The ubiquitin-proteasome pathway has been validated as a therapeutic target for mulfiple myeloma (MM) by our group and others through the demonstrafion ofthe acfivity of bortezomib in both the relapsed/refractory and up-ft-ont settings. Because of its broad impact on intracellular proteolysis, however, this proteasome inhibitor induces anfi-apoptotic effects at the molecular level that decrease its efficacy, and at the clinical level it induces toxicifies such as peripheral neuropathy that limit its ufility. A more targeted approach, therefore, such as by inhibiting a specific E3 ubiquitin ligase responsible for ubiquitinafion of only a small subset of client proteins, would likely be more effective and better tolerated. We have obtained evidence that second-generation small molecule inhibitors ofthe HDM-2 E3 ligase, which is best known for its role in p53 ubiquitinafion, induce anfi-proliferative effects in MM models irrespective of their p53 status; that these agents activate a p53-dependent type I cell death program, as well as p53-independent type II cell death, or autophagy; and that they interact synergistically with different classes of chemotherapeutics in wild type and mutant p53 backgrounds. These and other findings led us to our central hypothesis, that HDM-2 inhibitors are promising novel agents that can be used as chemosensitizers in a p53 status-adapted approach to personalize MM therapy. To evaluate this possibility, and to translate these agents into the clinic, our proposed specific aims will: 1. Further define the molecular mechanisms of acfion of HDM-2 inhibitors in MM, including their impact on type I and II cell death, and the role of p53 and HDM-2 in these processes; 2. Delineate the pathways by which HDM-2 inhibitors sensifize MM to type l-inducing chemotherapeutics such as anthracyclines, death receptor agonists, and Bcl-2 inhibitors in wild type p53 models, and to mTOR inhibitors in mutant p53 models; and 3. Pilot an HDM-2 inhibitor as a single agent in a phase I study evaluafing its impact and mechanism of cell death induction in patients with relapsed/refractory MM in preparafion for later studies of an individualized p53 status-adapted approach.