Our studies demonstrate that Erk1/2i + CDK4/6i inhibited MM cell survival and induced mitochondrial-dependent apoptosis, associated with downregulation of key target molecules c-myc, p-RSK, p-S6, p-RB, and E2F1 in MM cell lines and patient cells with complex genetic profiles. This evidence concerns the gene E2F1 and Miyoshi myopathy.