PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma

Abstract

This analysis describes the pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that supported selection of the isatuximab (anti-CD38 monoclonal antibody) dosing regimen alongside its early clinical development in patients with relapsed/refractory multiple myeloma (RRMM). The PK/PD mathematical model characterized the variations of patient serum M-protein concentrations, the primary marker of tumor burden in multiple myeloma (MM). Three separate PK/PD models were built sequentially as data became available from phase I clinical trials. The primary PK/PD analysis was initiated using monotherapy phase I study data (n = 122), followed by analysis of data collected from phase Ib combination studies with lenalidomide and dexamethasone (Rd, n = 40) and then with pomalidomide and dexamethasone (Pd, n = 31). Using the PK/PD model, abnormal "myeloma" protein (M-protein) profiles under different isatuximab dosing regimens were simulated. Overall, simulations revealed that regimens which included a loading period of four weekly administrations followed by administration every 2 weeks thereafter (QW4-Q2W), reduced M-protein levels more than a Q2W regimen without a loading period. For isatuximab monotherapy, a 20 mg/kg dose induced greater reduction in serum M-protein levels compared with doses equal or lower than 10 mg/kg. For isatuximab in combination with either Rd or Pd, simulations yielded no substantial benefit in terms of M-protein reduction between isatuximab 10 mg/kg and 20 mg/kg. These PK/PD analyses supported the use of isatuximab 10 mg/kg QW4-Q2W in combination with Pd in the phase III trial.

FIGURE 1

Model predictions of M‐protein profiles under different isatuximab dose regimens. Q2W, administration every 2 weeks; QW4‐Q2W, weekly administration for 4 weeks followed by every 2 weeks thereafter

FIGURE 2

Model predictions of M‐protein profiles under different isatuximab dose regimens in mono‐ and combination therapy. (a) Comparison of median predicted serum‐M protein concentrations between isatuximab monotherapy (10 and 20 mg/kg QW4–Q2W) and each combination therapy isatuximab 10 mg/kg QW4–Q2W with lenalidomide or pomalidomide. (b) Comparison of median predicted serum M‐protein concentrations between isatuximab 10 mg/kg QW4–Q2W and 20 mg/kg QW4–Q2W on each combination with lenalidomide or pomalidomide. d, dexamethasone; P, pomalidomide; Q2W, administration every 2 weeks; QW4‐Q2W, weekly administration for 4 weeks followed by every 2 weeks thereafter; R, lenalidomide