FDA Approves Daratumumab and Hyaluronidase-fihj With Quadruplet Regimen for Newly Diagnosed Multiple Myeloma

On January 27, 2026, the FDA approved daratumumab and hyaluronidase-fihj (Darzalex Faspro; Janssen Biotech) in combination with bortezomib (Velcade; Takeda), lenalidomide (Revlimid; Celgene Corporation), and dexamethasone (Decadron; Amneal; quadruplet regimen; D-VRd) for the treatment of adults with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT).¹ This milestone extends the use of subcutaneous daratumumab in a quadruplet frontline regimen, underscoring advances in therapeutic options for patients with NDMM who cannot undergo ASCT.¹

Regimen Background and Clinical Context

Daratumumab is a human monoclonal antibody that targets CD38, a surface protein expressed on MM cells. The addition of hyaluronidase enables subcutaneous administration, making it easier to administer, especially compared to traditional IV administration.² Over the last decade, daratumumab-based regimens have become an essential part of MM treatment, with approval in a wide range of disease settings, including relapsed and refractory disease, as well as doublet, triplet, and quadruplet regimens.³

Previous studies have demonstrated the need to incorporate daratumumab in combination with conventional drugs such as bortezomib (a proteasome inhibitor), lenalidomide (an immunomodulator), and dexamethasone (a corticosteroid) to achieve deeper and more prolonged responses and to improve progression-free survival (PFS).⁴ Bortezomib blocks the proteasome, leading to apoptosis of tumor cells, and lenalidomide affects the immune response and tumor microenvironment interactions.⁴ Dexamethasone potentiates anti-tumor effects and reduces pro-inflammatory effects.

FDA-Approved Indication and Clinical Evidence

The FDA approval of D-VRd in NDMM patients ineligible for ASCT is supported by data from the CEPHEUS study (NCT03652064), a global, open-label, randomized study comparing D-VRd with standard VRd alone as initial therapy in patients who are transplant-ineligible or deferred transplant.^1,5 Efficacy of the quadruplet regimen was determined by assessment of key endpoints such as the rate of measurable residual disease (MRD) negativity and PFS, with the quadruplet regimen demonstrating superior efficacy.⁵

In the CEPHEUS trial, a higher rate of MRD negativity—a powerful predictor of long-term outcome—was observed with the DVRd regimen compared to VRd alone. Additionally, an independent review showed a favorable PFS hazard ratio with the quadruplet regimen, supporting its clinical benefit in this patient population. These results are consistent with emerging data from peer-reviewed publications showing that subcutaneous daratumumab in combination with VRd improves response rates compared with VRd alone.⁵

Data from the peer-reviewed phase 3 CEPHEUS study published in Nature Medicine further reinforce the clinical utility of daratumumab plus VRd in patients with transplant-ineligible or transplant-deferred NDMM, reporting substantial improvements in MRD negativity and response rates versus VRd alone. Notably, higher complete response (CR) rates and sustained MRD-negative status were observed among those receiving the quadruplet regimen, highlighting enhanced disease control.⁶

Conclusion

According to the FDA prescribing information, safety considerations are generally consistent with what is known about daratumumab and quadruplet regimens, including infusion-related reactions, cytopenias, increased infection risk, and effects on blood compatibility tests.¹ The subcutaneous route with hyaluronidase has a different safety profile, and it is important to monitor hematologic parameters and manage adverse reactions in accordance with guidelines.

This approval represents an important milestone in the expansion of treatment options for eligible NDMM patients who are transplant-ineligible and may now have access to a powerful quadruplet therapy that may help deepen responses and potentially halt disease progression. The ease of administering daratumumab subcutaneously with other agents may also help improve the patient experience in the outpatient setting for oncologic care.

REFERENCES

1. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. Published 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. FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. FDA. Published May 1, 2020. Accessed January 27, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-multiple-myeloma

3. Chaplin F. Daratumumab approved by FDA for frontline use. Multiple Myeloma Hub. Published May 8, 2018. Accessed January 27, 2026. https://multiplemyelomahub.com/medical-information/daratumumab-approved-by-fda-for-frontline-use

4. A New Multiple Myeloma Indication for Daratumumab and Hyaluronidase-fihj. AACR. Accessed January 27, 2026. https://www.aacr.org/patients-caregivers/progress-against-cancer/a-new-multiple-myeloma-indication-for-daratumumab-and-hyaluronidase-fihj

5. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025;31(4):1195-1202. doi:10.1038/s41591-024-03485-7