S V Rajkumar

..The purpose of this review is to summarize recent advances and provide an evidence-based approach to the treatment of multiple myeloma...

..To determine if thalidomide plus dexamethasone yields superior response rates compared with dexamethasone alone as induction therapy for newly diagnosed multiple myeloma...

..We propose that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript...

..Major toxicities of thalidomide include constipation, sedation, skin rash, fatigue and peripheral neuropathy. This paper summarizes the current status of thalidomide in multiple myeloma...

..To determine whether bone marrow (BM) angiogenesis progressively increases along the spectrum of plasma cell disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) to advanced myeloma...

..Patients who have risk factors, such as deletion 13 or translocation t(4;14) or t(14;16), are candidates for novel, more aggressive treatments...

..This relationship was independent of the disease activity and of the PC burden in the marrow. The increased angiogenesis may promote plasma cell proliferation and enable PC migration into the circulation...

..Thalidomide, an agent with antiangiogenic properties, is effective in relapsed myeloma. We report the results of a study combining thalidomide and dexamethasone as initial therapy for myeloma...

..2-Methoxyestradiol (2ME2) is an endogenous product of estradiol metabolism with antiangiogenic and antineoplastic properties. We report on the first phase II trial of 2ME2 in multiple myeloma...

..pylori infection (33%) by serology, breath or stool testing between patients with MGUS and those with negative monoclonal protein studies. There was no evidence of resolution of MGUS with H. pylori therapy...

..This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib...

..This paper reviews the available data on angiogenesis in myeloma, and summarizes the role of thalidomide therapy in this disease. The pharmacology and toxicity of thalidomide are also discussed...

..Angiogenesis is correlated with the plasma cell labeling index but not the bone marrow plasma cell percentage. A simple visual grading of angiogenesis is an efficient alternative to microvessel density estimation...

..Major toxicities associated with the use of thalidomide include constipation, sedation, skin rash, fatigue, and peripheral neuropathy. This article summarizes the current status of thalidomide therapy in cancer...

..The presence of an abnormal kappa/lambda FLC ratio in the serum was associated with a higher risk of MGUS progression (relative risk 2.5; 95% confidence interval: 1.6-4.0; P < 0.001)...

..Rev/Dex is a highly active regimen with manageable side effects in the treatment of newly diagnosed myeloma...

..Studies are ongoing to determine its role as initial treatment for myeloma. Trials are also underway combining thalidomide with other active agents. This article summarizes the current status of thalidomide therapy in myeloma...

..We recommend collection of PBSC within 6 months of initiation of therapy with lenalidomide containing regimens to minimize the risk of mobilization failures...

..007. BM MVD at the time of initial diagnosis is an important prognostic factor for OS and PFS in patients undergoing autologous transplantation as frontline therapy for myeloma...

..It is also prognostic for poor survival and PFS following SCT for myeloma. We recommend that all three methods of estimating BMPC% be routinely performed and that the highest value be used for prognostic purposes...

..6 months for Dex and were not reached for Thal-Dex and Len-Dex groups, P=0.2. For patients undergoing early ASCT for myeloma, the nature of initial treatment utilized has no long-term impact on the outcome of ASCT...

..Although not conclusive, this result lends further support to the hypothesis that angiogenesis is a relevant therapeutic target in myeloma...

..The combination of pomalidomide and dexamethasone (Pom/dex) is highly active and well tolerated in patients with lenalidomide-refractory myeloma...

..65). The lack of response to initial induction therapy does not appear to preclude a good response to SCT. We recommend that patients with primary refractory MM be offered early SCT...

..Thalidomide has significant activity in early-stage myeloma and has the potential to delay progression to symptomatic disease. This approach must be further tested in randomized trials...

..Patients who relapse within 12 months of an auto-SCT have a poor outcome and should be offered trials evaluating novel treatment approaches...

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..18. No significant differences were observed in the progression-free and overall survival at 1 year post transplant. Single agent dexamethasone appears to be an effective alternative to VAD for induction therapy prior to HDT in myeloma...

..This article addresses the extent to which eligibility to undergo HSCT is a favorable prognostic feature and explores prognostic factors within the subset of eligible patients...

..VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested...

..Additional randomized trials are needed to determine if thalidomide will delay progression to active multiple myeloma...

..Sorafenib, through multiple mechanisms exerts potent anti-myeloma activity and these results favor further clinical evaluation and development of novel sorafenib combinations...

..3% vs 9.2%, P = .058) and peripheral neuropathy (10.4% vs 0.9%, P < .001). Len/dex appears well-tolerated and more effective than thal/dex. Randomized trials are needed to confirm these results...

..The purpose was to evaluate the incidence and risk factors of thromboembolism associated with lenalidomide therapy in newly diagnosed myeloma...

..To systematically study the association of monoclonal gammopathy of undetermined significance (MGUS) with all diseases in a population-based cohort of 17,398 patients, all of whom were uniformly tested for the presence or absence of MGUS...

..2%) of those had translocation (11;14)(q13;q32) for an overall prevalence of the abnormality of 55%. IgH translocations are common in AL, especially the t(11;14)(q13;q32)...

..These data indicate that therapies targeting apoptotic pathways may be effective in MM treatment and warrant clinical evaluation of ABT-737 and similar drugs alone or in combination with other agents in the setting of MM...

..008), but platelet transfusion requirements did not differ (P=0.95). We concluded that thalidomide does not substantially affect peripheral cell mobilization or engraftment...

..INTERPRETATION AND CONCLUSIONS: The median time to disease progression in patients with multiple myeloma who receive initial therapy with Thal/Dex and who do not undergo ASCT is 18 months...

..The prevalence of skin eruptions was not diminished by the concurrent use of systemic corticosteroids. Most skin eruptions were mild and did not necessitate withdrawal of lenalidomide therapy...

..A system including both these risk factors allows better prediction of outcome...

..Conversely, the 75% of patients remaining have more favorable outcomes using existing - albeit non-curative - therapeutic options...

..Trisomy of chromosome 13 was rare ( <2%). Even among patients with abnormal karyotypes, specific chromosome abnormalities can impart biologic variability in myeloma, including several monosomies, hypodiploidy and abnormalities of 1p...

..07). The expression of CD138, CD56 and CD54 were higher among the CD45- PCs. This study demonstrates important biological correlates of CD45 expression on myeloma cells...

..02). Angiogenesis is increased in solitary plasmacytoma and is a significant predictor of progression to myeloma and provides further evidence of its importance in the pathogenesis of myeloma...

..In addition, MRK003 caused an upregulation of pAkt, indicating crosstalk with the PI3K/Akt pathway. We evaluated MRK003 in combination with Akt1/2 kinase inhibitor and observed synergy in killing MM and NHL cell lines examined...

..We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease...

..Overall survival measured from trial entry was significantly shorter for patients with treatment-emergent EMD compared with those who did not have EMD, (median 16 months versus not reached, P=0.002)...

..001). These findings suggest that the serum FLC ratio at initial diagnosis is an important predictor of prognosis in myeloma, and can be incorporated into the ISS for improved risk stratification...

..Future studies of Waldenström macroglobulinaemia should report minor responses because they are associated with clinically meaningful benefits. This trial was registered at http://www.clinicaltrials.gov as #NCT00005609...

..These results need confirmation in larger, prospectively designed studies...

..These have shown significant clinical activity as single agents. Trials are ongoing to incorporate these new agents into the various stages of treatment and to combine them with other effective treatment modalities, including ASCT...

..The role of supportive care strategies for patients with bone disease, such as the use of bisphosphonates, is also discussed...

..01; IL-6, 24% versus 70% at 2 years, P = 0.01). None of the other parameters predicted response or PFS, and no significant changes in cytokine levels occurred with therapy...

..The addition of Thal to standard ZLD produces anti-tumor responses whereas ZLD alone does not. Thal/ZLD also prolongs TTP from AMM to MM. This study provides the rationale for further studies in patients with AMM to delay chemotherapy...

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..Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study...

..CONCLUSIONS: Thalidomide is useful in the treatment of patients with relapsed multiple myeloma and produced durable response in approximately one third of patients, with median response duration of nearly 1 year...

..Phase III trials of thalidomide in newly diagnosed symptomatic multiple myeloma or smoldering/indolent disease are ongoing...

..5% vs. 4.2%, P = 0.129) were higher with Rd. Results of this case-matched analysis suggest that there is significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results...

..We conclude that the number of circulating PCs measured by flow cytometry in patients with newly diagnosed MM is an independent predictor of survival...

..This study validates the high-risk features defined by FISH and CG in the Mayo risk-stratification model for patients with MM predominantly treated with novel therapies based on immunomodulatory agents...

..8; 95% CI, 1.1-3.00; P=0.018). The finding that HLC-pair suppression predicts progression in MGUS and occurs several years before malignant transformation has implications for myeloma biology...

..The finding of increased angiogenesis in myeloma provides the rationale for the study of antiangiogenic therapy in this disease...

..However, there was no significant change in MVD following transplant (P=0.8, paired t-test). Abnormal bone marrow angiogenesis appears to persist in the bone marrow following ASCT for CML, at least in the short term...

..Prior chemotherapy had failed and five (16%) patients had experienced relapse following stem cell transplantation. Ten (38%) of the 26 patients who had received at least two cycles of therapy obtained a response...

..The pathophysiologic basis for this should be determined because elevated bone turnover, for example, might be treatable...

..2 years vs 2.3 years, respectively; P = .01)...

..03). The presence of Delta13 is an important and independent adverse prognostic factor in newly diagnosed MM and is associated with specific biological features...

..4, and 6.5 months, respectively. CMCs at the time of ASCT is an independent prognostic factor and in combination with cytogenetics provides a powerful scoring system that stratifies patients and guides management...

..To identify and assess the clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma (MM)...

..We conclude that the degree of bone marrow angiogenesis is a prognostic marker in patients with multiple myeloma and does not decrease significantly after therapy...

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..This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs...

..Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months...

..We have concisely reviewed the current knowledge regarding mechanisms of its anti-neoplastic activity and the results of various clinical trials in oncology...

..The median survival of symptomatic patients is 65 months. Patients without symptoms should not be treated...

..Demonstration of the presence of VEGFR2 in our study provides a potential biological explanation for the preclinical activity observed with VEGFR2 inhibitors...

..CONCLUSION: There is a dramatic increase in fractures around the time of diagnosis of myeloma, most of which are pathologic fractures. The most important predictor of overall fracture risk is oral corticosteroid use...

..In conclusion, FS associated with monoclonal gammopathy does not appear to confer an additional risk of subsequent evolution to MM. ESRD occurs late in the disease process...

..This article reviews the current status of thalidomide for the treatment of non-plasma-cell malignancies...

..The active inhibition of angiogenesis in MGUS is lost with progression, and the angiogenic switch from MGUS to NMM may involve a loss of inhibitory activity...

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..Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc...

..The risk of progression of MGUS of IgM type to lymphoma or related disorders averaged 1.5% per year throughout the period of observation...

..This paper provides the current criteria for diagnosis, staging, risk stratification and response assessment of MM...

..Both 1q21 gain and increase gene expression level were significantly associated with reduced survival. However, neither is an independent prognostic marker in MM on multivariate Cox proportional hazard analysis...

..The remaining 20% are characterised by absence of IgH expression; we aimed to assess prevalence of a corresponding precursor entity, light-chain MGUS...

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..The kidney is affected by immunoglobulin light chain amyloidosis (AL) in more than 50% of patients who present with the disease, but long-term predictors for and outcomes after renal replacement therapy are not well described...

..In summary, serum immunoglobulin profiles are unique in POEMS syndrome as compared with other plasma cell disorders...

..This approach warrants further investigation to confirm this and define the role of vaccine therapy in myeloma...

..0; 95% CI, 1.4 to 2.8) and MGUS probands (RR, 3.3; 95% CI, 2.1 to 4.8). The increased risk of MGUS in first-degree relatives of MGUS or MM patients implies shared environment and/or genetics...

..This review discusses the current status of front-line therapy in younger patients with myeloma who are candidates for stem cell transplantation...

..To examine whether the outcome of patients with primary systemic amyloidosis (AL) has improved over time and to identify predictors of early mortality in patients with AL...

..To conduct in vitro studies as well as a phase 2 clinical trial in patients with smoldering or indolent multiple myeloma to determine if interleukin 1 (IL-1) inhibitors can delay or prevent active myeloma...

..It also highlights the importance of achieving at least a 90% reduction in the FLC-diff to improve the outcome of patients with light-chain AL...

..Because myeloma is an incurable malignancy, strategies to delay or prevent progression in high-risk patients are of considerable importance...