Daratumumab Combo Earns EU Approval in Newly Diagnosed Multiple Myeloma

The decision from the European Commission follows a positive opinion from the Committee for Medicinal Products for Human Use recommending the daratumumab regimen’s approval, which was issued in February 2025.

The European Commission has approved an extended indication for subcutaneous daratumumab (Darzalex) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) as a treatment for adults with newly diagnosed multiple myeloma (NDMM), according to a press release from the developer, Janssen-Cilag International NV.¹

The decision from the European Commission follows a positive opinion from the Committee for Medicinal Products for Human Use recommending the daratumumab regimen’s approval, which was issued in February 2025.²

Supporting data for the approval came from the phase 3 CEPHEUS trial (NCT03652064), in which investigators evaluated the safety and efficacy of D-VRd vs VRd alone for patients with transplant-ineligible or transplant-deferred NDMM.³ With a median follow-up of 58.7 months, minimal residual disease (MRD)–negative status (10^–5) with a complete response (CR) or better occurred in 60.9% of patients in the D-VRd arm vs 39.4% of those in the VRd arm (OR, 2.37; 95% CI, 1.58-3.55; P < .0001). Additionally, 48.7% and 26.3% of patients in each respective arm had sustained MRD-negative status for at least 12 months (OR, 2.63; 95% CI, 1.73-4.00; P < .0001).

A CR or better was reported in 81.2% of patients who received D-VRd vs 61.6% of those who were treated with VRd (OR, 2.73; 95% CI, 1.71-4.34; P < .0001). Additionally, data showed that the median progression-free survival (PFS) was not reached with the addition of daratumumab vs 52.6 months with VRd (HR, 0.57; 95% CI, 0.41-0.79; P < .0005).

The safety profile of D-VRd in the CEPHEUS trial was comparable with prior reports of each individual agent. The most common grade 3/4 toxicities in the D-VRd and VRd arms, respectively, included neutropenia (44.2% vs 29.7%), thrombocytopenia (28.4% vs 20.0%), anemia (13.2% vs 11.8%), peripheral neuropathy (8.1% vs 8.2%), diarrhea (12.2% vs 9.2%), and COVID-19 (11.2% vs 4.6%).

“Multiple myeloma is a complex and evolving disease. Starting with more effective regimens in the frontline setting offers patients the best chance of sustained long-term outcomes by preventing disease resistance and relapse,” Katja Weisel, MD, deputy director and professor of hematology/oncology in the Department of Oncology, Hematology and Bone Marrow Transplantation with the Department of Pneumonology at University Medical Center Hamburg-Eppendorf in Germany, stated in the press release.¹ “The subcutaneous [D-VRd] regimen delivers an effective and convenient new standard of care for patients with [NDMM], regardless of transplant eligibility, with responses that are deep and durable and translate into significantly reduced risk of disease progression or death.”

In the international, open-label, phase 3 CEPHEUS trial, 395 patients were randomly assigned to receive D-VRd (n = 197) or VRd alone (n = 198). All patients received lenalidomide at 25 mg orally on days 1 to 14 for cycles 1 to 8 and days 1 to 21 for cycles 9 and beyond; bortezomib at 1.3 mg/m² twice weekly on days 1, 4, 8, and 11 of each 21-day cycle for the first 8 cycles; and dexamethasone at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1 to 8 and then 40 mg on days 1, 8, 15, and 22 for cycles 9 and beyond.⁴ Additionally, patients in the experimental arm received daratumumab at 1800 mg subcutaneously once every week on cycles 1 to 2, every 3 weeks on cycles 3 to 8, and once every 4 weeks for cycle 9 and beyond.

The trial’s primary end point was the MRD-negative rate. Secondary end points included PFS, overall response rate, overall survival, time to response, and duration of response.

References

1. European Commission approves Johnson & Johnson’s subcutaneous DARZALEX (daratumumab)-based quadruplet regimen for the treatment of patients with newly diagnosed multiple myeloma, regardless of transplant eligibility. News release. Janssen-Cilag International NV. April 7, 2025. Accessed April 16, 2025. https://tinyurl.com/ymszt9nb
2. Johnson & Johnson’s DARZALEX (daratumumab) subcutaneous-based regimen receives positive CHMP opinion for patients with newly diagnosed multiple myeloma, regardless of transplant eligibility. News release. Janssen-Cilag International NV. February 28, 2025. Accessed April 16, 2025. https://tinyurl.com/3nd44796
3. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. Published online February 5, 2025. doi:10.1038/s41591-024-03485-7.
4. A study comparing daratumumab, VELCADE (Bortezomib), lenalidomide, and dexamethasone (D-VRd) with VELCADE, lenalidomide, and dexamethasone (VRd) in participants with untreated multiple myeloma and for whom hematopoietic stem cell transplant is not planned as initial therapy. ClinicalTrials.gov. Updated April 3, 2025. Accessed April 16, 2025. https://clinicaltrials.gov/study/NCT03652064