Bortezomib in relapsed and relapsed/ refractory multiple myeloma

Proteasome inhibition was validated as a rational therapeutic approach when bortezomib (VELCADE ^®), the first-in-class proteasome inhibitor, was approved by the Food and Drug Administration in 2003. This initial approval, which was for multiple myeloma patients who had received at least two prior therapies, and whose disease had demonstrated progression on the last of these, also made bortezomib the first new agent to be available for myeloma in over a decade. Since that time, further studies of bortezomib both alone, and as part of rationally designed, molecularly based combination regimens, have shown the versatility of this agent, and made it a universally accepted standard of care. Importantly, this use of bortezomib has been associated with ever increasing overall response rates and response qualities, and, most importantly, long-term outcome measures, including overall survival. These findings have rightfully entrenched bortezomib as one of the most important parts of our chemotherapeutic armamentarium against multiple myeloma. In this chapter, we will review the role of bortezomib as a single-agent, and in combination with other chemotherapeutics, to combat myeloma in the relapsed and relapsed/refractory settings. Also, emerging data about retreatment with bortezomib will be presented to provide insights into the possible role of this agent in the modern era, in which patients may have already been previously treated as part of induction therapy with bortezomib. Finally, approaches that show promise to overcome primary or secondary resistance to bortezomib will be examined, to determine if this agent may be of benefit in a number of myeloma settings in each individual patient.