Patients with standard-risk multiple myeloma did not experience improved overall survival with indefinite lenalidomide maintenance compared to stopping after 2 years, according to new findings that challenge the current standard practice of continuing maintenance until disease progression.

In the analysis, published recently in The New England Journal of Medicine, researchers reported that patients randomly assigned to receive continuous lenalidomide therapy had virtually identical 7-year overall survival to those assigned to stop treatment after 2 years. 

Patients on indefinite therapy also experienced more grade 3 or higher toxicities and had a higher risk for second primary cancers than did 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 Rochester, 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 have been discussed in a range of cancer types, including lung cancer, melanoma, and chronic lymphocytic leukemia.

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 2 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 1 through 21 of a 4-week cycle; 260 were randomly assigned to receive the drug indefinitely until disease progression and 256 were randomly assigned to receive it for 2 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 7 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 7 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 nonmelanoma skin cancer, the 5-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 nonhematologic 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 2 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 prior to 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,” said Mohyuddin. The trial was likely “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 noninferiority study would have been almost impossible to conduct,” he added, “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,” Mohyuddin said.

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,” Hira Mian, MD, of McMaster University in Hamilton, Ontario, Canada, and Luciano J. Costa, MD, PhD, of the University of Alabama at Birmingham, wrote.

Amgen provided carfilzomib for the study, but was not involved in trial design, data analysis, interpretation, manuscript writing, or the decision to submit the manuscript for publication. No other drug manufacturers were involved in the trial. Kumar reported being a consultant to several pharmaceutical companies. Mohyuddin reported no disclosures.