PIWIL1 inhibition facilitates the sensitivity of MM cells to doxorubicin, bortezomib, and dexamethasone by decreasing the MM stem cell population and regulating stem cell pluripotency genes, including NANOG, OCT4, and SOX2. These data determine the role of PIWIL1 as a pan-resistance target, and PIWIL1 could serve as a novel therapeutic target for reversing chemoresistance in patients with refractory/relapsed MM. Here, NANOG is linked to Miyoshi myopathy.