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Subcutaneous Daratumumab Approaches EU Approval in High-Risk Smoldering Myeloma

The EMA’s CHMP has issued a positive opinion regarding the use of subcutaneous daratumumab in high-risk smoldering myeloma.

Multiple myeloma| Image Credit:   © Curie - stock.adobe.com

Multiple myeloma| Image Credit:

© Curie - stock.adobe.com

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of subcutaneous formulation of daratumumab (daratumumab and hyaluronidase-fihj; Darzalex Faspro) for use as a single agent in adult patients with smoldering multiple myeloma that is at high risk of developing multiple myeloma.1

The recommendation is supported by findings from the phase 3 AQUILA study (NCT03301220), which showed that at a median follow-up of 65.2 months (range, 0-76.6), the risk of disease progression or death was 51% lower with daratumumab (n = 194) than with active monitoring (n = 196; HR, 0.49; 95% CI, 0.36-0.67; P < .001).2 The median progression-free survival (PFS) was not reached (NR; 95% CI, 66.7-not evaluable) vs 41.5 months (95% CI, 26.4-53.3) in the respective arms;3 the 5-year PFS rates were 63.1% and 40.8%.2 Moreover, 7.7% and 13.3% of patients died at the time of data cutoff (HR, 0.52; 95% CI, 0.27-0.98); the 5-year overall survival rates in the respective arms were 93.0% and 86.9%.

“The positive recommendation from the CHMP marks an important step towards addressing the needs of people living with high-risk smouldering multiple myeloma,” Ester in’t Groen, EMEA Therapeutic Area Head Haematology at Johnson & Johnson Innovative Medicine, stated in a news release.1 “Early disease intervention with daratumumab has the potential to reduce the risk of progression to active multiple myeloma or death by 51% for patients with high-risk disease. Pending European Commission approval, patients and physicians will have an option to treat high-risk smouldering multiple myeloma, with the aim to intercept this complex blood cancer before it develops into active disease and importantly, before end-organ damage occurs.”

Assessing AQUILA: Design, Treatment, Objectives

The open-label, multicenter, randomized, phase 3 trial enrolled patients with a confirmed diagnosis of smoldering multiple myeloma per International Myeloma Working Group (IMWG) criteria within the past 5 years of enrollment.2 Patients were at least 18 years of age, had measurable disease, and an ECOG performance status of 0 or 1. They also were considered to be at high risk for progression to active multiple myeloma.

They were randomly assigned 1:1 to receive single-agent subcutaneous daratumumab or undergo active monitoring. Those in the former arm were given 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. They received treatment for a total of 39 cycles, for 36 months, or until progressive disease. Those in the latter arm were not given disease-specific treatment.

Stratification factors included number of risk factors linked with progression to multiple myeloma (<3 vs ≥3), presence of a serum M-protein level of at least 30g per liter (yes vs no), the presence of IgA smoldering multiple myeloma (yes vs no), the degree of immunoparesis (reduced levels of 2 uninvolved immunoglobulins vs reduced levels of less than 2 uninvolved immunoglobulins), the presence of a serum FLC ratio of at least 8 (yes vs no), and the percentage of clonal plasma cells in bone marrow (>50% to <60% vs ≤50%).

The trial’s primary end point was PFS, and secondary end points included overall response rate and complete response per a validated computer algorithm that was in accordance with IMWG response criteria, as well as disease progression per IMWG biochemical or SLiM–CRAB criteria, start of frontline treatment for active multiple myeloma, and death from any cause.

The clinical cutoff date for the data published in New England Journal of Medicine was May 1, 2024. Baseline patient characteristics were balanced between the arms. The median age was 64 years (range, 31-86) and the median time from initial diagnosis of smoldering multiple myeloma to randomization was 0.72 years (range, 0-5.0). In the daratumumab and active monitoring arms, around half of patients were male (49.0% vs 47.4%), most were White (83.0% vs 82.7%), had an ECOG performance status of 0 (85.1% vs 81.6%), had IgG myeloma (65.5% vs 70.4%), 10% to no higher than 20% of clonal plasma cells in bone marrow (63.9% vs 52.0%), and under 3 risk factors for progression to multiple myeloma (79.4% vs 79.6%).

Safety Spotlight

Any adverse effects (AEs) occurred in 96.9% of those in the daratumumab arm vs 82.7% of those in the active monitoring arm; they were grade 3 or 4 for 40.4% and 30.1% of patients, respectively. The most common AEs experienced by those in the daratumumab and active monitoring arms were fatigue (34.2%; 13.3%), upper respiratory tract infection (30.1%; 7.7%), diarrhea (27.5% vs 5.1%), arthralgia (26.9%; 17.9%), nasopharyngitis (25.4%; 11.7%), back pain (23.8%; 19.4%), and insomnia (22.3%; 2.6%). The most common grade 3 or 4 AE was hypertension, and that was reported in 5.7% and 4.6% of patients, respectively.

Serious AEs occurred in 29.0% of those who received daratumumab vs 19.4% of those who underwent active monitoring, the most common of which was pneumonia (3.6%; 0.5%). AEs proved to be fatal for 2 patients in the daratumumab arm vs 4 patients in the active monitoring arm. Second primary cancers were observed in 9.3% of those in the daratumumab arm vs 10.2% of those in the active monitoring arm.

Looking Beyond

In November 2024, a supplemental biologics license application seeking the approval of subcutaneous daratumumab as a monotherapy in patients with high-risk smoldering myeloma was submitted to the FDA.4 In May 2025, the FDA’s Oncologic Drugs Advisory Committee voted 6 to 2 in favor of the risk/benefit profile of subcutaneous daratumumab for use in this population, which currently has no approved therapies.3

References

  1. Darzalex (daratumumab) receives the first positive CHMP opinion for patients with high-risk smoldering multiple myeloma. News release. Janssen-Cilag International NV. June 20, 2025. Accessed June 20, 2025. https://www.jnj.com/media-center/press-releases/darzalex-daratumumab-receives-the-first-positive-chmp-opinion-for-patients-with-high-risk-smouldering-multiple-myeloma
  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 June 20, 2025. https://www.youtube.com/live/iSGFdhMgh1E
  4. Johnson & Johnson submits applications in the U.S. and EU seeking approval of Darzalex Faspro/Darzalex (daratumumab) as subcutaneous monotherapy for high-risk smouldering multiple myeloma. News release. Johnson & Johnson. November 8, 2024. Accessed June 20, 2025. https://www.jnj.com/media-center/press-releases/johnson-johnson-submits-applications-in-the-u-s-and-eu-seeking-approval-of-darzalex-faspro-darzalex-as-subcutaneous-monotherapy-for-high-risk-smoldering-multiple-myeloma

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