The molecular basis of monoclonal gammopathy of undetermined significance (MGUS) progression to a malignant monoclonal gammopathy remains poorly understood. It was recently suggested that this process involves the suppression of innate and adaptive immunity. In this study, we examined immunogenic differences in bone marrow plasma cells among individuals without gammopathy (controls) and patients with MGUS, multiple myeloma (MM), and plasma cell leukemia. We detected differences in major histocompatibility complex (MHC) class I expression, MHC class I chain-related molecule A, and CD95 that were more evident between MGUS and MM samples; there appeared to be a critical imbalance between natural killer (NK)-cell activating and inhibitory signals during the transition from MGUS to MM. Our results indicate that the human leukocyte antigen (HLA) class I(bright), MICA(dim/-), and CD95(dim/-) immunophenotype reported in myeloma cells may result from an extensive interaction of malignant cells with cytotoxic T and NK cells and appears to be immunoedited for the evasion of immunosurveillance.