Prerna Mewawalla, MD, on Rethinking Indefinite Myeloma Maintenance

For more than 20 years, multiple myeloma treatment has rested on 2 ideas: hit the disease harder and treat the disease longer. Both have extended survival, but according to Prerna Mewawalla, MD, director of the Stem Cell Transplant Program at Allegheny Health Network and associate professor at Drexel University College of Medicine, one of them has outlived its evidence.

“Longer at some point just became forever without ever proving the need for forever,” she said in an interview with The American Journal of Managed Care^®.

Early trials compared maintenance with no maintenance, and maintenance won. Continuous therapy was then adopted for everyone. Since then, induction regimens have become more effective and produce deeper responses, and patients have excellent options at relapse. Mewawalla noted that the benefit of a fifth or sixth year of maintenance is likely marginal and probably smaller than the toxicity it causes.

ENDURANCE (NCT07456865), an Eastern Cooperative Oncology Group trial led by Shaji Kumar, MD, leader, Cancer Risk Assessment, Early Detection and Interception Research Program, Mayo Clinic Comprehensive Cancer Center, randomized 516 patients equally to lenalidomide (Revlimid; Bristol Myers Squibb) for 2 years or indefinitely after induction. Participants were ineligible for transplant or deferred, and only standard-risk patients were randomized.

Two years vs indefinite lenalidomide produced no difference in overall survival. Progression-free survival numerically favored continuous maintenance but was not statistically significant. The indefinite arm, however, had more grade 3 or higher nonhematologic toxicity and more second cancers at 5 years, around 11% vs 8%, “so you’re getting, probably, not much benefit at all, with real cumulative toxicity and no survival gain,” Mewawalla said.

The cleanest application of these data is to the population studied, but Mewawalla stressed that fixed-duration treatment should be individualized. “I don’t think 2 is a magic number,” she said, adding that tolerability and response matter, and ENDURANCE did not account for minimal residual disease (MRD). She favors stopping after sustained MRD negativity, at least 1 year apart. The study also supports stopping in patients who are not MRD-negative but have a good response and are struggling with fatigue or gastrointestinal adverse effects, as the risk of relapse is low.

For transplant-eligible patients, who were not studied, Mewawalla expects the findings to extrapolate because posttransplant responses are deeper, although ENDURANCE used VRd (Velcade [bortezomib], Revlimid [lenalidomide], and dexamethasone) rather than today’s daratumumab-VRd.