Purpose: The aim of the study was to verify the hypothesis that the cMet oncogene is implicated in chemio-and novel drug resistance in multiple myeloma.Experimental Design: We have evaluated the expression levels of cMET/phospho-cMET (p-cMET) and the activity of the novel selective p-cMET inhibitor (SU11274) in multiple myeloma cells, either sensitive (RPMI-8226 and MM.1S) or resistant (R5 and MM.1R) to anti-multiple myeloma drugs, in primary plasma cells and in multiple myeloma xenograft models.Results: We found that resistant R5 and MM.1R cells presented with higher cMET phosphorylation, thus leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited a higher susceptibility to the SU11274 inhibitory effects on viability, proliferation, chemotaxis, adhesion, and to its apoptogenic effects. SU11274 was able to revert drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMET-dependent activation of mitogen-activated protein kinase pathway. The cMET and p-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or on drug resistance than on those from patients at diagnosis, complete/partial remission, or from patients with monoclonal gammopathy of unknown significance. Viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients was markedly inhibited by SU11274. Importantly, SU11274 showed higher therapeutic activity in R5-than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reverted bortezomib resistance.Conclusion: Our findings suggest that the cMET pathway is constitutively activated in relapsed and resistant multiple myeloma where it may also be responsible for induction of drug resistance, thus providing the preclinical rationale for targeting cMET in patients with relapsed/refractory multiple myeloma.

We evaluated the safety and efficacy of plerixafor, subsequent to disease-specific chemotherapy followed by granulocyte-colony stimulating factor (G-CSF), in 37 multiple myeloma (MM) or lymphoma patients, who were candidates for autologous stem cell transplantation (ASCT) predicted as poor mobilizers (PMs). Patients were identified as predicted PMs according to the history of a previously failed mobilization attempt or the presence of ≥1 factors predicting an unsuccessful harvest, such as advanced disease, prior extensive radiotherapy, or prolonged treatment, with stem cell poisons, advanced age, or extensive bone marrow involvement. Plerixafor (0.24 mg/kg) was administered subcutaneously for up to 3 consecutive days while continuing G-CSF for 9 to 11 hours before the planned apheresis. Plerixafor administration was safe and no significant adverse events were recorded. We observed a median 4-fold increase (range: 1.4-32) in the number of circulating CD34(+) cells following plerixafor compared with baseline CD34(+) cell concentration (from a median of 5 cells/μL, range: 1-32, to a median of 32 cells/μL, range: 6-201). Twenty-seven of the 37 patients (14 of 17 with MM and 13 of 20 with lymphoma) had ≥2×10(6) CD34(+) cells/kg collected in 1-3 apheretic procedures. Of the 27 patients rescued with plerixafor, 24 (13 MM, 11 lymphoma) have been transplanted with plerixafor-mobilized peripheral blood stem cells, showing a rapid and durable hematologic recovery. Our results suggest that the addition of plerixafor to G-CSF after disease-oriented chemotherapy is safe and allows for a satisfactory harvest in order to perform a safe ASCT, in a relevant proportion of lymphoma and MM patients considered to be PMs.