Quantitative clinical pharmacology analysis to support the dose escalation of elranatamab + nirogacestat in the MagnetisMM-4 study

Abstract Background Elranatamab (ELRA) is a bispecific antibody (BsAb) targeting B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells. In the phase 2 MagnetisMM-3 study (NCT04649359), ELRA demonstrated deep, durable responses with manageable safety in patients with relapsed or refractory multiple myeloma (RRMM) and no prior BCMA-directed therapy (Lesokhin et al, Nat Med 2023). MagnetisMM-4 (NCT05090566) is a phase 1b/2 umbrella trial evaluating ELRA in combination with other anti-cancer treatments for patients with MM. Gamma-secretase inhibitors (GSIs) block BCMA cleavage, potentially enhancing efficacy of BCMA-directed therapy (Pont et al, Blood 2019; Portuguese et al, Blood 2024). Here, we present the interim quantitative clinical pharmacology analysis to inform dose escalation of the combination of ELRA plus nirogacestat (NIRO), a GSI. Methods At the time of this analysis, three dose escalation cohorts had been completed, which evaluated NIRO 100 mg BID plus ELRA 4 mg weekly (dose level [DL] 1), plus ELRA 12 mg QW (DL2), and plus ELRA 32 mg QW (DL3). Pharmacokinetic data of ELRA plus NIRO were analyzed in comparison with their monotherapy profiles to explore potential drug-drug interaction (DDI). Dose-response analysis for safety was performed to inform the selection of further NIRO doses to mitigate the gastrointestinal toxicity. A quantitative systems pharmacology (QSP) model leveraging data across other ELRA clinical trials and literature data on BCMA BsAb plus GSI combinations was used to predict the efficacy of various dose combinations of ELRA plus NIRO. Results Eighteen patients received the combination treatment at three dose levels (DL1, n=2; DL2, n=6; DL3, n=10). The dose-normalized exposure of ELRA plus NIRO generally appeared comparable to their monotherapy profiles suggesting absence of DDI. However, NIRO exposure showed high inter-individual variability. The majority of patients (89%, 16/18) had baseline sBCMA below 100 ng/mL. In responders (n=10), the free sBCMA level generally dropped rapidly following ELRA administration. NIRO dose reductions from 100 mg BID to 100 mg QD were reported in 10/18 patients (55.6%), while 16.7% (3/18) of the patients on 100 mg QD further reduced the dose to 50 mg QD. The gastrointestinal adverse events (normalized by treatment duration) were >2-fold lower after dose reductions to 100 mg QD. The QSP model predicted favorable overall response rate for lower baseline sBCMA patients both in NIRO 100 mg QD with either ELRA 32 mg QW or 76 mg QW. Patients with high baseline sBCMA are predicted to have the greatest gain of efficacy with the ELRA plus NIRO combination vs ELRA monotherapy. If tolerable, the QSP model predicts that ELRA 76 mg QW plus NIRO 100 mg QD will achieve superior efficacy compared with ELRA 32 mg QW plus NIRO 100 mg QD in high sBCMA patients. Conclusions The pharmacokinetic, pharmacodynamic, dose-response analysis, and QSP modeling support NIRO 100 mg QD to improve safety and further dose escalation of ELRA to 76 mg QW to maximize efficacy in patients with high baseline disease burden/sBCMA.