Updated Myeloma Trial Shows Lenalidomide Maintenance Post-Transplant Improves Progression-Free But Not Overall Survival
A new analysis of the multiple myeloma IFM 2005-02 trial showed that lenalidomide (Revlimid) maintenance prolongs progression-free survival after stem cell transplantation, but does not improve overall survival. This is possibly attributed to the shorter survival time after first disease progression than is observed in patients receiving placebo, investigators suggested.
The study, presented by Michel Attal, MD, of the Centre Hospitalier Regional Universitaire Hôpital Purpan in Toulouse, France, was met with some surprise by attendees at a session during the 55th American Society for Hematology (ASH) Annual Meeting and Exposition (Abstract 406). Debate and proposed explanations by myeloma experts during the discussion will be presented in a future edition of The ASCO Post.
IFM 2005-02 Trial
IFM 2005-02 was a randomized, placebo-controlled phase III trial that investigated the efficacy of lenalidomide maintenance after transplantation in 614 myeloma patients under 65 years old whose disease had not progressed after first-line autologous stem cell transplant. Patients were randomly assigned to maintenance therapy with lenalidomide (10–15 mg/d) or placebo until disease progression. The initial findings were reported after a median follow-up of 45 months.
The initial analysis found an improvement in progression-free survival but not overall survival, and the investigators hypothesized that the discrepancy might stem from insufficient follow-up and therefore a low number of reported deaths, or to worse outcomes after progression in the lenalidomide arm, possibly due to clonal selection and/or induced resistance with lenalidomide therapy.
“We felt that a follow-up analysis was required to answer this,” Dr. Attal said. The data cutoff for this subsequent analysis was November 2013, which was at 67 months postrandomization and 77 months postdiagnosis. No patient in the placebo arm received lenalidomide before disease progression, but about half the patients underwent a second transplant sometime in their disease course, he indicated.
New Analysis Looks Closely at Progression
In the new analysis, median progression-free survival from randomization was 46 months with lenalidomide and 24 months with placebo (P < .001) but median overall survival was still not significantly improved with maintenance, despite the longer 77 months of follow-up. Median overall survival was 81 and 82 months in the two study groups, respectively (P = .80), Dr. Attal reported.
“The discrepancy between progression-free survival and overall survival was still present,” he said. “We believe the poor outcome after progression for patients in the lenalidomide maintenance group is the most reliable hypothesis.”
Describing the “poor outcome after progression” in the lenalidomide maintenance arm, Dr. Attal called attention to the median second progression-free survival, which was the time from the first progression to the second progression. In this scenario, the placebo arm was superior, with median second progression-free survival of 24 months vs 13 months with lenalidomide (P = .001).
About 50% of patients received an immunomodulatory drug–based regimen upon first progression, and in this group median second progression-free survival was 19 months with placebo and 8 months with lenalidomide (P = .003). For the 25% of patients receiving a bortezomib (Velcade)-based regimen, median progression-free survival was 8 and 9 months, respectively (P = .28). For the 25% of patients who received no new agents, median progression-free survival was 30 months vs 18 months, respectively (P = .06).
Dr. Attal suggested that the reduced second progression-free survival with maintenance may be due to clonal selection or secondary resistance, suggested by the median progression-free survival in the immunomodulatory drug group and the no new agent group.
Second primary malignancies totaled 21 (7%) in the placebo arm and 37 (13%) in the lenalidomide arm, for a cumulative incidence of 20.6 per 1,000 patient-years with placebo and 33.7 with lenalidomide, a statistically significant difference (P = .025). The lenalidomide cohort also had more severe neutropenia (51% vs 18%).
Meaning of the Findings
The meaning of these findings, according to Dr. Attal, is that “the benefit of lenalidomide maintenance is an early benefit, occurring in the first 2 years. Then, in the lenalidomide maintenance arm, we see the late negative impact of maintenance due to emergence of resistance,” he suggested.
While Dr. Attal declined to make a treatment recommendation based on the data, he did agree with Sundar Jagannath, MD, the Director of the Multiple Myeloma Program at Mount Sinai Hospital, New York, that it helps to view the findings for their relevance in elderly patients, as compared to younger newly diagnosed patients. An overall survival benefit has been shown for lenalidomide maintenance in older patients, including the FIRST trial presented at an ASH Plenary Session, he noted.
For full disclosures of the study authors, view the study abstract on the ASH website.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
