IMROZ Trial of Isa-VRd Shows Superior PFS in Transplant-Ineligible Myeloma

Thierry Facon, MD

The phase 3 IMROZ trial (NCT03319667) demonstrated that treatment with isatuximab-irfc (Sarclisa) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Isa-VRd), followed by Isa-Rd maintenance, significantly improves progression-free survival (PFS) in patients with newly diagnosed, transplant-ineligible multiple myeloma. This regimen was shown to be more effective than the standard VRd regimen followed by Rd maintenance.¹

The results, presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and published simultaneously in The New England Journal of Medicine, highlight the potential of Isa-VRd as a superior treatment option, offering a substantial advancement in the management of this patient population.

At a median follow-up of 59.7 months, patients treated with Isa-VRd (n = 265) followed by isa-Rd experienced a median PFS that was not reached (NR) compared with 54.34 months (95% CI, 45.207-NR) in patients treated with VRd alone (HR, 0.596; 98.5% CI, 0.406-0.876; log-rank P = .0005). Notably, the 60-month PFS rate was 63.2% in the investigational group vs 45.2% in the control arm. This PFS benefit was seen across most subgroups, including some difficult-to-treat populations with negative prognostic factors.

"IMROZ is the first global, phase 3 study of an anti-CD38 monoclonal antibody in combination with VRd in patients with transplant-ineligible myeloma. In this presentation, we [showed] that the IMROZ regimen led to a statistically significant improvement in PFS, deep response rates with statistically significant improvements in complete response [CR] and minimal residual disease [MRD]–negative CR, sustained in MRD negativity, and a safety profile consistent with that of each agent,” lead study author Thierry Facon, MD, stated in a presentation of the data.

Facon is a professor of hematology in the Department of Hematology at Lille University Hospital in France.

In May 2024, the FDA granted priority review to the supplemental biologics license application seeking the approval of Isa-VRd for the treatment of patients with newly diagnosed, transplant-ineligible multiple myeloma, based on data from IMROZ.³

The global, prospective, randomized, open-label study was conducted at 102 sites across 21 countries. Investigators enrolled patients 80 years of age or younger with newly diagnosed multiple myeloma who were not considered eligible for transplant due to advanced age or comorbidities.¹

Patients were randomly assigned 3:2 to the Isa-VRd arm and VRd arm. In the experimental arm, patients received 10 mg/kg of intravenous isatuximab once per week for the 5 weeks during the first 42-day cycle, then once every 2 weeks for cycles 2 to 4 of 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 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. After induction, continuous treatment in the experimental arm was comprised of 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; and 20 mg of dexamethasone once per week. Patients in the control arm received Rd using the same dosing regimen.

Treatment continued until disease progression, unacceptable toxicities, or patient withdrawal. Notably, patients in the control arm who experienced disease progression during continuous therapy were permitted to cross over to receive Isa-Rd.

The primary end point was PFS, and key secondary end points included CR rate, MRD-negative CR rate, very good partial response (VGPR) or better rate, and overall survival (OS).

The median age of patients in both treatment arms was 72.0 years in the Isa-VRd arm (range, 60-80) and VRd arm (range, 55-80). Three percent of patients in the Isa-VRd group were under 65 years of age, 27.5% were 65 to less than 70 years of age, 43.4% were 70 to less than 75 years of age, and 26% were between 75 to 80 years of age. In comparison, 5% of patients in the VRd group were under 65 years of age, 26% were 65 to less than 70 years of age, 37.6% were 70 to less than 75 years of age, and 31.5% were between 75 to 80 years of age.

An ECOG performance status of 0, 1, and 2 was observed in 46.4%, 42.3%, and 10.9% of patients in the Isa-VRd arm, respectively. In the VRd arm, these respective rates were 43.6%, 45.9%, and 10.5%. Additionally, 24.9% of patients in the Isa-VRd group had an estimated glomerular filtration rate of less than 60 mL/min/1.73 m² compared with 34.3% in the VRd group. Per the Revised Multiple Myeloma International Staging System, 88.3% of patients in the Isa-VRd arm had stage I or II disease; 10.9% had stage III disease; and 0.8% were not classified. In the VRd arm, these respective rates were 86.7%, 11.6%, and 1.7%.

Furthermore, 78.1%, 15.1%, and 7.2% of patients in the Isa-VRd group were classified as standard-risk, high-risk, or high-risk with 1q21-positive disease, respectively. In the VRd group, these respective rates were 77.3%, 18.8%, and 8.3%. Notably, 35.8% and 38.7% of patients were 1q21-positive in the Isa-VRd and VRd groups, respectively, and 12.1% and 12.7% of patients harbored 1q21 amplifications, respectively. Moreover, deletion 17p was detected in 5.7% and 5.0% of patients in the Isa-VRd and VRd groups, respectively. Extramedullary disease at study entry was observed in 6.8% of patients in the Isa-VRd group and 3.3% of patients in the VRd group.

Although OS data were immature at data cutoff, an interim OS analysis showed a favorable trend for Isa-VRd (HR, 0.776; 95% CI, 0.407-1.48). The 5-year OS rate was 72.3% and 66.3% for patients treated with Isa-VRd vs VRd, respectively.

The overall response rate was 91.3% for Isa-VRd and 92.3% for VRd. Notably, the CR or better rate was 74.7% for Isa-VRd and 64.1% for VRd (P = .01). The VGPR or better rate was 89.1% and 82.9% for Isa-VRd and VRd, respectively (odds ratio [OR], 1.729; 95% CI, 0.994-3.008).

In the intention-to-treat population, 58.1% of patients treated with Isa-VRd were MRD negative compared with 43.6% of those given VRd (OR, 1.791; 95% CI, 1.221-2.62). The rate of patients who achieved an MRD-negative CR 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 46.8% and 24.3% of patients, respectively (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 Isa-VRd arm vs 32.79 months (95% CI, 17.51-45.11) in the VRd arm.

Additionally, as measured by the EORTC QLQ-30 GHS, overall quality of life remained stable over time in both groups, with no negative impact from adding isatuximab.

In the safety population, the median treatment duration was 53.2 months for the Isa-VRd arm (n = 263) and 31.3 months for the VRd arm (n = 181). At data cutoff, 47.2% and 24.3% of patients, respectively, were still on treatment.

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.6% of patients in the Isa-VRd group and 98.3% of patients in the VRd group. Grade 3 or higher TEAEs were reported in 91.6% and 84.0% of patients, respectively. The incidence of grade 5 TEAEs was 11.0% for Isa-VRd and 5.5% for VRd. Serious TEAEs occurred in 70.7% and 67.4% of patients, respectively.

TEAEs leading to definitive treatment discontinuation were observed in 22.8% of patients given Isa-VRd and 26.0% of patients administered VRd. The event rate per patient-year was 13.39 (Isa-VRd) and 12.69 (VRd) for any-grade TEAEs. 1.17 and 0.99 for grade 3 or higher TEAEs; 0.03 and 0.02 for grade 5 TEAEs; 0.37 and 0.43 for serious TEAEs; 0.07 and 0.09 for TEAEs leading to treatment discontinuation.

"The exposure-adjusted incidence rates suggest the difference in incidence of grade 5 TEAEs between arms was largely driven by the difference in treatment exposure," Facon said in the presentation.

Any-grade AEs of note included neutropenia (Isa-VRd, 87.5%; VRd, 80.1%); infections (91.3%; 96.7%), including pneumonia (30.0%; 19.3%) and upper raspatory infections (34.2%; 33.7%); diarrhea (54.8%; 48.6%); peripheral sensory neuropathy (54.4%; 60.8%); and cataract (38.0%; 25.4%). Notably, any-grade invasive second primary malignancies included solid tumors (8.4%; 4.4%) and hematologic malignancies (1.1%; 1.1%)

REFERENCES:

1. 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.

2. Facon T, Dimopoulos M-A, 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

3. Sarclisa accepted for FDA priority review for the treatment of transplant-ineligible newly diagnosed multiple myeloma. News release. Sanofi. May 27, 2024. Accessed June 3, 2024. https://tinyurl.com/53hhdwwj