Proliferating MM cells generate a hypoxic milieu within the TME and produce various pro-angiogenic modulators including hypoxia inducible factor-1α (HIF-1α), VEGF, bFGF, HGF, platelet-derived growth factor (PDGF), angiopoietin-1 (Ang-1), osteopontin, MMPs (MMP-2 and MMP-9), and heparanase, all of which contribute to EC proliferation and migration, ECM degradation, and neovascularization (29–32). This evidence concerns the gene HPSE and Miyoshi myopathy.