Subcutaneous Isatuximab Administration By an on-Body Delivery System (OBDS) in Combination with Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Phase 1b Expansion Study Results

Introduction: Intravenous (IV) administration of isatuximab (Isa) in combination with pomalidomide and dexamethasone (Pd) is approved for patients (pts) with relapsed/refractory multiple myeloma (RRMM). Subcutaneous (SC) delivery allows for a shorter duration of administration (within several minutes) compared with the currently approved IV route, optimizing convenience of administration and healthcare resources and enhancing comfort and quality of life of patients (pts). Prior results of the Phase 1b study (NCT04045795) defined the recommended phase 2 dose (RP2D) of SC Isa at 1400 mg and showed comparable safety and efficacy for both IV and SC routes of Isa administration in combination with Pd, in pts with RRMM. The on-body delivery system (OBDS), a wearable bolus injector applied to the abdomen by a healthcare professional, administered SC Isa in the expansion cohort, demonstrating very good local tolerability with a short follow-up. Here, we present updated results of this phase 1b trial.

Methods: This multicenter, open-label, Phase 1b study evaluated SC vs IV Isa + Pd in pts with RRMM and ≥2 prior lines of treatment (LOT). Pts were randomized to SC by infusion pump (IP)1000 mg and IV 10 mg/kg or to IP1400 mg and IV. SC Isa administration at the RP2D via OBDS was evaluated in an expansion cohort. Primary endpoints were safety and pharmacokinetics (PK). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and CD38 receptor occupancy.

Results: A total of 56 pts were randomized and treated: 12 with Isa IV, 12 with Isa IP1000, 10 with Isa IP1400, and 22 with Isa OBDS. On May 28, 2022, 33% IV, 25% IP1000, 30% IP1400, and 59% of OBDS pts remained on treatment. The median follow-up was longer for IV (24 mo), IP1000 (29 mo), IP1400 (23 mo) cohorts than the OBDS (10 mo) cohort due to sequential accrual. At study entry, 67% of IV, 33% of IP1000, 60% of IP1400, and 50% of OBDS pts had International Staging System stage II-III disease, and ≥50% of pts in each cohort had received ≥3 prior LOT. 50% of IV patients were refractory to immunomodulatory drugs and proteasome inhibitors, as well as 66.7% of IP1000, 40% of IP1400 and 72.7% of OBDS cohorts, respectively. Treatment-related G3-4 treatment emergent adverse events (TEAE) occurred in 91.7% pts of the IP1000 cohort and approximately 80% in the IV, IP1400 and OBDS cohorts (Table 1). Serious treatment-related TEAEs occurred in 16.7% pts of the IV, 25% in the IP1000, 50% in the IP1400 and 13.6% in the OBDS cohort.

Isa administration was well tolerated, with infrequent infusion reactions (IRs) (≤10% in each cohort, all G2), only at first administration, and none in the OBDS cohort. The median duration of OBDS injections was 10 min, and all injections were successfully completed with no interruption. There was good local tolerability: 5 (22.7%) pts experienced 7 injection site reactions, all G1, out of 404 administrations (1.73%), including 5 injection site erythemas, 1 injection site hemorrhage, and 1 injection site induration.

Grade ≥3 laboratory neutropenia was observed in 83% of IV patients and ~90% of SC patients, OBDS and IP. Febrile neutropenia occurred in 1 (4.5%) patient in the IV, 2 (20%) pts in the IP1400 and 1 (4.5%) in the OBDS cohorts.

Flat SC dosing resulted in variability in Isa PK exposure generally comparable to the body weight based IV dosing, supporting the choice of a flat SC dose. Grade ≥3 laboratory neutropenia, febrile neutropenia, and infections were consistent across weight ranges (<65 kg, 65-85 kg, >85 kg).

Best overall responses, median PFS, and duration of follow-up are presented (Table 2). ORR in pts treated at the RP2D was 75.0%, and 66.7% in the IV and IP1000 cohorts. Due to data availability, results of minimal residual disease assessments will be presented at the conference.

Conclusions: These updated results with longer follow-up of SC Isa administration via OBDS at the RP2D of 1400 mg showed a safety profile consistent with IV administration, with no IRs, excellent local tolerability and efficacy comparable to that observed in the phase 3 ICARIA study with IV Isa, in combination with Pd. Isa SC administration by OBDS is well tolerated, has a short duration of injection, and provides a convenient hands-free option with controlled delivery. Based on these results and OBDS performance, a non-inferiority phase 3 trial of Isa-SC with OBDS versus Isa-IV is ongoing (NCT05405166). Clinical trial information: NCT04045795. Funding: Sanofi.

Quach:Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: receipt of free drug for investigator-initiated study, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: receipt of free drug for investigator-initiated study, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role, receipt of free drug for investigator-initiated study , Research Funding; CSL: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role , Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role, receipt of free drug for investigator-initiated study , Research Funding. Ocio:GSK: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen, BMS/Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Pfizer, Sanofi, Takeda: Consultancy; Sanofi: Consultancy, Honoraria; Amgen, BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Sanofi, Takeda: Honoraria; Pfizer: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy; Oncopeptides: Consultancy, Honoraria; Janssen, Takeda: Speakers Bureau. Oriol:Janssen: Consultancy; Sanofi: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Tsukada:Sanofi: Honoraria. Sunami:Otsuka: Research Funding; Takeda: Research Funding; Ono: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Research Funding; GSK: Research Funding; Celgene: Research Funding; BMS: Honoraria, Research Funding; AbbVie: Research Funding; Sanofi: Honoraria, Research Funding. Madan:Janssen, Amgen, GSK, BMS, Karyopharm, Oncopeptide, Pfizer: Honoraria, Speakers Bureau. Semiond:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Yu:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Macé:Sanofi: Current Employment. Suzan:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Moreau:AbbVie, Janssen, Celgene, Amgen, and Sanofi: Honoraria.