Identification of PSMB4 and PSMD4 as novel target genes correlated with 1q21 amplification in patients with smoldering myeloma and multiple myeloma

Multiple myeloma (MM) is a malignant plasma cell (PC) dyscrasia characterized by heterogeneous biological features and genetic alterations, resulting in a wide range of disease courses.1,2 Despite all the therapeutic strategies developed in the last three decades, MM is still incurable, and almost all patients will inevitably experience disease progression and eventually relapse.3 Among all the genetic abnormalities, the amplification of the 1q21 region is one of the most frequent cytogenetic abnormalities occurring in malignant PC and it has become a new prognostic factor in MM patients.4,5 The incidence of gain and/or amplification of the 1q21 locus (1q21+) increases with disease progression. It can be detected in around 30-45% of patients with smoldering MM (SMM) and newly diagnosed MM (NDMM), and in around 70% of relapsed/refractory MM patients (RRMM).6 The impact of 1q21 on disease progression at an early stage has not been widely investigated. A few studies have suggested that the acquisition of extra 1q21 copies may play a role in disease progression.7,8 In fact, SMM patients with 1q21+ may be more likely to progress to MM than patients without 1q21+.8 Recent studies have demonstrated that the 1q21 copy number has a different impact on the responsiveness to MM treatments, especially proteasome inhibition (PI).9 PI is a well-established anti-cancer treatment approach used in MM. Throughout the years, the implementation of PI drugs as part of standard MM therapy has continued to improve the quality of life and clinical outcomes of MM patients. Furthermore, additional copies of 1q21 have been associated with PI resistance and recurrence of the disease in patients with 1q21+, limiting the long-term medical utility of PI.9,10 Recent studies have demonstrated that patients with 1q21+ treated with combination treatment with bortezomib (Bor) have inferior progression-free survival and overall survival compared to patients who do not present 1q21+.11 Similar results were observed when patients harboring 1q21 ampliSeveral genes are known to be deregulated upon the amplification of the 1q21 locus;9 nonetheless, the pathogenic and their possible role as druggable targets is not fully understood. In our study, we analyzed primary MM bone marrow (BM) PC from both SMM and NDMM patients to identify genes