The U.S. Food and Drug Administration (FDA) has approved daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for adults with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. Approval was based on the Phase III CEPHEUS trial, which demonstrated significantly higher minimal residual disease (MRD) negativity rates and improved progression-free survival (PFS) compared with VRd alone.
Clinical Takeaway
Daratumumab-based quadruplet therapy significantly deepens responses and prolongs progression-free survival in transplant-ineligible patients with newly diagnosed multiple myeloma.
Daratumumab and Hyaluronidase-fihj Profile & Mechanism
- Profile: Anti-CD38 monoclonal antibody co-formulated with hyaluronidase for subcutaneous administration
- Mechanism: Daratumumab targets CD38 on plasma cells, inducing tumor cell death through immune-mediated cytotoxicity and direct apoptosis. Hyaluronidase facilitates rapid subcutaneous dispersion and absorption.
- Target Population: Adults with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant
- Delivery System: Subcutaneous injection
- Treatment Schedule: Administered in combination with bortezomib, lenalidomide, and dexamethasone (VRd) per prescribing information
CEPHEUS Study Design (NCT03652064)
- Study Design: Phase III, open-label, randomized, active-controlled trial
- Study Objective: To evaluate the efficacy and safety of daratumumab and hyaluronidase-fihj plus VRd versus VRd alone
- Participants: 395 patients with newly diagnosed multiple myeloma
- 197 assigned to daratumumab-VRd
- 198 assigned to VRd
Eligible patients were considered ineligible for autologous stem cell transplant based on age, comorbidities, or lack of planned transplant as initial therapy
- Primary Endpoints:
- Overall MRD negativity rate
- PFS per independent review committee using the International Myeloma Working Group (IMWG) criteria
- Secondary Endpoints:
- Complete response or better
- Sustained MRD negativity
- Duration of response
- Overall survival
Study Outcomes
- Primary Endpoint:
- MRD Negativity: Achieved in 52.3% of patients treated with daratumumab-VRd compared with 34.8% of those receiving VRd alone (p = 0.0005)
- PFS: Daratumumab-VRd significantly reduced the risk of disease progression or death, with a hazard ratio of 0.60 (95% CI, 0.41-0.88; p = 0.0078)
- Key Secondary Endpoints:
- Depth of Response: Higher rates of complete response or better and sustained MRD negativity were observed with daratumumab-VRd compared with VRd alone
- Durability of Benefit: PFS benefit was consistent across evaluated subgroups, supporting the clinical relevance of deeper responses achieved with the daratumumab-based quadruplet
- Overall Survival: Data were immature at the time of approval and continue to be followed
Regulatory Milestones
- Approval Date: January 27, 2026
- Regulatory Pathway: Standard FDA approval
- Approval Review: Included use of the FDA Assessment Aid to facilitate regulatory review
Safety
- Overall Adverse Effects (AEs):
- Hypersensitivity and administration-related reactions
- Infections
- Neutropenia
- Thrombocytopenia
- Embryo-fetal toxicity
- Interference with blood compatibility testing
- Cardiac toxicity in patients with light-chain (AL) amyloidosis
- Severity of Toxicity:
- Hematologic and infectious adverse events were clinically significant and consistent with the known safety profile of daratumumab-based regimens
- Treatment Modifications:
- Dose interruptions, supportive care, and monitoring are recommended according to prescribing information
While AEs are common, the safety profile is manageable with proactive monitoring and adherence to guidelines, allowing patients to derive meaningful efficacy benefits with appropriate supportive care.
Development Status
- Current Status: FDA-approved for transplant-ineligible newly diagnosed multiple myeloma
- Prescribing information: Available at Drugs@FDA
- Side Effect Reporting: Healthcare professionals are encouraged to report negative side effects to the FDA
Sources:
Janssen Biotech, Inc. (2026). Darzalex Faspro (daratumumab and hyaluronidase-fihj) prescribing information. Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
National Library of Medicine. (2026). CEPHEUS: Daratumumab plus bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in participants with untreated multiple myeloma not planned for hematopoietic stem cell transplant (ClinicalTrials.gov Identifier: NCT03652064). https://clinicaltrials.gov/study/NCT03652064
U.S. Food and Drug Administration. (2026, January 27). FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-newly
