Myeloma is treatable but incurable because current therapies can't successfully control cancer cell division. We have identified two novel therapeutic targets that promote cancer cell division, Cdk4 and Cdk6, and demonstrated that they are completely inhibited in patient myeloma cells by PD 0332991, an orally bioactive small molecule. PD 0332991 also prevents human myeloma tumor growth in animal models, and strikingly enhances the killing of myeloma cells by other therapies. A randomized Phase I/II clinical trial for PD 0332991-Velcade will soon be initiated. This work will complement the trial and advance the development of PD 0332991-based combination therapy.