Daratumumab Combo Receives EU CHMP Recommendation in NDMM

Daratumumab would become the sole anti-CD38 agent available for all newly diagnosed multiple myeloma types if approved.

Daratumumab (Darzalex) has received a recommendation for EU approval by the Committee for Medicinal Products for Human Use (CHMP) as a subcutaneous formulation in the frontline setting combined with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (daratumumab-VRd) to treat adult patients with newly diagnosed multiple myeloma (NDMM), according to a news release from the drug’s developer, Janssen-Cilag International NV.¹

The decision is supported by data from the phase 3 CEPHEUS study (NCT03652064). Results from the trial published in Nature Medicine and presented at the 2024 American Society of Hematology Annual Meeting and Exposition revealed that the addition of daratumumab to VRd resulted in a significantly higher minimal residual disease (MRD)-negativity rate with complete response (CR) or better.^2,3 At a 10^-5 sensitivity, 60.9% of the daratumumab-VRd arm achieved MRD-negativity with at least a CR vs 39.4% of the VRd arm (OR, 2.37; 95% CI, 1.58-3.55; P <.0001). Overall MRD-negativity rates were consisted across prespecified subgroups.

Additional efficacy data revealed that progression-free survival (PFS) outcomes were significantly improved with daratumumab-VRd vs VRd alone; the median PFS was not reached vs 52.6 months with the respective regimens (HR, 0.57; 95% CI, 0.41-0.79; P = .0005). Additionally, the estimated 54-month PFS rates were 68.1% (95% CI, 60.8%-74.3%) vs 49.5% (95% CI, 41.8%-56.8%), respectively. PFS outcomes were consistent across prespecified subgroups.

Daratumumab would become the sole anti-CD38 agent available for all NDMM types if approved.

“It is increasingly evident that to continue optimizing outcomes in multiple myeloma, we must intervene early with the most effective therapies first,” Edmond Chan, MBChB, MD (Res), EMEA Therapeutic Area Lead of Hematology at Johnson & Johnson Innovative Medicine, said in the news release.¹ “Today’s positive recommendation, based on the CEPHEUS study, brings us closer to offering daratumumab-VRd as a treatment option for patients with NDMM, regardless of transplant eligibility. Together, with results from the [phase 3] PERSEUS study [NCT03710603], this demonstrates the potential of daratumumab-based regimens as a foundational frontline therapy for all patient types.”

Adult patients with transplant-ineligible or deferred NDMM with an ECOG performance status score of 0 to 1 in the open-label phase 3 CEPHEUS study were randomly assigned 1:1 to receive daratumumab-VRd (n = 197) or VRd alone (n = 195). Patients were stratified by International Staging System (ISS) disease stage and age or transplant eligibility.

Patients in the trial received eight 21-day cycles of VRd treatment, which initially consisted of 1.3 mg/m² of subcutaneous bortezomib on days 1, 4, 8, and 11; 25 mg of oral lenalidomide on days 1 to 14; and 20 mg of oral or intravenous dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 or days 1, 4, 8, and 11 in those older than 75 years or with a BMI of less than 18.5 kg/m². Following the first 8 cycles, bortezomib was discontinued and patients continued to receive 28-day cycles of Rd, which consisted of 25 mg of oral lenalidomide on days 1 to 21 and 40 mg of oral dexamethasone on days 1, 8, 15, and 22 or 20 mg once weekly for those older than 75 years or with a BMI less than 18.5 kg/m² until unacceptable toxicity or disease progression.

Those in the daratumumab-VRd group additionally received 1800 mg of subcutaneous daratumumab with 2000 U/ml¹ of recombinant human hyaluronidase PH20 weekly in cycles 1 and 2, every 3 weeks in cycles 3 to 8, and every 4 weeks following until disease progression or unacceptable toxicity.

The primary end point of the study was MRD-negativity rate. Key secondary end points included CR or greater rate, PFS, and sustained MRD-negativity rate.

The most common any-grade treatment-emergent adverse effects (TEAEs) in the experimental and control arms included diarrhea (56.9% vs 59.0%), peripheral sensory neuropathy (55.8% vs 61.0%), neutropenia (55.8% vs 39.0%), thrombocytopenia (46.7% vs 33.8%), and peripheral edema (42.1% vs 39.0%). Additionally, the most common grade 3 or 4 TEAEs in the respective arms included neutropenia (44.2% vs 29.7%), thrombocytopenia (28.4% vs 20.0%), anemia (13.2% vs 11.8%), lymphopenia (12.2% vs 10.3%), and diarrhea (12.2% vs 9.2%).

Serious TEAEs occurred in 72.1% and 67.2% of the quadruplet and triplet arms, the most common being pneumonia in 13.7% vs 12.8%, respectively.

References

1. 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 March 3, 2025. https://tinyurl.com/3nd44796
2. 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
3. Zweegman S, Facon T, Hungria V, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib, lenalidomide and dexamethasone (VRd) versus alone in patients with transplant-ineligible newly diagnosed multiple myeloma or for whom transplant is not planned as initial therapy: analysis of minimal residual disease in the Cepheus trial. Blood. 2024;144(suppl 1):362. doi:10.1182/blood-2024-200871