Quantitative Systems Pharmacologist Pfizer, United States
Disclosure(s):
Kamrine Poels, PhD: No relevant disclosure to display
Objectives: Bispecific antibodies (BsAb) are a rapidly evolving treatment modality for multiple myeloma (MM). Elranatamab, an approved BsAb, forms an immune synapse between T-cells via surface marker CD3 and B-cell maturation antigens (BCMA) on tumor cells1. Membrane-bound BCMA can undergo shedding from the cell surface, leading to circulation of soluble BCMA (sBCMA), which is associated with disease burden and reduces drug exposure and may impact efficacy. Establishing a recommended dose based on non-clinical and early clinical data can be challenging especially for drugs with complex dynamics such as BsAb and for a disease with a shed target. We use QSP to form a framework that can help inform dosing decisions for elranatamab monotherapy in relapsed/refractory multiple myeloma (RRMM) patients.
Methods: Here, we develop a mathematical model that captures the mechanism of action of elranatamab and corresponding disease dynamics for MM patients using datasets from studies MagnetisMM-1 and MagnetisMM-32-3. Important properties affecting disease response and progression, such as shedding of BCMA receptors, drug-binding to sBCMA, and T-cell exhaustion are accounted for. We also form virtual populations (VPop) that represent variability in biological, pharmacological, and tumor-related parameters from clinical participants to inform clinical dose-response relationships, and to identify biological determinants of clinical response.
Results: Simulations predict 76 mg weekly (QW) as the optimal dose regimen that would benefit most RRMM patients, especially those with high sBCMA. Additionally, the simulations suggest a left-shift in the bell-shaped dose-response curves among virtual responders, supporting gradual reduction of the dosing intensity after persistent response. Specifically, our model advocated a dosing transition from QW to every 2 weeks (Q2W).
Conclusions: Our mechanistic model supported the dosing regimen in the phase 2 MagnetisMM-3 study. This modeling platform continues to be used to inform dosing recommendations for elranatamab studies with combination treatments or in earlier treatment lines. Additionally, this framework can be expanded and applied to the next generation of CD3 BsAbs.
