Resistance to proteasome inhibitors and other targeted therapies in myeloma Craig T. Wallington-Beddoe, 1,2,3 Magdalena Sobieraj-Teague, 2,4 Bryone J. Kuss 2,4 and Stuart M. Pitson 1,3 1 Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia, 2 College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, 3 School of Medicine, University of Adelaide, and 4 SA Pathology, Adelaide, Australia Summary The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and established therapies. Proteasome inhibitors, immunomodulatory agents and mon- oclonal antibodies are the most well known and studied classes of novel agents targeting myeloma, with histone deacetylase inhibitors, nuclear export inhibitors and several other approaches also being actively investigated. However, in parallel with the development and clinical use of these novel myeloma therapies is the emergence of novel mecha- nisms of resistance, many of which remain elusive, particu- larly for more recently developed agents. Whilst resistance mechanisms have been best studied for proteasome inhibi- tors, particularly bortezomib, class effects do not universally apply to all class members, and within-class differences in efficacy, toxicity and resistance mechanisms have been observed. Although immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression, the unique cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within-class differences in clinical efficacy and resistance patterns. This review describes the major classes of novel therapies for myeloma, highlights the major clinical trials within each class and discusses known resistance mechanisms. Keywords: immunomodulatory agent, monoclonal antibody, myeloma, novel therapy, proteasome inhibitor, resistance mechanisms. Multiple myeloma (MM) is an incurable malignancy of plasma cells that generally occurs in older individuals with a median age at diagnosis of 69 years and a median overall survival of 6–7 years (Kumar et al, 2014; Rollig et al, 2015). With an age-adjusted incidence of six per 100 000 per year in the USA and Europe, it is one of the most common haematological cancers, however, the increased prevalence of MM in older individuals can limit the use of traditional chemotherapeutic and novel therapies due to poorer perfor- mance status and co-morbidities (Rollig et al, 2015). Over the past two decades there has been an explosion of novel agents that have dramatically improved overall response rates (ORR), progression-free survival (PFS) and overall survival (OS). Accordingly, the median OS for 2001–2005 was 4Á6 years, increasing to 6Á1 years for 2006–2010 (Kumar et al, 2014). In recent years, the introduction of novel agents into multi-drug treatment regimes has dramatically improved remission rates, however, disease relapse frequently occurs (Rollig et al, 2015). Plasma cells secrete immunoglobulin in response to infec- tion and a range of other stimuli which requires folding in the endoplasmic reticulum (ER) lumen prior to secretion from the cell, resulting in a degree of ER stress due to mis- folded protein (Vincenz et al, 2013). ER stress is heightened in MM due to the high, sustained production of monoclonal immunoglobulin and a build up of misfolded protein within the ER lumen. This ER stress activates three ER membrane stress sensors, protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcrip- tion factor 6 (ATF6) in a homeostatic process termed the Unfolded Protein Response (UPR) (Vincenz et al, 2013). Activation of the UPR results in a global reduction in protein translation and the upregulation of ER chaperones and fold- ing machinery to cope with the misfolded protein load, thereby rectifying the high ER stress levels that initiated the process. However, high sustained levels of ER stress can over- whelm the corrective capacity of the UPR, which turns from a pro-survival, homeostatic mechanism to one that commits the MM cell to apoptosis. By inhibiting the 26S proteasome and preventing the degradation of misfolded proteins, pro- teasome inhibitors induce ER stress and a terminal UPR (Vincenz et al, 2013). However, there are other mechanisms through which these agents exert their activity. Indeed, stud- ies have demonstrated the ability of proteasome inhibitors to Correspondence: Dr Craig Wallington-Beddoe, Department of Haematology, Flinders Medical Centre, Bedford Park SA 5042, Australia E-mail: craig.wallington-beddoe@sa.gov.au review ª 2018 John Wiley & Sons Ltd British Journal of Haematology, 2018, 182, 11–28 First published online 20 April 2018 doi: 10.1111/bjh.15210