Multiple myeloma (MM) is a clonal plasma cell malignancy which is frequently diagnosed in patients over 65 years of age. Because of an aging population, the incidence of MM has increased nearly 1 percent annually since 1975 and it is anticipated that the number of cases will nearly double by 2034 [1]. The introduction of novel agents such as the proteasome inhibitor bortezomib (BTZ) has significantly improved overall survival of patients with MM during the past decade. Therapeutic efficacy is related to the exquisite dependence of MM cells on proteasomal degradation of unfolded proteins to maintain proteostasis. However, progression towards BTZ-refractory disease occurs in the majority of MM patients. Unfortunately, once MM patients become refractory to BTZ, their median overall survival has been reported to be less than 1 year [2]. Moreover, in a pivotal phase 2 study with the second-generation proteasome inhibitor carfilzomib (CFZ), less than a 25% response rate was achieved in BTZ-treated patients who had relapsed [3]. These results indicate that the majority of MM cells that became resistant to BTZ were also resistant to CFZ. Clearly, to extend the life expectancy of patients with MM, it is essential to elucidate the underlying mechanisms of acquired proteasome inhibitor resistance.