Lenalidomide Improves Survival in Smoldering MM Compared with Observation

The standard of care for smoldering multiple myeloma (SMM), a precursor to MM, is observation. However, a 2015 study published in The New England Journal of Medicine suggests that lenalidomide plus dexamethasone improves time to progression of MM and overall survival (OS) for patients with high-risk SMM compared with observation. However, the study had some limitations that weakened the adoption of this regimen as standard of care: Patients were not screened with advanced imaging techniques, it used a definition of high-risk disease that is not routinely available, and combination therapy limited the ability to isolate the effect of lenalidomide.

 In the randomized, phase II/III E3A06 intergroup trial, researchers assessed the effect of single-agent lenalidomide compared with observation for patients with intermediate- or high-risk SMM. Lenalidomide improved progression-free survival (PFS; primary endpoint) in these patients, according to results presented at the 2019 ASCO Annual Meeting.

In an initial phase II run-in, all patients received lenalidomide to demonstrate safety. Eligible patients had ≥10% plasmacytoses and abnormal serum free light chain ratio (<0.26 or >1.65). Forty-four patients were enrolled in phase II, and 182 patients were randomized in phase III to receive lenalidomide (n=90) or observation (n=92). Patients were stratified based on time since SMM diagnosis (≤1 year vs. >1 year). Baseline characteristics were similar. Eighty-percent of phase II patients and 51% of phase III patients are no longer receiving lenalidomide mostly due to adverse events (AEs) or patient withdrawal.

Grade 3/4 nonhematologic AEs occurred in 28% of phase III patients, of which fatigue was most common (n=5). The grade 4 hematologic AE rate was 5.7%, mostly due to neutropenia (n=4).

The overall response rate (ORR) was 47.7% in phase II and 48.9% in phase III for the lenalidomide arm. ORR was 0% for the observation arm.

Median follow up was 71 months in phase II and 28 months in phase III. The three-year PFS rate was 87% in the phase II cohort. One-, two-, and three-year PFS was 98%, 93%, and 91% for lenalidomide and 89%, 76%, and 66% for the observation cohorts (hazard ratio = 0.28; P=0.0005). See TABLE for all PFS outcomes.

Three-year cumulative incidence of invasive secondary primary malignancies was 5.2% in the lenalidomide cohort and 3.5% in the observation cohort. The researchers reported no difference in quality of life scores between the treatment groups.

 “In conjunction with the [previous] data, this trial may support a change in clinical practice,” the researchers concluded.


Lonial S, Jacobus SJ, Weiss M, et al. E3A06: Randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma. Abstract #8001. Presented at the 2019 ASCO Annual Meeting, Chicago, IL, June 2, 2019.


Phase II PFS
One year0.98
Three years0.87
Five years0.78
One year0.980.89
Three years0.930.76
Five years0.910.66
PFS = progression-free survival