sBLA Submitted to FDA for Subcutaneous Daratumumab Plus VRd in Transplant-Eligible Multiple Myeloma

FDA

A supplemental biologics license application (sBLA) seeking the approval of daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) induction and consolidation therapy alongside lenalidomide maintenance for adult patients with newly-diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT) has been submitted to the FDA. ¹

According to a press release from Johnson & Johnson, the sBLA is supported by findings from the phase 3 PERSEUS (NCT03710603) trial, which was presented during the 2023 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

At a median follow-up of 47.5 months (range, 0-54.4), the estimated 4-year progression-free survival (PFS) rate was 84.3% vs 67.7% among patients who received D-VRd (n = 355) compared with those treated with VRd alone (n = 354), respectively (HR, 0.42; 95% CI, 0.30-0.59; P < .0001). Moreover, the overall response rate was 96.6% (95% CI, 94.2%-98.2%) vs 93.8% (95% CI, 90.7%-96.1%), respectively, complete response or better (≥CR) rate was 87.9% vs 70.1%, respectively, (P < .0001), the stringent complete response (sCR) rate was 69.3% vs 44.6%, respectively, and the complete response (CR) rate was 18.6% vs 25.4%, respectively.²

"We are committed to changing the course of multiple myeloma through building combination regimens such as D-VRd with complementary mechanisms of action. The daratumumab and hyaluronidase–based quadruplet therapy demonstrated a clinically significant reduction in the risk of progression or death for transplant-eligible, newly diagnosed patients with multiple myeloma," Craig Tendler, MD, vice president, Clinical Development, Diagnostics, and Global Medical Affairs, Johnson & Johnson Innovative Medicine, said in a press release. "Patients are most likely to experience their deepest and most durable responses during the first line of treatment with D-VRd. This regimen has the potential to improve long-term outcomes for newly diagnosed patients and we look forward to working with the FDA on the review of this application."¹

PERSEUS was an open-label, multicenter study that enrolled patients who were 18 to 70 years old with newly diagnosed multiple myeloma who were eligible for high-dose therapy and ASCT and had an ECOG performance status of 2 or less. Patients were randomly assigned 1:1 to receive subcutaneous daratumumab plus VRd induction therapy before transplantation, followed by VRd consolidation therapy after transplantation, and lenalidomide maintenance therapy or VRd induction and consolidation therapy and lenalidomide maintenance.²

The primary end point was PFS. Secondary end points included ≥CR rate, minimal residual disease (MRD)–negativity rate, and overall survival (OS).

Baseline characteristics were generally well balanced between the 2 arms; the median age was 61 years (range, 32-70) vs 59 years (range, 31-70) in the D-VRd and VRd arms, respectively. Most patients in both arms were male (59.4% vs 57.9%), White (93% vs 91.2%), had an ECOG performance status of 0 (62.3% vs 65%), had IgG measurable disease (57.5% vs 52.3%), had ISS stage I disease (52.4% vs 50.4%), and had standard cytogenetic risk (74.4% vs 75.1%). The median time since diagnosis of multiple myeloma was 1.2 months (range, 0-46.5) vs 1.1 months (range, 0.1-184.6), respectively.

Additional findings from the trial demonstrated the MRD-negativity rate at a sensitivity threshold of 10−5 was 75.2% vs 47.5% in the investigational and control arm, respectively (P < .001); the respective 12-month rates of sustained MRD negativity were 64.8% vs 29.7%. At a threshold of 10−6, the MRD-negativity rates were 61.5% vs 32.2%, respectively. Notably, OS data were immature; death occurred in 34 patients in the D-VRd group compared with 44 in the VRd arm.

In terms of safety, adverse effects (AEs) of any grade occurred in 99.4% of patients in the D-VRd arm (n = 351) compared with 99.1% in the VRd arm (n = 347). The most common any-grade AEs in both arms included infection (86.9% vs 76.7%, respectively), neutropenia (69.2% vs 58.8%), and diarrhea (61% vs 54.2%). Serious AEs (57% vs 49.3%), grade 3 or 4 AEs (91.5% vs 85.6%), AEs leading to treatment discontinuation (8.8% vs 21.3%), and AEs occurring after the start of treatment and leading to death (3.7% vs 4.6%) were reported in both arms.

Daratumumab and hyaluronidase was previously approved by the FDA in May 2020for the treatment of adult patients with newly diagnosed or relapsed/refractory multiple myeloma. The subcutaneous formulation has to date gained approval for 8 indications in multiple myeloma, including 3 for frontline treatment in newly diagnosed patients who are transplant eligible or ineligible.^1,3

References

1. Johnson & Johnson submits supplemental Biologics License Application to U.S. FDA seeking approval of DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)-based regimen for the treatment of patients with transplant-eligible, newly diagnosed multiple myeloma. News release. January 30, 2024. Accessed January 31, 2024. https://www.prnewswire.com/news-releases/johnson--johnson-submits-supplemental-biologics-license-application-to-us-fda-seeking-approval-of-darzalex-faspro-daratumumab-and-hyaluronidase-fihj-based-regimen-for-the-treatment-of-patients-with-transplant-eligible-newly-302048440.html
2. 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
3. FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. FDA. May 1, 2020. Accessed January 31, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-multiple-myeloma