High-dose melphalan with autologous stem cell transplantation is an important consolidative strategy for treating multiple myeloma. However, a core question is the timing of intensive treatment when combination regimens such as lenalidomide, bortezomib, and dexamethasone (RVD) can achieve deep responses with minimal toxicity. Recently, the Intergroupe Francophone du Myélome (IFM) reported the results of a large phase III trial, IFM 2009, that was designed to answer the question of when to undergo autologous stem cell transplantation: upfront as part of the initial treatment, versus at time of relapse.
In this trial, all patients (N=700) received standard induction with RVD for three cycles followed by stem cell collection. The patients were then randomized to upfront transplant with high-dose melphalan and autologous stem cell transplantation, followed by consolidation with two additional cycles of RVD. The other half went on to five additional cycles of RVD for a total of eight cycles. Following completion of initial treatment, both groups received maintenance lenalidomide for one year. The median progression free survival (PFS) was significantly longer in the upfront arm than in the deferred arm, 50 versus 36 months (p<0.001). Depth of response was also higher in patients who received intensive therapy initially, based on achieving complete response (59% vs. 48%; p=0.03) and absence of minimal residual disease (MRD; 79% vs. 65%; p<0.001). (Of note, MRD was measured by a flow cytometry assay with a sensitivity of 1´10-4, which is less sensitive than current assasys such as by next- generation sequencing.) Overall, patients who were MRD-negative had improved PFS and overall survival (OS) compared with MRD-positive patients (HR, 0.3 and 0.34, respectively). However, at four years, OS was similar, at 81 percent versus 82 percent between the MRD-negative and MRD-positive arms, respectively. As expected, there were more adverse events related to myelosuppression and gastrointestinal adverse effects in the upfront transplant arm. Also of interest were four cases of acute myelogenous leukemia in the upfront arm versus one case in the deferred arm.
The results from this study are key for helping to frame the discussion with patients about the timing of transplant. The induction regimen of RVD used in the study reflects current practice, especially given the recent SWOG trial showing superiority of the triplet compared with lenalidomide and dexamethasone.1 The trial illustrates the importance of depth of response correlating with improved outcomes, and an upfront approach provides a means for achieving this. Despite the significant improvement in PFS, there was no OS advantage. This is likely a reflection of the evolving maturity of the data. Importantly, in the deferred arm, 21 percent of patients were not able to receive a salvage transplant due to refractory disease, and there were also an increased number of myeloma-related deaths.
In Brief
The DETERMINATION trial (NCT01208662) is an ongoing investigation in the United States that parallels the IFM study with the same trial design. The DETERMINATION trial is actively accruing patients, and the findings from this study will be an important complement to the IFM study. The main difference in the U.S. arm of the trial is the duration of maintenance lenalidomide. In the U.S. arm, patients are maintained until relapse, whereas in the IFM study, maintenance was for one year only. Maintenance lenalidomide is increasingly becoming adopted as standard practice in the United States based on trials showing improvement in PFS, and in a meta-analysis, improvement in OS.2 Results from DETERMINATION will provide greater clarity on how long to use maintenance lenalidomide and whether longer maintenance will narrow the gap in PFS between upfront and deferred transplant approaches. Additionally, the larger number of patients, when combined with the IFM study, may help identify subgroups who benefit more from upfront transplant. In the IFM study, there was no statistically significant improvement in PFS for patients with high-risk disease, based on International Staging System (ISS) III staging or by cytogenetics, though this may reflect the smaller number of patients in these groupings. Finally, there will be more robust data from MRD assessments using a more sensitive sequencing assay, which is relevant since achieving MRD negative status resulted in improved disease control irrespective of treatment arm. This may help clarify if patients who are MRD negative may consider a deferred transplant approach. Overall, the results from the U.S. arm, combined with the IFM 2009 results, will provide valuable guidance on the place of autologous stem cell transplantation and help individualize treatment for newly diagnosed patients.
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Competing Interests
Dr. Yee and Dr. Raje indicated no relevant conflicts of interest.
