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For newly diagnosed multiple myeloma, lenalidomide maintenance is typically continued indefinitely, until the disease progresses, but how long that benefit truly lasts has never been clear. The phase 3 ENDURANCE trial, published in the New England Journal of Medicine, tested whether stopping at 2 years gives up anything compared with staying on the drug for good, and found that it did not, at least for patients at standard risk who did not receive an up-front stem-cell transplant.
After induction with a proteasome inhibitor and lenalidomide, 516 patients were randomly assigned to indefinite-duration lenalidomide (260 patients) or a fixed 2-year course (256 patients). The primary endpoint was overall survival. At a median follow-up of 86 months, survival was essentially identical. There were 80 deaths in each group, and 7-year overall survival was 68.6% with indefinite therapy and 69.0% with the fixed course, a difference of −0.4 percentage points (95% CI, −9.0 to 8.3; P = 0.93).
Progression-free survival numerically favored continued treatment, at 36.1% versus 29.7% at 7 years, but the difference was not statistically significant (6.4 percentage points; 95% CI, −2.6 to 15.4). Staying on the drug also came at a cost in tolerability. Grade 3 or higher nonhematologic adverse events occurred in 48.2% of the indefinite-duration group versus 31.5% of the fixed-duration group, and the 5-year cumulative incidence of second primary cancers, excluding nonmelanoma skin cancer, was 11.2% with indefinite therapy versus 8.3% with the fixed course.
For plans and clinicians evaluating an open-ended, high-cost maintenance regimen, the findings present a practical question. Continuing lenalidomide until progression commits standard-risk patients to years of additional drug exposure, added toxicity, and a higher burden of second cancers, without a measurable gain in survival over a defined 2-year course. Because both approaches yielded the same overall survival, the decision reduces to weighing a modest and statistically uncertain gain in disease control against clear harms and the ongoing burden and cost of open-ended treatment. The result applies specifically to standard-risk patients who did not undergo up-front transplantation, and does not settle the question for high-risk disease or transplant recipients, where longer maintenance may still be warranted.
