Serum beta2-microglobulin (Sbeta2M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sbeta2M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sbeta2M less than 3.5 mg/L plus serum albumin > or = 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sbeta2M > or = 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and > or = 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. CONCLUSION) The new ISS is simple, based on easy to use variables (Sbeta2M and serum albumin), and recommended for early adoption and widespread use.

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Bortezomib is superior to high-dose dexamethasone for the treatment of patients with multiple myeloma who have had a relapse after one to three previous therapies.

BACKGROUNDThis open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODSWe randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTSThe median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P = 0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P = 0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively). CONCLUSIONSConsolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928. 896T h e ne w e ngl a nd jou r na l o f m e dicine H igh-dose chemotherapy plus autologous stem-cell transplantation, as compared with conventional chemotherapy, prolongs progression-free survival and overall survival among patients with newly diagnosed multiple myeloma.1-4 and it is currently the standard of care for patients who are younger than 65 years of age. However, since autologous stem-cell transplantation has substantial toxic effects and requires prolonged hospitalization, the comparison with less toxic, orally administered treatments is important. Immunomodulatory drugs and proteasome inhibitors have significantly improved outcomes in patients, regardless of whether they are eligible for transplantation. 5-18These improvements have raised questions about the role of transplantation in comparis...

Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein o15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. 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. Leukemia Monoclonal gammopathy of undetermined significanceMonoclonal gammopathy of undetermined significance (MGUS) is defined as a serum M protein o30 g/l, o10% clonal plasma cells (PCs) in the bone marrow (BM) and, most importantly, the absence of end-organ damage that can be attributed to the PC proliferative disorder (Table 1). End-organ damage is characterized by CRAB (hypercalcemia, renal insufficiency, anemia, bone lesions) related to the PC proliferative disorder. 1 Prevalence of MGUSMGUS was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older.2 Age-adjusted rates were higher in men than in women (4.0 vs 2.7%). The prevalence of MGUS was 5.3% among persons 70 years of age or older and in 8.9% of men older than 85 years of age. The size of the M protein was o1.5 g/dl in 80% and X2 g/dl in only 4.5%.2 The prevalence of MGUS in African Americans 3,4 and Africans 5 is approximately double that in Caucasians, whereas the prevalence in Japanese is lower than in Caucasians. 6 The prevalence of MGUS in first degree relatives of patients with MGUS is increased suggesting a genetic factor. 7,8 Only 21% of 70-year-old patients with MGUS have been recognized during routine clinical practice in a large population-based cohort.

The incidence of venous thromboembolism (VTE) is more than 1 per thousand annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with < or = 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.

Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microRNAs (miRNAs), a class of small noncoding RNAs targeting multiple mRNAs, has revealed a new level of gene expression regulation. To determine whether miRNAs play a role in the malignant transformation of plasma cells (PCs), we have used both miRNA microarrays and quantitative real time PCR to profile miRNA expression in MM-derived cell lines (n ‫؍‬ 49) and CD138؉ bone marrow PCs from subjects with MM (n ‫؍‬ 16), monoclonal gammopathy of undetermined significance (MGUS) (n ‫؍‬ 6), and normal donors (n ‫؍‬ 6). We identified overexpression of miR-21, miR-106bϳ25 cluster, miR181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17ϳ92 cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17ϳ92 cluster, were shown to down regulate expression of SOCS-1, a gene frequently silenced in MM that plays a critical role as inhibitor of IL-6 growth signaling. We also identified p300-CBP-associated factor , a gene involved in p53 regulation, as a bona fide target of the miR106bϳ25 cluster, miR-181a and b, and miR-32. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis.PCAF ͉ SOCS-1 ͉ tumor suppressor gene ͉ MGUS ͉ plasma cells

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