Background: Multiple myeloma (MM) is an incurable plasma cell malignancy. Precursor conditions include monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM). Immune surveillance is paramount for keeping the malignancy in check, whereas a dysfunctional immune system is suspected to promote disease progression. Methods: We performed flow cytometric immune panel analyses including T-cell, B-cell, natural killer (NK) cell and dendritic cell (DC) subsets in MGUS, SMM, and MM patients between 2018-2021. Immune panels were analyzed on fresh peripheral blood samples drawn at diagnosis. The patient population were MGUS (n=28), SMM (n=19) and MM (n=94). Samples from MGUS and SMM patients were combined into a single group (asymptomatic) and were compared to MM patients (symptomatic). Lymphocytes were identified by CD45+ expression resolving against side-scattered light on a bivariate plot. B cell and NK cell antigen expression profiles were assessed from this lymphocyte population. T cell subsets were further determined by CD3+. The percent gated for each marker was summarized by cohort using the appropriate descriptive statistics and compared using the Mann-Whitney U exact test. Analyses were performed in SAS v9.4 (Cary, NC) using a two-sided α=0.05. Results: Compared to MGUS/SMM patients, MM patients had a significant lower proportion of naive B cells, NK cells, and cytolytic NK cells, and a significant higher proportion of cytolytic T cells at diagnosis (Table). Consistent with prior studies, we demonstrated an increase in exhaustion markers. There was a trend toward a higher population of CD8+ exhausted T cells in MM patients compared to MGUS/SMM patients. Since the follow up for this study was short, survival data is not mature. Conclusions: This study demonstrates the immune imbalance that occurs between myeloma precursor conditions and MM. There is a shift in certain cell subsets in the immune microenvironment that alters tumor immunosurveillance and tumor cell killing favoring disease progression. In data not shown, we are currently analyzing the bone marrow microenvironment and its relation to disease progression. Follow up studies could assess if therapeutic intervention could reverse the imbalance, restore homeostatic equilibrium with the goal of controlling disease long-term.