Critical role for cyclin D/Rb pathway in multiple myeloma. The 5 TC molecular subtypes of myeloma are characterized by either direct (solid arrow) or indirect (dashed arrow) dysregulation of a D cyclin. Cyclin D together with CDK4 and 6 is involved in G1-S cell cycle progression by phosphorylating and inactivating Rb. This reaction is inhibited by the CDK inhibitors INK4a-d. In addition to cyclin D, other members that are targeted by genetic mutation in MM are highlighted (p16 by methylation, p18 by small homozygous deletions, and Rb by monoallelelic deletion).