CLINICAL OUTCOMES PREDICTION FOR NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS TREATED WITH THALIDOMIDE-DEXAMETHASONE AND AUTOLOGOUS STEM CELL TRANSPLANTATION BY 8-GENE SIGNATURE OF CD138+ PLASMA CELLS

Background. Efficacy of Thalidomide-dexamethasone (TD) as induction therapy in preparation for autologous stem cell transplantation (ASCT) in multiple myeloma provided the basis for the design of the phase II “Bologna 2002”study incorporating TD into double autotransplantation as up-front therapy for younger patients (pts) with newly diagnosed disease. Aim. We performed a molecular study aimed at identifying a gene expression profile (GEP) signature predictive of attainment of at least near complete response (nCR) to TD and subsequent autotransplantation. Methods. For this purpose, we analyzed bone marrow samples obtained at diagnosis from 112 pts who received TD before double ASCT. The differential gene expression of CD138+ enriched plasma cells was evaluated by means of expression microarray using the Affymetrix platform. Significant expression results were validated by Real-time PCR. Results. Two subsequent study phases were planned. Firstly, a GEP supervised analysis was performed on a training set of 32 pts, allowing to identify 157 probe sets differentially expressed (P<0.05) in pts with at least nCR (e.g. responders) versus those who failed at least nCR (e.g. non responders) to TD induction therapy. Most of the 157 genes resulted down expressed in responder pts and were mainly involved in cell cycle and apoptosis regulation. In particular, signaling pathways which might be affected by the de-regulated expression of genes in responding pts, are the MAPK signaling pathway (Ppp3r1, PRKY, PRKX, FAS, ATF2, MAP4K3 and DUSP4), the Wnt signaling pathway (Ppp3r1, PRKY, PRKX and CCND2) and the p53 pathway (CCND2, FAS, CCNDE and MDM2).In the second phase of the study, we generated an 8-gene GEP signature which predicted at diagnosis the probability to achieve at least a nCR after TD induction therapy. The performance of this assay was subsequently validated by Real-time PCR in a training set of 80 pts: 36 pts were predicted as responders to TD , whereas 44 as non responders. The post autotransplantation outcome was analyzed according to Real-time expression results. On an intention-to-treat basis, the rate of CR, either immunofixation negative or positive, was 51.4% among CR-predicted ps and 23% (P=0-001) in the subgroup of 44 NR-predicted pts. The 65-months probability of OS for CR-predicted pts was 72% as compared to 41% for those who were predicted to be NR (P=0.03). The projected rates of TTP and PFS at 55 months for CR-predicted and NR-predicted pts were 69% vs. 34% (P=0.003) and 55% vs. 19% (P=0.01), respectively. Conclusions. These results can be an important first step to identify at diagnosis those pts who are more likely to respond favorably to a particular treatment strategy. Supported by the Università di Bologna, Ricerca Fondamentale Orientata (RFO) (M.C.), Fondazione Carisbo and the Italian Association against Leukemia, (BolognAil).