Subcutaneous Daratumumab Approved by EC in Smoldering Multiple Myeloma

Results from the AQUILA trial led to the approval of subcutaneous daratumumab for patients with smoldering multiple myeloma at risk of developing the disease.

The European Commission has approved daratumumab as a monotherapy, subcutaneous formulation (daratumumab and hyaluronidase-fihj; Darzalex Faspro), for adult patients with smoldering multiple myeloma who are at high-risk of developing the disease, according to a press release from Johnson & Johnson.1

The approval is based on results from the phase 3 AQUILA study (NCT03301220), which assessed subcutaneous daratumumab vs active monitoring for patients with the aforementioned disease.2

Topline data from the trial showed a median of 65.2 months of follow-up, with the risk of disease progression or death being 51% lower in the daratumumab arm vs the active monitoring arm (HR, 0.49; 95% CI, 0.36-0.67; P <.001). There was a statistically significant improvement in progression-free survival (PFS), and 63.1% of patients in the daratumumab arm vs 40.8% in the active monitoring arm were alive and progression-free at 60 months. Additionally, the 5-year overall survival rates were 93.0% vs 86.9%, respectively (HR, 0.52; 95% CI, 0.27-0.98).

In the daratumumab arm, there was an increased overall response rate (ORR) of 63.4% vs 2.0% in the active monitoring arm (P <.001). The median time from first-line multiple myeloma treatment in the daratumumab arm was not reached compared with 50.2 months in the active monitoring arm (HR, 0.46; 95% CI, 0.33-0.62; P <.0001).

“This new indication for daratumumab [subcutaneous] is an exciting step forward in addressing a long-standing unmet clinical need for those diagnosed with high-risk smoldering multiple myeloma and is the first time a treatment has been approved for this patient population,” Ester in ’t Groen, EMEA Therapeutic Area Head Haematology, Johnson & Johnson Innovative Medicine, said in the press release.1 “It means that eligible patients no longer have to live with the uncertainty or fear of waiting for progression to occur without active treatment, instead having the option to intercept the disease with therapeutic intervention.”

The AQUILA trial randomly assigned patients 1:1 to receive either 1800 mg of subcutaneous daratumumab coformulated with recombinant human hyaluronidase PH20 weekly in cycles 1 and 2, biweekly in cycles 3 to 6, and every 4 weeks thereafter in 28-day cycles; or receive active monitoring. Patients receiving daratumumab were given treatment for either 39 cycles, 36 months, or until progressive disease. If they were in the active monitoring arm, they were not given disease-specific treatment.

The primary end point was PFS. Secondary end points included ORR and complete response rate, disease progression, start of frontline treatment, or death from any cause.

The safety profile remained consistent with previous results, and there was a low rate of treatment discontinuation due to treatment-emergent adverse effects (TEAEs). In 40.4% of patients in the daratumumab arm and 30.1% in the active monitoring arm, grade 3/4 TEAEs were noted. The most common was hypertension in 5.7% vs 4.6%.

Treatment discontinuation due to TEAEs was low with 5.7% in the daratumumab arm. Fatal TEAEs occurred in 1.0% in the daratumumab arm and 2.0% in the active monitoring arm.

“With today’s approval, Johnson & Johnson has an innovative therapy for every stage of the disease. We can now offer physicians and patients the option to treat with daratumumab earlier, significantly delaying progression and the need for more intensive, continuous therapy, as well as extending overall survival. We remain steadfast in our mission to get in front of cancer,” Jordan Schecter, MD, vice president and Disease Area Leader, Multiple Myeloma, Johnson & Johnson Innovative Medicine, said in the press release.1

In May 2025, the FDA convened an Oncologic Advisory Drug Committee meeting to discuss AQUILA trial results and their sufficiency to support a favorable benefit/risk ratio for patients with this disease. The committee voted 6-2 in favor of the results.3

References

1. European Commission approves DARZALEX® (daratumumab) as the first licensed treatment for patients with high-risk smouldering multiple myeloma. News release. Johnson & Johnson. July 23, 2025. Accessed July 23, 2025. https://tinyurl.com/bvhyv2vk
2. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. Daratumumab or active monitoring of high-risk smoldering multiple myeloma. N Engl J Med. 2025;392(18):1777-1788. doi:10.1056/NEJMoa2409029
3. May 20, 2025, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed July 23, 2025. https://tinyurl.com/3mmjsyyz