Isa-VRd Regimen Demonstrates Robust Efficacy Across Age and Frailty Groups in Newly Diagnosed Multiple Myeloma

New data presented at the 2025 American Society of Hematology Annual Meeting strongly reinforce the effectiveness and broad applicability of the isatuximab (Isa, Sarclisa; Sanofi) regimen combined with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) for patients newly diagnosed with multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT).¹

A pooled post hoc analysis, drawing on data from the pivotal phase 3 IMROZ study (NCT03319667) and a phase 1b study (TCD13983), examined the Isa-VRd regimen across subgroups stratified by age and frailty criteria, concluding that the treatment exhibits consistent efficacy in hard-to-treat populations, including the elderly and those defined as frail.¹

The drug, administered as isatuximab-irfc, is an antineoplastic agent that interferes with the growth of cancer cells, leading to their eventual destruction by the body.² The previous IMROZ study had already associated Isa-VRd followed by Isa-Rd maintenance with a significant progression-free survival (PFS) benefit in patients with NDMM ineligible for ASCT. A prior post-hoc analysis of IMROZ also indicated that Isa-VRd remained an effective option for frail patients, despite this group typically experiencing worse outcomes.¹

Patient Subgroups in the IMROZ Pooled Analysis

The comprehensive pooled analysis included 336 patients, with participants drawn from the Isa-VRd arm of the global, randomized IMROZ study (n=265) and the multicenter phase 1b study (n=73). The median age of the combined population was 71 years, ranging from 49 to 87 years.¹

Researchers stratified the total population by baseline age (<75 years, n=271; and >75 years, n=65) and further analyzed outcomes based on frailty, which was determined using the simplified International Myeloma Working Group score.¹

A significant difference in frailty status was observed between the age cohorts: only 14.4% of patients aged 75 or younger were frail, whereas nearly two-thirds (64.6%) of patients older than 75 years met the frailty criteria.¹

Efficacy Maintained Across Age and Frailty

The primary findings demonstrated sustained effectiveness of the Isa-VRd regimen regardless of age or frailty, bolstering confidence in its use for a wide array of patients with NDMM.¹

Crucially, median PFS was not reached in the overall population, nor was it reached in either age subgroup. Similarly, median PFS was not reached when comparing nonfrail and frail patients. These results support the conclusion of consistent efficacy across all analyzed subgroups.¹

Overall response rates (ORR) were remarkably high and comparable between the 2 age groups: 93% for patients aged 75 years or younger and 92.3% for those older than 75. High rates of complete response (CR) or better were achieved in both cohorts (72% and 67.7%, respectively).¹

Although ORR remained robust, a slight decrease in response was observed among frail patients within each age cohort. For patients aged 75 or younger, the ORR was 95.7% for nonfrail individuals versus 76.9% for frail individuals. For those older than 75 years, nonfrail patients achieved a 100% ORR compared to 88.1% for frail patients.¹

Sustained Deep Responses Highlighted by MRD Negativity

The analysis also utilized central laboratory testing to evaluate minimal residual disease (MRD) negativity at a high sensitivity level of 10^-5. The rates of MRD negativity achieved alongside a CR or stringent complete response (sCR) were similar between the age cohorts: 53.5% in the 75 years or younger group and 50.8% in the group older than 75 years.¹

Looking at durability, the rates of 24-month sustained MRD negativity were 32.8% for the younger cohort and 23.1% for the older cohort. When focusing specifically on frail subgroups, the sustained 24-month MRD-negative rates were 34.9% for nonfrail and 20.5% for frail patients aged 75 or younger. For the over 75 years subgroup, nonfrail patients demonstrated a 34.8% sustained MRD negativity rate compared to 16.7% for frail patients. The similarity of sustained MRD negativity rates between the 2 cohorts further demonstrates consistent efficacy.¹

Managing Safety and Tolerability With Isa-VRd

Isa-VRd was reported as generally well tolerated. However, the pooled safety analysis reflected the increased clinical challenges often seen in elderly and frail populations.

Rates of grade 3 or higher treatment-emergent adverse events (TEAEs) were slightly higher in the older groups (95.4% in patients aged >75 years) compared to the younger group (87.8% in patients aged <75 years). More significant differences were noted in serious TEAEs, which occurred in 73.8% of patients older than 75 years and 66.8% of patients 75 years or younger. Within the younger group, frail patients experienced serious TEAEs at a notably higher rate (81.6%) than nonfrail patients (64.4%).¹

Definitive treatment discontinuation due to adverse events was also higher in frail patients: 31.6% for frail patients in the younger group and 28.6% for frail patients in the older cohort.¹

The researchers concluded that this pooled analysis provides strong evidence supporting the broad use of the Isa-VRd regimen in patients with NDMM ineligible for ASCT, showing that its efficacy remains consistent across both younger and older patients regardless of frailty status.

REFERENCES

1. Ocio E, Perrot A, San-Miguel J, et al. Efficacy and safety of isa-vrd in elderly patients with or without frailty criteria: pooled analysis of imroz and phase 1b studies in newly diagnosed multiple myeloma patients. Presented at: American Society of Hematology 2025 Annual Meeting. December 6, 2025. Accessed December 8, 2025.
   

2. Isatuximab-irfc (intravenous use). Mayo Clinic. Updated August 1, 2025. Accessed December 8, 2025. https://www.mayoclinic.org/drugs-supplements/isatuximab-irfc-intravenous-route/description/drg-20484127