Proteasome inhibition is an effective treatment strategy for multiple myeloma. 
With improving survival, attention is increasingly focusing on ease of 
administration and toxicity profile. Ixazomib is an investigational, orally 
bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or 
refractory multiple myeloma were enrolled on this phase 1 trial to evaluate 
safety and tolerability and determine the maximum tolerated dose (MTD) of 
single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD 
determination, patients were enrolled to 4 different cohorts based on 
relapsed/refractory status and prior bortezomib and carfilzomib exposure. The 
MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 
nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 
patient. Common drug-related adverse events were thrombocytopenia (43%), 
diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed 
rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine 
(18%) patients achieved a partial response or better, including 8 of 30 (27%) 
evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long 
terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This 
trial was registered at www.clinicaltrials.gov as #NCT00963820.