CHMP Recommends Subcutaneous Daratumumab Plus VRd for Newly Diagnosed Myeloma

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the approval of an indication extension for subcutaneous daratumumab (Darzalex) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) for the treatment of adult patients with newly diagnosed multiple myeloma, irrespective of transplant eligibility.1

The positive opinion was supported by data from the phase 3 CEPHEUS trial (NCT03652064). Findings presented at the 21st International Myeloma Society Annual Meeting demonstrated that patients with transplant-ineligible or -deferred newly diagnosed multiple myeloma treated with subcutaneous daratumumab plus VRd (n = 197) achieved a minimal residual disease (MRD)–negativity rate of 60.9% at a 10-5 sensitivity compared with 39.4% for those given VRd alone (n = 198; odds ratio [OR], 2.37; 95% CI, 1.58-3.55; P < .0001).2

The complete response (CR) or better rate was 81.2% in the daratumumab arm vs 61.6% in the VRd arm (OR, 2.73; 95% CI, 1.71-4.34; P < .0001).

“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, stated in a 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 newly diagnosed multiple myeloma, 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.”

In July 2024, the FDA approved daratumumab and hyaluronidase-fihj subcutaneous daratumumab; Darzalex Faspro) in combination with VRd for induction and consolidation in patients with newly diagnosed multiple myeloma who are candidates for autologous stem cell transplant (ASCT), based on data from PERSEUS.3 In September 2024, Johnson & Johnson submitted a supplemental biologics license application seeking the approval of subcutaneous daratumumab in combination with VRd for the treatment of adult patients with newly diagnosed multiple myeloma for whom ASCT is deferred or those who are ineligible for ASCT, based on data from CEPHEUS.4

CEPHEUS Overview

The phase 3 study enrolled patients with newly diagnosed multiple myeloma who were ineligible for ASCT or had ASCT deferred.2 An ECOG performance status of 0 to 2 and a frailty score of 0 to 1 were also required.

Patients were randomly assigned 1:1 to receive daratumumab plus VRd or VRd alone. During the first 8 cycles, patients in both arms received bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21-day cycle; lenalidomide at 25 mg per day on days 1 to 14 of each cycle; and dexamethasone at 20 mg per day on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle. In the experimental arm, daratumumab was given at 1800 mg per week in cycles 1 and 2, then once every 3 weeks in cycles 3 to 8.

In cycle 9 and beyond, where cycles were 28 days, patients in the experimental arm received daratumumab at 1800 mg once every 4 weeks plus 25 mg of lenalidomide per day on days 1 to 21 and dexamethasone at 40 mg per day on days 1, 8, 15, and 22. Patients in the control arm received the same regimen of lenalidomide and dexamethasone in cycle 9 and beyond. Treatment in both arms continued until disease progression or unacceptable toxicity.

The overall MRD-negative CR rate served as the trial’s primary end point. Secondary end points included progression-free survival (PFS), sustained MRD-negative CR rate for at least 12 months, CR or better rate, and overall survival (OS).

Additional Efficacy and Safety Findings

The overall MRD-negativity rates at a 10-6 sensitivity were 46.2% for daratumumab plus VRd vs 27.3% for VRd (OR, 2.24; 95% CI, 1.48-3.40; P = .0001). Furthermore, 48.7% of patients in the experimental arm achieved sustained MRD negativity at a 10-5 sensitivity for at least 12 months compared with 26.3% of patients in the VRd arm (OR, 2.63; 95% CI, 1.73-4.00; P < .0001).

The median PFS was not reached in the daratumumab arm vs 52.6 months in the VRd arm (HR, 0.57; 95% CI, 0.41-0.79; P = .0005). The respective 54-month PFS rates were 68.1% and 49.5%.

OS data were not mature, and no statistically significant difference was observed between the 2 arms. However, a trend favoring the daratumumab-based regimen was observed (HR, 0.85; 95% CI, 0.58-1.24).

Grade 3/4 treatment-emergent adverse effects (TEAEs) were reported in 92.4% of patients in the daratumumab arm vs 85.6% of patients in the VRd arm. TEAEs led to discontinuation of all study drugs in 7.6% and 15.9% of patients, respectively. Grade 5 non–COVID-19 TEAEs were reported in 10.7% of patients in the experimental arm vs 7.7% of patients in the control arm.

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. Johnson & Johnson. February 28, 2025. Accessed February 28, 2025. https://www.jnj.com/media-center/press-releases/johnson-johnsons-darzalex-daratumumab-subcutaneous-based-regimen-receives-positive-chmp-opinion-for-patients-with-newly-diagnosed-multiple-myeloma-regardless-of-transplant-eligibility
2. Usmani SZ, Facon T, Hungaria V, et al. Daratumumab SC + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: results of the phase 3 CEPHEUS study. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-63.
3. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. FDA. July 30, 2024. Accessed February 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-multiple
4. Johnson & Johnson files for U.S. FDA approval of Darzalex Faspro-based quadruplet regimen for newly diagnosed multiple myeloma patients for whom transplant is not planned. News release. Johnson & Johnson. September 30, 2024. Accessed February 28, 2025. https://www.investor.jnj.com/news/news-details/2024/Johnson--Johnson-files-for-U.S.-FDA-approval-of-DARZALEX-FASPRO-based-quadruplet-regimen-for-newly-diagnosed-multiple-myeloma-patients-for-whom-transplant-is-not-planned/default.aspx