RCT: Daratumumab Monotherapy Prevents Progression in High-Risk Smoldering Multiple Myeloma

Background: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder that can progress to active multiple myeloma, especially when risk factors place patients in a high-risk subset. Although daratumumab has been approved for multiple myeloma, no treatments have been approved for high-risk SMM. This study (AQUILA) examined whether subcutaneous daratumumab could prevent or significantly delay progression to symptomatic myeloma.

Objective: To evaluate the effectiveness of subcutaneous daratumumab monotherapy versus active monitoring in prolonging time to disease progression (defined by SLiM–CRAB criteria) or death in patients with high-risk SMM.

Methods: In this open-label phase 3 trial, 390 patients with high-risk SMM were randomly assigned (1:1) to either daratumumab (1800 mg subcutaneously) or active monitoring. Daratumumab was administered weekly for cycles 1–2, every two weeks for cycles 3–6, and then every four weeks for up to 39 cycles (36 months) or until confirmed disease progression. Active monitoring followed the same schedule for disease evaluations without any specific therapy. The primary endpoint was progression-free survival (PFS), assessed by an independent committee. Secondary endpoints included overall survival, response rates, and time to subsequent therapy.

Results: After a median follow-up of 65.2 months, disease progression or death occurred in 34.5% of patients in the daratumumab group compared to 50.5% in the active-monitoring group (HR, 0.49; 95% CI, 0.36–0.67; p<0.001). At five years, the PFS rate was 63.1% with daratumumab and 40.8% with active monitoring. Overall survival was also higher in the daratumumab arm: 93.0% versus 86.9% at five years (HR for death, 0.52; 95% CI, 0.27–0.98). Treatment discontinuation due to adverse events was low (5.7%), and no new safety signals emerged. Grade 3 or 4 adverse events, primarily hypertension (5.7% vs. 4.6%), occurred at similar rates in both arms. Infections of grade 3 or 4 were more frequent with daratumumab (16.1% vs. 4.6%), including COVID-19 pneumonia, yet overall tolerability remained acceptable. Patient-reported outcomes, including quality-of-life measures, were largely preserved in both groups during the study.

Conclusions: Subcutaneous daratumumab monotherapy substantially delayed progression to symptomatic multiple myeloma and improved overall survival among patients with high-risk SMM. The safety profile was consistent with prior daratumumab studies, suggesting a favorable risk–benefit balance. Early intervention with daratumumab may thus alter the disease trajectory for select patients, sparing them from end-organ damage and improving long-term clinical outcomes.

Implications for Practice: While active monitoring has been the standard of care for high-risk SMM, these findings support early therapeutic intervention for patients with multiple high-risk features. Clinicians should remain cautious, however, when generalizing across different risk stratification models. Additional research on optimal treatment durations, combination strategies, and real-world outcomes will further refine patient selection and management of high-risk SMM.

Study Strengths and Limitations: This trial featured robust follow-up (median of over five years) and clear outcome definitions. However, the classification of high-risk features has evolved, and certain populations (e.g., Black patients) were underrepresented. These factors may limit the generalizability of the findings in broader clinical settings.

Future Research: Ongoing trials are investigating alternative dosing schedules, combination regimens (e.g., daratumumab-based quadruplets), and the role of minimal residual disease monitoring to optimize patient outcomes. Additional studies will clarify whether more intense or shorter treatments might maintain efficacy with fewer side effects.

Reference: Dimopoulos MA, Voorhees PM, Schjesvold F, Cohen YC, Hungria V, Sandhu I, Lindsay J, +29, for the AQUILA Investigators. Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2409029