FDA Approves Isatuximab Plus VRd for Newly Diagnosed, Transplant-Ineligible Multiple Myeloma

FDA

The FDA has approved isatuximab-irfc (Sarclisa) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) for adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT).¹

The regulatory decision was supported by data from the phase 3 IMROZ trial (NCT03319667). Findings presented at the 2024 ASCO Annual Meeting² and simultaneously published in the New England Journal of Medicine³ showed that treatment with Isa-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 < .001).² At a median follow-up of 59.7 months, patients treated with isatuximab plus VRd (n = 265) experienced a median progression-free survival (PFS) that was not reached (NR; 95% CI, NR-NR) vs 54.34 months (95% CI, 45.207-NR) for those given VRd alone (n = 181).²

IMROZ was an open-label, randomized, phase 3 study conducted at 93 sites in 21 countries that enrolled patients between 18 and 80 years of age with symptomatic, previously untreated multiple myeloma who had measurable disease and were ineligible for ASCT. Transplant ineligibility was defined as an age of 65 years or older, or preexisting comorbidities. Key inclusion criteria consisted of an ECOG performance status of 2 or less.³

Patients were randomly assigned 3:2 to receive isatuximab plus VRd or VRd alone. In the experimental arm, isatuximab was given at 10 mg/kg once per week for the 5 weeks during the first 42-day cycle, then once every 2 weeks for cycles 2 to 4 as induction therapy. VRd given as induction therapy in both arms consisted of 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.²

Following induction, patients in the experimental arm received continuous treatment in 4-week cycles featuring 10 mg/kg of isatuximab once every 2 weeks during cycles 5 to 17, then once every 4 weeks thereafter; 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 received Rd using the same dosing regimen. During the continuous treatment phase, patients in the control arm who experienced disease progression were allowed to cross over to receive isatuximab plus Rd.

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

PFS served as the trial's primary end point. Secondary end points included complete response (CR) rate; the rate of patients with minimal residual disease (MRD) negativity and a CR; the rate of very good partial responses (VGPRs) or better; and overall survival (OS).

Additional data showed the overall response rate (ORR) was 91.3% in the isatuximab arm, which included a stringent CR (sCR) rate of 10.9%, a CR rate of 63.8%, a VGPR rate of 14.3%, and a PR rate of 2.3%. The CR or better and VGPR or better rates were 74.7% and 89.1%, respectively. In the control arm, the ORR was 92.3%, including an sCR rate of 5.5%, a CR rate of 58.6%, a VGPR rate of 18.8%, and a PR rate of 9.4%. The respective CR or better and VGPR or better rates were 64.1% (P = .01) and 82.9% (odds ratio [OR], 1.729; 95% CI, 0.994-3.008).

The MRD-negativity rates were 58.1% for the isatuximab arm vs 43.6% in the control arm (OR, 1.791; 95% CI, 1.221-2.627). The respective rates of patients with a CR and MRD negativity were 55.5% and 40.9% (OR, 1.803; 95% CI, 1.229-2.646; P = .003). Notably, 46.8% of patients in the experimental arm sustained MRD negativity for at least 12 months compared with 24.3% of patients in the control arm (OR, 2.729; 95% CI, 1.799-4.141).

The median time to MRD negativity was 14.72 months (95% CI, 11.53-24.08) in the isatuximab arm vs 32.79 months (95% CI, 17.51-45.11) in the control arm.

At a median follow-up of 5 years, OS data remained immature. 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 control arm.

The most common adverse effects reported in at least 20% of patients in the experimental arm included upper respiratory tract infection, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19.¹

References

1. FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. September 20, 2024. Accessed September 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-bortezomib-lenalidomide-and-dexamethasone-newly-diagnosed-multiple
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. Facon T, Dimopoulos MA, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. Published online June 3, 2024. doi:10.1056/NEJMoa2400712