Multiple myeloma management with lenalidomide, bortezomib and dexamethasone associated with prolonged progression-free survival

1. The use of lenalidomide, bortezomib and dexamethasone (RVD) with transplantation was associated with a significantly longer progression-free survival compared to RVD therapy alone.

2. There was no difference in overall survival between the two therapeutic approaches.

Evidence Rating Level: 1 (Excellent) 

Study Rundown: The standard of therapy for newly diagnosed multiple myeloma patients less than 65 years old has been high-dose chemotherapy and autologous stem-cell transplant. The associated toxicity and requirement for hospitalization during treatment has given rise to using of immunomodulatory drugs and proteasome inhibitors. More importantly, the combination of these agents has improved rates of complete response and outcomes, for both transplant and non-transplant eligible patients. Though these benefits exist, there remains questions regarding the timing and role of transplantation. As such, this phase 3 trial compared induction with 3 cycles of RVD, consolidation with a further 5 cycles of RVD, then 2 additional cycles of RVD, versus 3 cycles of RVD, consolidation with high-dose melphalan and stem-cell transplantation, then 2 additional cycles of RVD. Both arms received lenalidomide maintenance therapy for 1 year. The transplantation arm had longer median progression free survival compared to RVD alone. However, there was no difference in overall survival, and the transplantation arm had higher rates of neutropenia, gastrointestinal disorders and infections. The major strength of this study is its methods randomized controlled trial) and large study numbers, significant enough to power the study and enable valid conclusions to be drawn.

Click to read the study in NEJM

Relevant Reading: Autologous transplantation and maintenance therapy in multiple myeloma

In-Depth [randomized controlled trial]: This study examined the impact of transplantation in treating multiple myeloma patients under the age of 65. Randomization was to either induction with 3 cycles of RVD, consolidation with a further 5 cycles of RVD, then 2 additional cycles of RVD, versus 3 cycles of RVD, consolidation with high-dose melphalan and stem-cell transplantation, then 2 additional cycles of RVD. The primary endpoint was progression-free survival.

Of the 764 patients screened for study eligibility, 700 patients were ultimately enrolled in the study, 350 were randomized to the transplant arm and 350 to the RVD alone arm. The rate of complete response was 48% in the RVD-along group versus 59% in the transplantation group (p = 0.03). The median duration of follow-up after randomization was 44 months in the RVD-alone group, and 43 months in the transplantation group. Median progression-free survival was 36 months in the RVD-alone group, versus 50 months in the transplantation group (adjusted HR for disease progression or death, 0.65; 95%CI 0.53-0.80; p < 0.001. Overall survival between the two groups at 4 years did not significantly differ (82% RVD-alone, versus 81% transplantation; HR 1.16, 95%CI 0.80 -1.68; p = 0.87). In terms of toxicity, grade 3 or 4 adverse events were significantly more common in the transplantation group compared to the RVD-alone group with respect to hemapoetic and lymphatic-system disorders (95%vs 64%, p < 0.001), gastrointestinal disorders (28% vs 7%, p < 0.001), and infections (29% vs 9%, p < 0.001).

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