Ixazomib is the first investigational oral proteasome inhibitor to be studied 
clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple 
myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, 
thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) 
received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day 
cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) 
occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 
patients received in 4 expansion cohorts. Patients received a median of 4 cycles 
(range, 1-39); 18% received ≥12 cycles. Eighty-eight percent had drug-related 
adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), 
and rash (40%); drug-related grade ≥3 events included thrombocytopenia (37%) and 
neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% 
(no grade ≥3). Two patients died on the study (both considered unrelated to 
treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma 
exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 
response-evaluable patients, 15% achieved partial response or better (76% stable 
disease or better). These findings have informed the subsequent clinical 
development of ixazomib in multiple myeloma. This trial was registered at 
www.clinicaltrials.gov as #NCT00932698.