Indefinite lenalidomide (IMiD) maintenance fails to improve OS vs 2-year fixed-duration in standard-risk, non-transplant NDMM

Lenalidomide is an oral immunomodulatory drug (IMiD) commonly used as maintenance “until progression” after frontline proteasome inhibitor–lenalidomide induction in transplant-ineligible NDMM; ENDURANCE (Phase 3; NCT01863550) tested whether that should be continuous or capped at 2 years. Standard-risk NDMM patients not planned for up-front ASCT were randomized after induction to indefinite-duration lenalidomide (n=260) vs fixed-duration lenalidomide for 2 years (n=256); at median 86 months’ follow-up, 7-year OS was essentially identical (68.6% vs 69.0%; difference −0.4 percentage points; 95% CI −9.0 to 8.3; P=0.93) with 80 deaths per arm, while 7-year PFS was numerically higher with indefinite therapy (36.1% vs 29.7%; difference 6.4 percentage points; 95% CI −2.6 to 15.4). Toxicity burden favored stopping at 2 years: grade ≥3 nonhematologic AEs were higher with indefinite lenalidomide (48.2% vs 31.5%), and 5-year cumulative incidence of second primary cancers (excluding non-melanoma skin cancers) was numerically higher with indefinite therapy (11.2% vs 8.3%); importantly, prior benchmarks in transplant-ineligible NDMM show continuous lenalidomide-based approaches can improve PFS vs fixed duration without necessarily improving OS, aligning with this “PFS signal, OS flat” pattern.