A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory light-chain (AL) amyloidosis

Vaishali Sanchorawala, Giovanni Palladini, Vishal Kukreti, Jeffrey A. Zonder, Adam D. Cohen, David C. Seldin, Angela Dispenzieri, Arnaud Jaccard, Stefan O. Schönland, Deborah Berg, Huyuan Yang, Neeraj Gupta, Ai-Min Hui, Raymond L. Comenzo and Giampaolo Merlini

Key points

  • In this often frail population, weekly ixazomib 4.0 mg, the dose used in MM, was generally well tolerated with a manageable safety profile.

  • Ixazomib is active in RRAL patients with encouraging hematologic (52%) and organ (56%) response rates.


This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory AL amyloidosis (RRAL). Ixazomib was administered to adult patients with RRAL after ≥1 prior line of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1–4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naïve and PI-exposed patients) at the maximum tolerated dose (MTD). 27 patients were enrolled; 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities; 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade ≥3 AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up 16.9 months). Weekly oral ixazomib appears to be active in RRAL patients, with a generally manageable safety profile. The study was registered at; NCT01318902. A phase 3 study is ongoing (NCT01659658).

  • Submitted March 3, 2017.
  • Accepted May 18, 2017.