Isatuximab Plus VRd Wins Japanese Approval for Transplant-Ineligible, Newly Diagnosed Myeloma

Japan’s Ministry of Health, Labour and Welfare has approved isatuximab (Sarclisa) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for transplant.1

The regulatory decision was supported by data from the phase 3 IMROZ trial (NCT03319667). Findings presented at the 2024 ASCO Annual Meeting showed that at a median follow-up of 59.7 months, isatuximab plus VRd reduced the risk of disease progression or death by 40.4% compared with VRd alone (HR, 0.596; 98.5% CI, 0.406-0.876; P = .0005).2 The median PFS was not reached (NR} in the experimental arm (n = 265) compared with 54.34 months (95% CI, 45.207-NR) in the control arm (n = 181). The 60-month PFS rates were 63.2% and 45.2%, respectively.

“In recent years, new multiple myeloma cases have increased steadily in Japan and other Asian-Pacific nations, creating a need for new treatment approaches, particularly in the front-line setting,” Olivier Nataf, global head of Oncology at Sanofi, stated in a news release.1 “While [isatuximab]-based combinations have been approved for [patients with] relapsed or refractory [multiple myeloma] in Japan, this approval represents the first indication for certain newly diagnosed patients. We are pleased to offer physicians an important new option for their patients earlier in the treatment journey, building upon our continued commitment to advancing innovative oncology treatments in difficult-to-treat hematologic malignancies around the world.”

In September 2024, the FDA approved isatuximab-irfc in combination with VRd for adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT), based on data from IMROZ.3

IMROZ Overview

The IMROZ trial enrolled patients with newly diagnosed multiple myeloma who were no more than 80 years of age and deemed ineligible for ASCT due to age or comorbidities.2

Enrolled patients were randomly assigned in a 3:2 fashion to receive isatuximab plus VRd or VRd alone. In the experimental arm, isatuximab was given at 10 mg/kg once per week for the first 5 weeks of the first 42-day cycle, then once every 2 weeks for cycles 2 to 4 as induction therapy. In both arms, VRd was given as induction therapy and comprised bortezomib at 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 for 4 cycles; lenalidomide at 25 mg per day on days 1 to 14 and 22 to 35 for 4 cycles; and dexamethasone at 20 mg per day on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 for 4 cycles.

After induction, the continuous treatment portion comprised 4-week cycles where isatuximab was given at 10 mg/kg once every 2 weeks during cycles 5 to 17, then once every 4 weeks thereafter in the experimental arm. During the continuous treatment portion, patients in both arms also received 25 mg of lenalidomide per day on days 1 to 21 of each cycle and 20 mg of dexamethasone once per week in each cycle. Patients in the control arm who experienced disease progression during continuous treatment were allowed to cross over to receive isatuximab plus Rd.

Treatment continued until progressive disease, unacceptable toxicity, or patient withdrawal.

PFS served as the trial’s primary end point. Secondary end points comprised complete response (CR) rate, minimal residual disease (MRD)–negative CR rate, very good partial response (VGPR) or better rate, and overall survival (OS).

Additional Efficacy and Safety Data

Further efficacy findings demonstrated that the overall response rate was 91.3% in the isatuximab arm vs 92.3% in the VRd arm. The CR or better rates were 74.7% and 64.1%, respectively (P = .01). The respective VGPR or better rates were 89.1% and 82.9% (odds ratio [OR], 1.729; 95% CI, 0.994-3.008).

The overall MRD-negativity rates at 10-5 sensitivity were 58.1% for the isatuximab arm vs 43.6% for the VRd arm (OR, 1.791; 95% CI, 1.221-2.627). The MRD-negative CR rates were 55.5% and 40.9%, respectively (OR, 1.803; 95% CI, 1.229-2.646; P = .003). MRD negativity was sustained for at least 12 months in 46.8% of patients in the experimental arm vs 24.3% of patients in the control arm (OR, 2.729; 95% CI, 1.799-4.141).

OS data were immature at the time of this analysis; however, a trend favoring the isatuximab regimen was observed (HR, 0.776; 95% CI, 0.407-1.48). The 60-month OS rates were 72.3% for the isatuximab arm vs 66.3% for the VRd arm.

Safety findings showed that any-grade treatment-emergent adverse effects (TEAEs) occurred 99.6% of patients in the experimental arm (n = 263) vs 98.3% of patients in the control arm (n = 181). The rates of grade 3 or higher TEAEs were 91.6% and 84.0%, respectively. Grade 5 TEAEs were reported in 11.0% of patients in the isatuximab arm vs 5.5% of patients in the VRd arm. TEAEs led to definitive treatment discontinuation in 22.8% of patients in the experimental arm vs 26.0% of patients in the control arm.

References

1. Sarclisa approved in Japan for patients with newly diagnosed multiple myeloma. News release. Sanofi. February 25, 2025. Accessed February 25, 2025. https://www.sanofi.com/assets/dotcom/pressreleases/2025/2025-02-25-06-00-00-3031655-en.pdf
2. Facon T, Dimopoulos MA, Leleu XP, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). J Clin Oncol. 2024;42(suppl 16):7500. doi:10.1200/JCO.2024.42.16_suppl.7500
3. FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. September 20, 2024. Accessed February 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-bortezomib-lenalidomide-and-dexamethasone-newly-diagnosed-multiple