Mezigdomide monotherapy is efficacious in PDX models of KMT2A-r and NPM1c AML in vivo. (A) DFAM-68552 (KMT2A-AF6) PDX. Median survival: vehicle, 118.5 days (n = 8); MEZI, 152 days (n = 7); P = .016. Peripheral blood leukemia burden: P < .05 for all time points after day 0. (B) DFAM-68555 (KMT2A-AF9) PDX. Median survival: vehicle, 29 days (n = 8); lenalidomide (LEN), 53.5 days (n = 8); MEZI, 66 days (n = 8); vehicle vs LEN, P = .0032; vehicle vs MEZI, P = .0002; LEN vs MEZI, P < .0001. Peripheral blood leukemia burden: vehicle vs LEN or MEZI (P < .05 for day 10 time point); LEN vs MEZI (P < .05 for all time points assessed). (C) MSK-017D (KMT2A-AF9) PDX. Median survival: vehicle, 172.5 days (n = 8); LEN, 224 days (n = 7); MEZI, 287 days (n = 7); vehicle vs LEN, P = .0004; vehicle vs MEZI, P = .0001; LEN vs MEZI, P = .0198 (threshold for statistical significance P = .0167 with Bonferroni correction for multiple comparisons). Peripheral blood leukemia burden depicted from beginning of first treatment period to beginning of second treatment period: vehicle vs LEN (P < .05 for days 12, 20, 29, 44, 61, and 105); vehicle vs MEZI (P < .05 for all time points shown after day 0); and LEN vs MEZI (P < .05 for days 44 and beyond). (D) DFAM-16835 (NPM1c) PDX. Median survival: vehicle, 58 days (n = 7); MEZI, 135 days (n = 8); P < .0001. Peripheral blood leukemia burden: P < .05 for all time points after day 0. (E) CBAM-44728 (KMT2A-AF10) PDX. Median survival: vehicle, 59 days (n = 5); MEZI, 137 days (n = 5); P = .0198. (A-E) Survival analyses by log-rank (Mantel-Cox) test for survival curves. Peripheral blood leukemia burden quantified as percentage of CD45⁺ cells (mouse + human) that were human CD45⁺ and analyzed by 2-way ANOVA with Tukey multiple comparisons test or multiple t tests depending on number of treatment groups. The shaded blue area represents the treatment period.