Long-term lenalidomide maintenance shows no survival advantage in multiple myeloma

For patients with newly diagnosed multiple myeloma not undergoing an autologous stem cell transplant, indefinite lenalidomide maintenance has long been standard care despite limited evidence to guide the optimal duration of treatment. A randomized phase 3 clinical trial by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), published today in the New England Journal of Medicine, found more toxicity with no survival benefit from continuing treatment until disease progression compared with stopping after 2 years. 

With a median follow-up of 7 years, overall survival rates in the ENDURANCE study (E1A11, NCT01863550) were almost identical between patients who continued lenalidomide until disease progression and those who stopped after 2 years. Overall survival was 69.0% in the continuous treatment group and 68.6% in the limited duration group. 

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 myeloma patients. Fixed duration treatment can significantly reduce healthcare costs, especially given the improving survival of patients with myeloma."

Shaji K. Kumar, MD, lead author, hematologist, Mayo Clinic in Rochester, MN, and co-chair of the ECOG-ACRIN Myeloma Committee 

Maintenance therapy is a lower-intensity treatment given after initial therapy to help keep the cancer under control. Current guidelines generally recommend long-term lenalidomide therapy; however, it is associated with increased costs, toxicity, and reduced quality of life. 

Previous studies supporting lenalidomide maintenance did not specify how long maintenance should continue for patients not undergoing stem cell transplantation. Most patients cannot continue treatment until progression due to side effects and cost, yet clinicians hesitate to stop maintenance therapy given uncertainty about the optimal duration. 

"For patients, maintenance therapy is not just another medication. It becomes part of everyday life. One of the most common questions patients ask is how long treatment should continue. ENDURANCE provides patients and physicians with evidence to help guide shared decisions about the benefits and burdens of long-term maintenance therapy," said Yelak Biru, a survivor of multiple myeloma and member of ECOG-ACRIN. 

In the trial, 516 patients with newly diagnosed multiple myeloma who had completed induction therapy were randomized 1:1 to receive either continuous lenalidomide until progression or to stop treatment after 2 years. All patients were standard risk based on biomarker testing: no evidence of del17p, t(14;16), or t(14;20). 

Median progression-free survival was 42.5 months in the indefinite treatment group and 38.9 months in the limited duration group. The 5-year cumulative incidence of second primary cancers (excluding non-melanoma skin cancer) was 11.2% for indefinite and 8.3% for limited lenalidomide. More adverse events occurred with indefinite versus limited lenalidomide: grade 3-5 treatment-related non-hematologic toxicity rates were 23.5% and 16.9%, respectively. 

"Cooperative group research plays a unique role in answering important clinical questions that extend beyond the development of new drugs. ENDURANCE was uniquely designed to answer two fundamental questions in the treatment of newly diagnosed multiple myeloma: what is the best initial treatment strategy, and how long should maintenance therapy continue? By addressing both questions in a single long-term randomized trial, ENDURANCE provides an evidence base that will continue to inform patient care for years to come," said senior author S. Vincent Rajkumar, MD, a hematologist at Mayo Clinic, and chair of the ECOG-ACRIN Myeloma Committee. "I estimate that the results of this trial can reduce Medicare spending by over $1 billion," he added. 

At the start of the trial, researchers compared the effectiveness of standard initial (induction) treatment with VRd (bortezomib, lenalidomide, and dexamethasone) versus KRd. This combination treatment includes carfilzomib, a drug similar to bortezomib that had been shown in other trials to be effective in treating multiple myeloma. Based on the study's initial results (Kumar SK. Lancet Oncol. August 2020) and long-term follow-up (Kumar SK. J Clin Oncol. May 2025), the investigators recommended no change to the standard initial treatment of VRd. 

The ENDURANCE (E1A11) trial was funded by the National Cancer Institute, one of the US National Institutes of Health. The trial is led by ECOG-ACRIN and conducted through the NCI's National Clinical Trials Network (NCTN). Additional support was provided by Amgen.