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

Introduction: 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) drug 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 prior lines of therapy, including lenalidomide and a proteasome inhibitor. Pts were randomized 2:1 to Cohorts 1a (SC-1000 mg) or 1b (IV-10 mg/kg). After evaluation of Isa SC safety, PK and CD38 receptor occupancy (RO) in Cohort 1a, new pts were randomized to Cohorts 2a (SC-1400 mg) or 2b (IV-10 mg/kg). SC and IV Isa were administered once weekly for 4 weeks (Cycle 1) and then once every 2 weeks in subsequent cycles (QW/Q2W) in combination with Pd; SC Isa was delivered through a syringe pump. Primary endpoints assessed safety including dose-limiting toxicity (DLT), injection site reactions (ISR), and PK parameters. Main secondary endpoints were overall response rate (ORR), progression-free survival (PFS), CD38 RO, and patient-reported outcomes (PRO).

Results: A total of 34 pts were randomized and treated: 12 pts Isa IV 10 mg/kg + Pd, 12 pts Isa SC1000 + Pd, 10 pts Isa SC1400 + Pd. As of March 31, 2021, 7 pts (58%) IV, 4 pts (33%) SC1000, and 7 pts (70%) SC1400 remained on study treatment. Median time from initial MM diagnosis to first study treatment was ~5 years, and the median (range) number of prior lines of therapy was: 3.5 (2-7) in IV, 3.0 (2-6) in SC1000, and 2.5 (1-4) in SC1400 pts. At study entry, International Staging System (ISS) stage II-III was 58.4% in IV, 33.3% in SC1000 and 60% in SC1400 pts; median weight and beta-2 microglobulin rate tended to be higher in SC1400 compared to SC1000 pts, respectively (86.9 kg vs 70.3 kg and 3.55 mg/L vs 2.65 mg/L). 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 (IR) were infrequent (≤10% across cohorts, all Grade [G] 2); in each cohort, 1 single episode of IR occurred in 1 patient each, only at first injection. Local tolerability of SC injection was very good with only a single episode of G2 ISR (erythema and pain) in SC1400 cohort. Similar occurrence of ≥G3 treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and neutropenia occurred across cohorts. There were no TEAEs leading to death, definitive treatment discontinuation, or premature discontinuation of Isa (Table 1). One DLT was reported in each SC cohort: G4 neutropenia (SC1000) and G3 pulmonary infection (SC1400); both pts resumed study treatment after corrective treatment and dose modification. No maximum tolerated dose was identified. ORR, ≥ very good partial response, and complete response were 66.7%, 33%, and 16.7% in the IV cohort; 66.7%, 41.7%, and 25% in the SC1000 cohort, and 80%, 40%, and 20% in the SC1400 cohort, respectively. At 8 mos, PFS-free rate was 73% in the IV and SC1000 cohorts, and 89% in the SC1400 cohort (Figure 1). After the first Isa administration, C _max and AUC _1week of the SC1000 and SC1400 mg doses were comparable and lower than those after IV administration, in agreement with SC slower absorption. After the 4 weekly Isa administrations (Cycle 1), the exposures (C _trough at 4 weeks) of SC1000 and SC1400 doses were comparable and higher than those after IV administration. The comparable exposure of the 2 SC cohorts despite the different doses (1000 mg and 1400 mg) was attributed to the unbalanced distribution of influential PK covariates, as beta-2 microglobulin and weight. High CD38 receptor saturation by Isa on bone marrow plasma cells was reached for both SC doses; mean (%) CD38 RO was 76 (68.2; 86.1) in IV, 80 (74.7; 84.2) in SC1000, and 81 (78.6; 83.2) in SC1400 cohorts with a smaller range at 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. IRs were infrequent, occurring only at first injection and local tolerability of Isa SC was very good. Efficacy results were comparable with the Phase 3 ICARIA study. Higher C _trough at 4 weeks (PK best predictor of Isa efficacy) was achieved following SC administration compared with IV administration. Isa SC + Pd administration appears to be a promising and convenient option for pts with RRMM.

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