Evaluating Combination Dosing Regimens of the Anti-BCMA ADC Belantamab Mafodotin and Monoclonal Antibody Belantamab in Relapsed or Refractory Multiple Myeloma Using QSP modeling

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The poster was presented at ACoP 2026

Authors: Jingqi Q. X. Gong (1), Galina Lebedeva (2), Alexandra Diakonova (2), Geraldine Ferron-Brady (1), Oleg Demin (2), John D. Clements (1)

Affiliation: (1) GSK, Upper Providence, PA, USA, (2) InSysBio

Objectives: A quantitative systems pharmacology (QSP) model has been developed that characterizes B-cell maturation antigen (BCMA) target engagement and the downstream pharmacology of anti BCMA agents in relapsed or refractory multiple myeloma (RRMM). The objective was to inform potential dosing regimens for the coadministration of an anti BCMA antibody drug conjugate (ADC; belantamab mafodotin) and an anti BCMA monoclonal antibody (mAb; belantamab) by evaluating predicted target engagement/receptor occupancy (RO) and downstream pharmacology.

Methods: A QSP model was constructed to represent 1) BCMA target expression and turnover, 2) systemic pharmacokinetics (PK) of the anti-BCMA agents, 3) drug–target binding and internalization, and 4) downstream pharmacology with regards to M-protein. The model was calibrated and validated against published and internal data from RRMM studies of anti BCMA ADC (belantamab mafodotin)[1] and anti BCMA mAb (SEA-BCMA[2] and belantamab[3,4]). Simulations assessed simultaneous and staggered dosing regimens to predict the effects of coadministration on ADC systemic exposure, target engagement, and biomarker changes. Sensitivity analyses explored the impact of variability in target expression, binding affinities, and PK parameters.

Results: Model simulations suggest that simultaneous dosing maintained target engagement while avoiding large increases in ADC systemic exposure compared to ADC alone. Across a wide range of tested regimens and parameter variability, the presence of the anti BCMA mAb produced minimal displacement of the ADC from target sites. Simulations across a range of combination doses point to a less than additive effect on M-protein level compared to the effect delivered by single agents. The simulations also predicted RO of both anti-BCMA ADC and anti-BCMA mAb under various combination regimens, providing mechanistic evidence for the potential contributions of both agents. The simulations showed that a decrease in M-protein level was associated with higher RO for both ADC and anti-BCMA mAb, with the naked antibody being the dominant contributor to RO across all tested doses given the higher dose. Sensitivity analyses indicated that these conclusions were robust to plausible inter patient variability in BCMA levels and drug PK/PD properties.

Conclusions: A validated QSP model for BCMA targeted therapies in RRMM predicted that simultaneous, continued coadministration of belantamab mafodotin and belantamab achieves target engagement with only modest predicted increases in systemic ADC exposure. These modeling results enhance the understanding of these BCMA-targeting agents in clinical development and may inform combination study design decisions. The approach illustrates how mechanistic, model-based evaluations can inform combination strategies and optimize clinical program planning for similar BCMA-targeted ADC/naked mAb dosing strategies.

Funding: GSK

Citations: [1] Nooka A, et al. Hemasphere. 2023;7(Suppl):27–28.

[2] Hoffman JE, et al. Blood. 2022;140(Suppl 1):10160–10162.

[3] Quach H, et al. J Clin Oncol. 2025;43(Suppl 16):7550.

[4] Quach H, et al. Presented at the 2025 European Hematology Association Congress. Abstract PF783.