PSME3 and PSME4 are drug-resistance genes and are associated with inferior outcomes in myeloma patients. (a)The clinical significance of PSME3 and PSME4 in the GEO datasets of MM patient data was investigated. The expression of PSME3 and PSME4 was compared in plasma cells from healthy donors (NPC, n=22), individuals with monoclonal gammopathy of undetermined significance (MGUS, n=44), individuals with smoldering multiple myeloma (SMM, n=12) and newly diagnosed MM patients (n=351) from the total therapy 2 (TT2) datasets (GSE5900 & GSE2658). (b) The levels of PSME3 and PSME4 at baseline and after relapse (GSE31161) were compared (P<0.05, t test). (c) Western blots assay was utilized to detect the protein level of PA28γ (PSME3) and PA200 (PSME4) in purified CD138+ cells from new diagnosed (NDMM) (n=4) and relapsed MM patients (RRMM) (n=5). Normal plasma cells (n=2) were utilized as control. (d) PA28γ (PSME3) and PA200 (PSME4) expression in a panel of MM cell lines with normal plasma cells as control. (e and f) Kaplan-Meier analysis was performed in MM patients with varying levels of PA28γ (PSME3) (P<0.0001, log rank test). and PA200 (PSME4) in MMRF-CoMMpass clinical trial. (P=0.0037, log rank test). *P < 0.05; ***P < 0.001.