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 DRiving Excellence in Approaches to Multiple Myeloma (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 end points, 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, whereas 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 ss 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 maximal effect. Efficacy and safety end points 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 every 3 weeks), 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? In the DRiving Excellence in Approaches to Multiple Myleloma (DREAMM-1) and DREAMM-2 clinical trials, belantamab mafodotin demonstrated deep and durable clinical responses in patients with relapsed/refractory multiple myeloma, but ocular adverse events were observed. WHAT QUESTION DID THIS STUDY ADDRESS? What belantamab mafodotin dose, schedule, and dose-modification strategies could potentially improve in the ocular safety profile without compromising efficacy compared with the approved regimen of 2.5 mg/kg every 3 weeks? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? A simulation framework integrating efficacy (including related dropout), ocular safety (including related dose modifications), and pharmacokinetic data predicted that lower doses of belantamab mafodotin, longer time between doses, or a different dose-modification algorithm could provide an improved benefit-risk profile compared with the approved regimen. HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? This robust framework addressed the complex interplay between patient characteristics, pharmacokinetics, and efficacy and safety end points and allowed for simulations with dose modification. This framework concept can be applied to other drugs, end points, and clinical settings to support dose optimization and justification in an integrated benefit-risk evaluation.