Kinetics of Nirogacestat-Mediated Increases in B-cell Maturation Antigen on Plasma Cells Inform Therapeutic Combinations in Multiple Myeloma.

ABSTRACT: B-cell maturation antigen (BCMA) is the target of several investigational and approved drugs for multiple myeloma. BCMA expressed on plasma cells (PC) and multiple myeloma cells is cleaved by the enzyme γ-secretase, reducing membrane-bound BCMA (mbBCMA) receptor density. γ-Secretase inhibitors (GSI) have been shown to increase mbBCMA density and may enhance efficacy of BCMA-targeted therapies. The pharmacodynamic profile of the GSI nirogacestat was evaluated in multiple myeloma cell lines and a phase I study in healthy volunteers. In multiple myeloma cell lines, mbBCMA density and soluble BCMA concentrations were measured before and after short-duration nirogacestat exposure and at serial time points following washout. In the phase I study, 23 participants were administered a single oral dose of nirogacestat 50, 150, or 300 mg or repeated doses of 100 mg every 12 hours for up to 48 hours; mbBCMA density on PCs (from whole blood and bone marrow) and nirogacestat plasma concentrations were measured at baseline and postdose. After single-dose administration, serum nirogacestat concentrations rapidly increased (Tmax ∼1 hour), and a two-compartment model with linear absorption and clearance best described nirogacestat pharmacokinetics. In multiple myeloma cells and healthy volunteers’ PCs, nirogacestat resulted in rapid and robust increases in mbBCMA density, with increases up to 20-fold within 4 to 8 hours of exposure. Concomitant decreases in soluble BCMA were observed. Nirogacestat is currently being evaluated in combination with several BCMA-directed therapeutic agents in patients with multiple myeloma. Elucidating the kinetics of BCMA in response to nirogacestat is key to guiding dosing and therapeutic strategies in multiple myeloma.

SIGNIFICANCE: GSIs can enhance multiple myeloma therapies targeting BCMA by increasing mbBCMA on plasma cells. In response to the GSI nirogacestat, mbBCMA rapidly and robustly increased in vitro and in vivo. Elucidating nirogacestat's effects on BCMA kinetics will guide potential multiple myeloma dosing strategies.