A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

• Type of Material: Article
• Authors: Jesús F. San-Miguel, Centro de Investigación Biomédica en Red de Cáncer; Maria-Asunción Echeveste Gutierrez, Hospital Universitario Donostia; Ivan Spicka, Charles University Prague; María-Victoria Mateos, Instituto Biosanitario de Salamanca; Kevin Song, University of British Columbia; Michael D. Craig, West Virginia University; Joan Bladé, Institut d’Investigacions Biomèdiques August Pi i Sunyer; Roman Hajek, Ostrava University; Christine Chen, Princess Margaret Cancer Center; Alessandra Di Bacco, Millennium Pharmaceuticals, Inc.; Jose Estevam, Millennium Pharmaceuticals, Inc.; Neeraj Gupta, Millennium Pharmaceuticals, Inc.; Catriona Byrne, Millennium Pharmaceuticals, Inc.; Vickie Lu, Millennium Pharmaceuticals, Inc.; Helgi van de Velde, Millennium Pharmaceuticals, Inc.; Sagar Lonial, Emory University
• Language: English
• Date: 2018-08-31
• Publisher: Ferrata Storti Foundation
• Publication Version: Final Published Version
• Copyright Statement: ©2018 Ferrata Storti Foundation. Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3324/haematol.2017.185991
• Title of Journal or Parent Work: Haematologica
• ISSN: 0390-6078
• Volume: 103
• Issue: 9
• Start Page: 1518
• End Page: 1526
• Grant/Funding Information: This study was sponsored by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
• Keywords: PROTEASOME INHIBITOR IXAZOMIB; INITIAL TREATMENT; BORTEZOMIB; Science & Technology; Hematology; WORKING GROUP; Life Sciences & Biomedicine; STEM-CELL TRANSPLANTATION; TWICE-WEEKLY IXAZOMIB; PLUS LENALIDOMIDE-DEXAMETHASONE; OPEN-LABEL; UP DATA; TRIAL
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by Tsingle-agent ixazomib maintenance, in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma. Primary phase I objectives were to determine the safety and recommended phase II dose of ixazomib-melphalan-prednisone. The primary phase II objective was to determine the complete plus very good partial response rate. In phase I, patients were enrolled to 4 arms investigating weekly or twice-weekly ixazomib (13 28-day cycles or nine 42-day cycles) plus melphalan-prednisone. In phase II, an expansion cohort was enrolled at the recommended phase II ixazomib dose. Of the 61 patients enrolled, 26 received the recommended phase II dose (ixazomib 4.0 mg [days 1, 8, 15] plus melphalan-prednisone 60 mg/m2[days 1-4], 28-day cycles). Of 2 the 61 enrolled patients, 36 (13 of 26 in the recommended phase II dose cohort) received single-agent ixazomib maintenance (days 1, 8, 15; 28-day cycles). In phase I, 10/38 patients reported dose-limiting toxicities in cycle 1, including grade 3 and/or 4 neutropenia (n=6) and thrombocytopenia (n=4). Complete plus very good partial response rate was 48% (48% at recommended phase II dose), including 28% (22%) complete response or better; responses deepened during maintenance in 34% (33%) of evaluable patients. After median follow up of 43.6 months, median progression-free survival was 22.1 months. Adverse events were mainly hematologic events, gastrointestinal events, and peripheral neuropathy. This study demonstrates the feasibility, tolerability, and activity of ixazomib-melphalan-prednisone induction and single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma patients. clinicaltrials.gov identifier 01335685.