FDA Approves Subcutaneous Daratumumab for Smoldering Multiple Myeloma

The FDA has approved daratumumab and hyaluronidase-fihj (Darzalex Faspro) for the treatment of adult patients with high-risk smoldering multiple myeloma (SMM), making the CD38-directed antibody the first treatment approved in this setting.^1,2

Approval of the subcutaneous daratumumab formulation was based on findings from the phase 3 AQUILA study, which compared 3 years of daratumumab therapy vs active monitoring in patients with intermediate- and high-risk SMM. After a median follow-up of 65.2 months (range, 0-76.6), the median progression-free survival (PFS) was not reached with daratumumab monotherapy compared with 41.5 months with active monitoring, translating to a 51% reduction in the risk of disease progression or death (HR, 0.49; 95% CI, 0.36-0.67; P <.0001).²

Data from the AQUILA study shared at the 2024 ASH Annual Meeting showed that the 60-month PFS rates were 63.1% and 40.7% with daratumumab and active monitoring, respectively.³ The median time to first-line treatment for active myeloma was also improved with daratumumab at not reached vs 50.2 months, respectively (HR, 0.46; 95% CI, 0.33-0.62; P <.0001).

Regarding safety, adverse events (AEs) in the AQUILA study were generally consistent with previous studies exploring subcutaneous daratumumab. AEs occurring in 20% or more of patients treated with subcutaneous daratumumab included upper respiratory tract infection, musculoskeletal pain, fatigue, diarrhea, rash, sleep disorder, sensory neuropathy, and injection site reactions.²

The approval follows the recommendation of the FDA’s Oncologic Drugs Advisory Committee. The panel convened in May 2025 and voted 6 to 2 that the results of the AQUILA study provided sufficient evidence of a favorable benefit-risk ratio for subcutaneous daratumumab (Darzalex Faspro) for patients with high-risk SMM.⁴

“Until now, patients diagnosed with smoldering multiple myeloma only have the option to watch and wait for any active signs of progression to active disease,” Peter Voorhees, MD, Atrium Health/Levine Cancer Institute, Charlotte, NC, stated in a press release. “Results from AQUILA demonstrated Darzalex Faspro significantly delayed disease progression, underscoring the role of early disease intervention for patients with high-risk smoldering multiple myeloma.”²

AQUILA Study Background

The open-label, multicenter, multinational AQUILA trial enrolled 390 patients with high-risk SMM at clinical sites across 23 countries between December 10, 2017, and May 27, 2019. Overall, 390 patients with high-risk SMM were randomized 1:1 to either subcutaneous daratumumab monotherapy (n = 194) or active monitoring (n = 196) for 36 months or until confirmation of disease progression, whichever occurred first.³

Patients were eligible for the trial if they were aged at least 18 years; had a confirmed diagnosis of smoldering multiple myeloma per International Myeloma Working Group criteria; had measurable disease; had an ECOG performance status of 0 or 1; and were at high risk for progression to active myeloma.

The primary end point was PFS, with secondary end points including objective response rate, time to first-line treatment for myeloma, PFS on first-line treatment for myeloma, and overall survival.

According to the FDA, the label for daratumumab and hyaluronidase-fihj includes 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

The FDA label recommends that patients receive daratumumab at 1800/30,000 units (1800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over a period of approximately 3 to 5 minutes.¹

REFERENCES

1. FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma. Published online and accessed November 6, 2025. https://tinyurl.com/2vb674jn

2. DARZALEX FASPRO^® is the first and only treatment approved by the U.S. FDA for patients with high-risk smoldering multiple myeloma. Published online and accessed November 6, 2025. https://tinyurl.com/ys5tunwv

3. 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

4. Meeting of the Oncologic Drug Advisory Committee. FDA. May 20, 2025. Accessed November 6, 2025. https://tinyurl.com/5n7mwvjt