Multiple myeloma (MM) is still incurable B-cell malignancy affecting more than 14,000 Americans annually. Myeloma tumor cells can survive even the most aggressive treatment available today, leading to disease relapses. The long-term goal of this project is to develop more effective cytostatic therapies to eradicate myeloma cells. We recentiy made a novel and exciting discovery that anti-p2-microglobulin (P2M) monoclonal antibodies (mAbs) had strong apoptotic activity in both established myeloma cell lines and primary myeloma cells from patients. The mAbs selectively target and kill myeloma cells in coculture with normal hematopoietic cells without damaging normal blood cells, including CD34+ stem cells. Anti-p2M mAbinduced apoptosis in myeloma cells were not blocked by soluble p2M (10-100 ng/mL, 3- to 30-fold higher than that in most MM patients, which are about 3 jag/mL), IL-6, or other myeloma growth and survival factors. The mAbs induced cell death via inhibiting P13K/Akt and ERK, activating JNK, and compromising mitochondrial integrity, leading to cytochrome c release and activation of a caspase-9-dependent cascade. Furthermore, the mAbs were also active and therapeutic in vivo in xenograft mouse models of myeloma. Thus, we hypothesize that anti-p2M mAbs may be used as therapeutic agents to treat patients with MM. This hypothesis will be tested by the following aims. Aim 1 will examine the mechanisms of anti-p2M mAbinduced apoptosis in myeloma cells. Using normal plasma or B cells as controls, we will define the role of surface MHC class I and class l-like molecules in these responses, and examine surface proteins binding to, the downstream kinases, and intracellular signaling and apoptosis pathways induced by anti-p2M mAbs. Aim 2 will utilize immune effector cells or molecules to enhance the efficacy of anti-p2M mAbs, Aim 3 will develop strategies to enhance the efficacy of anti-p2M mAbs to induce apoptosis in myeloma cells by combining with novel antimyeloma agents, and Aim 4 will perform pre-clinical and clinical studies to examine the safety and toxicity profiles of the mAbs.