The oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double-blind, placebo-controlled Phase III TOURMALINE-MM1 study of ixazomib-Rd (IRd) versus placebo-Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression-free survival versus placebo-Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo-Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long-term IRd treatment. Safety data from TOURMALINE-MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.

Alfred Health Monash University Melbourne Australia

Dana Farber Cancer Institute Boston MA USA

Department of Haematology and Bone Marrow Transplantation Tel Aviv Medical Centre Tel Aviv Israel

Department of Haematology and Stem Cell Transplantation St István and St László Hospital Semmelweis University Budapest Hungary

Department of Haematology UMC Utrecht Cancer Centre Utrecht The Netherlands

Department of Haematooncology University Hospital Ostrava Ostrava Czech Republic

Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA USA

Division of Hematology and Oncology Froedtert Hospital and the Medical College of Wisconsin Milwaukee WI USA

Division of Hematology Mayo Clinic Rochester MN USA

McGill University Health Center Royal Victoria Hospital Montreal Canada

Millennium Pharmaceuticals Inc a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Cambridge MA USA

Servicio de Hematología Hospital Universitario de Salamanca Salamanca Spain

Universitätsklinik Würzburg Medizinische Klinik und Poliklinik 2 Würzburg Germany

University Hospital Hôtel Dieu Nantes France

University of Perugia SC Oncoematologia AO S Maria di Terni Terni Italy

Wellington Blood and Cancer Centre Wellington Regional Hospital Wellington New Zealand

Wilhelminenspital der Stadt Wien Vienna Austria

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