Our results demonstrate that: i) in the BM of tumor-bearing mice, IL-15-activated NK cells have a numerical and functional advantage in the short time-frame compared to the IL-12/15/18 counterpart, allowing a superior tumor clearance capacity; ii) in vivo re-stimulation of donor NK cells with a single dose of IL-15 promotes long-term anti-tumor effect of NK cells pre-activated with IL-12/15/18; iii) inhibition of CXCR3/ligand axes potentiates the ability to infiltrate BM and enhances anti-MM activity of IL-15 activated NK cell. Here, IL15 is linked to neoplasm.