FDA Approves Isatuximab/VRd in Newly Diagnosed Multiple Myeloma

Findings from the phase 3 IMROZ trial support the FDA approval of the combination therapy for newly diagnosed not eligible for ASCT multiple myeloma.

The FDA has approved isatuximab-irfc (Sarclisa) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Isa-VRd) as a treatment for patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for autologous stem cell transplant, according to the FDA.¹

Supporting Data

The approval for Isa-VRd was supported by findings from the phase 3 IMROZ trial (NCT03319667), in which investigators evaluatedthe combination for patients with transplant-ineligible NDMM. Investigators previously presented trial findings at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and published them in the New England Journal of Medicine.^2,3

Findings showed that patients treated with Isa-VRd followed by maintenance Isa-Rd experienced a statistically significant progression-free survival benefit (PFS) compared with patients treated with VRd alone; median PFS was not reached (NR) vs 54.34 months (95% CI, 45.207-NR; HR, 0.60; 98.5% CI, 0.406-0.876; log-rank P = .0005). Additionally, 60-month PFS rates were 63.2% and 45.2%, respectively, with PFS benefit seen across most subgroups in the investigational arm, including those with negative prognostic factors.

Interim overall survival (OS) analysis revealed favorability with Isa-VRd (HR, 0.776; 95% CI, 0.407-1.48), with 5-year OS rates of 72.3% and 66.3% observed for the investigational and control groups, respectively. Furthermore, the overall response rate (ORR) for Isa-VRd and VRd were 91.3% and 92.3%, respectively, with complete response (CR) or better rates of 74.7% and 64.1% (P = .01) and very good partial response (VGPR) or better rates of 89.1% and 82.9% (odds ratio [OR], 1.729; 95% CI, 0.994-3.008).

Among patients in the intent-to-treat population, minimal residual disease (MRD)–negative status was observed in 58.1% of patients treated with Isa-VRd vs 43.6% of the control arm (OR, 1.791; 95% CI, 1.221-2.627). MRD-negative CR rates were 55.5% and 40.9%, respectively (OR, 1.803; 95% CI, 1.229-2.646; P = .003), with MRD negativity sustained for at least 12 months in 46.8% and 24.3% of respective patients (OR, 2.729; 95% CI, 1.799-4.141). Additionally, median time to MRD negativity was 14.72 months (95% CI, 11.53-24.08) vs 32.79 months (95% CI, 17.51-45.11) in the Isa-VRd and VRd groups.

The FDA approved isatuximab at a recommended dose of 10 mg/kg administered intravenously.

Expert Perspective

“The significant [PFS] benefit observed with [isatuximab] combination therapy compared [with] VRd is important and encouraging for patients with [NDMM]. Effective frontline therapy has the potential to modify the course of the disease, which is a key outcome for transplant-ineligible patients who often [have] high rates of attrition in later lines of therapy. The IMROZ results demonstrate the promise of [isatuximab] as a backbone to frontline therapy, which may improve long-term outcomes for this incurable disease,” Thierry Facon, MD, said in a press release on the ASCO presentation of the IMROZ trial results.⁴

Facon is the lead investigator of the IMROZ trial, a professor in the Department of Hematology at Lille University Hospital in Lille, France, and a member of the French Academy of Medicine.

IMROZ Trial Design

In the trial, the primary end point was PFS. Secondary end points included CR rate, MRD-negative CR rate, VGPR or better rate, and OS. Transplant-ineligible patients 80 years or younger with NDMM in the prospective, open-label study across 102 sites and 21 countries were randomly assigned 3:2 to receive isa-VRd or VRd alone.

Patients received 10 mg/kg of isatuximab intravenously once weekly for 5 weeks in the first 42-day cycle, followed by every other week up to cycle 4 during induction therapy. During induction, both arms received 1.3 mg/m2 of bortezomib on days 1, 4, 8, 11, 22, 25, 29, and 32 for 4 cycles; 25 mg of lenalidomide 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.

Following induction, treatment in the experimental arm occurred in 4-week cycles consisting of 10 mg/kg of isatuximab every other week from cycles 5 to 17, and once every 4 weeks in further cycles. In both arms, 25 mg of daily lenalidomide up to day 21 and 20 mg of once weekly dexamethasone was administered. Treatment continued until progression, unacceptable toxicity, or withdrawal of consent, with the option for patients within the control group to receive Isa-VRd if they experienced disease progression.

Within the Isa-VRd and VRd groups, 47.2% and 24.3% of patients were receiving treatment as of the cut-off date of September 26, 2023. The median treatment duration was 53.2 months and 31.3 months in the Isa-VRd and VRd arms, respectively.

Adverse Events

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.6% and 98.3% of patients in the Isa-VRd and VRd groups. Grade 3 or higher TEAEs were reported in 91.6% and 84.0% of these patients, respectively. The incidence of grade 5 TEAEs was 11.0% and 5.5%, respectively, with serious TEAEs occurring in 70.7% and 67.4% of patients. TEAEs leading to treatment discontinuation were observed in 22.8% of the experimental group and 26.0% of the control group.

Common any-grade AEs in the Isa-VRd and VRd groups included neutropenia (87.5% vs 80.1%); infections (91.3% vs 86.7%), including pneumonia (30.0% vs 19.3%) and upper respiratory infections (34.2% vs 33.7%); diarrhea (54.8% vs 48.6%); peripheral sensory neuropathy (54.4% vs 60.8%); and cataract (38.0%; 25.4%).

Isa-VRd previously earned FDA priority review in transplant-ineligible NDMM in May 2024.⁵

References

1. FDA approves istauximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. News release. September 20, 2024. Accessed September 20, 2024. https://shorturl.at/B8d3c
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
4. ASCO: Sarclisa is first anti-CD38 to significantly improve progression-free survival in combination with VRd for newly diagnosed transplant-ineligible multiple myeloma in phase 3. News release. Sanofi. June 3, 2024. Accessed August 7, 2024. https://tinyurl.com/5exfukej
5. Press release: Sarclisa accepted for FDA priority review for the treatment of transplant-ineligible newly diagnosed multiple myeloma. News release. Sanofi. May 27, 2024. Accessed May 28, 2024. https://tinyurl.com/5xa545er