The Magic Number Is Three (Or Is It?)
Published on: November 01, 2012
Dr. Leleu has research grants and receives lecture fees and board honoraria from Celgene and Janssen.
Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR /IFM 2005-04 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30:2475-2482.
Patients with multiple myeloma (MM) usually respond favorably to initial therapy and experience a prolonged period of progression-free survival (PFS). However, the disease invariably recurs, and time to relapse shortens with successive treatments. Ultimately, the disease becomes refractory to therapy. The median survival time for patients with MM is in the range of five to seven years, with a median time from diagnosis to first relapse of approximately three years. Clearly, there is a need to improve treatment of relapsed disease with a goal of improving survival. To address this issue, the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplant initiated a prospective, multicenter, phase III study comparing the efficacy and safety of a triple drug combination (bortezomib, thalidomide, and dexamethasone [VTD]) with a dual combination (thalidomide and dexamethasone [TD]) in patients with MM progressing or relapsing after treatment with high-dose chemotherapy with autologous stem cell rescue. Overall, 269 patients were randomly assigned to receive either bortezomib (1.3 mg/m2 intravenously) or no bortezomib in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg daily for 4 days once every three weeks). Treatment cycles were 21 days, and the duration of treatment was one year. The bortezomib was given twice weekly for two consecutive weeks (days 1, 4, 8, and 11) followed by a 10-day rest period for the first 8 cycles (6 months). Subsequently, the schedule of bortezomib was days 1, 8,15, and 22 followed by a 20-day rest period (42-day cycle) for 4 cycles over a total of 6 months. Overall, the complete response plus near-complete response rate was significantly higher (45% vs. 25%; p=0.001), and the median duration of response was significantly longer (17.2 vs. 13.4 months; p=0.03) with VTD compared with TD. The median time to progression (a primary endpoint of the study) was significantly longer with VTD, 19.5 versus 13.8 months; p=0.001. However, with a median follow-up of 30 months, there was no survival difference between the two groups. Toxicity was greater with VTD compared with TD, especially the incidence of peripheral neuropathy, 41 percent versus 18 percent, respectively. More importantly, the incidence of grade 3 and worse neuropathy was significantly higher in the VTD cohort compared with the TD, 31 percent versus 14 percent (p=0.001). The authors also reported higher rates of grade 3 or worse infectious complication and thrombocytopenia in the VTD arm. Thus, the three-drug regimen was more effective than the two-drug regimen in the treatment of MM at first relapse after high-dose chemotherapy followed by autologous stem cell rescue, but the VTD regimen was associated with a significantly worse toxicity profile than the TD regimen with no survival difference observed between to two regimens.
When used as initial treatment for MM, VTD has demonstrated a high complete response rate and prolonged PFS in patients with either standard or high-risk genetic features. Additionally, the use of the VTD combination in the post-transplantation setting induced molecular responses in a subset of patients, many of whom experienced long periods of treatment-free remission. The current study shows that response rates and PFS are significantly better with the three-drug regimen than the two-drug regimen, but overall survival between the two study arms was not significantly different, and the toxicity profile of the three-drug regimen was unfavorable compared with that of the two-drug regimen. The higher incidence of grade 3 or worse neuropathy in the VTD-treated group is likely a consequence of concomitant use of thalidomide and bortezomib. The next generation of immunomodulatory drugs and proteasome inhibitors will almost certainly replace thalidomide and bortezomib, respectively, and the toxicity profiles of the newer combinations will likely be more favorable than their older counterparts. A more favorable toxicity profile would increase enthusiasm for a triple-drug regimen, but an impact on overall survival would really make three the magic number.
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