Lenalidomide as Maintenance in Transplant Myeloma Population Still Debated
While the FIRST trial in transplant-ineligible patients demonstrated the benefit of continuous lenalidomide, studies in younger transplant patients yielded conflicting results for maintenance lenalidomide, especially with regard to an overall survival (OS) advantage.
Mayo Clinic investigators performed a systematic review and meta-analysis of existing outcome data – updated with data from ASH – to evaluate the role of lenalidomide as maintenance therapy.
They identified 4 randomized controlled trials (IFM 2005-02, CALGB 100104, MM-015, and RV-MM-PI209) that met the inclusion criteria, involving 1935 patients who received lenalidomide 10 mg daily after induction or transplant, continued until progression.
Meta-Analysis Shows PFS but Not OS Benefit
“All 4 studies showed an improvement in PFS [progression-free survival], with an overall 51% reduction in risk of progression (P<.001),” reported Preet Paul Singh, MD. “There was modest [but nonsignificant] improvement in OS with lenalidomide maintenance, with 2 studies showing a benefit and 2 not showing any, resulting in a modest 23% reduction in risk (P=.071).”
But the use of lenalidomide maintenance was also associated with a 62% increase in the risk of second primary malignancies (P=.006), as well as a 4.9-fold increased risk of neutropenia (P<.001), a 2.7-fold increase in thrombocytopenia (P<.001), a 2.3-fold risk in fatigue (P=.01), and a 3.2-fold increase in venous thromboembolism (P=.02).
“The subset of patients benefitting the most from lenalidomide maintenance is not yet defined, and the risks and benefits should be discussed with all patients,” Singh said.
Lenalidomide Maintenance in Updated IFM 2005-02 Analysis
Similarly, a new analysis of the multiple myeloma IFM 2005-02 trial showed that lenalidomide maintenance prolongs PFS after stem cell transplantation but does not improve OS. The results are contradictory to those of the CALGB 100104 trial, which found an OS benefit and therefore established the lenalidomide maintenance paradigm.
IFM 2005-02 was a randomized, placebo-controlled phase 3 trial that investigated the efficacy of lenalidomide maintenance after transplantation in 614 myeloma patients younger than 65 years who had not progressed after first-line autologous stem cell transplant. Patients were randomized to maintenance with lenalidomide (10-15 mg/day) or placebo until disease progression.
The initial analysis found an improvement in PFS but not OS. To evaluate why no OS benefit was found, the investigators conducted a follow-up analysis.
In the new analysis, median PFS from randomization was 46 months with lenalidomide and 24 months with placebo (P<.001), but despite the longer 77-month follow-up, median OS was still not significantly improved with maintenance lenalidomide, being approximately 80 months in each arm (P=.80).
“The discrepancy between PFS and OS was still present,” said Michel Attal, MD, of the Centre Hospitalier Regional Universitaire Hôpital Purpan in Toulouse, France. “This is possibly attributed to the shorter survival time after first disease progression in the maintenance arm than is observed in patients receiving placebo.”
Attal called attention to the median second PFS, which was the time from the first progression to the second progression. In this scenario, the placebo arm was superior, with a median second PFS of 24 months versus 13 months with lenalidomide (P=.001). He suggested that the reduced second PFS with maintenance may be the result of resistance clones that emerge after extended treatment with lenalidomide.
Second primary malignancies were also almost twice as high in the lenalidomide arm, and rates of severe neutropenia were 3 times higher.
The meaning of these findings, according to Attal, is that “the benefit of lenalidomide maintenance is an early benefit, occurring in the first 2 years,” after which resistance emerges and creates “a late negative impact of maintenance.”