Conventional therapy of MM with oral melphalan and pred-nisone was developed in the 1960s, results in median overall survival of about 36 months, and is still the standard for patients who are not treated with high-dose (200 mg) melphalan and stem cell support. Two randomized controlled studies in patients under the age of 65 have shown that this latter therapy extends median overall survival by about 12 months. Recently two new agents, thalidomide (1999) and bortezomib (2003) have shown remarkable activity in MM and are rapidly changing the management and outcome for patients. Both of these agents have unique and novel mechanisms of action, appear to be more effective in MM than in other malignancies, and are postulated to target both the MM cell, and its supporting microenvironment. Thalidomide was originally marketed as a sedative, but was withdrawn in the 1960s because of terato-genicity. It has many activities, including inhibition of angio-genesis, inhibition of TNF-a signaling, and T-cell stimulatory activity. Several derivative compounds have been developed to overcome the devastating side effects, and two of these are showing promise in early clinical trials: CC5013 (Revimid) and CC4047 (Actimid). Bortezomib is the first of a new class of drug that targets the proteasome. Cancer cells in general, and MM cells in particular, appear to be particularly dependent on proteasome function, and reliably undergo apoptosis when its function is inhibited by 60% or more. Although the exact nature of the critical proteins that accumulate is still unclear, some of the implicated candidates include cell cycle regulated proteins, p53-mdm2, NfKB-IkB and caspases. An important challenge for the future will be determining the critical pathways by which these novel therapies exert their actions in MM and developing a rational approach to their clinical development. The long-term promise is that a detailed knowledge of the molecular pathogenesis, together with the availability of specific targeted therapies, will allow the individualized tailoring of a non-toxic cocktail that will effectively control the disease and its devastating complications.
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