What the ENDURANCE Trial Reveals About Discontinuing Lenalidomide in Myeloma

Sagar Lonial, MD, of the Winship Cancer Institute of Emory University, evaluates recent findings he and his colleagues, led by Shaji Kumar, MD, published in The New England Journal of Medicine, which demonstrated no overall survival benefit for continuous lenalidomide (Revlimid) maintenance over a fixed 2-year regimen in newly diagnosed multiple myeloma. Although these findings could be interpreted as a mandate to stop lenalidomide maintenance at two years for all patients, Lonial cautions that such a conclusion oversimplifies complex clinical variables.

First, the ENDURANCE study (NCT01863550) analyzed non-transplant cohorts receiving induction regimens like lenalidomide, bortezomib (Velcade), and dexamethasone or carfilzomib (Kyprolis), lenalidomide, and dexamethasone, which do not reflect modern standards of care. Expected overall survival for these historic cohorts is lower than what contemporary regimens achieve. Second, treatment decisions must account for individual patient factors, including response depth and adverse events. Continuous maintenance inherently carries increased toxicity, requiring clinicians to weigh cumulative adverse events and potential dose adjustments or holidays, against therapeutic benefits, particularly for patients who have not achieved complete remission. Rather than applying an arbitrary 2-year cutoff, Lonial emphasizes using minimal residual disease (MRD) status to guide maintenance duration, pointing to sustained MRD negativity across 2 time points 12 months apart as a far more rational driver for discontinuation.

Looking forward, the evolving International Myeloma Society (IMS) definition of cure increasingly centers on successful treatment cessation. Modern clinical trials are shifting away from indefinite treatment paradigms toward endpoint-driven discontinuation strategies. Although the ENDURANCE trial confirms that stopping maintenance after 2 years causes no harm in its specific trial population, discontinuation should ultimately be a shared, individualized decision based on induction regimen context, drug tolerability, and MRD depth. The ultimate goal in myeloma management is not merely matching survival curves, but maximizing the proportion of patients who remain disease-free and cured at 5 years and beyond.