High glucose metabolism provides sufficient energy for cancer cells and is enabled by metabolic enzymes. PFKFB3 (6-phosphofructo-2-kinase) accelerates the synthesis of fructose 2,6-bisphosphate (F2,6P2), which is a powerful allosteric regulatory activator of 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme of glycolysis. The aim of this study was to investigate the anti-myeloma function and underlying mechanism of suppressing PFKFB3 via PFK15 (1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one). The role of PFK15 in killing multiple myeloma (MM) cells was evaluated by cytotoxicity and apoptosis assays, flow cytometry and Western blotting. The oral hypoglycemic drug metformin (Met) was found to inhibit PFKFB3 protein expression by gene chip and Western blotting techniques in our study. PFK15 also demonstrated a synergistic effect with metformin to eliminate MM cells. Taken together, our findings indicate that PFK15 inhibits MM cell proliferation through the PFKFB3/MAPKs/STAT signaling pathway. The combination therapy of PFK15 and metformin may be a promising anticancer drug regimen for the treatment of MM.