The Hematologist

May-June 2011, Volume 8, Issue 3

Induction Combination Novel Agent Therapies in Myeloma

Kenneth C. Anderson, MD Kraft Family Professor of Medicine
Harvard Medical School; Dana-Farber Cancer Institute, Boston, MA

Published on: May 01, 2011

Dr. Anderson serves on advisory committees for Celgene and Millennium. 

Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 

In this study, Cavo and colleagues from Italy report on the relative efficacy of thalidomide and dexamethasone (TD) versus bortezomib-thalidomide-dexamethasone (VTD) used both as initial therapy and as consolidation treatment after high-dose melphalan and stem cell transplantation in multiple myeloma (MM). The primary metric of efficacy was complete response (CR) or near complete response (nCR) rate after induction therapy. Importantly, the rate of CR or nCR was 31 percent after VTD versus 11 percent after TD (p < 0.0001). Moreover, rates of CR, nCR, or very good partial response (VGPR) were higher with VTD than TD after first transplant, after second transplant, and with consolidation therapy. The estimated three-year rate of progression-free survival (PFS) was greater after VTD than TD, at 68 percent versus 56 percent, respectively (p<0.006). However, the estimated three-year overall survival (OS) rate was not statistically different, at 86 percent versus 84 percent post VTD and TD, respectively (p=0.30). Grade 3 or 4 adverse events occurred in 56 percent of patients on VTD and in 33 percent of patients on TD (p<0.0001), including 10 percent versus 2 percent grade 3 or 4 neuropathy after VTD and TD, respectively, which resolved in the majority of cases.

Novel agents have now been shown to be efficacious to treat relapsed and refractory, relapsed, and newly diagnosed MM. In transplant-eligible patients, two drug induction regimens, including dexamethasone with thalidomide, lenalidomide, or bortezomib, achieve high extent and rate of response prior to transplantation, which portends improved outcomes post-transplant. In patients with relapsed MM, three drug regimens incorporating novel agents, such as VTD or lenalidamide VD (RVD), have shown activity even in patients whose disease is resistant to either single novel-agent therapy. Excitingly, three drug regimens, such as VTD, RVD, or cyclophosphamide VD, achieve responses in the majority of patients with newly diagnosed MM, with an unprecedented extent of response, including some molecular complete responses. Cavo and colleagues in this study for the first time report a randomized trial comparing two versus three novel drug combination therapies, not only as induction therapy prior to autologous stem cell transplantation, but also as consolidation treatment. Remarkably, at every point along the disease course, including pre-transplant, after first transplant, after second transplant, and as consolidation, there were statistically significant increases in overall and extent of response with VTD versus TD. Of note, there was an upgrade in extent of response related to consolidation VTD therapy post-transplant, as has been observed with use of lenalidomide, further confirming incorporation of novel therapy in this fashion. As in multiple previous studies, incorporation of bortezomib overcame the adverse effects of t(4;14). And most importantly, molecular responses were more frequently achieved with VTD, a depth of response not previously achieved in MM except after allografting, when it portends prolonged disease-free survival. Finally, these unprecedented results achieved with incorporation of induction combination novel therapies into the transplant paradigm further support the rationale for ongoing studies to determine the contribution of high-dose therapy to this outcome.

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