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The prognosis of patients with multiple myeloma (MM) has improved dramatically with the introduction of new therapeutic drugs, but the disease eventually becomes drug-resistant, following an intractable and incurable course. A myeloma niche (MM niche) develops in the bone marrow microenvironment and plays an important role in the drug resistance mechanism of MM. In particular, adhesion between MM cells and bone marrow stromal cells mediated by adhesion molecules induces cell adhesion-mediated drug resistance (CAM-DR). Analyses of the role of mitochondria in cancer cells, including MM cells, has revealed that the mechanism leading to drug resistance involves exchange of mitochondria between cells (mitochondrial transfer) via tunneling nanotubes (TNTs) within the MM niche. Here, we describe the discovery of these drug resistance mechanisms and the identification of promising therapeutic agents primarily targeting CAM-DR, mitochondrial transfer, and TNTs.