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Background: Minimal residual disease (MRD) is one of the most relevant prognostic factors in patients with multiple myeloma (MM); however, the impact of maintenance therapy on MRD levels remains unclear. Among patients with newly diagnosed MM (NDMM) who received lenalidomide maintenance until they developed disease progression, the role of MRD status as a predictor of progression-free survival (PFS) was evaluated by multiparameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) analysis.Methods: Seventy-three patients with NDMM enrolled in the RV-MM-EMN-441 (clinical trials.gov identifier, NCT01091831) and RV-MM-COOP-0556 (clinicaltrials.gov identifier, NCT01208766; European Myeloma Network EMN02/HO95 MM Trial) phase 3 trials who achieved at least a very good partial response after intensification/consolidation were included. The median patient age was 57 years (interquartile range, 53-61 years), and all patients received lenalidomide maintenance until they developed progression. MRD was evaluated on bone marrow after intensification/consolidation, after 6 courses of maintenance, and every 6 months thereafter until clinical relapse using both ASO-RQ-PCR (sensitivity, 10-5 ) and MFC (sensitivity, from 10-4 to 10-5 ).Results: After intensification/consolidation, 33 of 72 patients (46%) achieved a molecular complete response (m-CR), and 44 of 70 (63%) achieved a flow complete response (flow-CR). Almost 27% of patients who were MRD-positive after consolidation became MRD-negative during maintenance. After a median follow-up of 38 months, PFS was prolonged in patients who achieved negative MRD status during maintenance according to results from both ASO-RQ-PCR analysis (hazard ratio, 0.29; 95% confidence interval, 0.14-0.62; P = .0013) and MFC (hazard ratio, 0.19; 95% confidence interval, 0.09-0.41; P < .001). The impact of negative MRD status on PFS was similar in all subgroups (ASCT and no-ASCT; International Staging System stages I, II, and III; high-risk and standard-risk cytogenetics), and the two techniques were highly correlated.Conclusions: MRD status is a stronger predictor of PFS than standard risk factors, and lenalidomide maintenance further increases the rate of negative MRD results. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma is associated with a significant risk of venous thromboembolism (VTE), causing substantial levels of morbidity and mortality. The thrombogenicity of myeloma is multifactorial, with disease‐ and treatment‐related factors playing important roles. Immunomodulatory drugs (IMiDs) and high‐dose dexamethasone, in particular, are known to enhance the thrombotic potential of myeloma. For this reason, assessment of the VTE risk has long been advocated prior to treatment initiation in patients with myeloma requiring IMiD‐based regimens. However, despite routine use of thromboprophylaxis, these patients can still develop VTE and its sequelae. The optimum choice and dose of thromboprophylactic drug is not entirely clear, and with this, there is growing interest regarding use of the direct oral anticoagulants in this setting. In this review we discuss the pathogenesis of thrombosis in multiple myeloma, its relation to some of the commonly used chemotherapeutic regimens, current risk stratification and the evidence supporting the different anticoagulants used as thromboprophylaxis. We propose an amended risk stratification, and consider management of challenging patients, including those with renal impairment and recurrent thrombosis. [ABSTRACT FROM AUTHOR]

Abnormal activation of MET/ HGF ( Hepatocyte Growth Factor) pathway has been described in several tumours and increased HGF plasmatic levels have been detected in patients with aggressive multiple myeloma (MM). MET and HGF m RNA expression was investigated in 105 samples of purified plasma cells derived from newly diagnosed MM patients treated with bortezomib-based induction therapy. Gene expression was compared with response to therapy and clinical outcome. MET gene copy number was also evaluated. MET m RNA expression was higher in CD138+ than in CD138− cells (median 76·90 vs. 11·24; P = 0·0009). Low MET m RNA expression characterized patients with better response (complete response or very good partial response) compared to other patients (median 56·10 vs. 134·83; P = 0·0006). After a median follow-up of 50 months, patients with high MET m RNA expression displayed a worse progression-free survival ( PFS; P = 0·0029) and overall survival ( OS; P = 0·0023) compared to those with low MET m RNA levels. Patients with both high MET m RNA expression and high β2-microglobulin level (>5·5 mg/l) had further worse median PFS ( P < 0·0001) and OS ( P < 0·0001). Patients carrying 4 MET gene copies (8 out of 82, 9·8%) also had a short PFS. High MET m RNA expression identifies patients with dismal PFS and OS and the combination with high β2-microglobulin further characterizes patients with worse outcome. [ABSTRACT FROM AUTHOR]

Cereblon ( CRBN) has recently been identified as a target for immunomodulatory drugs ( IMi Ds) and its downregulation has been linked to resistance to lenalidomide. Here, we studied CRBN expression by real time polymerase chain reaction in 49 bone marrow samples of newly diagnosed patients with multiple myeloma treated with lenalidomide and dexamethasone. Median CRBN expression was 3·45 in patients who achieved complete response, and 3·75, 2·01, 0·78, and 0·70 in those with very good partial response, partial response, stable disease and progressive disease respectively. CRBN expression levels correlated significantly with response to lenalidomide treatment ( r = 0·48; P < 0·001). Among established prognostic parameters, only beta-2-microglobulin correlated with cereblon ( r = 0·66; P < 0·001). A close association of CRBN with interferon regulatory factor 4 ( IRF4) ( P < 0·001) and with CTNNB1 ( P < 0·001) was found. Overall, a statistically significant association between baseline CRBN expression and response in MM patients treated with lenalidomide is shown. CRBN expression is closely associated with IRF4, which is an important target of IMi D therapy. [ABSTRACT FROM AUTHOR]