Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma

Abstract

Background: High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation.

Methods: We randomly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD (350 patients) or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD (350 patients). Patients in both groups received maintenance therapy with lenalidomide for 1 year. The primary end point was progression-free survival.

Results: Median progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P=0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P<0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy.

Conclusions: Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches. (Supported by Celgene and others; IFM 2009 Study ClinicalTrials.gov number, NCT01191060 .).

Figure 1.. Kaplan-Meier Curves for Progression-free Survival and Overall Survival according to Treatment Group.

Panel A shows progression-free survival. Median progression-free survival was 36 months in the RVD group and 50 months in the placebo group (hazard ratio, 0.65; P <0.001) Panel B shows overall survival. The overall survival 4 years after randomization was similar in both arms (hazard ratio, 1.14; P=0.43).

Figure 2.. Forest Plot of Progression-free Survival, showing Hazard Ratios by Patient Subgroups.

The figure shows that the progression-free survival benefit associated with transplantation was consistent across all subgroups of patients defined by age, sex, type of myeloma, International Staging System stage, or cytogenetic features. The position of each square represents the point estimate of the treatment effect; horizontal lines represent 95% confidence intervals.