Linking the activity of bortezomib in multiple myeloma and autoimmune diseases.

Since their introduction to the clinic 10 years ago, proteasome inhibitors have become the cornerstone of anti-multiple myeloma therapy. Despite significant progress in understanding the consequences of proteasome inhibition, the unique activity of bortezomib is still unclear. Disappointing results from clinical trials with bortezomib in other malignancies raise the question of what makes multiple myeloma so sensitive to proteasome inhibition. Successful administration of bortezomib in various immunological disorders that exhibit high antibody production suggests that the balance between protein synthesis and degradation is a key determinant of sensitivity to proteasome inhibition because a high rate of protein production is a shared characteristic in plasma and myeloma cells. Initial or acquired resistance to bortezomib remains a major obstacle in the clinic as in vitro data from cell lines suggest a key role for the β5 subunit mutation in resistance; however the mutation was not found in patient samples. Recent studies indicate the importance of selecting for a subpopulation of cells that produce lower amounts of paraprotein during bortezomib therapy.