Isatuximab Plus VRd Earns CHMP Recommendation for Newly Diagnosed, Transplant-Ineligible Myeloma

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The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended the approval of 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 autologous stem cell transplant (ASCT).¹

The positive opinion was based on data from the phase 3 IMROZ trial (NCT03319667), which were presented at the 2024 ASCO Annual Meeting and published in the New England Journal of Medicine.^2,3 Findings 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; log-rank P = .0005).² Per independent review committee assessment, patients treated with isatuximab plus VRd (n = 265) achieved a median progression-free survival (PFS) that was not reached (NR) and a 60-month PFS rate of 63.2%; those in the VRd arm (n = 181) experienced a median PFS of 54.34 months (95% CI, 45.207-NR) and a 60-month PFS rate of 45.2%.

“The positive CHMP opinion is an important step forward for people with transplant-ineligible newly diagnosed multiple myeloma for whom effective frontline therapy may improve long-term outcomes,” Dietmar Berger, MD, PhD, chief medical officer and global head of development at Sanofi, stated in a news release.¹ “If approved, this [isatuximab]-based combination could establish a new standard-of-care treatment approach for patients in the European Union, helping to address a critical care gap in multiple myeloma treatment, and reinforcing [isatuximab’s] potential as the anti-CD38 therapy of choice.”

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 ASCT, based on data from IMROZ.⁴

The phase 3 trial enrolled patients 79 years of age or younger with transplant-ineligible, newly diagnosed multiple myeloma.² Patients were randomly assigned 3:2 to receive isatuximab plus VRd or VRd alone.

During induction therapy, which lasted for 4 6-week cycles, patients in the experimental arm received isatuximab at 10 mg/kg once per week on days 1, 8, 15, 22, and 29 of the first 42-day cycle, then once every 2 weeks in cycles 2 to 4. 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.

During the continuous treatment period, which consisted of 4-week cycles, patients in the experimental arm received isatuximab at 10 mg/kg on days 1 and 15 of cycles 5 to 17, then day 1 of cycle 18 and subsequent cycles. Patients in both arms received lenalidomide at 25 mg on days 1 to 21 plus dexamethasone on days 1, 8, 15, and 22 in cycle 5 and beyond. Treatment continued until progressive disease, unacceptable toxicity, or patient withdrawal. Notably, patients in the control arm who experienced disease progression during the continuous treatment portion of the study were allowed to cross over to receive isatuximab plus lenalidomide and dexamethasone.

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

Additional data showed that the overall response rate was 91.3% in the isatuximab arm vs 92.3% in the VRd arm. Best overall responses in the experimental arm included stringent CR (10.9%), CR (63.8%), VGPR (14.3%), and PR (2.3%). These respective rates in the control arm were 5.5%, 58.6%, 18.8%, and 9.4%. The CR or better rate was 74.7% in the isatuximab arm vs 64.1% in the VRd arm (odds ratio [OR], 1.729; 95% CI, 0.994-3.008; P = .01).

The MRD-negativity rate at a 10–5 sensitivity was 58.1% in the isatuximab arm vs 43.6% in the VRd arm (OR, 1.791; 95% CI, 1.221-2.627). The median time to MRD negativity was 14.72 months (95% CI, 11.53-24.08) in the experimental arm vs 32.79 months (95% CI, 17.51-45.11) in the control arm.

Additionally, 55.5% of patients in the isatuximab arm experienced an MRD-negative CR vs 40.9% of patients in the VRd arm (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 remained immature, but a trend favoring the isatuximab regimen was observed (HR, 0.776; 95% CI, 0.407-1.48).

Safety and tolerability data for the isatuximab regimen were consistent with previously reported data for the combination.1 Grade 5 treatment-emergent adverse effects (TEAEs) occurred in 11.0% of patients in the isatuximab arm vs 5.5% of patients in the VRd arm.² The rates of grade 3 or higher TEAEs were 91.6% and 84.0%, respectively. The respective rates of serious TEAEs were 70.7% and 67.4%. 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 recommended for EU approval by the CHMP to treat transplant-ineligible newly diagnosed multiple myeloma. News release. Sanofi. November 15, 2024. Accessed November 15, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-11-14-16-42-42-2981448
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. 2024;391(17):1597-1609. doi:10.1056/NEJMoa2400712
4. FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. September 20, 2024. Accessed November 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-bortezomib-lenalidomide-and-dexamethasone-newly-diagnosed-multiple