FDA Approves Subcutaneous Daratumumab for High-Risk Smoldering Multiple Myeloma

The FDA has approved daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) for the treatment of adult patients with high-risk smoldering multiple myeloma.¹

The regulatory decision was supported by data from the phase 3 AQUILA trial (NCT03301220), which demonstrated that patients treated with subcutaneous daratumumab (n = 194) experienced a median progression-free survival (PFS) that was not reached compared with 41.5 months for those who underwent active monitoring (n = 196; HR, 0.49; 95% CI, 0.36-0.67; P < .0001).^1,2

How was the AQUILA trial designed?

The phase 3, open-label, randomized trial enrolled 390 patients at least 18 years of age with high-risk smoldering multiple myeloma who had a confirmed diagnosis for no more than 5 years.^1,2 Patients were required to have an clonal plasma cells in bone marrow of at least 10%, and they needed to have at least 1 of the following risk factors: serum M-protein level of at least 30 g/L; IgA disease; immunoparesis with reduced levels of 2 uninvolved immunoglobulin isotypes; serum involved/uninvolved free light chains between 8 and 100; or clonal plasma cells in bone marrow of more than 50% to less than 60%.² An ECOG performance status of 0 or 1 was also mandatory.

Patients were randomly assigned 1:1 to receive subcutaneous daratumumab or undergo active monitoring with no disease-specific treatment. In the experimental arm, subcutaneous daratumumab was given in 28-day cycles at 1800 mg once per week in cycles 1 and 2, then once every 2 weeks in cycles 3 to 6, and then once every 4 weeks in subsequent cycles. Treatment continued for 39 cycles or 36 months.

PFS per independent review committee assessment according to International Myeloma Working Group SLiM-CRAB criteria served as the trial's primary end point. Secondary end points included overall response rate, time to first-line treatment for multiple myeloma, PFS on first-line treatment for multiple myeloma, and overall survival (OS).

What other efficacy and safety data were reported from the AQUILA trial?

Findings presented at the 2024 ASH Annual Meeting showed that patients in the daratumumab arm also experienced an OS benefit vs active observation (HR, 0.52; 95% CI, 0.27-0.98). The 60-month OS rates were 93.0% for the daratumumab arm vs 86.9% for the monitoring arm.

Additionally, daratumumab was associated with prolonged PFS on first-line treatment for multiple myeloma (HR, 0.58; 95% CI, 0.35-0.96).

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 96.9% of patients in the daratumumab arm (n = 193) vs 82.7% of patients in the active monitoring arm (n = 196). The rates of grade 3/4 TEAEs were 40.4% and 30.1%, respectively. Grade 5 TEAEs occurred at respective rates of 1.0% and 2.0%. The most common grade 3/4 TEAE was hypertension, reported in 5.7% of patients in the experimental arm vs 4.6% of patients in the control arm.

TEAEs led to treatment discontinuation in 5.7% of patients in the daratumumab arm, and 46.6% of patients in this group required dose modifications due to TEAEs.

Notably, COVID-19 TEAEs were reported in 8.8% of patients in the daratumumab arm compared with 5.1% of patients in the monitoring arm. The rates of serious COVID-19 TEAEs were 2.6% and 0.5%, respectively. COVID-19 led to death in 1.0% of patients in the experimental arm vs no patients in the control arm.

What is the safety and dosing information for subcutaneous daratumumab in smoldering multiple myeloma?

The prescribing information for subcutaneous daratumumab features warnings and precautions for hypersensitivity and other administration reactions, cardiac toxicity in patients with light chain amyloidosis, infections, neutropenia, thrombocytopenia, embryo-fetal toxicity, and interference with cross-matching and red blood cell antibody screening.¹

Subcutaneous daratumumab is recommended at a dose of 1800 mg of daratumumab and 30,000 units of hyaluronidase.

References

1. FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma. FDA. November 6, 2025. Accessed November 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-high-risk-smoldering-multiple-myeloma
2. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. Phase 3 randomized study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma: primary results of the Aquila study. Blood. 2024;144(supplement 1):773. doi:10.1182/blood-2024-201057