Mezigdomide in combination with menin inhibition is efficacious and can prevent and overcome MEN1 mutations in vivo. (A-B) Burden of disease assessments in the DFAM-68555 (KMT2A-AF9) and DFAM-22359 (NPM1c) PDXs. Burden of disease (percentage of CD45+ cells that were human CD45+) assessment on 9th and 20th day of treatment respectively. (A) One-way ANOVA testing between all groups for bone marrow disease burden and differentiation (percentage of human CD45+ cells that expressed CD11b and/or CD14). Differences between treatment groups shown. (B) DFAM-22359 (NPM1c) PDX. Two-way ANOVA testing between all treatmentgroups for bone marrow, spleen, and peripheral blood disease burden. No statistical difference between MEZI 0.5 mg/kg 2× daily and MEZI 3 mg/kg 1× daily (with or without revumenib), all other comparisons between groups with P ≤ .001. (C-D) DFAM-68555 PDX. (C) Leukemia-free survival analysis on left, peripheral blood leukemic burden on right; n = 10 per cohort. P values displayed are for survival differences between groups with threshold for statistical significance P = .0167 with Bonferroni correction for multiple comparisons. (D) Frequency of MEN1T349M mutation in relapsed VTP-50469 monotherapy mouse depicted with # in panel C via ddPCR. (E-F) CBAM-44728 (KMT2A-AF10) PDX. (E) Leukemia-free survival analysis: vehicle (n = 6) vs any treatment group (n = 6), P = .0007. Other P values displayed are for survival differences between groups with threshold for statistical significance P = .0083 with Bonferroni correction for multiple comparisons. (F) Frequency of MEN1T349M mutation in relapsed mice that received VTP-50469 by ddPCR; mice listed in chronological order of relapse (left-to-right). (G-H) CPCT-0023 (KMT2A-AF10) PDX. (G) Leukemia-free survival analysis: vehicle (n = 6) vs MEZI (n = 8), P = .0045; vehicle vs VTP-50469 monotherapy (n = 8) or Combination (n = 8), P < .0001. P values displayed are for survival differences between groups with threshold for statistical significance P = .0083 with Bonferroni correction for multiple comparisons. (H) MEN1 Sanger sequencing at codons corresponding to amino acid residues M327 and T349 in a mouse euthanized pre-treatment (left) and in a VTP-50469 monotherapy mouse that acquired resistance on treatment (right). (I-J) Humanized CrbnV380E/I391V C57BL/6 mice. (I) Western blot from mice treated with a single dose of MEZI at doses listed, mice euthanized 5 hours after dose, and lysis buffer added to cells 9 hours after dose. (J) White blood cell (WBC) count, lymphocyte count, and neutrophil + monocyte count after 21 days of treatment and then 1 week after end of treatment course.

Mezigdomide in combination with menin inhibition is efficacious and can prevent and overcome MEN1 mutations in vivo. (A-B) Burden of disease assessments in the DFAM-68555 (KMT2A-AF9) and DFAM-22359 (NPM1c) PDXs. Burden of disease (percentage of CD45+ cells that were human CD45+) assessment on 9th and 20th day of treatment respectively. (A) One-way ANOVA testing between all groups for bone marrow disease burden and differentiation (percentage of human CD45+ cells that expressed CD11b and/or CD14). Differences between treatment groups shown. (B) DFAM-22359 (NPM1c) PDX. Two-way ANOVA testing between all treatmentgroups for bone marrow, spleen, and peripheral blood disease burden. No statistical difference between MEZI 0.5 mg/kg 2× daily and MEZI 3 mg/kg 1× daily (with or without revumenib), all other comparisons between groups with P ≤ .001. (C-D) DFAM-68555 PDX. (C) Leukemia-free survival analysis on left, peripheral blood leukemic burden on right; n = 10 per cohort. P values displayed are for survival differences between groups with threshold for statistical significance P = .0167 with Bonferroni correction for multiple comparisons. (D) Frequency of MEN1T349M mutation in relapsed VTP-50469 monotherapy mouse depicted with # in panel C via ddPCR. (E-F) CBAM-44728 (KMT2A-AF10) PDX. (E) Leukemia-free survival analysis: vehicle (n = 6) vs any treatment group (n = 6), P = .0007. Other P values displayed are for survival differences between groups with threshold for statistical significance P = .0083 with Bonferroni correction for multiple comparisons. (F) Frequency of MEN1T349M mutation in relapsed mice that received VTP-50469 by ddPCR; mice listed in chronological order of relapse (left-to-right). (G-H) CPCT-0023 (KMT2A-AF10) PDX. (G) Leukemia-free survival analysis: vehicle (n = 6) vs MEZI (n = 8), P = .0045; vehicle vs VTP-50469 monotherapy (n = 8) or Combination (n = 8), P < .0001. P values displayed are for survival differences between groups with threshold for statistical significance P = .0083 with Bonferroni correction for multiple comparisons. (H) MEN1 Sanger sequencing at codons corresponding to amino acid residues M327 and T349 in a mouse euthanized pre-treatment (left) and in a VTP-50469 monotherapy mouse that acquired resistance on treatment (right). (I-J) Humanized CrbnV380E/I391V C57BL/6 mice. (I) Western blot from mice treated with a single dose of MEZI at doses listed, mice euthanized 5 hours after dose, and lysis buffer added to cells 9 hours after dose. (J) White blood cell (WBC) count, lymphocyte count, and neutrophil + monocyte count after 21 days of treatment and then 1 week after end of treatment course.

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