Daratumumab Outperforms Observation in High-Risk Smoldering Multiple Myeloma

For patients with smoldering multiple myeloma, an asymptomatic precursor disease of active multiple myeloma, observation is the current standard of care. According to Meletios A. Dimopoulos, MD, and colleagues, early treatment may confer benefit for individuals at high risk for progression to active multiple myeloma. However, no treatments are currently approved for smoldering multiple myeloma.

The human IgGκ monoclonal antibody targeting CD38, daratumumab, is approved in combination with standard regimens, as well as monotherapy, for multiple myeloma. Results of the phase 2 CENTAURUS study indicated single-agent activity in patients with intermediate-risk or high-risk smoldering multiple myeloma.

Data from that study influenced the daratumumab dosing strategy for the phase 3, open-label, multicenter, randomized  AQUILA trial (NCT03301220). In the AQUILA trial, researchers examined whether progression to active multiple myeloma in patients with high-risk smoldering multiple myeloma would be delayed with subcutaneous daratumumab monotherapy compared with active monitoring. Dr. Dimopoulos and colleagues reported results of the primary analysis of data from AQUILA in the New England Journal of Medicine.

Eligible patients were randomized to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment continued for 39 cycles, 36 months, or until disease progression was confirmed. Progression-free survival or death from any cause was the primary end point of interest.

The total study cohort included 390 eligible patients who were enrolled from December 10, 2017, through May 27, 2019. Of those, 194 were in the daratumumab group, and 196, in the active-monitoring group. One patient in the daratumumab group did not receive the assigned treatment. By the clinical cutoff date of May 1, 2024, 127 patients in the daratumumab group had completed 39 cycles or 36 months of treatment, and 80 in the active-monitoring group had completed 36 months of active monitoring.

At a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower in the daratumumab group compared with the active-monitoring group (hazard ratio [HR], 0.49; 95% CI, 0.36-0.67; P<0.001). At 5 years, progression-free survival in the daratumumab group was 63.1% versus 40.8% in the active-monitoring group. Fifteen patients in the daratumumab group (7.7%) and 26 in the active-monitoring group (13.1%) died (HR, 0.52; 95% CI, 0.27-0.98). Overall survival at 5 years in the daratumumab group was 93.0% versus 86.9% in the active-monitoring group.

Hypertension was the most common grade 3 or 4 adverse event, occurring in 5.7% of patients in the daratumumab group and 4.6% of patients in the active-monitoring group. In the daratumumab group, 5.7% of patients discontinued treatment due to adverse events. No new safety concerns were identified.

The researchers cited the differing and evolving criteria used to define high-risk smoldering multiple myeloma as an important limitation to the study results. The criteria used in AQUILA were based on data available at the time of study development, before the Mayo 2018 risk criteria were established.

In summary, the authors said, “With a median follow-up of more than 5 years, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death than active monitoring among patients with high-risk smoldering multiple myeloma. Daratumumab had an acceptable safety profile in patients with smoldering multiple myeloma.”