Isa-VRd Shows Efficacy and Safety in Frail Transplant-Ineligible Myeloma

Isatuximab-irfc (Sarclisa) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Isa-VRd) improved survival and response rates while demonstrating a tolerable safety profile compared with bortezomib, lenalidomide, and dexamethasone (VRd) in patients with transplant-ineligible, newly diagnosed multiple myeloma who were considered frail, according to a post hoc subgroup analysis of the phase 3 IMROZ trial (NCT03319667) published in Haematologica.¹

With a median follow-up of 59.7 months, Isa-VRd demonstrated a median progression-free survival (PFS) of not reached (NR) vs 28.91 months with VRd in patients who were frail (HR, 0.518; 95% CI, 0.294-0.912; P = .0227) and NR vs 59.70 months, respectively, in patients who were not frail (HR, 0.615; 95% CI, 0.419-0.903; P = .0131). The 60-month PFS rate for patients who were frail was 52.6% with Isa-VRd vs 36.2% with VRd. For patients who were not frail, they were 66.6% vs 48.8%, respectively.

Additionally, the study authors noted that within all treatment arms, patients who were frail experienced worse PFS than those who were not frail (Isa-VRd: HR, 0.531; 95% CI, 0.335-0.842; P = .0071; VRd: HR, 0.487; 95% CI, 0.302-0.785; P = .0031). When stratifying for age, patients who were 75 years or younger and frail experienced better outcomes with Isa-VRd vs VRd (HR, 0.511; 95% CI, 0.232-1.125; P = .0953); in patients who were between 76 and 80 years and frail, the benefit of Isa-VRd vs VRd was not statistically significant (HR, 0.733; 95% CI, 0.348-1.544; P = .4139).

In patients with frailty in the intention-to-treat group, minimal residual disease (MRD) negativity was achieved by 47.8% of patients with Isa-VRd and 22.0% with VRd (OR, 3.250; 95% CI, 1.433-7.372; P = .0040), and complete responses (CRs) or better were achieved by 46.4% and 20.0%, respectively (OR, 3.459; 95% CI, 1.495-8.006; P = .0030). In patients who were not frail, MRD negativity and CRs or better was achieved by 58.6% of patients with Isa-VRd and 50.0% with VRd (OR, 1.413; 95% CI, 0.901-2.214; P = .1316).

Overall survival (OS) data were immature at the time of analysis. The 60-month OS rate was 48.8% with Isa-VRd and 43.7% with VRd in patients who were frail and 79.9% vs 74.9%, respectively, in patients who were not frail. A survival analysis stratified by cause of death due to disease progression vs not due to disease progression showed that, in the frail subgroup, 8.7% of patients with Isa-VRd and 20.0% with VRd died due to disease progression (HR, 0.426; 95% CI, 0.155-1.172; P = .983) vs 3.6% and 9.4%, respectively, in the non-frail subgroup (HR, 0.379; 95% CI, 0.149-0.963; P = .0414).

“This post hoc subgroup analysis of the IMROZ trial by frailty status demonstrated that Isa-VRd is an effective option with a manageable safety profile for [patients with frailty who are 80 years or younger], with [transplant-ineligible, newly diagnosed multiple myeloma], accounting for approximately one-third of patients in IMROZ,” wrote senior study author Thierry Facon, MD, a professor of Hematology in the Department of Hematology at Lille University Hospital in Lille, France, and coauthors.¹ “This is the first demonstration of a quadruplet regimen consisting of an anti-CD38 monoclonal antibody in combination with VRd that is safe and efficacious in all patients aged [80 years or younger] not eligible for transplant regardless of frailty status.”

A total of 446 patients were randomly assigned, in a 3:2 ratio, to receive either Isa-VRd followed by isatuximab with lenalidomide and dexamethasone or VRd followed by lenalidomide and dexamethasone. During the induction phase, VRd consisted of subcutaneous bortezomib as 1.3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32; oral lenalidomide at 25 mg on days 1 to 14 and days 22 to 35; and oral dexamethasone at 20 mg a day. Isatuximab was administered at 10 mg/kg weekly for cycle 1 and biweekly in subsequent cycles.

During continuous treatment, patients received 25 mg of lenalidomide per day and 20 mg of dexamethasone weekly; isatuximab was given intravenously at 10 mg/kg every 2 weeks and then, from cycle 18 onwards, every 4 weeks.

Eligible patients were 80 years or younger with transplant-ineligible, newly diagnosed multiple myeloma. Patients with an ECOG performance status greater than 2 were excluded.

Patients were considered frail with a simplified International Myeloma Working Group (IMWG) frailty score of 2 or higher and were not frail with a score of 0 or 1. Scores were calculated using age, ECOG performance status, and Charlson Comorbidity Index scores at baseline.

Regarding safety, in patients who were frail, treatment-emergent adverse events (TEAEs) of any grade occurred in 100.0% with Isa-VRd and 98.0% with VRd and, in patients who were not frail, 99.5% vs 98.4%, respectively. Of grade 3 or higher TEAEs, in patients who were frail, they occurred in 91.2% vs 88.0%, respectively, and in patients who were not frail, they occurred in 91.7% vs 82.0%. Of patients who were frail, grade 5 TEAEs were observed in 13.2% with Isa-VRd and 10.0% with VRd and, of patients who were not frail, in 10.4% vs 3.9%. The most common grade 3 or higher TEAE in the frail subgroup was neutropenia (36.8% with Isa-VRd and 16.0% with VRd).

Previously, the FDA approved Isa-VRd in transplant-ineligible, newly diagnosed multiple myeloma in September 2024 based on prior results from the IMROZ trial.²

References

1. Manier S, Dimopoulos MA, Leleu XP, et al. Isatuximab plus bortezomib, lenalidomide, and dexamethasone for transplant-ineligible newly diagnosed multiple myeloma patients: a frailty subgroup analysis of the IMROZ trial. Haematologica. Published online March 20, 2025. doi:10.3324/haematol.2024.287200
2. FDA approves istauximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. News release. September 20, 2024. Accessed April 7, 2025. https://shorturl.at/B8d3c