Our study (1) applies single-cell trajectory reconstruction to delineate the dynamic evolution of MM malignant subpopulations (C0–C3) with divergent angiogenic signatures; (2) directly link CREB3L2 TF activity to angiogenesis at the single-cell level by leveraging SCENIC‐inferred regulons; and (3) construct a prognostic signature that combines CREB3L2‐mediated transcriptional control with angiogenesis‐related gene expression. Here, CREB3L2 is linked to Miyoshi myopathy.