BACKGROUND: The combination of bortezomib, lenalidomide, and dexamethasone is a 
highly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an 
investigational, oral, proteasome inhibitor with promising anti-myeloma effects 
and low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess 
the safety, tolerability, and activity of ixazomib in combination with 
lenalidomide and dexamethasone in newly diagnosed multiple myeloma.
METHODS: We enrolled patients newly diagnosed with multiple myeloma aged 18 
years or older with measurable disease, Eastern Cooperative Oncology Group 
performance status 0-2, and no grade 2 or higher peripheral neuropathy, and 
treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 
1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, 
followed by maintenance therapy with ixazomib alone. In phase 1, we gave 
patients escalating doses of ixazomib (1·68-3·95 mg/m(2)) to establish the 
recommended dose for phase 2. The primary endpoints were maximum tolerated dose 
for phase 1, and the rate of very good partial response or better for phase 2. 
Safety analyses were done in all patients who received at least one dose of 
study drug; efficacy analyses were done in all patients who received at least 
one dose of study drug at the phase 2 dose, had measurable disease at baseline, 
and had at least one post-baseline response assessment. This study is registered 
at ClinicalTrials.gov, number NCT01217957.
FINDINGS: Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to 
phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 
1: one at a dose of ixazomib of 2·97 mg/m(2) and three at 3·95 mg/m(2). The 
maximum tolerated dose of ixazomib was established as 2·97 mg/m(2) and the 
recommended phase 2 dose was 2·23 mg/m(2), which was converted to a 4·0 mg fixed 
dose based on population pharmacokinetic results. Grade 3 or higher adverse 
events related to any drug were reported in 41 (63%) patients, including skin 
and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight 
patients, 12%), and thrombocytopenia (five patients, 8%); drug-related 
peripheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five 
patients discontinued because of adverse events. In 64 response-evaluable 
patients, 37 (58%, 95% CI 45-70) had a very good partial response or better.
INTERPRETATION: The all-oral combination of weekly ixazomib plus lenalidomide 
and dexamethasone was generally well tolerated and appeared active in newly 
diagnosed multiple myeloma. These results support the phase 3 trial development 
of this combination for multiple myeloma.
FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda 
Pharmaceutical International Company.