Studies of bortezomib, thalidomide, and lenalidomide have shown promising clinical activity in relapsed/refractory multiple myeloma (MM). Bortezomib alone and in combination with other agents is associated with high response rates, consistently high rates of complete response, and a predictable and manageable profile of adverse events. Thalidomide-based regimens have also shown substantial clinical activity. The accumulating experience from ongoing trials of bortezomib/lenalidomide/dexamethasone combinations in patients who have relapsed/refractory or newly diagnosed MM will provide critical information that will determine the possible role of this combination as the basic backbone for combination regimens for management of advanced MM.