P-207: A multi-center, phase 1b study to assess the safety, Pharmacokinetics and efficacy of subcutaneous Isatuximab plus Pomalidomide and Dexamethasone, in patients with Relapsed/Refractory Multiple Myeloma

Background Intravenous (IV) isatuximab (Isa) + pomalidomide and dexamethasone (Pd) is an approved regimen for the treatment of adults with relapsed/refractory multiple myeloma (RRMM). Subcutaneous (SC) delivery would optimize convenience of administration. Methods This multicenter, open-label, Phase 1b study evaluated the safety, pharmacokinetics (PK), and efficacy of SC vs IV Isa + Pd in patients (pts) with RRMM who had received ≥2 lines including lenalidomide and a proteasome inhibitor. Pts were randomized 2:1 to Cohorts 1a (SC–1000 mg) or 1b (IV–10 mg/kg) and, after evaluation of Isa SC safety, PK and CD38 Receptor Occupancy (RO), randomized to Cohorts 2a (SC–1400 mg) or 2b (IV). SC was delivered through a syringe pump. Primary endpoints assessed safety including dose-limiting toxicity (DLT), injection site reactions (ISR), and PK parameters. Key secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and CD38 RO. Results 34 pts were randomized and treated: 12 pts Isa IV 10 mg/kg + Pd, 12 pts Isa SC1000 + Pd, 10 pts Isa SC1400 + Pd. On March 31, 2021, 7 pts (58%) IV, 4 pts (33%) SC1000, and 7 pts (70%) SC1400 remained on study treatment. At study entry, International Staging System (ISS) stage II–III was 58% in IV, 33% in SC1000 and 60% in SC1400 pts. Due to sequential accrual, the median follow-up was longer in IV (15.1 months [mos]) and SC1000 (14.8 mos) cohorts than SC1400 (8.8 mos). Infusion reactions were infrequent (≤10% across cohorts, all Grade (G) 2), and only at first injection. Local tolerability of SC injection was very good with only a single episode of G2 ISR in SC1400 cohort. Similar occurrence of ≥G3 treatment emergent adverse events (TEAE), treatment-related TEAE, and neutropenia occurred across cohorts. One DLT was reported in each SC cohort: G4 neutropenia (SC1000) and G3 pulmonary infection (SC1400). No maximum tolerated dose was identified. ORR, ≥VGPR, and complete response were 67%, 33%, and 17% in the IV cohort; 67%, 42%, and 25% in the SC1000 cohort and 80%, 40%, and 20% in the SC1400 cohort, respectively. 8 mos PFS-free rate was 73% in the IV and SC1000 cohorts and 89% in the SC1400 cohort. Mean Ctrough after the 4th weekly administration was higher in the SC cohorts (339 µg/mL for SC1000, 338 µg/mL for SC1400) vs 235 µg/mL for IV cohort. High CD38 receptor saturation by Isa on bone marrow plasma cells was reached for both SC doses; mean CD38 RO was 76% in IV, 80% in SC1000, and 81% in SC1400. Conclusions The safety of Isa SC at 1000 mg and 1400 mg + Pd was consistent with the known safety profile associated with IV administration, with no new safety signals identified. Local tolerability of SC Isa was very good. Efficacy results were comparable with the Phase 3 ICARIA study. Higher Ctrough at 4 weeks (PK best predictor of Isa efficacy) was achieved following SC administration compared with IV. Isa SC administration appears to be a promising and convenient option. Funded by Sanofi.