FDA approval summary
On January 27, 2026, the U.S. Food and Drug Administration (FDA) approved daratumumab and hyaluronidase-fihj (Darzalex Faspro, Janssen Biotech, Inc.) in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for adults with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT).
The effectiveness of the Darzalex Faspro–VRd regimen has not been established in patients who declined ASCT as initial therapy.
CEPHEUS trial (NCT03652064)
Efficacy was evaluated in CEPHEUS (NCT03652064), an open-label, randomized, active-controlled trial in patients with newly diagnosed multiple myeloma who were ineligible for ASCT or refused ASCT as initial therapy.
- Design: open-label, randomized, active-controlled study
- Population: 395 patients with newly diagnosed multiple myeloma
- Darzalex Faspro–VRd arm: 197 patients
- VRd arm: 198 patients
- Regimens:
- Experimental arm: Darzalex Faspro + bortezomib + lenalidomide + dexamethasone (D-VRd)
- Control arm: VRd
The major efficacy outcome measures were:
- Overall minimal residual disease (MRD) negativity rate
- Progression-free survival (PFS) by independent review committee (IRC) based on International Myeloma Working Group (IMWG) response criteria
Efficacy results: higher MRD negativity and improved PFS
MRD negativity:
- Darzalex Faspro–VRd: 52.3%
- VRd: 34.8%
- p-value: 0.0005
PFS (IRC-assessed):
- PFS hazard ratio (HR): 0.60 (95% CI: 0.41, 0.88)
- p-value: 0.0078
These data show that adding subcutaneous daratumumab to the VRd backbone achieves deeper responses (higher MRD negativity) and prolongs PFS compared with VRd alone in transplant-ineligible newly diagnosed multiple myeloma.
Safety profile and key warnings
The prescribing information for Darzalex Faspro includes warnings and precautions for:
- Hypersensitivity and other administration reactions
- Infections
- Neutropenia
- Thrombocytopenia
- Embryo-fetal toxicity
- Interference with cross-matching and red blood cell antibody screening
- Cardiac toxicity in patients with light chain (AL) amyloidosis
Because of interference with blood compatibility testing, early coordination with transfusion services is recommended. In older and comorbid patients, infection risk and cytopenias require close monitoring and proactive supportive care.
Recommended dosing
Recommended Darzalex Faspro dose:
- 1,800 mg/30,000 units per administration
- 1,800 mg daratumumab + 30,000 units hyaluronidase
Refer to the prescribing information for detailed dosing recommendations for bortezomib, lenalidomide, and dexamethasone as part of the combination regimen.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
Editorial perspective (Morningglorysciences)
For transplant-ineligible newly diagnosed multiple myeloma, VRd has been a key standard of care. CEPHEUS now shows that adding subcutaneous daratumumab to VRd can deepen responses—reflected in higher MRD negativity—and prolong PFS, effectively moving an intensive CD38-antibody–based quadruplet into this vulnerable population.
At the same time, four-drug frontline therapy raises practical questions:
- How to manage increased myelosuppression and infection risk in older or frail patients
- How to balance the goal of deep remissions against treatment burden, clinic time, and quality of life
- How to integrate D-VRd into the broader treatment journey, including maintenance and options at first relapse
For many patients, the subcutaneous administration of daratumumab may at least partially offset the complexity of a quadruplet regimen by shortening chair time and avoiding prolonged infusions. In everyday practice, careful patient selection and dose tailoring will be critical to capture the benefits of deeper disease control without compromising tolerability.
Future data will need to clarify:
- Outcomes by age, frailty status, and comorbidity burden
- Real-world patterns of dose reductions, treatment discontinuation, and infection-related complications
- How D-VRd compares with other antibody-containing backbones and with emerging cellular therapies in earlier lines
*This article is based on the AACR “FDA Approval Alert” and FDA source documents, summarized and edited by Morningglorysciences.*
Comments