Bortezomib in the treatment of AL amyloidosis: targeted therapy?

n the current issue of the journal four papers are dedicated to the treatment, and the related toxicity, of conditions caused by the deposition of mono- clonal light chains, including AL amyloidosis and light chain cast nephropathy. In particular, the paper by Kastritis et al. 1 reports, for the first time, the outstand- ing efficacy of the proteasome inhibitor bortezomib in the treatment of AL amyloidosis. Why are cells secreting amyloidogenic monoclonal proteins so sensitive to these drugs? Recent evidence indicates that the effect of bortezomib on myeloma cells cannot be completely explained by the inhibition of the transcription nuclear factor-κB (NF-κB), and that the stress of the endoplasmic reticulum (ER) linked to their function as secretory cells contributes significant- ly to their sensitivity to proteasome inhibitors. Here we discuss the possible relationships between the syn- thesis and secretion of misfolded proteins, cell stress and the role of the ubiquitin-proteasome system. A detailed understanding of these key pathways is bound to improve the care of patients with plasma cell dyscrasias, including those with AL amyloidosis. Systemic AL amyloidosis is a protein misfolding dis- ease