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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|Prabhala, R H; Fulciniti, M; Pelluru, D et al. (2016) Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma. Leukemia 30:379-89|
|Magrangeas, Florence; Kuiper, Rowan; Avet-Loiseau, HervÃ© et al. (2016) A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma. Clin Cancer Res 22:4350-5|
|Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258|
|Dimopoulos, Meletios A; Orlowski, Robert Z; Facon, Thierry et al. (2015) Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma. Haematologica 100:100-6|
|Bianchi, Giada; Munshi, Nikhil C (2015) Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood 125:3049-58|
|Jagannathan, S; Vad, N; Vallabhapurapu, S et al. (2015) MiR-29b replacement inhibits proteasomes and disrupts aggresome+autophagosome formation to enhance the antimyeloma benefit of bortezomib. Leukemia 29:727-38|
|Hu, Y; Song, W; Cirstea, D et al. (2015) CSNK1Î±1 mediates malignant plasma cell survival. Leukemia 29:474-82|
|Hebraud, Benjamin; Magrangeas, Florence; Cleynen, Alice et al. (2015) Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience. Blood 125:2095-100|
|Mitsiades, Constantine S (2015) Therapeutic landscape of carfilzomib and other modulators of the ubiquitin-proteasome pathway. J Clin Oncol 33:782-5|
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