A comparison between subcutaneous isa-vrd from the isasocut study and intravenous isa-vrd from the imroz study in patients with transplant- ineligible newly diagnosed multiple myeloma

Abstract Introduction: Isatuximab (Isa) given intravenously (IV) with bortezomib, lenalidomide, and dexamethasone (VRd) is associated with a significant progression-free survival benefit in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (IMROZ study, NCT03319667). The efficacy and safety of subcutaneous (SC) Isa VRd, utilizing an innovative on-body injector (OBI), has recently been demonstrated in NDMM patients ineligible for transplant (ISASOCUT study, NCT05889221). The treatment administration schedules differed between these two studies, with the exception of Isa; mainly, bortezomib was administered twice weekly in IMROZ versus weekly in ISASOCUT. Bortezomib, although widely used and effective for NDMM patients, is associated with peripheral neuropathy (PN) as a key dose-limiting toxicity, often requiring dose reduction/ discontinuation. Here, the comparative safety and efficacy of the Isa OBI-VRd regimen from ISASOCUT and the Isa IV-VRd regimen from IMROZ are evaluated within the same follow-up time frame of 8 months following the first dose. Methods: Patients on Isa OBI-VRd (n=74) from ISASOCUT, a prospective, multicenter, phase 2 study, and patients in the Isa IV-VRd arm (n=265) from IMROZ, a global, randomized, phase 3 study, were included in this analysis. Isa OBI-VRd patients received fixed-dose Isa 1400mg weekly during cycle (C)1, then every 2 weeks (Q2W) up to C12, and then Q4W thereafter, with each cycle lasting 28 days. SC bortezomib (1.3mg/m2) was given twice weekly in C1 (D1, 4, 8,11), then weekly (D1, 8, 15) thereafter. Isa IV-VRd patients received Isa 10mg/kg weekly in C1, then Q2W, followed by Q4W from C18 onwards. SC bortezomib (1.3mg/m2) was given on Days 1, 4, 8, 11, 22, 25, 29, 32 from C1-4. C1 to 4 each lasted 42 days, with the remainder lasting 28 days each. A subgroup analysis was performed by age (<75 years, ≥75 years) at baseline, with safety and efficacy evaluated at 8 months following D1 of C1. Results: Baseline demographics and disease characteristics were generally similar between Isa OBI-VRd (ISASOCUT) and Isa IV-VRd (IMROZ) populations. In Isa OBI-VRd and Isa IV-VRd populations, 33.8% (n=25) and 26.0% (n=69) of patients were ≥75 years old, respectively, and 17.6% and 10.2% had Revised International System Stage III. In Isa OBI-VRd and Isa IV-VRd, the incidence of any treatment-emergent adverse events (TEAEs, any grade; 100% and 98.5%) and serious AEs (35.1% and 42.2%) were similar between the two populations and across age subgroups. The proportion of patients with systemic infusion reactions was lower with Isa OBI-VRd than with Isa IV-VRd for both age subgroups (<75 years: 8.2% vs 23.1%; ≥75 years: 8.0% vs 22.1%). Incidence of grade ≥3 respiratory infection was lower with Isa OBI-VRd than with Isa IV-VRd (6.1% vs 19.5%) in the <75 years subgroup, and similar (12.0% vs 13.2%) in the ≥75 years subgroup. Across both age subgroups, a lower incidence of grade ≥2 PN was observed with Isa OBI-VRd vs Isa IV-VRd (<75 years, 22.4% vs 37.9%; ≥75 years, 20.0% vs 42.6%), as well as for Grade 3 PN (<75 years, 2% vs 8.7%; ≥75 years, 0% vs 5.9%), and Grade 4 PN (<75 years, 0% vs 0.5%; ≥75 years, 0% vs 1.5%). Isa OBI-VRd was associated with a lower TEAE incidence leading to bortezomib dose reduction due to nervous system disorders across both age subgroups (Isa OBI-VRd vs Isa IV-VRd: <75 years, 14.3% vs 37.4%; ≥75 years, 28.0% vs 35.3%). Incidence of grade ≥3 nervous system disorder TEAEs leading to bortezomib dose reduction was 0% with Isa OBI-VRd in both age subgroups vs 6.7% and 5.9% with Isa IV-VRd in the <75 years and ≥75 years subgroups, respectively. In the intention-to-treat Isa OBI-VRd and Isa IV-VRd populations, the ≥very good partial response rates were 87.8% and 83.2% (relative risk [95% confidence interval (CI)]= 1.055 [0.934–1.192]), respectively, in the <75 years subgroup, and 80.0% and 82.6% (relative risk [95% CI]= 0.968 [0.774–1.211]) in the ≥75 years subgroup. Conclusions: The analysis of Isa OBI-VRd from the ISASOCUT study and Isa IV-VRd from the IMROZ study showed a lower incidence of PN with Isa OBI-VRd, regardless of age subgroup. This suggests that weekly bortezomib as administered in ISASOCUT may be more tolerable for patients than the twice weekly schedule given in IMROZ with regard to PN, while maintaining efficacy in those <75 years and ≥75 years old. In addition, this analysis further supports the efficacy and safety of the OBI delivery method.