2019 ASCO: Lenalidomide May Reduce the Risk of Smoldering Multiple Myeloma Progressing to Active Disease


Key Points

  • At 3 years, 91% of patients receiving lenalidomide did not show progression to active myeloma disease compared to 66% who did not receive the therapy.
  • These findings may support a change in clinical practice.

A phase III randomized trial (E3A06) by Lonial et al testing the effect of single-agent lenalidomide vs observation in patients with intermediate- or high-risk smoldering multiple myeloma has found that lenalidomide significantly reduces the risk of smoldering multiple myeloma progressing to active disease. The study will be presented during the 2019 ASCO Annual Meeting (Abstract 8001).

Smoldering multiple myeloma is a precursor to the development of myeloma, and, currently, the standard of care is observation until symptoms develop. However, this approach does not identify patients at high risk for developing myeloma who may benefit from early intervention. Data from an earlier randomized clinical trial by Mateos et al suggested that early treatment with lenalidomide plus dexamethasone for patients with high-risk smoldering myeloma delayed progression to active disease. However, those findings did not change standard of care for these patients. 

Study Methodology and Results

In the initial phase II run of this study, all patients received lenalidomide to demonstrate safety. Eligibility required ≥ 10% plasma cells and abnormal serum free-light chain ratio (< 0.26 or > 1.65). The primary endpoint was disease progression. Progression-free survival was estimated by the Kaplan-Meier method and compared using the one-sided stratified log-rank test.

The phase II run of this study enrolled 44 patients, and the phase III study enrolled 182 patients to either lenalidomide (n = 90) or observation (n = 92), stratified on time since smoldering multiple myeloma diagnosis ≤ 1 year vs > 1 year. Baseline characteristics were similar between the arms. Eighty percent of the patients in the phase II trial and 51% in the phase III trial were taken off lenalidomide due primarily to adverse events or patient withdrawal. 

Median follow-up was 71 months in the phase II trial and 28 months in the phase III trial. The overall response rate was 47.7% in the phase II study, and in the phase III study, was 48.9% for the lenalidomide arm and 0% for the observation arm. Three-year progression-free survival was 87% for the phase II cohort. The 1-, 2-, and 3-year progression-free survival was 98%, 93%, and 91%, respectively, for the lenalidomide arm and 89%, 76%, and 66%, respectively, for the observation arm (hazard ratio = 0.28, = .0005).

No difference in quality-of-life scores was noted between the arms. Among the lenalidomide-treated patients, grade 3 or 4 nonhematologic adverse events occurred in 28% of the phase III patients, with fatigue being the most common (n = 5). Grade 4 hematologic adverse events occurred in 5.7% of patients, primarily neutropenia (n = 4). Three-year cumulative incidence of invasive second primary malignancy was 5.2% (lenalidomide) and 3.5% (observation). 

Clinical Practice Relevance

“Overall, this trial represents the largest randomized trial in smoldering multiple myeloma to date. In conjunction with the Spanish data [Mateos et al], this trial may support a change in clinical practice,” concluded the study authors.

An important finding from this study was that both intermediate- and high-risk patients with smoldering myeloma benefited from treatment with lenalidomide, commented Sagar Lonial, MD, FACP, Chief Medical Officer at Winship Cancer Institute of Emory University and Professor and Chair, Department of Hematology and Medical Oncology at Emory School of Medicine, and lead author of this study, at an ASCO press briefing highlighting several key abstracts that will be presented during the 2019 ASCO Annual Meeting.

“Smoldering myeloma affects a heterogenous group of patients…. But what is really quite interesting is that every risk group appeared to benefit from early intervention. And when you put our trial together in aggregate with the Spanish trial, it’s pretty clear that early intervention is a prevention strategy—not a treatment strategy—which can reduce the risk of conversion to symptomatic myeloma and, at least in the Spanish study with longer follow-up, improves overall survival,” said Dr. Lonial.

“We need to differentiate the treatment of myeloma vs prevention,” he continued. “Prevention strategies are probably likely to be less intensive and may try and focus on enhancing immune surveillance of the existing malignant clones and preventing that clone from progressing, as opposed to the eradication of symptomatic disease.”

Disclosure: Funding for this study was provided by the National Institutes of Health. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.