Sub-Q Isatuximab Combo Offers Safety, Efficacy Profile Comparable With Phase 3 Results in IV Formulation

Results from a phase 1b study of subcutaneous (sub-Q) isatuximab, used in combination with pomalidomide and dexamethasone, produced safety and efficacy results consistent with those seen in the phase 3 study that led to FDA approval of intravenous (IV) isatuximab with this combination for treatment of relapsed and refractory multiple myeloma (RRMM), in patients who have received at least 2 prior therapies.

The findings were presented December 12, 2021, during the 63rd Annual American Society of Hematology Meeting and Exposition, held in Atlanta and online.

Isatuximab, sold as Sarclisa, was approved in March 2020 to treat certain patients with RRMM based on findings of the ICARIA-MM study, which found that isatuximab added to pomalidomide and dexamethasone demonstrated significant progression-free survival (PFS) of 11.53 months compared with 6.47 months with pomalidomide and dexamethasone alone (HR, 0.596; 95% CI: 0.44-0.81; P = .001).

This triplet combination also demonstrated an improved overall response rate (ORR) compared with pomalidomide and dexamethasone: 60.4% vs 35.3% (P <.0001).

Sub-Q drug delivery in multiple myeloma has been heralded by pharmacists as more convenient for patients and more efficient for hospital administrators; the arrival of sub-Q delivery for isatuximab gives this anti-CD38 therapy a feature achieved by a competitor, daratumumab.

The multicenter, open-label study presented at ASH 2021 evaluated the safety, pharmacokinetics (PKs), and efficacy of sub-Q vs IV isatuximab and pomalidomide in patients with RRMM who had received at least 2 prior treatments, including lenalidomide and a protease inhibitor.

Patients were randomized 2:1 to receive sub-Q 1000-mg isatuximab or IV 10-mg/kg isatuximab. Following evaluation of the safety, PKs, and CD38-receptor occupancy of isatuximab in the sub-Q formulation, new patients were randomized in 2 new cohorts to receive sub-Q 1400 mg or IV 10 mg/kg. Both formulations were administered once weekly for 4 weeks (cycle 1) and then every 2 weeks in combination with pomalidomide.

Primary end points assessed safety, including dose-limiting toxicity, injection-site reactions, and PKs parameters. Secondary end points included ORR, PFS, CD38 receptor occupancy, and patient-reported outcomes.

Of the 34 patients randomized and treated, 12 received IV isatuximab 10 mg/kg with pomalidomide, 12 received isatuximab sub-Q 1000 mg with pomalidomide, and 10 received isatuximab sub-Q 1400 with pomalidomide. As of March 31, 2021, 7 patients (58%) from the IV group, 14 patients (33%) from the sub-Q 1000-mg group, and 7 patients from the sub-Q 1400-mg group remained on treatment.

The median time from the initial multiple myeloma diagnosis to the first study treatment was approximately 5 years, and average prior lines of therapy were 3.5, with a range of 2 to 7 in the IV cohort, 2 to 6 in the sub-Q 1000-mg cohort, and 1 to 4 in the sub-Q 1400-mg group. When patients entered this study, the International Staging System classified them as 58.4%, 33.3%, and 60.0%, respectively. Due to time of accrual, follow-up was longer with the IV patients.

Safety. Infusion reactions were infrequent, with less than 10% across all groups, and all grade 2 and at the first infusion. Local tolerability of the sub-Q infusion was very good, with a single instance of grade 2 site reaction of erythema and pain. There were similar instances of grade 3 or higher treatment emergent adverse events and neutropenia across all groups and no treatment-related events that led to death or premature discontinuation. There was 1 case of neutropenia in the sub-Q 1000-mg group and 1 case of pulmonary infection in the sub-Q 1400-mg group. No maximum tolerated dose was identified.

Outcomes. At 8 months, PFS was 73% in the IV and sub-Q 1000-mg groups and 89% in the sub-Q 1400-mg group. ORR, very good partial, and complete response rates were 66.7%, 33%, and 16.7%, respectively, in the IV group; 66.7%, 41.7%, and 25% in the sub-Q 1000-mg group; and 80%, 40%, and 20% in the sub-Q 1400-mg groups.

The authors concluded that sub-Q isatuximab and pomalidomide administration “appears to be a promising and convenient option for patients with RRMM.”

Reference

Moreau P, Parmar G, Prince M, et al. 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. Presented at: 63rd Annual American Society of Hematology Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abstract 2744. Accessed December 15, 2021. https://ash.confex.com/ash/2021/webprogram/Paper147136.html