Abstract This study aimed at leveraging data from phase I/II clinical trials to build a nonlinear joint model of serum M‐protein kinetics and progression‐free survival (PFS) accounting for the effects of isatuximab (Isa), pomalidomide (Pom), and dexamethasone (Dex) in patients with relapsed and/or refractory multiple myeloma. Serum M‐protein levels and PFS data from 203 evaluable patients, included either in a phase I/II study ( n = 173) or in a phase I study ( n = 30), were used to build the model. First, we independently developed a longitudinal model and a PFS model. Then, we linked them in a nonlinear joint model by selecting the link function that best captured the association between serum M‐protein kinetics and PFS. A Claret tumor growth‐inhibition model accounting for the additive effects of Isa, with an E max function, Pom, and Dex on serum M‐protein elimination was selected to describe serum M‐protein kinetics. PFS was best described with a log‐logistic model and associations with baseline beta‐2 microglobulin level, age, and coadministration of Dex were identified. The instantaneous change in serum M‐protein level was found to be associated with PFS in the final joint model. Using model simulations, we retrospectively supported the Isa 10 mg/kg weekly for 4 weeks, then biweekly (QW/Q2W) dosing regimen of the ICARIA‐MM phase III pivotal study, and validated it using the same phase III pivotal study data.