Our preclinical studies confirmed that the combination of lenalidomide with Bortezomib targeting multiple myeloma (MM) cell in its microenvironment triggered dual apoptotic signaling. Our collaborators at the Dana Farber Cancer Institute (DFCI rapidly translated these data to a phase l/ll clinical trial of combination lenalidomide, Bortezomib and Dexamethasone (RVD) therapy in relapsed refractory MM which defined the MTD, favorable tolerability, and remarkable anti-MM activity. A phase l/ll trial of RVD in newly diagnosed MM patients showed 100% responses (^PR) even in high risk cytogenetic subgroups, including 48% CR/nCR and 74% SVGPR. These unprecedented rates and extent of response to initial therapy raise an important question regarding the role of high-dose therapy and stem cell transplantation (HDT) with RVD combination therapy. Our hypothesis is that the integration of HDT following induction with RVD combination therapy will improve outcome in MM. In this Project, we will randomize 1,000 patients to RVD versus RVD with HDT to determine whether addition of HDT improves time to progression, response, event free, and overall survival (Sp Aim la). We will determine whether known prognostic factors such as the International Staging System (a2 microglobulin and albumin), LDH, and FISH, as well as recently reported combination of ISS and FISH abnormalities, correlate with response and survival outcomes (Sp Aim lb).
In Specific Aim 2 we will evaluate whether further stringent CR definition predicts superior survival outcome. We will compare normalization of serum free light chain, immunophenotypic CR using multicolor flow cytometric immunophenotyping of MM cells in bone marrow, and molecular CR using ASO-PCR as measures to detect minimal residual disease to define stringent CR. This project will determine role of high-dose therapy In the era of novel agent therapy.
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|Hu, Y; Song, W; Cirstea, D et al. (2015) CSNK1?1 mediates malignant plasma cell survival. Leukemia 29:474-82|
|Moreau, Philippe; Cavo, Michele; Sonneveld, Pieter et al. (2014) Combination of international scoring system 3, high lactate dehydrogenase, and t(4;14) and/or del(17p) identifies patients with multiple myeloma (MM) treated with front-line autologous stem-cell transplantation at high risk of early MM progression-related J Clin Oncol 32:2173-80|
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|Chretien, Marie-Lorraine; Hebraud, Benjamin; Cances-Lauwers, Valérie et al. (2014) Age is a prognostic factor even among patients with multiple myeloma younger than 66 years treated with high-dose melphalan: the IFM experience on 2316 patients. Haematologica 99:1236-8|
|Samur, Mehmet Kemal (2014) RTCGAToolbox: a new tool for exporting TCGA Firehose data. PLoS One 9:e106397|
|Cottini, Francesca; Hideshima, Teru; Xu, Chunxiao et al. (2014) Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nat Med 20:599-606|
|Hebraud, B; Leleu, X; Lauwers-Cances, V et al. (2014) Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: the IFM experience on 1195 patients. Leukemia 28:675-9|
|Cooke, Susanna L; Shlien, Adam; Marshall, John et al. (2014) Processed pseudogenes acquired somatically during cancer development. Nat Commun 5:3644|
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