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Modakafusp alfa (TAK-573) is a novel, first-in-class fusion protein of a humanized anti-CD38 IgG4 kappa antibody fused to attenuated human interferon alfa-2b. It acts as an agonistic innate immunity enhancer through targeted interferon (IFN) signaling and has been investigated as an immune-oncology therapeutic agent in patients with relapsed/refractory multiple myeloma (RRMM). Population PK analysis and sequential PK-PD analysis of serum M-protein (MP) as a primary marker of tumor burden in RRMM were conducted using dose escalation (Part 1) and dose expansion (Part 2) data from 96 RRMM patients enrolled in the Phase 1/2 iinnovate-1 trial. After exploring various structural PK models with different levels of mechanistic complexity, a Michaelis-Menten approximation model that included an anti-drug antibody (ADA) binding model adequately captured the nonlinear PK of modakafusp alfa and the apparent time-varying impact of ADA on the PK. Body weight was a significant predictor of central volume of distribution (exponent of 0.51) but was not predictive of elimination-related parameters given both catabolic and likely target-mediated elimination processes. Serum MP data from patients evaluable at baseline were adequately characterized using the Claret tumor growth inhibition and drug resistance model, with antitumor drug effect using an E_max model. The population PK and PK-PD modeling results supported model-informed drug development for modakafusp alfa, including the switch from weight-based to fixed dosing and the selection of two fixed doses for the randomized dose extension (Part 3) phase of the trial to inform future optimal dose selection, which is consistent with the Project Optimus paradigm.