Multiple myeloma (MM) is the second most common blood cancer worldwide. Although significant improvements have been made with introduction of novel agents, relapsed or refractory MM is almost inevitable after a progression-free period. Unlike other hematological cancers, MM is often immersed in an acidic pH microenvironment. Few studies have attempted to address the acute impact of microenvironmental acidification on MM cells, but little is known about how tumor cells could sense, respond, reprogram, and ultimately adapt to the prolonged acidotic stress. Here, we generated and established a series of MM cell lines exposed to different time periods of extracellular acidity. We observed a distinct and long-term process of reversible adaptive eplasticity in acid-treated MM cells with altered proliferative responses, metabolic phenotype switches, reprogrammed mitochondrial dynamics and lipid droplet formation. Thirty-four target molecules were further identified to be significantly associated with the overall survival of MM patients - most of these were previously unable to be screened and detected by short-term analyses of the effects of microenvironmental acidity on MM cells
