FDA Approves Daratumumab and Hyaluronidase Plus VRd for Newly Diagnosed Multiple Myeloma

The FDA has approved daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT).¹

This regulatory decision was supported by data from the phase 3 CEPHEUS trial (NCT03652064), in which daratumumab and hyaluronidase plus VRd (n = 197) elicited a minimal residual disease (MRD) negativity rate of 52.3% vs 34.8% with VRd alone (n = 198; P = .0005).^1,2 The daratumumab-based combination also generated an improvement in progression-free survival (PFS), although the median pPFS was not reached (95% CI, not evaluable [NE]-NE) in both arms (HR, 0.60; 95% CI, 0.41-0.88; P = .0078).

“Quadruplet regimens for [patients with] transplant-ineligible myeloma [are] generally my approach for patients who are not frail and can tolerate an anti-CD38–based quadruplet,” Marc J. Braunstein, MD, PhD, said in an interview with OncLive^®. “The data between the transplant-eligible and -ineligible groups both support the efficacy of anti-CD38 quadruplet regimens in newly diagnosed myeloma.”

Braunstein is an associate professor in the Department of Medicine and co-director of the Hematology-Oncology System at the New York University (NYU) Grossman Long Island School of Medicine; as well as the director of the Hem/Onc Fellowship Program at NYU Langone Health.

What was the design of the CEPHEUS trial?

CEPHEUS randomly assigned 395 patients to receive subcutaneous daratumumab and hyaluronidase plus VRd, or VRd alone.¹ Daratumumab and hyaluronidase was administered at 1800mg/30,000 units once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 24, and once every 4 weeks beginning at week 25 until disease progression or unacceptable toxicity.²

MRD negativity rate served as the trial’s primary end point.³ Secondary end points included PFS per independent review committee based on International Myeloma Working Group response criteria, overall response rate (ORR), overall survival, and duration of response.

What additional CEPHEUS trial findings are important to note?

In the daratumumab arm, the median duration of treatment was 56.3 months (range, 0.1-64.6) vs 34.3 months (range, 0.5-63.8) with VRd alone.²

Among patients in the daratumumab arm with a complete response (CR) or better (n = 150), the MRD negativity rate was 68.7% (95% CI, 60.6%-76.0%). Among patients in the control arm who achieved a CR or better (n = 116), this rate was 59.5% (95% CI, 50.0%-68.5%). The sustained MRD negativity rates in these respective arms were 42.6% vs 25.3% (P = .0003).

In the daratumumab arm, the ORR was 97.0%, including stringent CRs (sCRs; 65.0%), CRs (16.2%), very good partial responses (VGPRs; 11.7%), and PRs (4.1%). In the VRD-alone arm, the ORR was 93.4%, including sCRs (44.9%), CRs (16.7%), VGPRs (24.7%), and PRs (7.1%).

What is important to note about the safety profile of daratumumab and hyaluronidase plus VRd in multiple myeloma?

The most frequently reported adverse effects (AEs) in the daratumumab arm were pneumonia (19%), COVID-19 (12%), thrombocytopenia (7%), and diarrhea (6%). In total, 16.8% of patients in this arm had fatal AEs, the most common being COVID-19 (4%), pneumonia (4%), and myocardial infarction (2%).

The prescribing information for daratumumab and hyaluronidase includes warnings and precautions for hypersensitivity and other administration reactions, neutropenia, infections, thrombocytopenia, embryo-fetal toxicity interference with cross-matching and red blood cell antibody screening, and cardiac toxicity in patients with light chain amyloidosis.

Notably, the efficacy of daratumumab and hyaluronidase plus VRd has not been determined among patients who have refused ASCT as initial therapy.

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://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-newly
2. Darzalex Faspro. Prescribing information. Johnson & Johnson; January 2026. Accessed January 27, 2026. https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf
3. 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. ClinicalTrials.gov. Updated January 20, 2026. Accessed January 27, 2026. https://clinicaltrials.gov/study/NCT03652064