A recent analysis has suggested that patients with standard-risk multiple myeloma did not experience improved overall survival with indefinite lenalidomide maintenance compared with stopping after two years, challenging the current standard practice of continuing maintenance until disease progression, reports Medscape Medical News.
In the analysis, published in The New England Journal of Medicine, researchers reported that patients randomly assigned to receive continuous lenalidomide therapy had virtually identical seven-year overall survival as those assigned to stop treatment after two years.
They wrote that patients on indefinite therapy also experienced more grade 3 or higher toxicities and had a higher risk for second primary cancers than those receiving fixed-duration therapy.
“The trial provides evidence against assuming that more treatment is better, the prevailing paradigm in the setting of myeloma,” said lead author Shaji Kumar, MD, of Mayo Clinic in Minnesota.
“Patients with standard-risk multiple myeloma not undergoing autologous stem cell transplant as part of upfront therapy do not need to continue indefinite maintenance with lenalidomide,” he told Medscape Medical News.
The findings add to the debate over fixed-duration vs indefinite therapy, which has been discussed in a range of cancer types, including lung cancer, melanoma, and chronic lymphocytic leukaemia.
In multiple myeloma, continuous lenalidomide maintenance until disease progression has become standard practice, although the optimal duration of therapy has remained uncertain.
The ENDURANCE trial enrolled adult patients with newly diagnosed multiple myeloma who were ineligible or were not planning to receive an upfront autologous stem-cell transplant.
In an earlier report from the ENDURANCE trial, researchers assessed whether induction with carfilzomib or bortezomib alongside lenalidomide and dexamethasone and found that triplet therapy with carfilzomib did not improve progression-free survival but was associated with more toxicity.
The current trial evaluated the optimal duration of maintenance therapy with lenalidomide: indefinite therapy vs two years of treatment. The study was designed to detect a relatively large (2.5-year) improvement in overall survival.
Participants received 15 mg of oral lenalidomide once daily on days one until 21 of a four-week cycle; 260 were randomly assigned to receive the drug indefinitely until disease progression and 256 were randomly assigned to receive it for two years. Treatment was stopped in the cases of progressive disease, unacceptable toxic effects, initiation of non-protocol therapy, or withdrawal of consent.
At a median follow-up of 86 months, there were 80 deaths in each treatment arm. Overall survival was nearly identical in the two groups at seven years’ follow-up – 69.0% in the fixed-duration group vs 68.6% in the indefinite group (difference, -0.4 percentage points; 95% CI, -9.0 to 8.3).
At seven years, progression-free survival was numerically lower in the fixed-duration group – 29.7% vs 36.1% with indefinite therapy – but the difference was not statistically significant (6.4 percentage points; 95% CI, -2.6 to 15.4).
Not including non-melanoma skin cancer, the five-year incidence of second primary cancers was lower in the fixed-duration group – 8.3% vs 11.2% with indefinite-duration lenalidomide. Indefinite therapy also came with a higher incidence of non-haematologic events of grade 3 or higher – 48.2% vs 31.5% with fixed-duration therapy.
Although transplant recipients were not included, Kumar said he believes this transplant group can also limit maintenance therapy to two years “as they are even less likely to benefit from indefinite therapy since they start maintenance at a deeper response”.
Manni Mohyuddin, MD, a myeloma specialist at the University of Utah in Salt Lake City, agreed the study offers “convincing evidence that finite duration [maintenance] therapy is feasible in myeloma”.
“Even before this study, I routinely told my patients there was no high-quality evidence that indefinite maintenance improved survival compared to finite duration maintenance,” said Mohyuddin, who was not involved in the research.
However, the 2.5-year difference in overall survival that the study was powered to detect was “always unlikely to happen”, Mohyuddin added. The trial was probably “destined to fail this endpoint from the beginning”.
The wide CIs around the efficacy estimates mean it’s impossible to rule out smaller effects in either direction. “But a better powered non-inferiority study would have been almost impossible to conduct,” he noted, “so I view these findings as the best we can get realistically in this situation.”
While Mohyuddin is already using finite-duration therapy for his patients, after tailoring for frailty and minimal residual disease, he said many doctors are still using indefinite maintenance therapy. “The new work will help change their practice.”
An accompanying editorial argues that the findings should prompt investigators to question the assumption that longer therapy is inherently better. Rather than asking investigators to prove when therapy can safely stop, future trials should require evidence that continuing treatment indefinitely provides additional benefit.
“The ENDURANCE trial is an important reminder that the burden of proof rests on the intervention, not its absence,” wrote Hira Mian, MD, of McMaster University in Hamilton, Ontario, Canada, and Luciano Costa, MD, PhD, of the University of Alabama at Birmingham.
Study details
Continuous or Fixed-Duration Maintenance Therapy in Multiple Myeloma
Shaji Kumar, Susanna Jacobus, Adam Cohen et al.
Published in The New England Journal of Medicine on 15 July 2026
Abstract
Background
Current treatment of newly diagnosed multiple myeloma involves lenalidomide maintenance therapy given until disease progression. The appropriate duration of maintenance therapy with lenalidomide has been unclear.
Methods
In this phase 3 trial, we enrolled patients with standard-risk newly diagnosed multiple myeloma who were not undergoing up-front autologous stem-cell transplantation. After induction treatment with a proteasome inhibitor–lenalidomide combination, patients were randomly assigned to receive indefinite-duration (continuous) lenalidomide or fixed-duration lenalidomide (for 2 years). The primary end point was overall survival; the trial had 80% power to detect a 50% increase in median survival (from 5 years to 7.5 years), with a two-sided alpha level of 5%, 395 patients undergoing randomization, and 204 deaths occurring during 9 years of follow-up.
Results
At the end of induction, 516 patients were randomly assigned to the indefinite-duration group (260 patients) or the fixed-duration group (256 patients). At a median follow-up of 86 months, overall survival did not differ significantly between the groups. With 80 deaths in each group, overall survival at 7 years was 68.6% in the indefinite-duration group and 69.0% in the fixed-duration group (difference, −0.4 percentage points; 95 confidence interval [CI], −9.0 to 8.3; P=0.93). Progression-free survival at 7 years was 36.1% in the indefinite-duration group and 29.7% in the fixed-duration group (difference, 6.4 percentage points; 95% CI, −2.6 to 15.4). The 5-year cumulative incidence of second primary cancers, excluding non-melanoma skin cancer, was 11.2% with indefinite-duration lenalidomide and 8.3% with fixed-duration lenalidomide. More adverse events occurred with indefinite-duration lenalidomide; the incidence of non-haematologic events of grade 3 or higher was 48.2% with indefinite-duration therapy and 31.5% with fixed-duration therapy.
Conclusions
In this phase 3 trial involving patients with standard-risk newly diagnosed multiple myeloma who were not undergoing up-front autologous stem-cell transplantation, indefinite-duration maintenance therapy after induction therapy did not result in significantly longer overall survival than fixed-duration maintenance therapy.
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