OS Does Not Improve With Continuous Vs Fixed Lenalidomide Dosing in NDMM

Indefinite-duration or continuous lenalidomide (Revlimid) maintenance did not significantly improve overall survival (OS) compared with a fixed 2-year duration in patients with standard-risk newly diagnosed multiple myeloma (NDMM) who were not undergoing up-front autologous stem cell transplantation (ASCT), according to findings from the phase 3 ENDURANCE (E1A11) trial (NCT01863550) published in The New England Journal of Medicine.¹ The results suggest that a defined 2-year course of maintenance may spare patients additional toxicity without compromising survival.

What did the ENDURANCE maintenance analysis show?

At a median follow-up of 86 months, OS did not differ significantly between the groups, with 80 deaths in each arm. The 7-year OS rate was 68.6% (95% CI, 62.1%-74.3%) with indefinite-duration lenalidomide and 69.0% (95% CI, 62.4%-74.7%) with fixed-duration lenalidomide (difference, −0.4 percentage points; 95% CI, −9.0 to 8.3; P = .93). Progression-free survival (PFS) at 7 years numerically favored continuous therapy at 36.1% (95% CI, 29.7%-42.4%) vs 29.7% (95% CI, 23.5%-36.1%) with fixed-duration treatment (difference, 6.4 percentage points; 95% CI, −2.6 to 15.4), though the difference was not statistically significant. The findings indicate that extending lenalidomide maintenance beyond 2 years did not translate into a survival benefit in this standard-risk population.

What were the safety and second-cancer findings?

Indefinite-duration lenalidomide was associated with more adverse events (AEs) than fixed-duration therapy. The incidence of nonhematologic AEs of grade 3 or higher was 48.2% with continuous therapy vs 31.5% with the 2-year course. The 5-year cumulative incidence of second primary cancers, excluding nonmelanoma skin cancer, was 11.2% with indefinite-duration lenalidomide and 8.3% with fixed-duration lenalidomide. Together, the toxicity and second-cancer findings underscore the added burden of prolonged maintenance in the absence of a survival gain.

“Patients in our trial had standard-risk multiple myeloma and were not receiving either a 4-drug induction or up-front autologous stem-cell transplantation, which makes generalization of the results to all patients with multiple myeloma difficult,” Shaji Kumar, MD, consultant in the Division of Hematology and the Department of Internal Medicine and a research chair in the Division of Hematology and Department of Internal Medicine at Mayo Clinic in Rochester, Minnesota, wrote with coauthors in the publication.¹ “However, the concept of fixed-duration therapy, especially as the treatments are becoming more efficacious, is relevant to all patients with multiple myeloma. With a longer duration of therapy adding toxicity and cost, randomized trials to define appropriate durations of treatment must be done in parallel or shortly after new treatments are approved.”

What was the ENDURANCE trial design?

In the phase 3 ENDURANCE (E1A11) trial, patients with standard-risk NDMM who were not undergoing up-front ASCT first received induction with a proteasome inhibitor and lenalidomide (Revlimid) combination with either bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) or carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd). At the end of induction, 516 patients were randomly assigned to indefinite-duration lenalidomide (n = 260) or fixed-duration lenalidomide for 2 years (n = 256). Standard risk was defined by the absence of del(17p), t(14;16), or t(14;20) on fluorescence in situ hybridization and the absence of a high-risk gene-expression signature.

The primary end point was OS.² Secondary end points included PFS, responses, treatment exposure, quality of life, AEs, and second primary cancers.

“It should not be assumed that a longer duration of therapy is likely to be better. Our results may have important implications for the cost of [multiple] myeloma therapy. Finally, stopping lenalidomide therapy at 2 years may also allow broader reuse of immunomodulatory drugs in patients who have a relapse after stopping maintenance therapy,” the study authors concluded.¹

References

1. 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. doi:10.1056/NEJMoa2600157
2. Bortezomib or carfilzomib with lenalidomide and dexamethasone in treating patients with newly diagnosed multiple myeloma. ClinicalTrials.gov. Updated September 8, 2025. Accessed July 16, 2026. https://tinyurl.com/2esdkptj