In results soon to be presented at the American Society of Clinical Oncology Annual Meeting (ASCO), the E3A06 phase 3 clinical trial has found that single-agent lenalidomide (Revlimid®, Celgene) improves progression-free survival in patients with asymptomatic high-risk smoldering multiple myeloma (SMM).
Smoldering multiple myeloma is a pre-cancerous, asymptomatic clonal plasma cell disorder with a high chance of progressing to multiple myeloma. Treatment for this condition has typically been limited to observation, with physicians acting on a "watch and wait" basis. Since it is now known that early therapy can benefit patients, especially those whose SMM is high risk, focus on treatment has increased.
A study by Mateos and colleagues reported in 2016 that lenalidomide/dexamethasone increased both time to developing multiple myeloma and overall survival in patients with high-risk SMM; however, as the researchers of the E3A06 trial explain, because Mateos and colleagues did not screen patients using advanced imaging techniques and because that study used a nonstandard definition of high risk, lenalidomide/dexamethasone combination therapy has not become the standard of care in SMM. The E3A06 study has now evaluated the efficacy of lenalidomide monotherapy in patients with intermediate- or high-risk SMM.
Phase 2 evaluated safety in 44 patients with asymptomatic high-risk SMM; phase 3 randomized 182 patients with asymptomatic high-risk SMM in a 1:1 ratio to receive either lenalidomide or observation, with a primary end point of progression-free survival. The median follow-up was 71 months for the phase 2 study and 28 months for the phase 3 study.
The three-year rate of invasive secondary primary malignancies was 5.2% for lenalidomide-treated patients, compared with 3.5% of patients in the observation arm. Lenalidomide produced an overall response rate of 47.7% in the phase 2 trial and an overall response rate of 48.9% in the phase 3 trial, compared with 0% for observation. For the phase 2 trial cohort, lenalidomide produced a three-year progression-free survival of 87% and a five-year progression-free survival of 78%. For the phase 3 cohort, progression-free survival was 91% for lenalidomide, compared with 66% for observation. Quality of life scores were similar for lenalidomide and for observation.
Of the lenalidomide-treated patients from the phase 2 trial, 80% have now discontinued this medication, owing largely to adverse events or patient withdrawal. Fifty-one percent of the phase 3 patients have also discontinued lenalidomide for similar reasons. In the phase 3 trial, 28% of lenalidomide-treated patients experienced grade 3/4 non-hematologic adverse events, with the most frequent being fatigue, experienced by 5 patients. Hematologic adverse events of grade 4 severity occurred in 5.7% of patients; neutropenia, experienced by 4 patients, was the most common.
"Overall, this trial represents the largest randomized trial in SMM to date," comment the authors of the study. "In conjunction with the [data from Mateo and colleagues' study], this trial may support a change in clinical practice."
For More Information
Clinicaltrials.gov (2019). Lenalidomide or observation in treating patients with asymptomatic high-risk smoldering multiple myeloma. NLM identifier: NCT01169337.
Lonial S, Jacobus SJ, Weiss M, et al (2019). E3A06: Randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma. J Clin Oncol, 37(suppl). Abstract 8001.
Mateos MV, Hernández MT, Giraldo P, et al (2016). Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol, 17(8):1127-1136. DOI:10.1016/S1470-2045(16)30124-3
Image credit: Michaela Reagan, Maine Medical Center Research Institute. Courtesy of the National Cancer Institute / Dana-Farber Harvard Cancer Center