Chronic extracellular acidosis drives metabolic plasticity and adaptive survival in multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy that evolves within the complex bone marrow microenvironment, where persistent extracellular acidosis exerts significant biological influence but remains insufficiently investigated. To elucidate the long-term impact of acidotic stress, we developed MM cell models chronically cultured under mildly acidic conditions, mimicking the gradual acidification seen during disease progression. This approach revealed a biphasic MM cellular response: early acidic exposure impaired proliferation, triggered apoptosis, and disrupted metabolic activity, whereas prolonged acidification induced a dynamic, reversible state marked by metabolic recovery, mitochondrial remodeling, and restored growth. Further transcriptomic profiling uncovered distinct gene expression programs associated with this chronic adaptation, including a set of acid-acclimated genes strongly correlated with disease stage and overall survival in MM patients. These findings suggest that extracellular acidosis is not a passive consequence of tumor metabolism, but a key determinant of MM progression by promoting adaptive metabolic plasticity and clonal evolution.