Daratumumab and Hyaluronidase-fihj Approved for High-Risk Smoldering Multiple Myeloma
Expert Perspectives · Lyn Brook · 2025-11-12
The FDA has approved daratumumab and hyaluronidase‑fihj (Darzalex Faspro®, Janssen Biotech) for the treatment of adults with high‑risk smoldering multiple myeloma (SMM). This approval marks the first therapy specifically approved for patients with high‑risk SMM, expanding the role of daratumumab to earlier stages of myeloma progression.
Why This Approval Matters
High‑risk SMM carries a significant risk of progression to symptomatic multiple myeloma, often within two years of diagnosis. Until this approval, active monitoring was the standard approach. The availability daratumumab and hyaluronidase‑fihj monotherapy for this population introduces a proactive treatment option that significantly delays progression to active disease, potentially altering the natural course of SMM.
Breaking Down the AQUILA Trial
Efficacy was evaluated in the AQUILA study (NCT03301220), a phase 3, open‑label trial enrolling 390 patients with high‑risk SMM.
Patients were randomized 1:1 to receive either daratumumab and hyaluronidase‑fihj monotherapy or active monitoring. The treatment regimen consisted of:
- 1,800 mg/30,000 units subcutaneous, once weekly during Weeks 1 through 8
- Once every two weeks during Weeks 9 through 24
- Once every four weeks starting at Week 25, continued for up to 39 cycles (approximately 36 months), or until progression or unacceptable toxicity.
Among the enrolled participants, 41% had two or more high‑risk features, including serum monoclonal protein >2 g/dL, involved‑to‑uninvolved free light chain ratio >20, and bone marrow plasma cells >20%.
The primary efficacy end point was progression‑free survival (PFS), defined as time to diagnosis of multiple myeloma or death, assessed by an independent review committee (IRC) per International Myeloma Working Group (IMWG) criteria. Results demonstrated a median PFS that was not evaluable in the daratumumab and hyaluronidase‑fihj arm versus 41.5 months in the active monitoring arm.
These results represent a 51% reduction in the risk of progression or death, establishing daratumumab as the first agent to show robust disease‑modifying potential in high‑risk SMM.
Managing Adverse Events
The prescribing information includes warnings and precautions for hypersensitivity and administration‑related 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.
Dosing and Administration
The recommended dose of daratumumab is 1,800 mg and 30,000 units of hyaluronidase administered subcutaneously over approximately three to five minutes, according to the prescribed dosing schedule. Treatment continues until diagnosis, unacceptable toxicity, or completion of 39 cycles.