Results from the primary analysis of a phase III AQUILA study, with a median follow-up of 65.2 months, show that subcutaneous daratumumab monotherapy was associated with a 51% lower risk of progression to active multiple myeloma or death among patients with high-risk smoldering multiple myeloma than active monitoring, the current standard-of-care for this patient population.
Baseline values for patient reported outcomes were similar to or slightly better than general population norms and were maintained over the study duration in both groups; values with daratumumab were similar to those with active monitoring, according to Prof. Meletios A. Dimopoulos of the Alexandra General Hospital, National and Kapodistrian University of Athens in Athens, Greece and colleagues who presented the results at the 66th ASH Annual Meeting along with a simultaneous publication in The New England Journal of Medicine on 9 December 2024.
The authors wrote in the background that patients with smoldering multiple myeloma who are at high risk for progression to active multiple myeloma may benefit from early treatment, although no treatments have been approved for this indication. The phase II CENTAURUS study showed that an anti-CD38 monoclonal antibody, daratumumab, had single-agent activity in patients with intermediate-risk or high-risk smoldering multiple myeloma. Results from that study supported the daratumumab dosing strategy chosen for the phase III AQUILA trial and confirmed the side-effect profile of daratumumab in patients with smoldering multiple myeloma.
In the phase III AQUILA study, the researchers randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary endpoint was progression-free survival (PFS); progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria.
Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.36 to 0.67; p < 0.001). At 5 years, PFS rate was 63.1% with daratumumab and 40.8% with active monitoring.
A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active monitoring group died (HR 0.52, 95% CI 0.27 to 0.98). Overall survival (OS) at 5 years was 93.0% with daratumumab and 86.9% with active monitoring.
Daratumumab had a predominantly low-grade safety profile in patients with smoldering multiple myeloma, which is consistent with the known profile of daratumumab monotherapy in patients with relapsed or refractory multiple myeloma. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.
The authors commented that their findings suggest that the use of daratumumab may delay or even prevent end-organ damage and progression to active multiple myeloma, providing clinical benefit independent of effecting a deep response. Furthermore, the use of daratumumab does not negatively affect patients’ quality-of-life.
Ongoing trials are exploring more intensive combination approaches. Although these more aggressive combination approaches are promising, longer follow-up is needed to determine whether a significant effect with respect to OS among patients with smoldering multiple myeloma can be achieved while balancing side effects.
The authors also commented that one important limitation across studies is that the criteria defining high-risk smoldering multiple myeloma have evolved over the years and differ among the studies, highlighting a need for more uniform criteria. Additionally, although this study may have implications regarding screening for monoclonal gammopathy of unknown significance, particularly in high-risk populations, screening recommendations require international consensus.
Reference
Dimopoulos MA, Voorhees PM, Schjesvold F, et al. for the AQUILA Investigators. Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. NEJM; Published online 9 December 2024. DOI: 10.1056/NEJMoa2409029