Summary In spite of major therapeutic advances there is an unmet need to gain fundamental insights into the pathogenesis of myeloma (MM) and develop newer approaches to prevent clinical malignancy. Our research program will build on our prior efforts in two areas- understanding the etio-pathogenesis of myeloma and harnessing host response to prevent cancer. In recent studies, we have discovered that chronic activation by lysolipids underlies the etiology of MM in nearly a third of patients. We have also developed new humanized mouse models that span the entire spectrum of malignancy, including precursor states. These advances set the stage for next studies to better understand how lipid-mediated inflammation may drive the development of myeloma and how to prevent it. Understanding these pathways may have implications for mechanisms underlying lipid-mediated inflammation in diverse states including obesity. MM and its precursor states are also an important model to probe basic questions about how to harness the biology of both adaptive and innate immune system to prevent cancer.