The proteasome inhibitor Bortezomib is used to treat multiple myeloma (MM). 
Bortezomib inhibits protein degradation by inactivating proteasomes' 
active-sites. MM cells are exquisitely sensitive to Bortezomib - exhibiting a 
low-nanomolar IC(50) - suggesting that minimal inhibition of degradation 
suffices to kill MM cells. Instead, we report, a low Bortezomib concentration, 
contrary to expectation, achieves severe inhibition of proteasome activity in MM 
cells: the degree of inhibition exceeds what one would expect from the small 
proportion of active-sites that Bortezomib inhibits. Our data indicate that 
Bortezomib achieves this severe inhibition by triggering secondary changes in 
proteasome structure that further inhibit proteasome activity. Comparing MM 
cells to other, Bortezomib-resistant, cancer cells shows that the degree of 
proteasome inhibition is the greatest in MM cells and only there leads to 
proteasome stress, providing an explanation for why Bortezomib is effective 
against MM but not other cancers.