Multiple Myeloma (MM) is a blood cancer of the B cell lineage characterized by monoclonal plasma cells. Most patients initially respond to the therapy but majority of them relapse and become refractory to treatment. These myeloma cells, which escape current modes of therapy. We name it tumor-initiating cells (TICs) in myeloma. Understanding the nature of myeloma-TICs will provide an opportunity to cure this disease by preventing its relapse. Through a systematical screening, our studies presented here demonstrated that CD24+ myeloma cells maintain the features of self-renewal and drug resistance in myeloma. We predict that anti-CD24 antibody may eliminate myeloma tumor initiating cells resulting in cure of myeloma disease or significant extension of patient survival. This proposal focuses on validating CD38+CD45CD24+ as TICs marker and its potential therapeutic role. Aim 1 determines the CD38+CD45-CD24+ phenotype in maintaining 'stemness' and its clinical relevance in primary myeloma samples. Aim 2 determines tumor-initiating characteristics of CD38+CD45-CD24+ cells. Aim 3 investigates the efficacy of humanized CD24 antibodies in killing myeloma tumor-initiating cells. The FY18 PRCRP Topic Area is myeloma; The FY18 PRCRP Military Relevance Focus Areas are that gaps in myeloma prevention, prognosis and treatment for extending patient survival. Myeloma is one of the common cancers seen among Veterans and each year cases will increase. Overall, this project has the potential to improve treatment outcome of all myeloma patients including veterans when we finish this project.