Daratumumab and Hyaluronidase-fihj Plus VRd Approved for Transplant-Ineligible Newly Diagnosed Multiple Myeloma
Expert Perspectives
By Lyn Brook
Published
The FDA has approved the subcutaneous CD38-directed antibody daratumumab and hyaluronidase-fihj (Darzalex Faspro®, Janssen Biotech) in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for adults with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT). This approval expands front-line therapeutic options for transplant-ineligible patients by integrating a monoclonal antibody into the established VRd backbone.
Why This Approval Matters
For patients with newly diagnosed multiple myeloma who cannot undergo ASCT due to age or comorbidities, achieving deep and durable responses early in the disease course is critical for long-term outcomes. The addition of daratumumab and hyaluronidase-fihj to the VRd triplet significantly increases the depth of response, as measured by minimal residual disease (MRD) negativity, and extends progression-free survival (PFS). This quadruplet regimen offers a potent new standard of care aimed at maximizing disease control from the outset of therapy.
Breaking Down CEPHEUS
Efficacy was assessed in CEPHEUS (NCT03652064), a phase 3, open-label, active-controlled trial involving 395 patients with newly diagnosed multiple myeloma who were ineligible for ASCT or had declined ASCT as initial therapy. Note that the effectiveness of this quadruplet has not been established specifically in those who refused ASCT as initial therapy.
Patients were randomized 1:1 to receive either:
Experimental arm: Daratumumab and hyaluronidase-fihj in combination with VRd (n=197)
Control arm: VRd alone (n=198)
The primary efficacy end points were the overall MRD negativity rate and PFS, as determined by an independent review committee using International Myeloma Working Group (IMWG) criteria. The trial results showed:
MRD negativity: 52.3% in the daratumumab and hyaluronidase-fihj plus VRd arm compared to 34.8% in the VRd arm
PFS: The hazard ratio was 0.60, representing a 40% reduction in the risk of disease progression or death
Managing Adverse Events
The prescribing information for daratumumab and hyaluronidase-fihj includes several important warnings and precautions:
Hypersensitivity and other administration-related reactions
Increased risk of infections
Hematologic toxicities, including neutropenia and thrombocytopenia
Embryo-fetal toxicity
Interference with blood bank cross-matching and red blood cell antibody screening
Cardiac toxicity specifically in patients with light chain (AL) amyloidosis
Dosing and Administration
The recommended dose of daratumumab and hyaluronidase-fihj is 1,800 mg daratumumab and 30,000 units hyaluronidase, administered subcutaneously.
Resources
Clinicaltrials.gov (2026). A study comparing daratumumab, VELCADE (bortezomib), lenalidomide, and dexamethasone (D-VRd) with VELCADE, lenalidomide, and dexamethasone (VRd) in participants with untreated multiple myeloma and for whom hematopoietic stem cell transplant is not planned as initial therapy. NLM identifier: NCT03652064.