The FDA has issued a complete response letter (CRL) to the supplemental biologics license application (sBLA) seeking the approval of daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for or have deferred autologous stem cell transplant (ASCT).¹
In an announcement on August 1, Johnson & Johnson explained that the CRL cited observations from facility inspections; the letter was not related to safety and efficacy data for D-VRd, and no additional clinical studies were requested. In a news release, Johnson & Johnson announced that there has been no impact on the product supply or commercial availability of subcutaneous daratumumab, and it remains available for use in other approved indications in the United States.
“We are working closely with the FDA and are confident in our ability to promptly resolve the matter,” Yusri Elsayed, MD, MHSc, PhD, global therapeutic area head of Oncology, Innovative Medicine, at Johnson & Johnson, stated in a news release. “Health care professionals and patients can be assured of no impact to the current use or supply of [daratumumab (Darzalex)] and [subcutaneous daratumumab], which are foundational therapies for treating multiple myeloma.”
The sBLA was supported by findings from the phase 3 CEPHEUS trial (NCT03652064), which demonstrated that patients receiving D-VRd achieved a significantly higher rate of minimal residual disease (MRD) negativity compared with those who received the standard triplet regimen of VRd.² In CEPHEUS, treatment with D-VRd (n = 197) led to an MRD-negativity rate of 60.9% at 10⁻⁵ sensitivity compared with a rate of 39.4% in the VRd-alone arm (n = 198; OR, 2.37; 95% CI, 1.58-3.55; P < .0001). Patients treated with the quadruplet regimen also experienced deeper clinical responses, with a complete response (CR) or better rate of 81.2% vs 61.6% with VRd alone (OR, 2.73; 95% CI, 1.71-4.34; P < .0001).
An Overview of the CEPHEUS Clinical Trial
CEPHEUS was a global, randomized trial that enrolled patients with newly diagnosed multiple myeloma who were ineligible for or had deferred ASCT. All patients had an ECOG performance status of 0 to 2 and a frailty score of 0 or 1.
Patients were randomly assigned to receive either D-VRd or standard VRd. In the D-VRd arm, subcutaneous daratumumab was administered at 1800 mg weekly for the first 2 cycles, then every 3 weeks during cycles 3 to 8. Bortezomib, lenalidomide, and dexamethasone were dosed in 21-day cycles. From cycle 9 onward, daratumumab was given every 4 weeks in combination with lenalidomide and dexamethasone; patients in the control arm continued lenalidomide and dexamethasone alone.
The primary end point was rate of MRD negativity with a CR or better. Secondary end points included progression-free survival (PFS), rate of sustained MRD negativity with a CR or better for at least 12 months, rate of CR or better, and overall survival (OS).
Additional findings showed that MRD negativity at a sensitivity of 10⁻⁶ was achieved in 46.2% of patients receiving D-VRd vs 27.3% of those treated with VRd (OR, 2.24; P = .0001). Sustained MRD-negativity lasting at least 12 months at a sensitivity of 10⁻⁵ was reported in 48.7% of patients in the D-VRd group compared with 26.3% of those in the VRd group (OR, 2.63; P < .0001).
The median PFS was not reached in the D-VRd group compared with 52.6 months for VRd alone (HR, 0.57; P = .0005). The 54-month PFS rates were 68.1% vs 49.5%, respectively. OS data were not yet mature, but a trend favoring D-VRd was observed (HR, 0.85), which strengthened when censoring for COVID-19–related deaths (HR, 0.69).
D-VRd’s Safety Profile
Grade 3/4 treatment-emergent adverse effects (TEAEs) were observed in 92.4% of patients receiving D-VRd and 85.6% of those receiving VRd alone. Discontinuation of all study drugs due to TEAEs occurred in 7.6% of D-VRd–treated patients and 15.9% of patients in the VRd group. Grade 5 non–COVID-19 TEAEs occurred in 10.7% of patients in the D-VRd arm vs 7.7% of those in the VRd arm.
Common all-grade TEAEs in the D-VRd vs VRd arms included blood/lymphatic disorders (82.7% vs 64.6%), neutropenia (55.8% vs 39.0%), thrombocytopenia (46.7% vs 33.8%), anemia (37.1% vs 31.8%), gastrointestinal disorders (79.7% vs 81.5%), and peripheral sensory neuropathy (55.8% vs 61.0%). Most peripheral neuropathy cases were low grade, with grade 3/4 neuropathy rates of 8.1% vs 8.2%, respectively.
References
- Update on U.S. regulatory review of supplemental biologics license application. News release. Johnson & Johnson. August 1, 2025. Accessed August 19, 2025. https://www.jnj.com/media-center/press-releases/update-on-u-s-regulatory-review-of-supplemental-biologics-license-application
- 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.