Multiple Myeloma is still incurable with the median survival of 3-4 years. Many novel therapies are being tested in clinical trials, with encouraging results. Velcade (bortezomib/PS-341) has shown promising clinical activity in patients with relapsed refractory myeloma. Nevertheless, the precise mechanism of action of PS-341 has not been delineated, and some patients fail to respond to PS-341 treatment. In this project, I will use two closely related cell lines - one extremely sensitive to PS-341 treatment and one very resistant, as models to determine the mechanisms of PS-341 sensitivity/resistance. Determining molecular markers of sensitivity (or resistance) will be useful in predicting responders versus non-responders to PS-341 treatment, at the same time enabling development of more focused, potent therapies, while eliminating adverse effects of current therapy.