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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]

Summary: In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development. [ABSTRACT FROM AUTHOR]