The obtained results contribute to provide a more comprehensive picture of the major drivers of the angiogenic switch during MM progression and of the role played by the Notch pathway: MM cells increase the expression levels of Jagged1, 2 and Notch1 and 2 receptors, promoting (1) homotypic activation of Notch signaling in MM cells that, in turn, results in the secretion of VEGF; (2) heterotypic activation of the angiogenic Notch signaling in ECs; and (3) heterotypic activation of Notch signaling in BMSCs that, in turn, boosts the secretion of VEGF, inducing a potent angiogenic signal. Here, JAG1 is linked to Miyoshi myopathy.