Alteration of RB pathway by both early and late pathogenic events. An early pathogenic event in tumors from seven of the translocation and cyclin D (TC) groups is dysregulation of one of the three CYCLIN D genes, either as a consequence of an Ig TLC (solid arrow), or by an unknown mechanism (dashed arrow). Increased expression of one of the Cyclin D proteins facilitates activation of CDK4 (or CDK6), which then phosphorylates and inactivates Rb so that E2F can facilitate G1>S cell cycle progression. This reaction is regulated by CDK inhibitors (INK4a-d), so that increased proliferation of some multiple myeloma (MM) tumors occurs only after a late oncogenic event that inactivates Rb or p18INK4c.