Benchmarking of forimtamig against other TCBs in preclinical models of MM. (A-B) Fresh bone marrow aspirates from patients with NDMM were depleted of CD138⁺ plasma cells and cocultured with RPMI-8226 (6 samples enrolled), MOLP-8 (9 samples enrolled), or AMO-1 (12 samples enrolled) tumor cells with a wide range of GPRC5D and BCMA RDs at a final E:T ratio of 5:1 in the presence of increasing concentrations of forimtamig, 1+1 GPRC5D TCB, 2+1 BCMA TCB, or an untargeted TCB control antibody at 0.007 nM; expression of CD25 on CD8 TILs was measured by flow cytometry after 48 hours; baseline CD25 expression, as detected by an untargeted TCB control, is represented by the horizontal black dotted line; cytokine secretion was analyzed in the supernatant of T-cell–myeloma cell line cocultures after 36 hours; graphs summarizing the mean + standard error of the mean (SEM) expression and statistics between groups were determined by 1-way ANOVA with Tukey posttest analysis. ∗P < .05; ∗∗P < .005; ∗∗∗P < .0005; ∗∗∗∗P < .0001. (C-D) Total BM cells from 9 patients with NDMM were cultured in the presence of increasing concentrations of forimtamig, 1+1 GPRC5D TCB, 2+1 BCMA TCB, or an untargeted TCB control at 0.007 nM; expression of CD25 on CD4 and CD8 TILs was measured by flow cytometry after 36 hours; baseline CD25 expression, as detected by an untargeted TCB control, is represented by the horizontal black dotted line; and graphs summarizing the mean + SEM expression and statistics between groups were determined by 1-way ANOVA with Tukey posttest analysis. ∗P < .05; ∗∗P < .005; ∗∗∗P < .0005. (E) Total BM cells from 13 patients with NDMM were cultured in the presence of the indicated concentration of TCBs for 36 hours; graphs summarizing the mean + SEM depletion of MMPCs as calculated by the frequency of CD38⁺CD138⁺ double-positive cells in relation to untreated TCB control; graphs summarizing the mean + SEM expression and statistics between groups were determined by 1-way ANOVA with Tukey posttest analysis. ∗P < .05; ∗∗P < .005; ∗∗∗P < .0005. (F) Humanized NSG mice (huNSG) were subcutaneously implanted with 2.5 × 10⁶ NCI-H929 tumor cells and when tumors reached 200 to 250 mm³ injected once a week IV with indicated TCB doses; tumor growth was measured over time using caliper and was plotted as individual spider plots for each of the 9 animals per group; animals treated with 2+1 BCMA TCB at 10 mg/kg were taken down after 2 cycles as they reached predefined termination criteria (see “Materials and methods”). TNFα, tumor necrosis factor α.