Smoldering multiple myeloma (SMM) is a heterogeneous disease. While observation is often sufficient for patients with low-risk disease, those with high-risk characteristics are more likely to develop symptomatic multiple myeloma (MM) and have poor outcomes. Early intervention in patients with high-risk disease may be an effective strategy to improve outcomes in this population. This was previously demonstrated in a Spanish trial, where lenalidomide plus dexamethasone prolonged progression-free survival (PFS) and overall survival (OS) compared to observation in high-risk SMM. However, this study included several limitations, including use of only conventional x-rays for screening, use of combination lenalidomide and dexamethasone, and use of a flow cytometry–based risk assessment that was not routinely available at that time.
At the 2019 Oncology Annual Meeting in Chicago, Sagar Lonial, MD (Winship Cancer Institute, Atlanta, Georgia, United States), presented results from the phase 2/3 E3A06 study (Abstract 8001), which compared lenalidomide monotherapy (25 mg d1-21 every 28 days) to observation in 182 patients with high-risk SMM. Magnetic resonance imaging (MRI) of the spine and pelvis, an imaging technique that is more sensitive at detecting disease than x-rays, was used in this trial. This trial included a phase 2 portion and a randomized phase 3 portion. The primary objective of the phase 2 portion was to evaluate the safety and success of stem cell mobilization. The randomized phase 3 portion compared PFS among patients receiving either lenalidomide or observation. In both portions of the trial, patients continued lenalidomide until disease progression or unacceptable toxicity. PFS was defined as both biochemical and CRAB (hypercalcemia, renal insufficiency, anemia, and bone lesions) progression due to the plasma cell disorder.
The focus of this report is phase 3 trial data. However, the PFS rates, response rates, and safety data were similar for patients receiving lenalidomide in the phase 2 portion of the trial. At a median follow-up of 35 months, lenalidomide significantly improved PFS compared to observation (HR 0.28, P = .0005). The estimated 3-year rate of PFS was 91% in the lenalidomide group compared to 66% in the observation group. The PFS benefit was consistent across all patient subgroups with the exception of black patients. Though this subgroup of patients was small (n = 31), it may indicate the difference in biology in these patients. In addition to the reduced risk of progression, a greater proportion of patients treated with lenalidomide compared to those under observation achieved a very good partial response (VGPR) or better (4.4% vs 0%) or a partial response (PR) or better (48.9% vs 0%).
Lenalidomide was associated with high rates of adverse events (AE), and 51% of patients in the lenalidomide arm discontinued treatment due to AEs. Most of the AEs were hematologic with neutropenia and anemia being most common. Despite AEs, lenalidomide did not significantly impact patient quality of life. A total of 4.5% of patients in the lenalidomide arm experienced invasive second primary malignancies, compared to 2.2% of patients in the observation arm. Dr Lonial concluded that these results taken in combination with the previously reported Spanish trial results support the use of early intervention for patients with high-risk SMM (Mayo 2018/IMWG risk criteria). The discussant of this abstract, Philip McCarthy, MD (Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States), highlighted that the definition of high-risk SMM for treatment intervention continues to evolve and that it remains to be seen if early intervention improves OS and whether more intensive ongoing strategies evaluating doublet and triplet therapies in this population can enhance the long-term benefit.