A meta-analysis of overall survival (OS) in 3 clinical trials of lenalidomide (Revlimid) maintenance therapy after high-dose melphalan (Alkeran) and autologous stem-cell transplantation (ASCT) for multiple myeloma showed long-term disease control and prolonged OS. A slightly increased risk for a secondary primary malignancy is outweighed by the OS benefit, said lead investigator Philip McCarthy, MD, Roswell Park Cancer Institute, Buffalo, NY, in an oral presentation at the 2016 American Society of Clinical Oncology annual meeting.
The majority of patients with multiple myeloma who have undergone ASCT will relapse or will have disease progression, even those patients who have a complete response to treatment, said Dr McCarthy.
In addition, he noted that although lenalidomide maintenance therapy has demonstrated an approximate 50% reduction in the risk for disease progression or death in previous studies, progression-free survival was the end point of those studies, not OS. All of the clinical trials included in Dr McCarthy’s meta-analysis had trends favoring lenalidomide maintenance therapy with respect to OS, and the prospective pooling of their patient-level data enabled a fully powered survival analysis.
The 3 phase 3 clinical trials of multiple myeloma—CALGB 100104 (Alliance), IFM 2005-02, and GIMEMA (RVMM-PI-209)—investigated the safety and efficacy of lenalidomide maintenance therapy administered after ASCT until disease progression, and included 605 patients receiving lenalidomide (ie, the maintenance arm) and 604 patients receiving placebo or no maintenance therapy (ie, the control arm). The median age was 58 years, and 24% of the patients had previous lenalidomide therapy induction. Adverse-risk cytogenetics (t[4;14] or del17p) were more common in the maintenance therapy arm than in the control arm (15% vs 10%, respectively).
In the pooled studies, the 7-year OS rate after a median follow-up of 80 months was 62% in the maintenance therapy arm and 50% in the control arm (hazard ratio [HR], 0.74; 95% confidence interval, 0.62-0.89; P = .001). The HRs favored lenalidomide for each of the trials considered separately (0.56 in CALGB; 0.91 in IFM; 0.66 in GIMEMA). In subgroup analyses, an OS benefit was observed with lenalidomide regardless of age, sex, or response after ASCT. The OS was greater, however, among patients with stronger post-ASCT responses. Dr McCarthy noted that the findings show that lenalidomide maintenance therapy is feasible for long-term disease control after ASCT.
In the IFM and CALGB studies, a secondary primary malignancy (SPM) signal was detected. Although lenalidomide maintenance therapy was discontinued in the IFM trial, the GIMEMA and CALGB study investigators elected to continue lenalidomide maintenance therapy.
For hematologic (HR, 2.03; P = .015) and solid tumors (HR, 1.71; P = .032), the cumulative incidence of SPMs was significantly higher in the lenalidomide maintenance therapy groups. Putting that finding in a risk–benefit context, Dr McCarthy commented, “There was a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival. So, the overall survival benefit of lenalidomide maintenance outweighs the risk of developing an SPM.”
Elaborating on the SPM risk versus the OS benefit, Markus Renschler, MD, Global Head for Hematology & Oncology Medical Affairs at Celgene, the manufacturer of lenalidomide, pointed out in an interview that, “While the absolute risk for a secondary primary malignancy was nearly doubled, the actual risk is very low. The 26% improvement in overall survival includes that risk.” He also pointed out that risk for an SPM is increased merely by having multiple myeloma and further by receiving chemotherapy, a bone marrow transplant, or radiation. Dr Renschler noted that in the IFM study, which discontinued lenalidomide maintenance therapy after the SPM increase was identified, the median survival duration was 5 months shorter than in the trials that continued lenalidomide maintenance therapy.
“Lenalidomide maintenance significantly prolongs overall survival post-ASCT and is feasible for long-term disease control after ASCT,” concluded Dr McCarthy. “Lenalidomide maintenance after ASCT can be considered a standard of care.”
Dr McCarthy noted that understanding the role of minimal residual disease detection and immune reconstitution after ASCT should lead to further improvements in OS. It is critically important, he observed, to develop early end points as surrogates for long-term outcomes and OS; otherwise, clinical trials may need to be continued for 10 years or longer.
