Could Lenalidomide Be a New Standard for High-Risk Smoldering Myeloma?

Results from a second clinical trial examining the use of lenalidomide treatment in patients with high-risk smoldering multiple myeloma may support a change in practice for these patients, where the standard of care has been observation.

At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, Sagar Lonial, MD, of Winship Cancer Institute, presented results of the E3A06 trial (abstract 8001), which showed an improvement in progression-free survival in patients treated with lenalidomide compared with those who underwent observation.

A previous Spanish trial testing lenalidomide/dexamethasone in smoldering myeloma showed improvement in progression-free and overall survival after this early intervention, but was limited by its use of conventional x-rays only, combination with dexamethasone, and flow-based risk assessment.

“Based upon our trial and the earlier Spanish trial with similar magnitude of benefit for lenalidomide or lenalidomide plus dexamethasone, we recommend early intervention for patients with high-risk smoldering multiple myeloma, as we feel that in these patients, the risk for developing end organ damage and comorbidity is high enough that continued observation does not make sense,” Lonial said.

E3A06 had two portions. Phase II enrolled 44 patients and was designed to evaluate safety and success of stem cell mobilization. Phase III enrolled 182 patients and randomly assigned them to lenalidomide or observation. Phase III was designed to compare progression-free survival, defined as biochemical progression and CRAB (calcium elevation, renal dysfunction, anemia, and bone disease) criteria related to the plasma cell proliferative process.

In the phase II trial, 47.7% of patients had a partial response or better, with 9.1% having a very good partial response or better. In phase III, 48.9% of patients assigned lenalidomide had a partial response or better compared with no patients assigned to observation.

With a median follow-up of 35 months, the 3-year progression-free survival rate was 91% with lenalidomide compared with 66% with observation (hazard ratio, 0.28; 95% CI, 0.12–0.63; P = .0005), which Lonial said “is almost identical to what the Spanish showed in their previous trial.”

In phase II, the 3-year progression-free survival was 87%, which is “tracking almost identical to the lenalidomide arm of the randomized trial,” with a 5 year expected progression-free survival of 78%.

According to Lonial, there was no difference in quality of life in the two arms of the trial associated with early therapy.

Most adverse events were hematologic with myelosuppression and anemia being the most common. Second primary malignancies occurred in 4.5% of patients assigned to lenalidomide compared with 2.2% assigned to observation.

In his discussion of the trial results, Philip L. McCarthy, MD, of Roswell Park Comprehensive Cancer Center, raised several questions about this early treatment of smoldering multiple myeloma that remain unknown, including whether a more intensive approach will improve long-term outcomes and whether early intervention will result in improved overall survival.