Calpain-2 inhibition alleviates hypercalcemia-driven multiple myeloma progression

Multiple myeloma (MM) is a malignant hematological disorder characterized by the neoplastic proliferation of plasma cells. Hypercalcemia is a common complication in MM and is often considered a secondary consequence of disease progression. When calcium levels are severely elevated, it can lead to coma in affected patients. However, whether hypercalcemia plays a direct role in MM progression remains unclear. Herein we found that high calcium concentrations promote MM cell proliferation and it was associated with calpain-2 (CAPN2). We also observed that CAPN2 expression is significantly increased in MM patients and correlates with poor prognosis. Furthermore, knockdown of CAPN2 inhibited MM cell proliferation both in vitro and in vivo via upregulation of FN14 and induction of apoptosis. Importantly, treatment with ALLN, a CAPN2 inhibitor, substantially suppressed MM cell proliferation in vitro and in vivo by inducing apoptosis. Notably, ALLN significantly enhanced the sensitivity of MM cells to commonly used clinical drugs bortezomib and doxorubicin, while exhibiting no obvious cytotoxicity in normal cells. These findings establish CAPN2 as a promising therapeutic target in MM, with its inhibitor serving as a potential lead compound for further clinical evaluation. Our study also elucidates the relationship between hypercalcemia, CAPN2, and malignant proliferation in MM cells, and expands the therapeutic landscape for MM patients.