Combination of forimtamig with CELMoDs. (A,C) Humanized NSG (huNSG) mice were subcutaneously implanted with NCI-H929 tumor cells and when tumors reached 200 mm³ injected once weekly IV with forimtamig at 0.1 mg/kg or combination with oral dosing of iberdomide at 10 mg/kg 5 times weekly (5q7d) starting at C1D2 or C3D2; tumor volume of individual mice was measured over time using a caliper; treatment was stopped after 7 forimtamig injections and mice were monitored for at least 2 additional weeks to check for tumor relapse; each group included 10 animals. (B,D) Serum was harvested from n = 5 animals 48 hours after C1 and C3 forimtamig dosing and 24 hours after iberdomide dosing and cytokine levels were measured by bioplex analysis; and graphs summarizing the mean ± SEM expression and statistical differences between multiple groups were determined by 1-way ANOVA with Tukey posttest analysis. ∗P < .05; ∗∗P < .005; ∗∗∗P < .0005. (E) huNSG mice were subcutaneously implanted with NCI-H929 tumor cells and, when tumors reached 200 mm³, injected once weekly with step-up doses of forimtamig at 0.0005, 0.002, and 0.04 mg/kg or combination with oral administration of 1 mg/kg or 3 mg/kg mezigdomide once weekly (1q7d), thrice weekly (3q7d), or 5 times weekly (5q7d). Tumor volume was measured over time using a caliper; treatment was stopped after 7 forimtamig injections and mice were monitored for at least 2 additional weeks to check for tumor relapse; each group included 10 animals. (F) Serum was harvested from n = 5 animals 48 hours after C1D1, C1D8, and C1D15 forimtamig dosing and 24 hours after mezigdomide dosing and cytokine levels were measured by bioplex analysis; graphs summarizing the mean ± SEM expression and statistical differences between multiple groups were determined by 1-way ANOVA with Tukey posttest analysis. ∗P < .05; ∗∗P < .005; ∗∗∗P < .0005. (G) NCI-H929 tumors were isolated from 3 animals of groups A, B, and F (supplemental Figure 7A) 48 hours after 0.002 mg/kg SUD and intratumoral T-cell number and phenotype was analyzed by flow cytometry; graphs summarizing the mean ± SEM expression and statistical differences between multiple groups were determined by 1-way ANOVA with Tukey posttest analysis. ∗P < .05; ∗∗P < .005; ∗∗∗P < .0005. (H-I) Total BM cells from 6 patients with NDMM were cultured in the presence of 0.1 nM forimtamig, 0.1 to 10 nM mezigdomide, or the combination for 96 hours and tumor cell lysis and expression of CD69, CD25, HLADR, CD107a, LAG-3, and PD-1 by CD8 lymphocytes was measured by flow cytometry; untreated and untargeted-TCB treated samples served as reference controls; graphs summarizing the mean ± SEM expression and statistical differences between multiple groups were determined by 2-way ANOVA with Tukey posttest analysis; and statistical analysis for activation markers was referenced against forimtamig monotherapy. ∗P < .05; ∗∗P < .005; ∗∗∗P < .0005; ∗∗∗∗P < .0001. MIG, monokine induced by gamma-interferon; MIP-1a, macrophage inflammatory protein-1 alpha; TNF-α, tumor necrosis factor α.