Proteomic Profiling of Multiple Myeloma (MM) Cells Using iTRAQ and Label-Free Quantitative Proteomics for the Prediction of Complete or near Complete Response (CR/nCR) In Frontline Treatment with Lenalidomide, Bortezomib, and Dexamethasone

Abstract 618 Introduction: Despite an increased number of new treatments, multiple myeloma (MM) remains mostly incurable. There is emerging evidence that achieving complete or near complete response (CR/nCR), or at least a 90% reduction of the disease (≥VGPR), in response to initial treatment when MM is most sensitive to chemotherapy is associated with improved progression-free survival (PFS) and possibly overall survival (OS). However, even with the most active regimens, a majority of patients (pts) with newly diagnosed MM achieve less than CR/nCR to initial therapy. The objective of this study is to establish predictors of response and drug resistance by applying proteomic profiling of MM. Here we present the analysis of differential proteomic profiling of baseline plasma cells (PCs) from pts with MM predicting achievement of CR/nCR after completion of a course of first line treatment with lenalidomide (Revlimid®), bortezomib (Velcade®), and dexamethasone (RVD) regimen. Methods: After obtaining informed consent from pts, we performed quantitative proteomic analysis of PCs isolated from bone marrow of 16 pts with previously untreated MM enrolled at the University of Michigan site in the Phase II portion of the multi-site frontline RVD clinical trial. Eight of the analyzed pts achieved CR/nCR, while the remaining had a lesser response (6 VGPR, 2 PR i.e ≥50% but Results: A total of 926 proteins were identified with high confidence (FDR Dytfeld et al. ASMS, 2009 ). Interestingly, one of these enriched networks of 50 proteins consisted of 26 proteins that were derived from our therapeutic response signature. Included within this network were canonical pathways involving vascular endothelial growth factor receptor 2, p53 binding protein homolog mdm2, p53, nucleoside-diphosphate kinase A/B and Bcl2. Conclusions: We analyzed proteomic characteristics of patient-derived MM cells using two independent proteomics platforms. As a proof of concept, analysis of PCs obtained from pts enrolled in the frontline RVD trial shows differential expression of 70 proteins in patients who achieved CR/nCR versus those with a lesser response. Consistent with our prior observations, differentially regulated proteins are involved in the c-Myc pathway, which has an established critical role in pathogenesis of MM. Validation studies of candidate proteins are in progress. This study was supported by a grant from the Multiple Myeloma Research Foundation. Disclosures: Off Label Use: Lenalidomide in combination with bortezomib and dexamethasone for the treatment of newly diagnosed Myeloma. Richardson: Millennium Pharmaceuticals, Inc.: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Novartis: Membership on an entity9s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity9s Board of Directors or advisory committees. Jakubowiak: Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria; Exelixis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding.