FDA Approves Daratumumab Quadruplet for Transplant-Ineligible Myeloma

The FDA approved daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) for adults with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT).¹

D-VRd is now the only anti-CD38 antibody-based regimen approved for all newly diagnosed patients, regardless of transplant eligibility. The approval is supported by the robust results of the phase 3 CEPHEUS trial (NCT03652064), which demonstrated that adding daratumumab to the standard VRd triplet improved both minimal residual disease (MRD) negativity rate and progression-free survival (PFS) in this patient population.

“D-VRd increased the depth and durability of responses, significantly reduced the risk of disease progression or death, and nearly doubled the rate of sustained [MRD]-negativity compared to VRd in patients ineligible for ASCT, solidifying this regimen as a potential standard of care for newly diagnosed patients with multiple myeloma,” said Saad Z. Usmani, MD, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center and CEPHEUS principal investigator, in a news release from Johnson & Johnson.²

The CEPHEUS Trial: Study Design and Efficacy

The CEPHEUS trial was a multicenter, randomized, open-label study involving 395 patients across 13 countries. Patients were randomly assigned to receive either the D-VRd quadruplet or the standard VRd triplet. The trial enrolled patients for whom ASCT was not an option due to age or clinical factors and did include patients who deferred ASCT. Secondary end points included PFS, sustained MRD negativity rate, MRD negativity at 1 year, overall response rate, overall survival, and safety.

The CEPHEUS trial is the first study to secure a quadruplet approval using MRD negativity as a primary end point, as MRD has been confirmed as a surrogate end point that is predictive of long-term survival.² At a median follow-up of 22 months, MRD negativity at 10^-5 sensitivity was 52.3% in the D-VRd arm compared with 34.8% in the VRd arm (P <.0005). Another key end point, PFS, also demonstrated benefit for the quadruplet with an HR of 0.60 (95% CI, 0.41-0.88; P =.0078).

At a median follow-up of 39 months, the proportion of patients maintaining MRD-negativity for 12 months or longer nearly doubled, reaching 42.6% with D-VRd vs 25.3% with VRd (P <.0003).

At a median follow-up of 59 months, D-VRd increased the depth of response, with 81.2% of patients achieving a complete response or better, compared with 61.6% for those on VRd alone. Overall survival data are not yet mature.

Safety and Administration

The subcutaneous formulation of daratumumab was used in this trial, with a fixed-dose injection of 1800 mg rather than with intravenous infusion. The safety profile of D-VRd was consistent with the known effects of its individual components. Adverse events occurring in at least 20% of patients included upper respiratory tract infections, sensory neuropathy, fatigue, diarrhea, and musculoskeletal pain.

Impact of Approval

This news follows the FDA approval for D-VRd in transplant-eligible patients in 2024 based on the phase 3 PERSEUS trial (NCT03710603),³ making quadruplet frontline therapy an option for patients with more or less favorable performance status, age, and comorbidities. A post hoc analysis presented at the 2025 International Myeloma Society showed that clinical benefit was seen in this trial regardless of changes in frailty status.⁴

The use of MRD negativity marks a new trend for faster approval of therapies in a disease with key unmet needs. The FDA recently issued new draft guidance on trials developed with this end point aimed at FDA approval.

“MRD-negativity is a potential predictor of prolonged progression-free and overall survival and D-VRd is now the only quadruplet regimen approved by the FDA based on a study with MRD-negativity as a primary end point,” stated Usmani in the news release.²

REFERENCES

1. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. January 27, 2026. Accessed January 27, 2026. https://tinyurl.com/yxmxft7a

2. DARZALEX FASPRO®-based quadruplet regimen approved in the U.S. for newly diagnosed patients with multiple myeloma who are transplant ineligible. News release. Johnson & Johnson. January 27, 2026. Accessed January 27, 2026. https://tinyurl.com/2afyknjd

3. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. News release. FDA. July 30, 2024. Accessed January 27, 2024. https://tinyurl.com/ejvk4c3p

4. Mian H, Facon T, Cook G, et al. Dynamic frailty analysis of transplant-ineligible patients with NDMM in the phase 3 MAIA and CEPHEUS trials of daratumumab + lenalidomide-dexamethasone and bortezomib-RD. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-21.