Molecular profiles of proteasome inhibition in plasma cell dyscrasias

Multiple myeloma and Waldenström's macroglobulinemia are 2 presently incurable plasma cell dyscrasias with clinicopathological similarities, as well as distinct differences. Bortezomib, a prototypic boronic dipeptide proteasome inhibitor, was recently approved for the treatment of relapsed refractory multiple myeloma. Its efficacy in this poor prognosis clinical setting has raised the possibility that proteasome inhibition may also be suitable for the treatment of other plasma cell disorders, such as Waldenstrom's macroglobulinemia. Herein, we review the principles underlying the use of gene expression profiling for delineation of the mechanisms of action of bortezomib against plasma cell dyscrasias, as well as for identification of potential predictors of the clinical activity of bortezomib. We also discuss how transcriptional profile data from tumor cells of bortezomib-treated patients can help build preclinical predictors of responsiveness to proteasome inhibition with the ultimate goal to develop prognostic models that will facilitate the rational design of a patient-specific therapeutic algorithm for bortezomib treatment.