Trial Questions Continuous Maintenance in Newly Diagnosed Myeloma

Maintenance therapy with continuous lenalidomide (Revlimid) did not significantly improve overall survival (OS) in patients with standard-risk, newly diagnosed multiple myeloma, the phase III ENDURANCE trial showed.

Among patients who received induction treatment with a proteasome inhibitor and lenalidomide, the OS rate at 7 years was 68.6% in the continuous maintenance group versus 69% in those who received fixed-duration lenalidomide for 2 years (P=0.93), reported Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.

Median progression-free survival (PFS) was also similar — 42.5 months in the continuous group versus 38.9 months in the fixed-duration group, with PFS rates at 7 years of 36.1% and 29.7%, respectively, they wrote in the New England Journal of Medicine.

In addition, there were more adverse events with continuous lenalidomide.

“These results reflect the importance of conducting prospective trials to determine appropriate durations of treatment,” noted Kumar and colleagues. “The lack of an improvement in overall survival with indefinite maintenance therapy reflects, to some extent, the improved efficacy of newer induction therapies and the newer treatments that are available at relapse.”

“The results suggest that the benefit from maintenance therapy can be achieved with a 2-year treatment duration, with further treatment mostly adding toxic effects,” they added.

In an editorial accompanying the study, Hira Mian, MD, of McMaster University in Hamilton, Ontario, and Luciano J. Costa, MD, PhD, of the University of Alabama at Birmingham, pointed out that the default practice has been indefinite maintenance, with the rationale that “more multiple myeloma therapy must be better.”

Testing the benefit of less therapy is difficult, they suggested, because these kinds of trials “require independent funding, cooperative infrastructure, and a willingness on the part of the investigator to randomly assign patients to receive less treatment.”

“The ENDURANCE trial represents precisely the academically driven trial that is needed in the field of multiple myeloma,” they wrote. “The next generation of multiple myeloma trials must ask not only which therapy to use but for how long — an approach that requires coordinated investment, genuine industry partnership, and the courage to challenge key assumptions in multiple myeloma, including the notion that treatments must be administered until progression.”

Kumar and team said that the ENDURANCE trial was designed to address two important questions. In the first randomization, they compared carfilzomib (Kyprolis), lenalidomide, and dexamethasone versus standard-of-care bortezomib (Velcade), lenalidomide, and dexamethasone as initial therapy to assess the antimyeloma efficacy of two proteasome inhibitors, finding that PFS was similar between arms.

In this second randomization, 516 patients who were not undergoing upfront autologous stem cell transplantation were assigned to receive continuous lenalidomide or fixed-duration lenalidomide. Median patient age was 65 years, 58-60% were men, 82-83% were white, and 11% were Black.

Among these patients, 57.7% had received carfilzomib, lenalidomide, and dexamethasone, and 42.3% had received bortezomib, lenalidomide, and dexamethasone as induction therapy.

All patients in the fixed-duration group either completed 2 years of maintenance therapy (56.7% of treated patients) or stopped earlier, while 42% of those in the continuous group discontinued therapy because of disease progression.

Among patients without progressive disease in the continuous group, 57.4% received lenalidomide for at least 3 years and 46.6% for at least 4 years.

Grade ≥3 hematologic and nonhematologic adverse events occurred in 62.4% of the continuous group versus 46.9% of the fixed-duration group, with treatment-related events occurring in 44.7% and 33.5%, respectively. Grade ≥3 nonhematologic adverse events occurred in 48.2% and 31.5%, respectively, with treatment-related events occurring in 23.5% and 16.9%.

Overall, 15.3% of patients in the continuous group and 9.8% of those in the fixed-duration group discontinued therapy due to adverse events, including fatigue, anemia, neutropenia, and diarrhea.

The 5-year cumulative incidence of second primary cancers with the exclusion of nonmelanoma skin cancer was 11.2% in the continuous group and 8.3% in the fixed-duration group.

In their editorial, Mian and Costa noted that it was uncertain whether the results will extend to high-risk patients. In addition, the trial did not address maintenance after four-drug induction regimens in the context of autologous transplant.

“However, if 2 years of lenalidomide therapy is sufficient in the context of a three-drug induction regimen in patients with standard-risk disease who have not undergone transplantation, it is not a dangerous leap to extrapolate that continued exposure of lenalidomide beyond 2 years is likely to be futile in patients who receive even more effective upfront treatment,” they wrote.