The purpose of these studies was to develop and characterize B-cell maturation antigen (BCMA)-specific peptide-encapsulated nanoparticle formulations to efficiently evoke BCMA-specific CD8+ cytotoxic T lymphocytes (CTL) with poly-functional immune activities against multiple myeloma (MM). Heteroclitic BCMA72-80 [YLMFLLRKI] peptide-encapsulated liposome or poly(lactic-co-glycolic acid) (PLGA) nanoparticles displayed uniform size distribution and increased peptide delivery to human dendritic cells, which enhanced induction of BCMA-specific CTL. Distinct from liposome-based nanoparticles, PLGA-based nanoparticles demonstrated a gradual increase in peptide uptake by antigen-presenting cells, and induced BCMA-specific CTL with higher anti-tumor activities (CD107a degranulation, CTL proliferation, and IFN-γ/IL-2/TNF-α production) against primary CD138+ tumor cells and MM cell lines. The improved functional activities were associated with increased Tetramer+/CD45RO+ memory CTL, CD28 upregulation on Tetramer+ CTL, and longer maintenance of central memory (CCR7+ CD45RO+) CTL, with the highest anti-MM activity and less differentiation into effector memory (CCR7- CD45RO+) CTL. These results provide the framework for therapeutic application of PLGA-based BCMA immunogenic peptide delivery system, rather than free peptide, to enhance the induction of BCMA-specific CTL with poly-functional Th1-specific anti-MM activities. These results demonstrate the potential clinical utility of PLGA nanotechnology-based cancer vaccine to enhance BCMA-targeted immunotherapy against myeloma.