Met Over-Expression Is a Prognostic Factor for Myeloma Patients Treated with Novel Agents.

Over-expression of the tyrosine kinase receptor Met has been reported in several solid tumors and increases cell proliferation, cell migration (scattering) and neoplastic angiogenesis. The Hepatocyte Growth Factor (HGF) is the only known Met ligand and the HGF/Met pathway seems to play a pivotal role in Multiple Myeloma (MM) pathogenesis. HGF is secreted by bone marrow stromal cells and Met is expressed at the surface of malignant plasma cells and endothelial cells. The phosphorylation of Met induced by HGF is a strong signal for cell growth and migration. The activity of the HGF/Met pathway and the heterogeneity of HGF/Met expression on MM cells suggest that the over-expression of Met could be a prognostic marker in MM patients.

To investigate the role of HGF/Met pathway as prognostic marker predictive of response rate, progression-free survival (PFS) and overall survival (OS) in MM patients treated with novel agents.

102 newly diagnosed MM patients received the PAD-Mel100-LP-L regimen (Palumbo A, Abs 159, ASH 2008): as induction, four 21-day PAD cycles (Bortezomib, Pegylated-lyposomal-doxorubicin, Dexamethasone); as transplantation, tandem Mel100 (Melphalan 100 mg/m2) followed by stem cell support; as consolidation four 28-day LP cycles (Lenalidomide plus Prednisone) followed by Lenalidomide alone as maintenance. Samples from 47 newly diagnosed patients enrolled in this study have been analyzed. On CD138+ and CD138- cells separated from bone marrow (BM) aspirate, HGF and Met mRNA levels have been evaluated using a quantitative Real-Time PCR (qRT-PCR) on Abi Prism 7900 (Applied Biosystems). The JUM2 cell line was used as a calibrator for relative quantification of mRNA using the σσCt approach and Gus has been used as housekeeping gene. The cut-off value of Met mRNA expression/percentage calibrator was selected according to Receiver Operating Characteristic (ROC) analysis.

mRNA expression of Met was higher in CD138+ cells than in CD138- cells (median 103, range 2 – 586 vs median 31, range 0-243 respectively; p=0.002). Met mRNA expression was significantly higher in CD138+ cells of patients with suboptimal response (partial response PR, stable disease SD, progression disease PD), compared with patients achieving complete response (CR) or very good partial remission (VGPR) (median 140 range 27-586 vs median 36.5 range 1-163 respectively; p=0.0001) (FIG 1A). With a median follow-up of 18 months, the 2-year PFS was 54% in patients with high Met mRNA expression and 87% in patients with low Met mRNA expression (p=0.007, FIG 1B); 2-year OS was 72% in patients with high Met mRNA expression and 95% in patients with low Met mRNA expression (p=0.047, FIG 1C). Patients with high levels of Met mRNA displayed albumin and beta-2-microglobuline levels similar to that observed in patients with low levels of Met mRNA. The BM plasma cells infiltration was also comparable (median 61% vs 65%) within the two groups. A similar percentage of patients in both groups showed the following cytogenetic abnormalities: t(4;14), t(14;16), del17 and del13. Interestingly, the percentage of patients carrying t(11;14) was higher in the group of patients with low Met mRNA levels in comparison with patients with high Met mRNA levels (28% vs 6%). mRNA expression of HGF was similar in responders and non responders patients and did not predict PFS and OS.

1) mRNA level of Met on CD 138+ cells is a biological marker predictive of response; 2) high level of Met mRNA at diagnosis delineates significantly inferior progression-free and overall survival in MM patients treated with both bortezomib and lenalidomide based regimens.

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Patriarca:Celgene: Honoraria. Caravita:Celgene: Consultancy. Ladetto:Celgene: Research Funding; Janssen-Cilag: Research Funding. Boccadoro:Celgene: Consultancy, advisory Committees, Research Funding; Janssen-Cilag: Consultancy, advisory Committees, Research Funding; Pharmion: Consultancy, advisory Committees, Research Funding. Palumbo:Celgene: Honoraria; Janssen-Cilag: Honoraria.