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

The European Medicines Agency’s Committee for Medicinal Products for Human Use has approved isatuximab-irfc (Sarclisa) in combination with standard-of-care bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd), for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.1

This expanded marketing authorization makes isatuximab the first anti-CD38 therapy available in combination with VRd for this patient population in the European Union (EU).

“While there have been many important advancements in multiple myeloma treatment over the past decade, there remains a significant unmet need in the front-line setting, particularly for transplant-ineligible patients,” Olivier Nataf, global head of oncology at Sanofi, stated in a news release. “With today’s decision the 27 countries in the EU will have access to a potentially transformative new combination regimen, marking a significant step forward in our mission to make a meaningful difference in multiple myeloma treatment.”

The regulatory decision was supported by data from the phase 3 IMROZ trial (NCT03319667), which were presented at the 2024 ASCO Annual Meeting.2 At a median follow-up of 59.7 months, isatuximab plus VRd significantly 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; log-rank P = .0005). Patients in the isatuximab plus VRd arm (n = 265) achieved a median progression-free survival (PFS) that was not reached (NR) and a 60-month PFS rate of 63.2% per independent review committee assessment. In comparison, the median PFS in the VRd-alone arm (n = 181) was 54.34 months (95% CI, 45.207-NR) and the 60-month PFS rate was 45.2%.

Additional analysis of minimal residual disease (MRD) negativity dynamics, presented at the 2024 ASH Annual Meeting, showed that transfusion-ineligible patients with newly diagnosed multiple myeloma receiving isatuximab plus VRd had higher rates of sustained MRD negativity at a sensitivity level of 10-5 compared with those treated with VRd alone.3 Specifically, 46.8% of patients in the isatuximab-VRd arm achieved MRD negativity sustained for 12 months or longer vs 24.3% in the VRd arm. Furthermore, 25.7% of patients in the isatuximab-VRd arm maintained MRD negativity for 36 months or longer, compared with 7.2% of patients in the VRd-alone group.

These data supported the FDA approval of isatuximab plus VRd for this same patient population in September 2024.1 In addition to approvals in the United States and EU, regulatory submissions for isatuximab in newly diagnosed multiple myeloma are under review in Japan and in China.

IMROZ Trial Design

The international, open-label study randomly assigned patients aged 79 years or younger with transplant-ineligible, newly diagnosed multiple myeloma in a 3:2 ratio to receive isatuximab plus VRd or VRd alone.2 Patients first underwent induction therapy, which consisted of four 6-week cycles. In the isatuximab plus VRd arm, patients received 10 mg/kg of isatuximab as induction therapy once per week on days 1, 8, 15, 22, and 29 of the first 42-day cycle, followed by once every 2 weeks in cycles 2 to 4. Both arms received VRd as induction therapy, which included 1.3 mg/m2 of bortezomib on days 1, 4, 8, 11, 22, 25, 29, and 32 for 4 cycles; 25 mg of lenalidomide per day on days 1 to 14 and 22 to 35 for 4 cycles; and 20 mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 for 4 cycles.

Continuous treatment in the isatuximab arm included 10 mg/kg of the agent on days 1 and 15 during cycles 5 through 17, followed by day 1 of cycle 18 and subsequent 4-week cycles. Both arms received received 25 mg of lenalidomide on days 1 to 21 plus dexamethasone on days 1, 8, 15, and 22 in cycle 5 and beyond. Treatment continued until disease progression, unacceptable toxicity, or withdrawal. Notably, patients in the control arm who progressed during continuous treatment were allowed to cross over to receive isatuximab plus lenalidomide and dexamethasone.

The trial’s primary end point was PFS, with complete response (CR) rate, MRD-negative CR rate, very good partial response or better rate, and overall survival serving as key secondary end points.

References

1. Sarclisa approved in the EU as the first anti-CD38 therapy in combination with standard-of-care VRd to treat transplant-ineligible newly diagnosed multiple myeloma. News release. Sanofi. January 22, 2025. Accessed January 22, 2025. https://www.sanofi.com/en/media-room/press-releases/2025/2025-01-22-06-00-00-3013183
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. Orlowski RZ, Dimopoulos M-A, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) in patients with newly diagnosed multiple myeloma (NDMM): analyses of minimal residual disease (MRD) negativity dynamics in the phase 3 Imroz study. Blood. 2024;144(suppl 1):770. doi:10.1182/blood-2024-203818