FDA Greenlights D-VRd Quadruplet for Newly Diagnosed Multiple Myeloma

Daratumumab and hyaluronidase-fihj (Darzalex Faspro; Janssen Biotech Inc) has a new FDA-approved indication as of today. Adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT) may now receive the CD38 monoclonal antibody in combination with the triplet of bortezomib (Velcade), a proteasome inhibitor; lenalidomide (Revlimid), an immunomodulatory drug; and dexamethasone (VRd), a steroid (D-VRd).^1,2

The approval is based on the results of the phase 3 CEPHEUS trial (NCT03652064), an open-label, randomized, active-controlled trial of patients ineligible for ASCT or who initially refused ASCT as therapy. The estimated study completion date for this ongoing trial is March 31.³

In the CEPHEUS trial, patients from North America, South America, and Europe were randomized 1:1 to either daratumumab and hyaluronidase-fihj plus VRd (n = 197) or VRd alone (n = 198).² The primary outcome of interest is the percentage of patients with minimal residual disease (MRD)–negative status prior to progressive disease of another antimyeloma therapy out to 2.5 years. Secondary outcomes of interest are progression-free survival (PFS); rates of MRD-negative status, durable MRD-negative status, overall response (ORR), very good partial response (VGPR) or better, and complete response (CR) or better; PFS on the next line of therapy; overall survival; time to response; duration of response; maximum observed serum concentration (C_max) of daratumumab; minimum observed serum concentration (C_min) of daratumumab; participants with anit-daratumumab antibodies; participants with anit-rHuPH20 antibodies; change from baseline in health-related quality of life via European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 item, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20-item, and EuroQol Five Dimension Five Level Questionnaire.

CEPHEUS data supporting the new indication are from 2 time points, with sensitivity evaluated at the threshold of 10^-5. At a median follow-up of 22 months, MRD-negative status was seen in 52.3% of the treatment cohort compared with 34.8% of the VRd-only cohort (P < .0005). Then, at the median follow-up of 39 months, patients sustaining their MRD-negative status for 12 months or more was 42.6% for those who received D-VRd vs 25.3% of the VRd-only cohort (P < .0003). There was a 40% overall reduced risk of disease progression or death seen from the quadruplet regimen (HR, 0.60; 95% CI, 0.41-0.88; P < .0078).

Looking out to 5 years, there was a nearly 20 percentage point difference in depth of response, again favoring D-VRd: 81.2% of patients achieved a complete response or better vs 61.6% from the VRd group.

Safety results remained consistent with previous analyses. Seen in at least 20% of patients each, common adverse events included upper respiratory tract infection, fatigue, motor dysfunction, constipation, sleep disorder, renal impairment, pyrexia, and decreased appetite.

At present, D-VRd is the only quadruplet regimen approved for patients with newly diagnosed disease, irrespective of transplant eligibility.⁴ This approval follows a complete response letter issued in August 2025 for the supplemental biologics license application for this indication, based on facility inspections, not the regimen’s safety or efficacy, which at the time were deemed “robust.”⁵

“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, Myeloma Service, Memorial Sloan Kettering Cancer Center and CEPHEUS principal investigator, in a statement. "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."

Usmani spoke to The American Journal of Care^® (AJMC^®) last year about the potential of D-VRd in newly diagnosed patients. He explained that the CEPHEUS data add to progress already seen in improving induction treatment for patients with newly diagnosed MM, as well as how being ineligible for transplant can impact treatment decisions.⁶

Daratumumab and hyaluronidase-fihj was approved as a subcutaneous monotherapy last year for high-risk smoldering MM at a dose of 1800/30,000 units, based on results from the AQUILA trial (NCT03301220).⁷

References

1. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. News release. 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. Understanding the VRd regimen for newly diagnosed myeloma. International Myeloma Foundation. Accessed January 27, 2026. https://www.myeloma.org/resource-library/understanding-vrd-regimen
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
4. Darzalex faspro-based quadruplet regimen approved in the U.S. for newly diagnosed patients with multiple myeloma who are transplant ineligible. News release. PR Newswire. January 27, 2026. Accessed January 27, 2026. https://www.prnewswire.com/news-releases/darzalex-faspro-based-quadruplet-regimen-approved-in-the-us-for-newly-diagnosed-patients-with-multiple-myeloma-who-are-transplant-ineligible-302671736.html
5. Update on U.S. regulatory review of supplemental biologics license application. News release. Johnson & Johnson. August 1, 2025. Accessed January 27, 2026. https://www.jnj.com/media-center/press-releases/update-on-u-s-regulatory-review-of-supplemental-biologics-license-application
6. Shaw ML, Usmani SZ. DVRd vs VRd in transplant-ineligible myeloma: insights from Saad Z. Usmani, MD, MBA. AJMC. June 18, 2025. Accessed January 27, 2026. https://www.ajmc.com/view/dvrd-vs-vrd-in-transplant-ineligible-myeloma-insights-from-saad-z-usmani-md-mba
7. Shaw ML. FDA approves daratumumab and hyaluronidase-fihj for high-risk MM. AJMC. November 6, 2025. Accessed January 27, 2026. https://www.ajmc.com/view/fda-approves-daratumumab-and-hyaluronidase-fihj-for-high-risk-mm