Multiple myeloma (MM) is still an incurable plasma cell malignancy with heterogeneity characterized by drug resistance and disease recurrence. Chromosome instability (CIN), served as the hallmark of cancers, is a key component of drug resistance, the acquisition of tumor heterogeneity, tumor progression and relapse, whereas the function of the CIN in cancer, especially its coordination with MM, is not clear. In this study, we elucidated that the expression of BUB1 beta (BUB1B) was elevated strikingly in MM patients and its high expression has been implicated in dictating malignant progression. Overexpression of BUB1B facilitated cellular proliferation and induced drug resistance in vitro and in a xenograft myeloma mouse model, while genetic targeting BUB1B abrogated this effect. Mechanistic studies unveiled that enforced expression of BUB1B evoked CIN to favor MM progression mainly through phosphorylating CEP170. Intriguingly, we discovered circBUB1B_544aa, which encoded by a circular RNA circBUB1B and contained BUB1B kinase catalytic center, played a synergistic role with BUB1B in evoking CIN through CEP170 activation. Besides, MM cells could secrete circBUB1B_544aa in MM microenvironment to interfere adjacent or distant cells. Thus, enzymatic catalytic center encoded by BUB1B and circBUB1B_544aa represents a strong predictor for drug-resistance and poor prognosis, which would shed light on the mechanisms underlying drug resistance and relapse in MM. Finally, siRNA targeting the common sequence of BUB1B and circBUB1B_544aa could significantly inhibit MM growth both in vitro and in vivo indicating that BUB1B is a promising and potential therapeutic target of MM.