Longitudinal Efficacy and Safety Modeling and Simulation Framework to Aid Dose Selection of Belantamab Mafodotin for Patients with Multiple Myeloma.

Belantamab mafodotin, a monomethyl auristatin F (MMAF)-containing monoclonal antibody-drug conjugate (ADC), demonstrated deep and durable responses in the DREAMM-1 and pivotal DREAMM-2 studies in patients with relapsed/refractory multiple myeloma. As with other MMAF-containing ADCs, ocular adverse events were observed. To predict the effects of belantamab mafodotin dosing regimens and dose modification strategies on efficacy and ocular safety endpoints, DREAMM-1 and DREAMM-2 data across a range of doses were used to develop an integrated simulation framework incorporating two separate longitudinal models and the published population pharmacokinetic model. A concentration-driven tumor growth inhibition model described the time-course of serum M-protein concentration, a measure of treatment response, while a discrete time Markov model described the time-course of ocular events graded with the GSK Keratopathy and Visual Acuity scale. Significant covariates included baseline β 2 -microglobulin on growth rate, baseline M-protein on kill rate, extramedullary disease on the effect compartment rate constant, and baseline soluble B-cell maturation antigen on E max. Efficacy and safety endpoints were simulated for various doses with dosing intervals of 1, 3, 6, and 9 weeks and various event-driven dose modification strategies. Simulations predicted that lower doses and longer dosing intervals were associated with lower probability and lower overall time with Grade 3+ and Grade 2+ ocular events compared with the reference regimen (2.5 mg/kg Q3W), with a less than proportional reduction in efficacy. The predicted improved benefit-risk profiles of certain dosing schedules and dose modifications from this integrated framework has informed trial designs for belantamab mafodotin, supporting dose optimization strategies.