Indefinite Myeloma Maintenance Shows No OS Benefit vs 2-Year Duration

Continuing lenalidomide (Revlimid) maintenance therapy indefinitely until disease progression did not improve overall survival (OS) compared with a fixed 2-year duration of treatment in patients with standard-risk, newly diagnosed multiple myeloma who did not undergo upfront autologous stem cell transplantation, according to results published in the New England Journal of Medicine.¹

The phase 3 ENDURANCE trial (NCT01863550), led by the ECOG-ACRIN Cancer Research Group, resulted in a 7-year OS rate of 68.6% in the indefinite-duration group and 69.0% in the fixed-duration group (0.4% difference; 95% CI, –9.0 to 8.3; P = .93). This trial provides the first randomized evidence to guide the optimal duration of lenalidomide maintenance in this setting.

“Knowing that maintenance therapy can safely end after a defined period may help reduce the demands of long-term treatment for patients,” S. Vincent Rajkumar, MD, a hematologist at Mayo Clinic in Rochester, Minnesota, and chair of the ECOG-ACRIN Cancer Research Group’s Myeloma Committee, stated in a news release. “These findings support informed, shared decision-making between physicians and patients.”²

Trial Design

Eligible patients had standard-risk newly diagnosed multiple myeloma, defined by the absence of del(17p), t(14;16), or t(14;20), and had not undergone upfront transplantation. After completing induction therapy with a proteasome inhibitor–lenalidomide combination, 516 patients were randomly assigned 1:1 to receive either indefinite-duration lenalidomide or fixed-duration lenalidomide for 2 years. The trial was powered to detect a 50% increase in median OS, from 5 to 7.5 years, and required 204 OS events over 9 years of follow-up for its primary analysis.¹

Earlier in the trial, investigators had also compared induction with bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) against carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd). Based on initial results and long-term follow-up data published separately, the investigators recommended no change to VRd as standard induction therapy, according to ECOG-ACRIN.³

No Survival Difference, More Toxicity With Indefinite Therapy

At a median follow-up of 86 months, OS did not differ significantly between the 2 groups, with 80 deaths occurring in each.¹ Progression-free survival (PFS) at 7 years was 36.1% in the indefinite-duration group and 29.7% in the fixed-duration group (6.4% difference; 95% CI, –2.6 to 15.4). The median PFS was 42.5 months in the indefinite-duration group and 38.9 months in the fixed-duration group.

More adverse events occurred with indefinite-duration therapy. The incidence of nonhematologic adverse events of grade 3 or higher was 48.2% with indefinite-duration lenalidomide compared with 31.5% with fixed-duration therapy; grade 3 to 5 treatment-related nonhematologic toxicity rates were 23.5% and 16.9%, respectively. The 5-year cumulative incidence of second primary cancers, excluding nonmelanoma skin cancers, was 11.2% with indefinite-duration lenalidomide compared with 8.3% with fixed-duration lenalidomide.

Investigator Perspectives and Next Steps

“The results of this trial are paradigm-shifting, given the current practice of continuous therapy until progression, and should pave the way for future trial designs to incorporate a defined duration of treatment for the majority of [patients with myeloma],” said lead author Shaji K. Kumar, MD, a hematologist at Mayo Clinic and cochair of the ECOG-ACRIN Myeloma Committee, in a news release.²

In addition to the potential reduction in toxicity, Rajkumar estimated that the findings could save Medicare more than $1 billion by enabling earlier discontinuation of lenalidomide.

The findings apply specifically to patients with standard-risk multiple myeloma who did not receive an upfront autologous transplant. Additional studies are underway to determine optimal maintenance duration in high-risk disease and to explore whether treatment duration could be tailored using measurable residual disease testing.

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. ECOG-ACRIN ENDURANCE trial findings published in the New England Journal of Medicine provide the first randomized evidence on the optimal duration of lenalidomide maintenance for patients with newly diagnosed multiple myeloma. News release. ECOG-AGRIN Cancer Research Group. July 15, 2026. Accessed July 20, 2026. https://tinyurl.com/2wbpn9x9

3. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(10):1317-1330. doi:10.1016/S1470-2045(20)30452-6