Proteasome inhibition represents one of the more important therapeutic targets 
in the treatment of multiple myeloma (MM), since by suppressing nuclear 
factor-κB activity, which promotes myelomagenesis, it makes plasma cells 
susceptible to proapoptotic signals. Bortezomib, the first proteasome inhibitor 
approved for MM therapy, has been shown to increase response rate and improve 
outcome in patients with relapsed/refractory disease and in the frontline 
setting, particularly when combined with immunomodulatory drugs and alkylating 
agents. Among second-generation proteasome inhibitors, ixazomib (MLN9708) is the 
first oral compound to be evaluated for the treatment of MM. Ixazomib has shown 
improved pharmacokinetic and pharmacodynamic parameters compared with 
bortezomib, in addition to similar efficacy in the control of myeloma growth and 
prevention of bone loss. Ixazomib was found to overcome bortezomib resistance 
and to trigger synergistic antimyeloma activity with dexamethasone, 
lenalidomide, and histone deacetylase inhibitors. Phase I/II studies using 
ixazomib weekly or twice weekly in relapsed/refractory MM patients suggested 
antitumor activity of the single agent, but more promising results have been 
obtained with the combination of ixazomib, lenalidomide, and dexamethasone in 
newly diagnosed MM. Ixazomib has also been used in systemic amyloidosis as a 
single agent, showing important activity in this difficult-to-treat plasma-cell 
dyscrasia. More frequent side effects observed during administration of ixazomib 
were thrombocytopenia, nausea, vomiting, diarrhea, fatigue, and rash, whereas 
severe peripheral neuropathy was rare. Here, we review the chemical 
characteristics of ixazomib, as well as its mechanism of action and results from 
preclinical and clinical trials.