Lenalidomide Treatment Delays Progression From Smoldering to Symptomatic Myeloma

Observation is the standard approach to managing most patients with smoldering multiple myeloma (MM), but results from a phase III study suggest that early treatment with lenalidomide can delay the progression from smoldering to symptomatic MM. This early intervention also reduced the risk of end organ damage, wrote the authors, led by Sagar Lonial, MD, from Emory University, in the Journal of Clinical Oncology.

“These findings represent a major change in practice,” Dr. Lonial told ASH Clinical News. “We now recommend offering patients who have high-risk smoldering multiple myeloma an early intervention – either lenalidomide, lenalidomide/dexamethasone, or a clinical trial – knowing that the first two options significantly reduce their risk of progression to symptomatic multiple myeloma in a randomized trial.”

The phase III trial enrolled patients who had been diagnosed with asymptomatic smoldering MM in the past 60 months. Smoldering MM risk was defined according to Mayo Clinic 2008 and 2018 criteria.

Prior to the randomization portion of the trial, researchers conducted a run-in phase II trial to evaluate safety, in which 44 patients were treated with single-agent lenalidomide. Next, in the phase III randomized portion, participants were randomized to observation (n=92) or lenalidomide (n=90). In the active-treatment group, lenalidomide 25 mg was administered on days 1-21 of a 28-day cycle. Patients continued on treatment or observation until disease progression, toxicity, or study withdrawal. The authors also noted that patients receiving lenalidomide received thrombosis prophylaxis at a suggested daily dose of aspirin 325 mg.

Baseline patient and disease characteristics were similar between the lenalidomide and observation arms, the authors noted. Median ages were 63 and 64 years, respectively, and similar portions of patients in each group had low (34% vs. 29%), intermediate (39% vs. 37%), or high-risk (28% vs. 34%) disease per Mayo 2018 criteria.

Median lenalidomide treatment duration was 33.5 cycles and 23 cycles for the phase II and III studies, respectively. Discontinuing study treatment was largely due to patient withdrawal or adverse events, the authors reported.

The primary endpoint of the phase III study was progression-free survival (PFS), defined as the time elapsed since randomization to the development of symptomatic MM, determined by evidence of end-organ damage related to the underlying disorder.

“We now recommend offering patients who have high-risk smoldering multiple myeloma an early intervention.”

—Sagar Lonial, MD

The 5-year PFS rate was 78%, with a 3-year cumulative incidence of progression of 10.4%. In the phase III randomized trial, over a median follow-up of 35 months (range = 30-37 months), 50% of lenalidomide-treated patients experienced a partial response or better. In the observation arm, there were no responses.

Lenalidomide was associated with a 72% relative risk reduction in the combined endpoint of disease progression or death, compared with observation (hazard ratio [HR] = 0.28; 95% CI 0.12-0.62; p=0.002). This also was associated with greater 1-, 2-, and 3-year PFS rates: 98%, 93%, and 91% versus 89%, 76%, and 66%, respectively.

In addition, researchers observed a higher cumulative incidence of progression at 3 years in the observation group versus the lenalidomide group (32% vs. 7%, respectively). There was no statistically significant difference in overall survival, however. A total of 4 deaths occurred in the observation arm during follow-up, compared with 2 in the lenalidomide arm (HR=0.46; 95% CI 0.08-2.53).

The 3-year cumulative incidence of invasive second primary cancers was low in both groups (5.2% in lenalidomide arm vs. 3.5% in observation arm).

The authors noted that “patients in all risk groups seemed to have an HR that favored early treatment …, but this was most pronounced in the Mayo 2018 high-risk category.” (See TABLE.)

According to Dr. Lonial, the magnitude of benefit with lenalidomide was one of the most surprising findings in the study. “We saw a 90% relative risk reduction at 3 years favoring early treatment versus observation,” he said. “This is a huge benefit and shows the impact of early intervention. It also supports the idea that prevention of CRAB [hypercalcemia, renal failure, anemia, and bone disease] is a major endpoint in early disease, and that this can be achieved with low-intensity treatment.”

Based on these findings, Dr. Lonial and researchers are evaluating whether more intensive treatment can further improve outcomes, including a study of lenalidomide plus dexamethasone, with or without daratumumab, in patients with high-risk smoldering MM. “There is a presumption that like with myeloma, more is better, but this may not be the case for smoldering myeloma and needs to be proven,” he said. “At this point, to change practice, we need to demonstrate additional benefit for more intensive treatment, and that should be the focus of future trials,” he noted.

Study authors report relationships with Celgene, the manufacturer of lenalidomide.


Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 October 25. [Epub ahead of print]