Author: Melissa Pozotrigo, PharmD, BCOP
Is Shorter Duration Therapy Less Effective Than Indefinite Maintenance?
The phase 3 ENDURANCE (E1A11) trial provides compelling evidence regarding the duration of lenalidomide maintenance in patients with standard-risk, newly diagnosed MM who did not undergo upfront autologous stem-cell transplantation. Lenalidomide maintenance has traditionally continued until disease progression or unacceptable toxicity, often for many years. ENDURANCE challenges this approach by demonstrating that indefinite maintenance did not improve survival compared with stopping treatment after two years. These findings have important implications for patient quality of life and healthcare spending.
ENDURANCE enrolled patients who received induction therapy with either bortezomib, lenalidomide, and dexamethasone or carfilzomib, lenalidomide, and dexamethasone. Patients with high-risk cytogenetic abnormalities—del(17p), t(14;16), or t(14;20)—were excluded. Following induction, 516 patients were randomly assigned to lenalidomide maintenance until disease progression or for a fixed duration of two years. After approximately seven years of follow-up, median progression-free survival was 42.5 months with continuous maintenance and 38.9 months with fixed-duration treatment, a difference that was not statistically significant. Seven-year overall survival was approximately 69% in both groups, indicating no meaningful survival advantage with indefinite treatment.
For managed care organizations, these findings support reconsideration of policies that implicitly encourage continuous lenalidomide maintenance in the absence of disease progression or toxicity. According to ENDURANCE, a two-year course is a clinically reasonable and economically responsible option for appropriately selected standard-risk, nontransplant patients. This represents a treatment paradigm shift that will have significant financial impact. Although generic lenalidomide has lower acquisition costs compared with branded Revlimid, prolonged treatment contributes to considerable cumulative expense. Continuous therapy also generates costs associated with laboratory monitoring, pharmacy management, clinical visits, supportive medications, dose modifications, and adverse-event management. Discontinuing lenalidomide after two years has the potential to eliminate years of treatment for some patients without compromising overall survival. As patients with MM are living longer, even moderate per-patient savings means substantial reductions in total plan expenditures.
Economic assessments should also account for treatment-related toxicity. Grade 3 or higher treatment-related nonhematologic adverse events occurred in 23.5% of patients receiving continuous therapy compared with 16.9% of those receiving fixed-duration maintenance. Clinically significant toxicity increased with prolonged exposure: grade 3 or higher nonhematologic adverse events occurred in 48.2% of patients receiving indefinite maintenance lenalidomide compared with 31.5% receiving fixed-duration therapy. Adverse events resulted in treatment discontinuation in approximately 18% versus 10% of patients, respectively, with fatigue, anemia, neutropenia, and diarrhea among the most common reasons. Managing these toxicities may require additional monitoring, medications, emergency or hospitalization. Reducing unnecessary exposure will therefore lower downstream medical costs while improving quality of life.
Fixed-duration therapy may also improve patient-centered outcomes. Despite the convenience of oral administration, daily maintenance creates ongoing treatment burden, financial toxicity, refill coordination, adherence challenges, and laboratory appointments. A planned treatment-free period may improve quality of life while reducing copayments, transportation costs, caregiver burden, and time away from work. The ENDURANCE study should pave the way for future trial designs to incorporate a defined duration of treatment.
Managed care organizations can incorporate a strategy where at approximately two years of maintenance, a structured clinical reassessment is performed that considers cytogenetic risk, depth and duration of response, measurable residual disease status when available, treatment tolerance, comorbidities, financial burden, and patient preference. Discontinuation can be supported for a standard-risk patient with sustained disease control and meaningful toxicity or treatment burden. Continued maintenance therapy should remain covered when there is documentation of persistent disease, incomplete response, evolving risk factors, or another patient specific factor.
The limitations of ENDURANCE must guide policy development. Study findings should not be extrapolated to patients with high-risk cytogenetics, patients receiving maintenance after transplantation, or those treated with contemporary anti-CD38-containing quadruplet induction regimens. The study evaluated lenalidomide monotherapy and therefore does not establish the appropriate duration of daratumumab-lenalidomide or proteasome inhibitor–based maintenance regimens. Measurable residual disease was also not used prospectively to determine treatment duration. Coverage criteria should explicitly recognize discontinuation as an evidence-based option while preserving access to continued treatment when clinically justified.
Implications for Providers, Patients, and Payers
ENDURANCE demonstrates that indefinite lenalidomide maintenance may not be superior to time-limited therapy for many standard-risk, nontransplant patients with newly diagnosed MM. Managed care organizations have an opportunity to reduce drug exposure, cumulative toxicity, treatment burden, and long-term costs without adversely affecting clinical outcomes. The appropriate response is a risk-adapted policy that promotes reassessment, shared decision-making, and individualized treatment duration decisions. This approach balances clinical benefit, patient-centered care, and responsible resource stewardship while respecting the limitations of the available evidence.
Reference
Kumar S, Jacobus S, Cohen A, et al. Continuous or fixed-duration maintenance therapy in multiple myeloma. N Engl J Med. 2026;395(3):221-232.