Background
Phase 3, open-label ECOG-ACRIN trial (E1A11/ENDURANCE, NCT01863550) addressing the optimal duration of lenalidomide maintenance in standard-risk newly diagnosed multiple myeloma (NDMM) in patients not proceeding to up-front autologous stem-cell transplant (ASCT). After proteasome inhibitor–lenalidomide induction, 516 patients were randomized to indefinite (continuous) versus fixed 2-year lenalidomide maintenance. Lenalidomide is an immunomodulatory agent; conventional maintenance is continued until progression.
Results
Interventions and follow up: Arm A: Indefinite-duration (continuous) lenalidomide maintenance until progression (n=260)
Arm B: Fixed-duration lenalidomide maintenance for 2 years (n=256)
Primary endpoint: Overall survival (OS)
mFollow up: 86 months
Results: OS (7-yr): 68.6% (continuous) vs 69.0% (fixed); difference −0.4 percentage points (95% CI −9.0 to 8.3); P=.93
PFS (7-yr): 36.1% vs 29.7%; difference 6.4 percentage points (95% CI −2.6 to 15.4) — numerically favors continuous, not significant
2nd primary malignancy (5-yr, excl NMSC): 11.2% (continuous) vs 8.3% (fixed)
Arm B: Fixed-duration lenalidomide maintenance for 2 years (n=256)
Primary endpoint: Overall survival (OS)
mFollow up: 86 months
Results: OS (7-yr): 68.6% (continuous) vs 69.0% (fixed); difference −0.4 percentage points (95% CI −9.0 to 8.3); P=.93
PFS (7-yr): 36.1% vs 29.7%; difference 6.4 percentage points (95% CI −2.6 to 15.4) — numerically favors continuous, not significant
2nd primary malignancy (5-yr, excl NMSC): 11.2% (continuous) vs 8.3% (fixed)
Adverse events
Grade ≥3 non-hematologic: 48.2% (continuous) vs 31.5% (fixed)
Overall: More adverse events with indefinite-duration lenalidomide
Overall: More adverse events with indefinite-duration lenalidomide
Conclusions
In standard-risk NDMM patients not undergoing up-front ASCT, indefinite-duration lenalidomide maintenance did not prolong OS versus a fixed 2-year course. PFS numerically favored continuous therapy but was not significant, while continuous therapy carried more toxicity and numerically more second primary cancers. A fixed 2-year maintenance is a reasonable option in this population.
Key Limitations
Population: Standard-risk, non-transplant patients only — not generalizable to high-risk or transplant-eligible NDMM, where continuous lenalidomide remains standard
Power: Powered for OS (to detect a 50% median improvement); the PFS difference favoring continuous therapy may be clinically relevant but underpowered
Design: Open-label maintenance; long-term OS potentially influenced by heterogeneous subsequent therapies
Endpoint: No MRD-guided analysis reported to identify who might safely stop
Power: Powered for OS (to detect a 50% median improvement); the PFS difference favoring continuous therapy may be clinically relevant but underpowered
Design: Open-label maintenance; long-term OS potentially influenced by heterogeneous subsequent therapies
Endpoint: No MRD-guided analysis reported to identify who might safely stop
Clinical Context
Lenalidomide maintenance until progression is standard after induction (CALGB 100104, IFM 2005-02, Myeloma XI, meta-analysis) and is FDA-approved. ENDURANCE informs the long-debated duration question: in standard-risk, transplant-deferred patients, a fixed 2-year course appears not to compromise OS while limiting toxicity, second cancers, and cost. NCCN and ESMO recommend lenalidomide maintenance without mandating a fixed stop date; these data support individualized, potentially time-limited maintenance in standard-risk disease, while continuous maintenance remains standard for transplant-eligible and higher-risk patients.