For patients with newly diagnosed multiple myeloma not undergoing an autologous stem cell transplant, indefinite lenalidomide maintenance resulted in more toxicity with no survival benefit from continuing treatment until disease progression compared with stopping after 2 years. Results from the randomized phase III ENDURANCE clinical trial by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) were published today in The New England Journal of Medicine.
With a median follow-up of 7 years, overall survival rates in the ENDURANCE study (E1A11, NCT01863550) were 69.0% in patients who continued lenalidomide until disease progression and 68.6% in those who stopped after 2 years.
“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 health-care costs, especially given the improving survival of patients with myeloma,” said lead author Shaji K. Kumar, MD, a hematologist at the Mayo Clinic in Rochester, 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.
ENDURANCE Study Details
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: there was 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 vs 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, of 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 induction treatment with bortezomib/lenalidomide/dexamethasone (VRd) vs carfilzomib/lenalidomide/dexamethasone (KRd). Based on the study’s initial results and long-term follow-up , the investigators recommended no change to the standard initial treatment of VRd.
Summary
Indefinite lenalidomide maintenance has long been standard care for standard-risk newly diagnosed multiple myeloma patients not undergoing stem cell transplants, despite little evidence to guide the optimal duration of treatment. The ECOG-ACRIN ENDURANCE trial, published in the New England Journal of Medicine, found more toxicity with no survival benefit from continuing maintenance beyond 2 years, providing evidence to change clinical practice.
DISCLOSURE: 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.
The full report, Continuous versus Fixed Duration Maintenance Therapy in Multiple Myeloma, is available at www.nejm.org.
