Multiple Myeloma: To T or Not to T, What Will the Answer Be?

Randomized Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib, and Dexamethasone (RVD) to High-Dose Treatment With Peripheral Autologous Stem Cell Transplant in the Initial Management of Myeloma in Patients Up to 65 Years of Age

Dana-Farber Cancer Institute, University Hospital, Toulouse, France (for the Intergroupe Francophone du Myelome), Celgene Corporation, and Janssen-Cilag, Ltd.

NCT01191060

One thousand patients, 65 years of age or less, with newly diagnosed multiple myeloma who are stem cell transplant candidates with adequate cardiac, pulmonary, renal, and hepatic function will receive one cycle of RVD and then be randomized to arms A or B, with stratification based on International Staging System criteria (stage I, II, or III) and cytogenetics (standard vs. high-risk vs. FISH failures). Subsequently, all patients will receive two additional courses of RVD and have collection of peripheral blood stem cells mobilized using cyclophosphamide and filgastrim. Patients in arm A receive an additional five cycles of RVD; those in arm B undergo treatment with high-dose melphalan and autologous stem cell transplant (ASCT) followed by two cycles of RVD. All patients then receive maintenance lenalidomide for at least one year, with ASCT used for patients in Arm A at relapse.

This clinical trial will compare the progression-free survival between Arms A and B, and therefore determine the added value of early use of ASCT in the context of RVD therapy. Response rates, time to progression, overall survival, toxicity, and definition of prognostic groups by gene expression profiling with determination of the best treatment in each group are secondary endpoints. Additionally, both quality of life and resource utilization data will be collected for use in economic evaluation models.

ASCT has been a standard of care in myeloma due to achievement of both high extent and frequency of response and to the prolonged progression-free survival compared with conventional chemotherapy. However, the availability of novel therapies, including bortezomib and lenalidomide, that have improved outcome has impacted the transplant paradigm. Both lenalidomide and bortezomib in combination with dexamethasone achieve high-quality responses pre-ASCT that portend improved outcome post-ASCT. Further, the combination of lenalidomide, bortezomib, and dexamethasone achieves responses universally, with 74 percent very good partial response or better and 52 percent complete and near complete responses, including molecular complete responses, when used as initial therapy without ASCT. Thus, the stage is set to examine the role of ASCT in the context of this remarkable response to combined novel therapies, a comparison that is arguably one of the most pressing issues in clinical myeloma research today. Already, the incorporation of novel therapies into induction therapy has increased response extent and frequency both before and after single ASCT, as well as prolonged, progression-free, and overall survival therafter, making the examination of RVD therapy with and without transplant especially timely.

Importantly, this study will not only compare clinical outcome between arms A and B, but also utilize gene expression profiling to define prognostic groups for each therapeutic arm, and carefully assess side effect profile, quality of life, and cost. Correlative studies will also evaluate the impact of various genomic variables including copy number alteration using single nucleotide polymorphism array technology, alternate splicing, microRNA profiling, and whole-genome sequencing at the time of diagnosis and relapse in order to characterize disease heterogeneity, mechanisms of sensitivity versus resistance, and molecular response rates, and to define new therapeutic targets, thus making the study a major advance toward personalized medicine in myeloma. Finally, it should add to the encouraging, emerging data suggesting that lenalidomide maintenance prolongs both progression-free and overall survival.