Subcutaneous Daratumumab Receives European Commission Approval in Smoldering Myeloma

The European Commission (EC) has approved daratumumab (Darzalex) monotherapy as a subcutaneous formulation for the treatment of patients with smoldering multiple myeloma at high risk for developing multiple myeloma.¹

In June 2020, the EC approved the subcutaneous formulation of daratumumab for the treatment of patients with multiple myeloma.² The regulatory decision was supported by data from the phase 2 PLEIADES (MMY2040) trial (NCT03412565) and the phase 3 COLUMBA (MMY3012) study (NCT03277105). Furthermore, the EC expanded the use of subcutaneous daratumumab in June 2021 for the treatment of patients with multiple myeloma who previously received 1 therapy that comprised a proteasome inhibitor (PI) and lenalidomide (Revlimid), and became lenalidomide refractory; and those who previously received 2 therapies, including a PI and later experienced disease progression on or after their last therapy.³

The approval of daratumumab for the treatment of patients with smoldering multiple myeloma was supported by data from the phase 3 AQUILA study (NCT03301220).¹ The study evaluated the efficacy and safety of fixed-duration subcutaneous daratumumab monotherapy (n = 194) compared with active monitoring (n = 196).

At a median follow-up of 65.2 months (range, 0-76.6), patients who were treated with subcutaneous daratumumab demonstrated statistically significant improved progression-free survival (PFS) vs patients who underwent active monitoring. Specifically, the PFS rate at 60 months was 63.1% vs 40.8% in the daratumumab and active monitoring arms, respectively (HR, 0.49; 95% CI, 0.36-0.67; P < .001). In patients who were retrospectively categorized as those with high-risk smoldering multiple myeloma, the median PFS was not reached in the daratumumab arm compared with 22.1 months in the active monitoring arm (HR, 0.36; 95% CI, 0.23-0.58). Additionally, the overall survival (OS) data also demonstrated significant improvement with subcutaneous daratumumab, with a 5-year OS rate of 93.0% vs 86.9% in the respective arms (HR, 0.52; 95% CI, 0.27-0.98).

“Until now, the absence of approved therapies for high-risk smoldering multiple myeloma has left clinicians with limited options beyond observation, despite evidence that 50% of this patient population progresses to active multiple myeloma within 2 years,” Meletios A. Dimopoulos, MD, a professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Greece, stated in a news release. “The approval of daratumumab offers the potential to change this trajectory. By intervening earlier in the disease course, we have a meaningful opportunity to delay or prevent progression to symptomatic disease, reduce irreversible end-organ damage, and extend the window of improved patient outcomes.”

Moreover, data demonstrated that the overall response rate (ORR) was higher in patients treated with subcutaneous daratumumab. In particular, the ORR was 63.4% vs 2.0% in the daratumumab and active monitoring arms, respectively (P < .001). Notably, the median time to first-line treatment for multiple myeloma was not reached vs 50.2 months, respectively (HR, 0.46; 95% CI, 0.33-0.62; nominal P < .0001).

“This new indication for [subcutaneous] daratumumab 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, the Therapeutic Area Head of Hematology at Johnson & Johnson Innovative Medicine, added in the news release. “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.”

Regarding safety, daratumumab demonstrated a consistent safety profile with previous studies in other indications. Of note, there were low rates of treatment discontinuations due to treatment-emergent adverse effects (TEAEs). Grade 3/4 TEAEs were observed in 40.4% and 30.1% of patients in the subcutaneous daratumumab and active monitoring arms, respectively. The most common grade 3/4 TEAE reported in at least 5% of the overall patient population was hypertension (daratumumab, 5.7%; active monitoring, 4.6%).

“Until now, there have been no approved treatment options for patients diagnosed with high-risk smoldering multiple myeloma,” Jordan Schecter, MD, vice president and Disease Area Leader, Multiple Myeloma at Johnson & Johnson Innovative Medicine, concluded in the news release. “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 OS. We remain steadfast in our mission to get in front of cancer.”

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://www.jnj.com/media-center/press-releases/european-commission-approves-darzalex-daratumumab-as-the-first-licensed-treatment-for-patients-with-high-risk-smouldering-multiple-myeloma
2. Genmab announces European marketing authorization for the subcutaneous formulation of Darzalex (daratumumab) for the treatment of patients with multiple myeloma. News release. Genmab. June 4, 2020. Accessed July 23, 2025. https://ir.genmab.com/news-releases/news-release-details/genmab-announces-european-marketing-authorization-subcutaneous
3. Darzalex (daratumumab) subcutaneous (sc) formulation becomes the first approved treatment for newly diagnosed systemic light chain amyloidosis in Europe and gains an additional approval in pre-treated multiple myeloma. News release. Johnson & Johnson. June 22, 2021. Accessed July 23, 2025. https://innovativemedicine.jnj.com/emea/darzalexrv-daratumumab-subcutaneous-sc-formulation-becomes-first-approved-treatment-newly-diagnosed