Daratumumab and Hyaluronidase-fihj–Based Quadruplet Regimen Approved in MM

On July 30, the FDA approved the use of a novel induction/consolidation quadruplet therapy for newly diagnosed multiple myeloma (MM) in those eligible for autologous stem cell transplant: subcutaneous daratumumab/hyaluronidase-fihj (Darzalex Faspro; Johnson & Johnson) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd).^1,2

This news follows J&J’s request for priority review by the FDA, meaning the pharma giant was requesting that a decision on the regimen’s approval be handed down in 6 months.³

The new treatment can be initiated as early as initial MM diagnosis in patients with previously untreated disease. An incurable blood cancer, MM is the second most common blood cancer in the world, with 35,000 new diagnoses expected in 2024 in the US alone.¹

Data from the ongoing open-label, randomized, active-controlled PERSEUS study (NCT03710603) served as the basis for the approval, with a primary outcome of interest of progression-free survival (PFS) via International Myeloma Working Group response criteria. Key secondary outcomes were complete response or better and minimal residual disease (MRD)–negative status. The phase 3 study, which is comparing patient outcomes with D-VRd vs VRd, is being conducted in 14 countries in Europe and Australia,¹ and it has an expected completion date of November 2029; it follows the positive safety and efficacy results seen in the phase 2 GRIFFIN trial (NCT02874742), for which a recent post hoc analysis confirmed daratumumab’s benefit in newly diagnosed MM.⁴

In PERSEUS, 709 patients were randomized 1:1 to D-VRd (n = 355) or VRd (n = 354), and they had to be 70 years or younger with an ECOG performance status of 0 to 2 to qualify for study enrollment.⁵ Similar to GRIFFIN, in which the PFS saw a 71% improvement (HR, 0.29; 95% CI, 0.06-1.48) with the quadruplet therapy,⁴ in PERSEUS, there was a 60% reduction in risk of disease progression or death (HR, 0.40; 95% CI, 0.29-0.57; P < .0001).

Treatment cycles in PERSEUS were 28 days. For those receiving D-VRD, there were 4 induction cycles with 1800-mg subcutaneous daratumumab, 1.3 mg/m² subcutaneous bortezomib, 5 mg oral lenalidomide, and 40 mg oral or intravenous dexamethasone. Consolidation was delivered over 2 cycles of 1800-mg daratumumab and an identical VRd regimen.⁵

The most common adverse effects seen with D-VRd—those occurring in 20% or more of patients—were peripheral neuropathy, fatigue, edema, pyrexia, upper respiratory infection, constipation, diarrhea, musculoskeletal pain, insomnia, and rash.¹

Further, there was a demonstrated significant advantage in both overall MRD negativity rate and MRD negativity among those who also achieved a complete response or better between the D-VRd and VRd cohorts, respectively¹:

• Overall: 57.5% vs 32.5%
• Complete response or better: 76.6% vs 58.5%

“There is a continued need for innovation and therapies that employ different targets and combinations to provide patients with treatment options at diagnosis and throughout the course of their disease,” Amrita Y. Krishnan, MD, professor and director of the Judy and Bernard Briskin Multiple Myeloma Center, City of Hope, said in a statement. “The efficacy data supporting this new quadruplet regimen, combined with its established safety and tolerability profile, provide compelling evidence that adding D-VRd upon initial diagnosis as compared to VRd can deepen responses and prolong remissions in the context of autologous stem cell transplantation.”²

Subcutaneous Darzalex Faspro was first approved by the FDA in May 2020 for indications in MM that included new diagnosis, transplant ineligibility, and relapsed or refractory disease.⁶ At that time, it was approved as a fixed-dose treatment, and with this newest approval, the recommended dose is 1800-mg daratumumab/30,000 units hyaluronidase.²

References

1. Darzalex Faspro (daratumumab and hyaluronidase-fihj)-based quadruplet regimen approved in the U.S. for patients with newly diagnosed multiple myeloma who are transplant-eligible. News release. Johnson & Johnson. July 30, 2024. Accessed July 31, 2024. https://www.jnj.com/media-center/press-releases/darzalex-faspro-daratumumab-and-hyaluronidase-fihj-based-quadruplet-regimen-approved-in-the-u-s-for-patients-with-newly-diagnosed-multiple-myeloma-who-are-transplant-eligible

2. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. News release. FDA. July 30, 2024. Accessed July 31, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-multiple

3. Priority review. FDA. January 4, 2018. Accessed July 31, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review

4. Shaw M. Final GRIFFIN trial data confirm daratumumab benefit against MM. The American Journal of Managed Care^®. July 10, 2024. Accessed July 31, 2024. https://www.ajmc.com/view/final-griffin-trial-data-confirm-daratumumab-benefit-against-mm

5. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

6. U.S. Food and Drug Administration approves Darzalex Faspro (daratumumab and hyaluronidase-fihj), a new subcutaneous formulation of daratumumab in the treatment of patients with multiple myeloma. News release. May 1, 2020. Accessed July 31, 2024. https://www.janssen.com/us/sites/www_janssen_com_usa/files/darzalex_faspro_approval_press_release_final.pdf