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
San-Miguel JF (1), Echeveste Gutierrez MA (2), Špicka I (3), Mateos MV (4), Song K (5), Craig MD (6), Bladé J (7), Hájek R (8), Chen C (9), Di Bacco A (10), Estevam J (10), Gupta N (10), Byrne C (10), Lu V (10), van de Velde H (10), Lonial S (11).
(1) Clinica Universidad de Navarra, Centro Investigación Medica Aplicada (CIMA), El Instituto de Investigación Sanitaria de Navarra (IDISNA), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Pamplona, Spain
(2) Hospital Universitario Donostia, San Sebastián, Spain.
(3) 1Medical Department - Clinical Department of Haematology, First Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic.
(4) Hospital Universitario de Salamanca, Instituto Biosanitario de Salamanca (IBSAL), Spain.
5 Division of Hematology, University of British Columbia, Vancouver, BC, Canada.
(6) Department of Medicine, West Virginia University, Morgantown, WV, USA.
(7) Department of Hematology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.
(8) Department of Haematooncology, University Hospital Ostrava, Faculty of Medicine, Ostrava University, Czech Republic.
(9) Cancer Clinical Research Unit, Princess Margaret Cancer Center, Toronto, ON, Canada.
(10) Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Atlanta, GA, USA.
(11) Winship Cancer Institute of Emory University, Atlanta, GA, USA.
This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by single-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 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.
CITATION Haematologica. 2018 Sep;103(9):1518-1526. doi: 10.3324/haematol.2017.185991. Epub 2018 Jun 28