Fig. 1: Schema of QSP and virtual population simulation framework.

The QSP model describes the dynamic changes in MM cells over time in the BM, which provides a generalized site-of-action compartment. A BsAb engages CD3 receptors on T cells and BCMA receptors on MM cells to form BsAb-CD3-BCMA dimers and trimers. Trimers can facilitate MM cell death, activate T cells, and lead to pro-inflammatory cytokine production that helps attenuate T-cell migration out of the BM compartment. MM cells produce paraproteins such as M-protein and FLC that can be used for assessment of responses in virtual patients. MM cells can shed sBCMA both in the BM and in circulation. A BsAb can bind to sBCMA, as well as T cells in circulation in the central compartment (binding not visualized in the schematic). Model parameters and initial states are varied when the model is initiated, and a trial patient is defined as a non-informed parametrization of the model. From trial patients, we select a population of plausible patients with tumor doubling times that fall within a range supported by the literature. We then select 120 virtual patients from the plausible patient pool such that their summary efficacy endpoints and paraprotein dynamics match those of the elranatamab trial patients. We repeat this step 10 times, selecting different sets of 120 virtual patients. BM bone marrow, BsAb bispecific antibody, FLC free light chain, MM multiple myeloma, PK pharmacokinetics, QSP quantitative systems pharmacology, sBCMA soluble B-cell maturation antigen.