Subcutaneous daratumumab monotherapy lowers the risk of progression to active multiple myeloma or death

Subcutaneous daratumumab significantly lowered the risk of progression to active multiple myeloma or death, with higher overall survival for patients with high-risk smoldering multiple myeloma in comparison with the standard treatment of active monitoring according to the results of the phase 3 AQUILA trial.

At a median of 65.2 months, daratumumab reduced the risk of disease progression by 51% in comparison with active monitoring (hazard ratio, 0.49; 95% CI, 0.36–0.67; p < .001). The 5-year progression-free survival rate also favored daratumumab over active monitoring (63.1% vs. 40.8%).

The phase 3 trial is an open-label, multicenter trial in which 390 patients with smoldering multiple myeloma were randomized to subcutaneous daratumumab monotherapy (n = 194) or active monitoring (n = 196). Daratumumab is a CD38 monoclonal antibody. Treatment was continued for 39 cycles or 36 months or until confirmed disease progression. A total of 127 patients (65.5%) in the daratumumab group completed the treatment, and 80 patients (40.8%) completed active monitoring, with disease progression being the most common reason for discontinuation of treatment in both arms (21.8% and 41.8%, respectively).

Hypertension was the most common grade 3 or 4 adverse event in both treatment arms (5.7% with daratumumab and 4.6% with active monitoring).

Investigators of the study said that the findings “suggest that the use of daratumumab may delay or even prevent end-organ damage and progression to active multiple myeloma, providing the clinical benefit independent of effecting a deep response.”¹

Ajay K. Nooka, MD, MPH, director of the Myeloma Program and professor in the Department of Hematology and Medical Oncology at the Winship Cancer Institute at Emory University, also points out that the results suggest the use of daratumumab as an early intervention not only prevents progression to myeloma but also likely results in improved overall survival. He points to the 7.7% of patients in the daratumumab arm who died versus the 13.3% of patients in the active monitoring arm. He underscores, however, that longer follow-up may be needed to clarify this end point.

Dr Nooka notes that since the enrollment of patients in the study from 2017 to 2019, the definition of high-risk smoldering multiple myeloma has changed. The current definition of progression from high-risk smoldering multiple myeloma to multiple myeloma, established by the Mayo Clinic in 2018, includes three independent risk factors: involved serum paraprotein level ≥2 g/dL, an uninvolved serum-free light chain ratio ≥100, and a bone marrow biopsy showing ≥20% plasma cells (validated later).

He says a post hoc subset analysis of the AQUILA study found that patients who qualified as having high-risk smoldering multiple myeloma benefited the most from daratumumab.

He also cites two additional phase 3 trials that have assessed different treatment strategies compared to active monitoring in this setting (the QuiRedex and Eastern Cooperative Oncology Group [ECOG] E3A06 trials), and he says that post hoc analyses of both these studies also showed that patients with high-risk smoldering multiple myeloma benefited the most from treatment (lenalidomide plus dexamethasone in the QuiRedex trial and lenalidomide monotherapy in the ECOG E3A06 trial).

“Identifying the right patient that would benefit from the intervention is the key,” he says. “These studies provide enough evidence for us to intervene in high-risk smoldering multiple myeloma.”