Multiple myeloma causes more than 10,000 deaths each year in the USA. The average survival is approximately four years warranting the development of innovative treatment regimens. Interventions with radiation can provide significant clinical benefit for myeloma patients as myeloma cells are highly sensitive to radiation. Our recent pre-clinical results with tissue culture lines, cells from patients with active myeloma, and using a myeloma mouse model demonstrate that the drug PS-341 is a potent and selective radiosensitizer. Studies have shown that owing to genomic instability associated with multiple myeloma, recently developed drugs including PS-341 (Bortezomib) are effective in only in 20-30% of patients. It is therefore important to search other drugs that can selectively enhance the toxicity of radiotherapy to myeloma cells. We now propose to evaluate a panel of four drugs in combination with radiation. We hypothesize that a clinical benefit to myeloma patients can be achieved by combining moleculary-targeted drugs with radiotherapy. In this grant we propose to combine such drugs with radiotherapy for designing a non-myeloablative (does not require stem cell rescue) Phase I/II treatment regimen for multiple myeloma.