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.
|O'Donnell, Elizabeth K; Laubach, Jacob P; Yee, Andrew J et al. (2018) A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol 182:222-230|
|Guo, Guangwu; Raje, Noopur S; Seifer, Charles et al. (2018) Genomic discovery and clonal tracking in multiple myeloma by cell-free DNA sequencing. Leukemia 32:1838-1841|
|Szalat, R; Samur, M K; Fulciniti, M et al. (2018) Nucleotide excision repair is a potential therapeutic target in multiple myeloma. Leukemia 32:111-119|
|Nair, Shiny; Sng, Joel; Boddupalli, Chandra Sekhar et al. (2018) Antigen-mediated regulation in monoclonal gammopathies and myeloma. JCI Insight 3:|
|Gullà, A; Hideshima, T; Bianchi, G et al. (2018) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32:996-1002|
|Mazzotti, Céline; Buisson, Laure; Maheo, Sabrina et al. (2018) Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv 2:2811-2813|
|Miannay, Bertrand; Minvielle, Stéphane; Magrangeas, Florence et al. (2018) Constraints on signaling network logic reveal functional subgraphs on Multiple Myeloma OMIC data. BMC Syst Biol 12:32|
|Samur, Mehmet Kemal; Minvielle, Stephane; Gulla, Annamaria et al. (2018) Long intergenic non-coding RNAs have an independent impact on survival in multiple myeloma. Leukemia 32:2626-2635|
|Singh, Irtisha; Lee, Shih-Han; Sperling, Adam S et al. (2018) Widespread intronic polyadenylation diversifies immune cell transcriptomes. Nat Commun 9:1716|
|Xu, Yan; Deng, Shuhui; Mao, Xuehan et al. (2018) Tolerance, Kinetics, and Depth of Response for Subcutaneous Versus Intravenous Administration of Bortezomib Combination in Chinese Patients With Newly Diagnosed Multiple Myeloma. Clin Lymphoma Myeloma Leuk 18:422-430|
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