My research focuses on understanding mechanism of transformation from precursor disease (monoclonal gammopathy of undetermined significance, MGUS; and smoldering myeloma, SMM) to multiple myeloma, and on identifying deregulated signaling proteins that can be targeted with novel therapeutic agents. Prior studies have shown cytogenetic abnormalities contribute to multiple myeloma pathogenesis and disease progression. We are currently conducting molecular profiling analysis designed to discover mutations in MGUS/SMM, and in paired samples from patients who progressed to multiple myeloma. We hypothesize that patients with MGUS/SMM accumulate distinct somatic oncogenic mutations and/or acquire epigenetic changes that play a role in the progression from precursor state to multiple myeloma. As part of our ongoing therapeutic program we have tested (pre-clinically and clinical trials), e.g., MEK inhibitors and second/third generation proteasome inhibitors. Also, we are developing immune cell anti-tumor strategies using, e.g., anti-KIR monoclonal antibody and second generation immunomodulatory drugs to facilitate NK and T-cell derived tumor killing. Based on preclinical studies, we develop/conduct investigator-initiated clinical (phase I and II) studies built on extensive correlative science. Our clinical program include natural history studies focusing on molecular profiling of MGUS and SMM patients; early treatment studies for high-risk SMM patients; and rationale treatment studies for newly diagnosed and for relapse/refractory multiple myeloma patients. Furthermore, to better detect early high-risk precursor disease and to define the role of imaging strategies to monitor treatment responses, we have developed a program focusing on functional imaging (e.g., whole body-PET/MRI, novel PET/CT tracers) in MGUS/SMM and multiple myeloma patients.