Multiple myeloma (MM) is a plasma cell malignancy characterized by an accumulation of malignant clonal plasma cells in the bone marrow (BM). In recent years, many effective anti-MM drugs have been developed including proteasome inhibitors and immunomodulators. Introduction of the proteasome inhibitor bortezomib has improved prognosis and survival in MM patients. However, upon prolonged drug treatment, myeloma cells acquire resistance to the given treatment including bortezomib, resulting in disease relapse. Studies have shown that the BM in myeloma patients is extensively hypoxic (1% O2) compared to the BM in healthy individuals. Hypoxia is a crucial microenvironmental factor that plays an important role in MM disease progression and drug resistance. Due to the development of drug resistance, MM remains an incurable disease with the median survival of only 3 to 5 years. Thus, novel therapeutic strategies are required to kill myeloma cells growing under physiological O2 conditions, including hypoxic microenvironments, and to overcome both acquired and hypoxia-induced drug resistance to improve MM patient survival and prognosis.