Exposure-response analyses for selection/confirmation of optimal isatuximab dosing regimen in combination with pomalidomide/dexamethasone treatment in patients with multiple myeloma.

Isatuximab is an approved anti-CD38 monoclonal antibody with multiple antitumor modes of action. An exposure-response (E-R) analysis using data from patients with relapsed/refractory multiple myeloma (RRMM) enrolled in a phase Ib clinical study who received isatuximab at doses from 5 to 20 mg/kg weekly for 1 cycle (4 weeks) followed by every 2 weeks thereafter (qw/q2w) in combination with pomalidomide/dexamethasone (n = 44) was first used to determine the optimal dose/schedule for the phase III ICARIA-MM study. It was complemented by an E-R analysis from a second phase Ib study of patients who received isatuximab at doses from 3 to 10 mg/kg q2w or 10 or 20 mg/kg qw/q2w in combination with lenalidomide/dexamethasone (n = 52). Plasma trough concentration at week 4 (CT4W) was the best predictor for response, and the benefit of the initial 4-weekly administration was confirmed. Although the predicted overall response rate (ORR) was higher at 20 mg/kg vs. 10 mg/kg, the 95% confidence intervals were overlapping. Considering the high probability of success to reach the targeted ORR of greater than or equal to 60%, 10 mg/kg qw/q2w was selected. Results of the E-R analysis from the lenalidomide/dexamethasone study and published disease modeling using data from both phase Ib clinical studies reinforced 10 mg/kg qw/q2w as the optimal dose/schedule for the phase III ICARIA-MM study. E-R analysis showed that higher CT4W was associated with higher ORR. Developed models supported the phase III isatuximab dosing regimen selection/confirmation of 10 mg/kg qw/q2w for use in combination with pomalidomide/dexamethasone in patients with RRMM.