FDA Approves Subcutaneous Isatuximab; Phase 3 Trial Shows MRD Benefit in Myeloma

On July 9, the U.S. Food and Drug Administration (FDA) approved the anti-CD38 monoclonal antibody isatuximab-irfc (Sarclisa Escena) for subcutaneous injection for multiple myeloma indications. The approval covers three specific indications: in combination with pomalidomide and dexamethasone for adult patients with multiple myeloma who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor; in combination with carfilzomib and dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy; and in combination with bortezomib, lenalidomide, and dexamethasone for adult patients with newly diagnosed multiple myeloma who are not eligible for an autologous stem cell transplant.

Efficacy of subcutaneously administered isatuximab in combination with pomalidomide and dexamethasone was evaluated in the open-label noninferiority IRAKLIA trial (NCT05405166), which randomly assigned 531 patients 1:1 to receive either subcutaneous isatuximab with the on-body delivery system (OBDS) or intravenous isatuximab. The overall response rate was 71.1% (95% CI = 65.2%–76.5%) in the subcutaneous arm and 70.5% (95% CI = 64.7%–75.9%) in the intravenous arm. Efficacy in combination with carfilzomib and dexamethasone was evaluated in the IZALCO study (NCT05704049) in 74 patients, yielding an overall response rate of 79.7% (95% CI = 68.8%–88.2%). Efficacy in combination with bortezomib, lenalidomide, and dexamethasone was evaluated in the IsaSocut study (NCT05889221) in 74 patients, with an overall response rate of 97.3% (95% CI = 90.6%–99.7%).

Separately, emerging data from the randomized phase 3 EMN24 IsKia trial (NCT04483739) showed that adding isatuximab to standard KRd therapy (carfilzomib, lenalidomide, and dexamethasone) significantly improved measurable residual disease (MRD) negativity in patients with newly diagnosed multiple myeloma. A total of 302 transplant-eligible patients were randomized to receive either the quadruplet therapy (Isa-KRd) or KRd alone as induction and post-transplant consolidation therapy. MRD negativity occurred in 77% of patients on the quadruplet therapy compared with 67% on KRd alone. The adverse effects reported in the Isa-KRd arm were deemed manageable overall, with the most significant adverse effect being a low white blood cell count.

In a separate indication, isatuximab monotherapy demonstrated promising hematologic response rates with a good safety profile among patients with relapsed/refractory light chain (AL) amyloidosis, according to results of a phase 2 study reported in the journal Blood. In the multicenter, cooperative group study, researchers treated 35 patients with R/R AL amyloidosis. The overall hematologic response rate was 77%, which included a hematologic complete response rate of 6% and very good partial response (VGPR) of 51%. The median time to a response was 1.1 months. A cardiac response was observed among 57% of evaluable patients with cardiac involvement, and the renal response rate was 50% among evaluable patients with renal involvement. The 24-month progression-free survival was 74% and the 24-month overall survival was 85%. There were 23% of patients who developed a grade 3-4 treatment-related adverse event, which included lymphopenia and infusion-related reactions. Two patients who had received prior treatment with daratumumab did not respond to isatuximab.

The recommended isatuximab dose is 1,400 mg administered as a subcutaneous injection with the CirCLIQ OBDS or with a syringe and infusion set for manual administration, in combination with the specified regimens. The prescribing information includes warnings and precautions for hypersensitivity and other administration reactions, neutropenia, infections, secondary primary malignancies, laboratory test interference, and embryo-fetal toxicity. Isatuximab received Orphan Drug designation.