EU Approval Sought for D-VRd in Newly Diagnosed Myeloma

A Type II variation application has been submitted to the European Medicines Agency (EMA) seeking the approval of D-VRd (daratumumab [Darazalex], bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone) for the treatment of adult patients with newly diagnosed multiple myeloma.¹

The submission is supported by data from the phase 3 CEPHEUS trial (NCT03652064), which showed that patients with newly diagnosed multiple myeloma who were ineligible for or deferred autologous stem cell transplant (ASCT) treated with D-VRd (n = 197) experienced higher rates of minimal residual disease (MRD) negativity at a 10-5 sensitivity compared with those given VRd alone (n = 198; odds ratio [OR], 2.37; 95% CI, 1.58-3.55; P < .0001).² Findings presented at the 21st International Myeloma Society Annual Meeting showed that the overall MRD-negativity rates were 60.9% vs 39.4%, respectively.

“[Although] we’ve seen significant progress in multiple myeloma treatment, there continues to be a tremendous opportunity to improve frontline therapies and ensure we are providing patients with better long-term outcomes,” Edmond Chan, MBChB, MD, EMEA therapeutic area lead hematology, Innovative Medicine, Johnson & Johnson, stated in a news release.¹ “The potential of this daratumumab subcutaneous-based regimen to transform outcomes for people with newly diagnosed multiple myeloma is incredibly promising, and today’s submission builds on our portfolio of phase 3 studies aimed at elevating the standard of care for all patients in the frontline treatment setting.”

In September 2024, Johnson & Johnson submitted a supplemental biologics license application to the FDA seeking the approval of daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) 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.³

In July 2024, the FDA approved D-VRd for induction and consolidation in patients with newly diagnosed multiple myeloma who are candidates for ASCT, based on findings from the phase 3 PERSEUS trial (NCT03710603).⁴

CEPHEUS enrolled patients with newly diagnosed multiple myeloma who were ineligible for ASCT or deferred ASCT.² Patients needed to have an ECOG performance status of 0 to 2 and a frailty score of 0 to 1.

Patients were randomly assigned 1:1 to receive daratumumab at 1800 mg once per week in cycles 1 and 2, then once every 3 weeks in cycles 3 to 8, in combination with 1.3 mg/m² of bortezomib on days 1, 4, 8, and 11 of each 21-day cycle, 25 mg of lenalidomide on days 1 to 14 of each cycle, and 20 mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle for 8 cycles; or VRd alone at the same dosing schedule. In cycle 9 and beyond, patients in the experimental arm received 1800 mg of daratumumab once every 4 weeks plus 25 mg of lenalidomide on days 1 to 21 and 40 mg of dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle; those in the control arm received Rd alone at the same dosing schedule.

The overall MRD-negativity rate with a complete response (CR) or better served as the trial’s primary end point. Key secondary end points included progression-free survival (PFS); the proportion of patients with sustained MRD negativity with a CR or better for at least 12 months; CR or better rate; and overall survival.

Additional data showed that patients treated with D-VRd experienced a CR or better rate of 81.2% vs 61.6% for those given VRd (OR, 2.73; 95% CI, 1.71-4.34; P < .0001). In the D-VRd arm, the stringent CR, CR, very good partial response (PR), and PR rates were 65.0%, 16.2%, 11.7%, and 4.1%, respectively. In the VRd arm, these rates were 44.4%, 17.2%, 25.3%, and 6.1%, respectively.

When tested at a 10-6 sensitivity, the overall MRD-negativity rates were 46.2% and 27.3% for D-VRd and VRd, respectively (OR, 2.24; 95% CI, 1.48-3.40; P = .0001).

MRD negativity at a 10-5 sensitivity was sustained for at least 12 months in 48.7% of patients in the D-VRd arm vs 26.3% of patients in the VRd arm (OR, 2.63; 95% CI, 1.73-4.00; P < .0001).

At a median follow-up of 58.7 months, patients in the experimental arm achieved a median PFS that was not reached compared with 52.6 months for those in the control arm (HR, 0.57; 95% CI, 0.41-0.79; P = .0005). The 54-month PFS rates were 68.1% and 49.5%, respectively.

Regarding safety, grade 3 or 4 treatment-emergent AEs (TEAEs) occurred in 92.4% of patients in the D-VRd arm compared with 85.6% of patients in the VRd arm. TEAEs led to discontinuation of all study drugs in 7.6% of patients treated with D-VRd and 15.9% of patients given VRd alone. Grade 5 non–COVID-19 TEAEs occurred in 10.7% of patients in the D-VRd arm vs 7.7% of patients in the VRd arm.

“[Subcutaneous] daratumumab–based therapies continue to be at the forefront of multiple myeloma research. CEPHEUS is the first registrational study with a primary end point of MRD negativity, supported by key secondary end points such as PFS,” Craig Tendler, MD, vice president of Clinical Development, Diagnostics, and Global Medical Affairs, Innovative Medicine, at Johnson & Johnson, added in a news release.¹ “The data from CEPHEUS add to the body of evidence for subcutaneous daratumumab in newly diagnosed multiple myeloma and, together with the results of the PERSEUS study, demonstrate the potential benefit of this quadruplet regimen for newly diagnosed patients, regardless of transplant eligibility.”

References

1. Johnson & Johnson submits application to the European Medicines Agency for Darzalex (daratumumab) SC-based quadruplet regimen for newly diagnosed multiple myeloma patients. News release. Johnson & Johnson. October 10, 2024. Accessed October 10, 2024. https://innovativemedicine.jnj.com/johnson-johnson-submits-application-to-the-european-medicines-agency-for-darzalex-daratumumab-sc-based-quadruplet-regimen-for-newly-diagnosed-multiple-myeloma-patients
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. 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 October 10, 2024. 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
4. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. FDA. July 30, 2024. Accessed October 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-multiple