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.