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 year 0.98
Three years 0.87
Five years 0.78
  Lenalidomide Observation
One year 0.98 0.89
Three years 0.93 0.76
Five years 0.91 0.66
PFS = progression-free survival