Why This Study Matters
Lenalidomide maintenance given until disease progression is the current standard of care after induction therapy for newly diagnosed multiple myeloma (NDMM), but no prior prospective trial had directly tested whether continuing indefinitely is actually better than a fixed, time-limited course. As induction regimens have deepened responses and maintenance durations have lengthened in practice, understanding whether prolonged treatment adds a survival benefit — or simply adds toxicity and cost — has become an increasingly important open question for clinicians managing long-term myeloma care.
This report, from the maintenance ("R2") randomization of the ECOG-ACRIN ENDURANCE (E1A11) trial, is the first prospective, randomized comparison of indefinite-duration versus fixed 2-year lenalidomide maintenance in standard-risk NDMM patients not undergoing up-front autologous stem-cell transplantation (ASCT).
Study Design
ENDURANCE (E1A11) is a randomized, open-label phase 3 trial conducted by the ECOG-ACRIN Cancer Research Group through the National Clinical Trials Network, in collaboration with the National Cancer Institute's Cancer Therapy and Evaluation Program. Patients were first randomized 1:1 to induction with VRd (twelve 3-week cycles) or KRd (nine 4-week cycles). Patients who completed induction without progression were then randomized 1:1, stratified by induction arm, to receive lenalidomide maintenance (15 mg orally, days 1–21 of a 4-week cycle) for either a fixed 2-year duration or indefinitely until disease progression.
The primary endpoint was overall survival from the time of maintenance randomization, with the trial designed to have 80% power to detect a 50% improvement in median survival (from 5 years to 7.5 years) at a two-sided alpha of 5%, targeting 395 patients and 204 deaths. In total, 1,087 patients were randomized 1:1 to induction (VRd or KRd), and 516 patients who completed induction without progression were then randomized 1:1 to lenalidomide maintenance at a dose of 15 mg on days 1–21 of each 28-day cycle. Enrollment ran from 2013 to 2019, with a median follow-up of 86 months.
Patient Population
Eligible patients had standard-risk newly diagnosed multiple myeloma and were not planned for up-front autologous stem-cell transplantation. Patients with high-risk disease features — t(14;16), t(14;20), del(17p) by FISH, elevated LDH, or high circulating plasma cell counts — were excluded, as they were being studied in a separate high-risk trial. At the maintenance randomization, 256 patients were assigned to the fixed-duration arm and 260 to the indefinite-duration arm; 58% overall had received KRd induction and 42% VRd. Baseline demographic and disease characteristics (ISS stage, ECOG performance status, cytogenetic risk) were well balanced between arms.
Primary Endpoint: Overall Survival
With 80 deaths recorded in each arm at a median follow-up of 86 months, 7-year overall survival was 69.0% (95% CI, 62.3–74.7) in the fixed-duration arm and 68.6% (95% CI, 62.1–74.3) in the indefinite-duration arm. The between-arm difference (indefinite minus fixed-duration) was −0.37 percentage points (95% CI, −9.03 to 8.29; P=0.933) — not statistically significant.
A landmark analysis performed 2 years from randomization was consistent with the primary analysis: the hazard ratio for overall survival was 1.06 (95% CI, 0.61–1.85) for indefinite versus fixed-duration maintenance. Restricted mean survival time at 7 years was 72.8 months (fixed-duration) versus 72.0 months (indefinite), a difference of −0.77 months (95% CI, −4.43 to 2.89) and an RMST ratio of 0.99 (95% CI, 0.94–1.04). At a second interim analysis, the data safety monitoring committee recommended release of results in part based on a futility assessment, at which point the conditional probability of a positive outcome was under 20%.
Progression-free survival, a key secondary endpoint, showed median PFS of 38.9 months (95% CI, 31.6–46.2) for fixed-duration maintenance versus 42.5 months (95% CI, 33.1–56.1) for indefinite-duration maintenance. 7-year PFS was 29.7% (95% CI, 23.5–36.1) versus 36.1% (95% CI, 29.7–42.4), a difference of 6.36 percentage points (95% CI, −2.63 to 15.40) favoring indefinite therapy numerically, though the confidence interval crossed zero.
Results of the current study suggest that continuous maintenance therapy with lenalidomide demonstrates no clear benefit on overall survival.
— Verbatim conclusion, study authors, New England Journal of Medicine (2026)
Subgroup Analyses
The full-text article states that overall survival and progression-free survival results by subgroup are presented in supplementary figures and tables, which were not included in the retrieved main-text source for this analysis. Specific subgroup-level hazard ratios, confidence intervals, or p-values are not specified in the available source and are therefore not reported here to avoid misrepresenting unpublished figures.
Safety Profile
More adverse events occurred with indefinite-duration lenalidomide. Grade ≥3 treatment-emergent adverse events (hematologic and non-hematologic combined) occurred in 46.9% of patients on fixed-duration maintenance versus 62.4% on indefinite-duration maintenance; treatment-related grade ≥3 events occurred in 33.5% versus 44.7% (P=0.009). Looking at non-hematologic toxicity alone, grade ≥3 treatment-emergent events occurred in 31.5% (fixed-duration) versus 48.2% (indefinite), and treatment-related events in 16.9% versus 23.5% (P=0.064).
Treatment discontinuation due to adverse events occurred in 10% of patients on fixed-duration maintenance versus 18% on indefinite-duration maintenance, most commonly for fatigue, anemia, neutropenia, and diarrhea.
| Adverse Event | Fixed-Duration (G1–2) | Fixed-Duration (G3–4) | Indefinite (G1–2) | Indefinite (G3–4) |
|---|---|---|---|---|
| Fatigue | 47.2% | 2.4% | 57.3% | 5.9% |
| Anemia | 42.9% | 3.5% | 49.4% | 2.7% |
| Diarrhea | 35.4% | 2.0% | 42.7% | 5.5% |
| Peripheral sensory neuropathy | 39.8% | 1.6% | 47.5% | 0.8% |
| Neutrophil count decreased | 28.0% | 17.7% | 26.7% | 28.2% |
| Lymphocyte count decreased | 30.3% | 5.9% | 35.7% | 8.6% |
| Hyperglycemia | 28.7% | 1.2% | 36.5% | 2.4% |
| Platelet count decreased | 29.5% | 2.0% | 38.0% | 2.7% |
Solicited treatment-emergent adverse events by grade, fixed-duration (N=254) versus indefinite (N=255) arms. Second primary cancers (excluding non-melanoma skin cancer) were reported in 26 patients on fixed-duration maintenance versus 31 on indefinite-duration maintenance; the 5-year cumulative incidence was 8.3% versus 11.2%, respectively.
Interpretation and Broader Context
The authors conclude that in standard-risk NDMM patients not undergoing up-front ASCT, indefinite-duration lenalidomide maintenance did not significantly improve overall survival compared with a fixed 2-year course, while exposing patients to more toxicity, a higher rate of treatment discontinuation, and a somewhat elevated risk of second primary cancers. They note the benefit of maintenance therapy appears achievable within a 2-year window, with additional treatment time contributing more risk than reward in this population.
Several caveats limit generalizability: the trial enrolled only standard-risk patients, did not include 4-drug induction regimens or up-front ASCT (settings where other trials such as DETERMINATION and IFM2009 show differing progression-free survival outcomes attributed partly to maintenance duration), and the optimal maintenance strategy in high-risk disease remains the subject of ongoing randomized trials. The authors also point out that lenalidomide maintenance costs exceed $1 billion annually in the United States, and that a shorter, fixed maintenance course could allow reuse of immunomodulatory drugs at relapse.
Future Directions
The authors note that ongoing trials are testing measurable residual disease (MRD)-negativity-guided approaches to individualize when maintenance therapy can be safely stopped, and that dedicated randomized trials are addressing optimal maintenance duration in high-risk myeloma and in patients who receive 4-drug induction or up-front stem-cell transplantation — populations not represented in this study.
In the ECOG-ACRIN ENDURANCE (E1A11) maintenance randomization, indefinite-duration lenalidomide maintenance failed to improve overall survival over a fixed 2-year course in standard-risk, non-transplant multiple myeloma patients (7-year OS 68.6% vs 69.0%, P=0.933), while producing significantly more grade ≥3 treatment-related toxicity (44.7% vs 33.5%) and a higher 5-year incidence of second primary cancers (11.2% vs 8.3%). Progression-free survival numerically favored indefinite therapy, but its confidence interval crossed zero. Given the added toxicity, cost, and cancer risk without a demonstrated survival benefit, the authors argue a fixed 2-year maintenance course is a reasonable standard for this population, while acknowledging the trial does not address high-risk disease or patients receiving up-front stem-cell transplantation.