Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Transplant-Ineligible Multiple Myeloma

Bortezomib in combination with lenalidomide and dexamethasone (VRd) represents a standard initial treatment option for both transplant-eligible and -ineligible patients with multiple myeloma.¹ The findings from a phase 1b study investigating the combination of isatuximab with VRd (Isa-VRd) demonstrated a favorable safety profile, initial clinical efficacy, and significant responses in patients who are ineligible for transplantation or who do not have immediate plans for autologous stem-cell transplant. IMROZ (NCT03319667) is the first global phase 3 study investigating the efficacy and safety of the anti-CD38, isatuximab, in combination with VRd in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM).¹

A total of 446 patients aged ≤80 years were randomized 3:2 to receive either Isa-VRd or VRd alone.^1,2 The primary efficacy endpoint was progression-free survival (PFS). Key secondary endpoints included complete response (CR) rate, minimal residual disease (MRD)-CR (next-generation sequencing, 10⁻⁵) rate, very good partial response rate or better, and overall survival (OS). Patient characteristics were well-balanced between arms.^1,2

The primary endpoint of IMROZ was met. At a median follow-up of 5 years (59.7 months), Isa-VRd followed by isatuximab with lenalidomide and dexamethasone (Isa-Rd) led to a statistically significant reduction in the risk of progression or death by 40.4%.¹ A benefit of PFS was noted with Isa-VRd compared with VRd in the majority of subgroups, including several challenging-to-treat populations characterized by adverse prognostic factors. Isa-VRd followed by Isa-Rd resulted in deep response rates, with a significant improvement in the MRD-negative CR rate, as well as higher rates of MRD negativity and sustained MRD negativity for ≥12 months.¹ At a median follow-up period of 5 years, OS data remain immature; nonetheless, a positive trend has been noted for the Isa-VRd treatment group, indicating a 22.4% reduction in risk when compared with the VRd group. Isa-VRd was well-tolerated, and the safety profile remains consistent with the known safety profiles of each agent. Serious treatment-emergent adverse events (TEAEs) were observed in 70.7% of patients in the Isa-VRd arm and 26.0% of patients in the VRd arm. In the Isa-VRd arm, TEAEs led to treatment discontinuation in 22.8% of patients versus 26% of patients in the VRd arm.¹

A frailty subgroup analysis was conducted of the IMROZ study.² Patients with a frailty score of 0/1 were considered non-frail, and those with scores ≥2 were classified as frail. After a median follow-up of 59.7 months, Isa-VRd led to improved median PFS versus VRd in both the frail and non-frail subgroups. Among frail patients, those who received Isa-VRd were more than twice as likely to achieve MRD negativity as those who received VRd (50.7% vs 22.8%, respectively, at 10⁻⁵ by next-generation sequencing).² The OS data are immature; however, there does not appear to be an increase in mortality in the Isa-VRd arm. The rates of TEAEs leading to treatment discontinuation were similar between arms in both the frail and non-frail subgroups.²

The improved effectiveness of Isa-VRd, followed by Isa-Rd, paired with a consistent safety profile, represents a vital treatment choice for frontline disease management, thereby establishing Isa-VRd as a new treatment option for patients aged ≤80 years with NDMM who are not candidates for transplantation.¹ In addition, considering the efficacy results and the acceptable safety profile, Isa-VRd serves as a significant treatment alternative for patients with treatment-ineligible NDMM, irrespective of their frailty status.²

References

1. Facon, T, Dimopoulos MA, Leleu X, 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). Presented at: International Myeloma Society 21st Annual Meeting & Exposition. September 25-28, 2024; Riocentro Rio de Janeiro, Brazil. Abstract 7500.

2. Manier S, Dimopoulos MA, Leleu AP, et al. Isatuximab plus bortezomib, lenalidomide, and dexamethasone (VRd) for newly diagnosed multiple myeloma (NDMM) transplant-ineligible patients: frailty subgroup analysis of IMROZ. Presented at: International Myeloma Society 21st Annual Meeting & Exposition. September 25-28, 2024; Riocentro Rio de Janeiro, Brazil. Poster P-426.