addition, LC-1 showed synergy with melphalan, bortezomib, and doxorubicin (combination indices of 0.72, 0.61, and 0.78, respectively), and was more effective when cells were cultured on fibronectin. These data show that LC-1 has activity in multiple myeloma cell lines and primary multiple myeloma cells, and its ability to inhibit NF-kappaB seems important for its cytotoxic effects. Furthermore, LC-1-induced transcriptional suppression of survivin and MCL1 provides a potential explanation for its synergy with conventional agents.
Department of Haematology, School of Medicine, Cardiff University, Cardiff


Dickens NJ, Walker BA, Leone PE, et al.
Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome.
Clin Cancer Res. 2010; 16(6):1856-64 [PubMed] Free Access to Full Article
PURPOSE: Myeloma is a clonal malignancy of plasma cells. Poor-prognosis risk is currently identified by clinical and cytogenetic features. However, these indicators do not capture all prognostic information. Gene expression analysis can be used to identify poor-prognosis patients and this can be improved by combination with information about DNA-level changes.
EXPERIMENTAL DESIGN: Using single nucleotide polymorphism-based gene mapping in combination with global gene expression analysis, we have identified homozygous deletions in genes and networks that are relevant to myeloma pathogenesis and outcome.
RESULTS: We identified 170 genes with homozygous deletions and corresponding loss of expression. Deletion within the "cell death" network was overrepresented and cases with these deletions had impaired overall survival. From further analysis of these events, we have generated an expression-based signature associated with shorter survival in 258 patients and confirmed this signature in data from two independent groups totaling 800 patients. We defined a gene expression signature of 97 cell death genes that reflects prognosis and confirmed this in two independent data sets.
CONCLUSIONS: We developed a simple 6-gene expression signature from the 97-gene signature that can be used to identify poor-prognosis myeloma in the clinical environment. This signature could form the basis of future trials aimed at improving the outcome of poor-prognosis myeloma.
Section of Haemato-Oncology, The Institute of Cancer Research, London
Research funded by:


Moore HE, Davenport EL, Smith EM, et al.
Aminopeptidase inhibition as a targeted treatment strategy in myeloma.
Mol Cancer Ther. 2009; 8(4):762-70 [PubMed]
Myeloma cells are highly dependent on the unfolded protein response to assemble folded immunoglobulins correctly. Therefore, targeting protein handling within a myeloma cell by inhibiting the aminopeptidase enzyme system, which catalyses the hydrolysis of amino acids from the proteins NH2 terminus, represents a therapeutic approach. CHR-2797, a novel aminopeptidase inhibitor, is able to inhibit proliferation and induce growth arrest and apoptosis in myeloma cells, including cells resistant to conventional chemotherapeutics. It causes minimal inhibition of bone marrow stromal cell (BMSC) proliferation but is able to overcome the microenvironmental protective effects, inhibiting the proliferation of myeloma cells bound to BMSCs and the increase in vascular endothelial growth factor levels seen when myeloma cells and BMSCs are bound together. Additive and synergistic effects are seen with bortezomib, melphalan, and dexamethasone. Apoptosis occurs via both caspase-dependent and non-caspase-dependent pathways with an increase in Noxa, cleavage of Mcl-1, and activation of the unfolded protein response. Autophagy is also seen. CHR-2797 causes an up-regulation of genes involved in the proteasome/ubiquitin pathway, as well as aminopeptidases, and amino acid deprivation response genes. In conclusion, inhibiting protein turnover using the aminopeptidase inhibitor CHR-2797 results in myeloma cell apoptosis and represents a novel therapeutic approach that warrants further investigation in the clinical setting.
Section of Haemato-Oncology, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG
Research funded by:


Hutchison CA, Bradwell AR, Cook M, et al.
Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis.
Clin J Am Soc Nephrol. 2009; 4(4):745-54 [PubMed] Free Access to Full Article
BACKGROUND AND OBJECTIVES: Extended hemodialysis using a high cut-off dialyzer (HCO-HD) removes large quantities of free light chains in patients with multiple myeloma. However, the clinical utility of this method is uncertain. This study assessed the combination of chemotherapy and HCO-HD on serum free light chain concentrations and renal recovery in patients with myeloma kidney (cast nephropathy) and dialysis-dependent acute renal failure.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: An open-label study of the relationship between free light chain levels and clinical outcomes in 19 patients treated with standard chemotherapy regimens and HCO-HD.
RESULTS: There were sustained early reductions in serum free light chain concentrations (median 85% [range 50 to 97]) in 13 patients. These 13 patients became dialysis independent at a median of 27 d (range 13 to 120). Six patients had chemotherapy interrupted because of early infections and did not achieve sustained early free light chain reductions; one of these patients recovered renal function (at 105 d) the remaining 5 patients did not recover renal function. Patients who recovered renal function had a significantly improved survival (P < 0.012).
CONCLUSION: In dialysis-dependent acute renal failure secondary to myeloma kidney, patients who received uninterrupted chemotherapy and extended HCO-HD had sustained reductions in serum free light chain concentrations and recovered independent renal function.
Department of Nephrology, Queen Elizabeth Hospital, Birmingham


Oakland RJ, Furtado NR, Timothy J, Hall RM
The biomechanics of vertebroplasty in multiple myeloma and metastatic bladder cancer: a preliminary cadaveric investigation.
J Neurosurg Spine. 2008; 9(5):493-501 [PubMed]
OBJECT: The vertebral column is the most common site for secondary bone metastases and lesions arising from hematological malignancies such as multiple myeloma (MM). These infiltrations can be lytic in nature and cause severe weakening of the vertebral body, an increased risk of fracture, and spinal cord compression leading to neurological deficit. Qualitatively it is apparent that increasing infiltration of these lytic lesions will have a deleterious effect on the mechanical behavior of the vertebrae. However, there is little quantitative information about the relationship between tumor deposits and the impact on the mechanical behavior of the vertebrae. In addition, there have been limited biomechanical assessments of the use of vertebroplasty in the management of these malignancies. The purpose of this preliminary study was to evaluate the mechanical behavior of lesion-infiltrated vertebrae from 2 malignant cancers and to investigate the effectiveness of vertebroplasty with and without tumor debulking.
METHODS: Individual vertebrae from 2 donor spines--one with MM and another with bone metastases secondary to bladder cancer-were fractured under an eccentric flexion load, from which failure strength and stiffness were derived. Alternate vertebrae defined by spinal level were assigned to 2 groups: Group 1 involved removal of lesion material with Coblation (ArthroCare Corp.) preceding vertebroplasty; Group 2 received no Coblation prior to augmentation. All vertebrae were fractured postaugmentation under the same loading protocol. Micro-CT assessments were undertaken to investigate vertebral morphology, fracture patterns, and cement distribution.
RESULTS: Multiple myeloma involvement was characterized by several small lesions, severe bone degradation, and multiple areas of vertebral shell compromise. In contrast, large focal lesions were present in the vertebrae with metastatic bladder cancer, and the shell generally remained intact. The mean initial failure strength of the vertebrae with metastases secondary to MM was significantly lower than in vertebrae with bone metastases secondary to bladder cancer (Load = 950 +/- 300 N vs 2200 +/- 750 N, p < 0.0001). A significant improvement in relative fracture strength was found postaugmentation for both lesion types (1.4 +/- 0.5, p < 0.001). Coblation provided a marginally significant increase in the same parameter postaugmentation (p = 0.08) and qualitatively improved the ease of injection and guidance of cement.
CONCLUSIONS: In the vertebral column, metastatic lesions secondary to bladder cancer and MM showed variations in the pattern of infiltration, both of which led to significant reductions in fracture strength. Account should be taken of these differences to optimize the vertebroplasty intervention in terms of the cement formulation, delivery, and any additional surgical procedure.
School of Mechanical Engineering, University of Leeds


Leone PE, Walker BA, Jenner MW, et al.
Deletions of CDKN2C in multiple myeloma: biological and clinical implications.
Clin Cancer Res. 2008; 14(19):6033-41 [PubMed] Free Access to Full Article
PURPOSE: Deletions of chromosome 1 have been described in 7% to 40% of cases of myeloma with inconsistent clinical consequences. CDKN2C at 1p32.3 has been identified in myeloma cell lines as the potential target of the deletion. We tested the clinical impact of 1p deletion and used high-resolution techniques to define the role of CDKN2C in primary patient material.
EXPERIMENTAL DESIGN: We analyzed 515 cases of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma using fluorescence in situ hybridization (FISH) for deletions of CDKN2C. In 78 myeloma cases, we carried out Affymetrix single nucleotide polymorphism mapping and U133 Plus 2.0 expression arrays. In addition, we did mutation, methylation, and Western blotting analysis.
RESULTS: By FISH we identified deletion of 1p32.3 (CDKN2C) in 3 of 66 MGUS (4.5%), 4 of 39 SMM (10.3%), and 55 of 369 multiple myeloma cases (15%). We examined the impact of copy number change at CDKN2C on overall survival (OS), and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared with cases that were intact at this region (22 months versus 38 months; P = 0.003). Using gene mapping we identified three homozygous deletions at 1p32.3, containing CDKN2C, all of which lacked expression of CDKN2C. Cases with homozygous deletions of CDKN2C were the most proliferative myelomas, defined by an expression-based proliferation index, consistent with its biological function as a cyclin-dependent kinase inhibitor.
CONCLUSIONS: Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma.
Section of Haemato-Oncology, The Institute of Cancer Research, 15 Cotswold Road, London
Research funded by:


Johnson DC, Corthals S, Ramos C, et al.
Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping.
Blood. 2008; 112(13):4924-34 [PubMed] Free Access to Full Article
A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of patients with multiple myeloma with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP)-based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in "functional regions" within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and side effects associated with myeloma therapy. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair, and cytokine balance. The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332.
Section of Haemato-Oncology, Institute of Cancer Research, London
Research funded by:


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