Daratumumab Decreased Progression Risk in High-Risk Smoldering MM

SLiM- and CRAB-based progression to multiple myeloma were lower in those treated with daratumumab.

Daratumumab (Darzalex) significantly reduced risk of disease progression or death vs active monitoring in patients with high-risk smoldering multiple myeloma, per data from the phase 3 AQUILA study (NCT03301220) presented at the 50th Annual Oncology Nursing Society Congress.

At a median follow-up of 65.2 months, daratumumab demonstrated a 51% reduction in the risk of disease progression or death vs active monitoring (HR, 0.49; 95% CI, 0.36–0.67; P < .001). The median progression-free survival (PFS) was not reached (NR) in the daratumumab group (n = 194) vs 41.5 months with active monitoring arm (n = 196); PFS rates at 72 months were 70.9% with daratumumab and 40.8% with active monitoring.

Additional findings showed SLiM-based progression to multiple myeloma occurred in 25.8% of patients treated with daratumumab compared with 33.2% in the active monitoring group. CRAB-based progression to multiple myeloma was also lower in the daratumumab arm (6.2%) vs the active monitoring arm (17.3%).

“Results from the phase 3 AQUILA study strongly support early intervention with subcutaneous daratumumab monotherapy for a fixed duration in patients with high-risk smoldering multiple myeloma, representing an opportunity to delay or avoid end-organ damage and progression to multiple myeloma, while preserving quality of life and extending survival,” lead study author Andrew J. Cowan, MD, of Fred Hutchinson Cancer Center, explained in a presentation of the data.

AQUILA Study Design

The phase 3 AQUILA study evaluated the efficacy and safety of subcutaneous daratumumab monotherapy compared with active monitoring in patients with high-risk smoldering multiple myeloma. Eligible patients were at least 18 years of age with high-risk smoldering multiple myeloma as defined by International Myeloma Working Group (IMWG) criteria. Patients were required to have undergone comprehensive imaging during screening, including whole-body PET/CT and MRI, to exclude the presence of active multiple myeloma. Central imaging review was conducted by an independent review committee (IRC).

Following eligibility confirmation, patients were randomly assigned in a 1:1 ratio to receive subcutaneous daratumumab monotherapy or undergo active monitoring. Daratumumab was administered at a dose of 1800 mg subcutaneously once per week in the first 2 28-day cycles, then every 2 weeks for cycles 3 through 6, and every 4 weeks for cycles 7 through 39, or until disease progression, death, or completion of therapy. Patients in the control group underwent observation with no disease-specific therapy per local institutional protocols.

The primary end point was PFS. Secondary end points included overall response rate (ORR), time to initiation of first-line treatment for multiple myeloma, PFS on first-line therapy, and overall survival (OS). Efficacy evaluations were performed every 3 months, and bone marrow assessments were conducted at least every 2 years.

Baseline Patient Demographics

Demographic and baseline disease characteristics were well balanced between the two arms. The median age was 63.0 years (range, 31-86) in the daratumumab arm and 64.5 years (range, 36-83) in the active monitoring arm. Female patients comprised 51.0% of the daratumumab group and 52.6% of the active monitoring group. Most patients had an ECOG performance status of 0—85.1% in the daratumumab group and 81.6% in the active monitoring group—and the remainder had a performance status of 1.

The median time from diagnosis of smoldering multiple myeloma to randomization was 0.80 years (range, 0.4-7.7) for patients in the daratumumab group and 0.87 years (range, 0.5-7.0) for those in the active monitoring group. Median bone marrow plasma cell percentages were similar in both arms: 20.0% (range, 8.0%-59.5%) in the daratumumab group and 20.0% (range, 10.0%-56.0%) in the active monitoring group.

With respect to the type of smoldering multiple myeloma, IgG was the most common subtype—observed in 65.5% of the daratumumab group and 70.4% of the active monitoring group. IgA subtype was present in 28.4% and 21.4% of patients in the two arms, respectively, and other subtypes accounted for 6.2% (daratumumab) and 7.1% (active monitoring) of patients.

Risk stratification according to AQUILA criteria showed that 79.4% and 79.6% of patients in the daratumumab and active monitoring arms, respectively, had fewer than 3 risk factors for progression to multiple myeloma; 20.6% and 20.4%, respectively, had 3 or more risk factors. Cytogenetic risk profiles indicated that 17.4% of patients in the daratumumab group and 12.2% in the active monitoring group had high-risk cytogenetics, defined as the presence of deletion 17p, translocation (4;14), or translocation (14;16).

Based on Mayo 2018 criteria, 23.2%, 39.7%, and 37.1% of patients in the daratumumab group were classified as low, intermediate, and high risk, respectively. In the active monitoring group, the distribution was 17.3%, 38.8%, and 43.9% for low, intermediate, and high risk, respectively.

Subgroup Analysis and Additional Efficacy Findings

The PFS benefit was observed consistently across all prespecified subgroups. These included stratifications by sex, age, race, region, weight, renal function, number of high-risk features, and cytogenetic risk profile. Notably, the benefit was most pronounced in patients retrospectively identified as high risk per the Mayo 2018 criteria (HR, 0.36; 95% CI, 0.23-0.56); the median PFS was NR in the daratumumab arm vs 22.1 months in the active monitoring group.

The ORR was significantly higher with daratumumab monotherapy at 63.4% compared with 2.0% for active monitoring (odds ratio, 83.80; 95% CI, 29.69–236.54; P < .001). Within the daratumumab arm, 29.9% of patients achieved a very good partial response or better, and 8.8% achieved a complete response or better.

Subsequent treatment data revealed that fewer patients in the daratumumab arm required initiation of first-line therapy for multiple myeloma (33.2%) compared with the active monitoring arm (53.6%). The most commonly initiated first-line regimen was bortezomib (Velcade) lenalidomide (Revlimid), and dexamethasone (VRd), received by 29.7% of patients in the daratumumab group and 27.6% in the monitoring group. Anti-CD38 antibody–based therapy was used in 25.0% and 33.3% of patients in the respective groups. The median time to initiation of first-line treatment for multiple myeloma was NR for the daratumumab group and was 50.2 months for the active monitoring group (HR, 0.46; 95% CI, 0.33-0.62).

Early intervention with fixed-duration daratumumab was associated with prolongation of OS (HR, 0.52; 95% CI, 0.27-0.98). A total of 41 deaths were recorded, including 15 in the daratumumab arm and 26 in the active monitoring arm. The leading causes of death were disease progression and treatment-related adverse effects (AEs).

Safety Analysis

“Daratumumab demonstrated a favorable safety profile, with a low rate [5.7%] of treatment discontinuation due to treatment-emergent AEs [TEAEs]. Patients maintained their health-related quality of life during daratumumab treatment compared with active monitoring,” Cowan and colleagues wrote.

Across the daratumumab and active monitoring arms, the overall incidence of any-grade TEAEs was 96.9% and 82.7%, respectively; grade 3/4 TEAEs were reported in 40.4% of daratumumab-treated patients vs 30.1% in the control arm. Hypertension was the most frequently reported grade 3/4 TEAE with daratumumab, occurring in 5.7% of patients compared with 4.6% in the active monitoring group.

Despite a higher frequency of serious TEAEs in the daratumumab group (29.0% vs 19.4%), the rate of treatment discontinuation due to TEAEs was low at 5.7%. Serious adverse effects such as grade 3/4 infections occurred in 16.1% of patients treated with daratumumab, with most being short in duration—approximately 95% of cases either resolved or recovered. Cytopenias of all grades were slightly more common in the daratumumab arm, including neutropenia (6.7%), anemia (4.7%), thrombocytopenia (2.6%), and lymphopenia (1.6%).

Systemic infusion-related reactions were reported in 16.6% of patients receiving daratumumab, although only 1.0% were grade 3/4 in severity. Local injection-site reactions, all grade 1/2, were observed in 27.5% of patients. The incidence of second primary malignancies was comparable between the arms (9.3% in daratumumab vs 10.2% in control). COVID-19–related TEAEs and serious COVID-19 effects occurred in both groups with slightly higher rates in the daratumumab cohort (8.8% vs 5.1%; serious TEAEs: 2.6% vs 0.5%).

References

1. Cowan AJ, Voorhees PM, Dimopoulos MA, et al. Phase 3 AQUILA study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma. Presented at: 50th Annual Oncology Nursing Society Congress; April 9-13, 2025; Denver, CO. I22