Multiple myeloma (MM) affects 15,000 new patients annually in the US, with 50,000 total patients, and remains incurable. Our preliminary in vitro and animal studies suggest a role for MM-host interactions in regulating MM cell growth, drug resistance, and migration in the bone marrow. Importantly, treatment strategies which target mechanisms whereby MM cells grow and survive in the bone marrow, including thalidomide and its potent immunomodulatory derivatives and proteasome inhibitor PS-341, can overcome classical drug resistance in preclinical and early clinical studies.