Abstract
Multiple myeloma (MM) is a plasma cell malignancy marked by profound immune dysfunction and substantial infection-related mortality. MM is preceded by the asymptomatic precursor states monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), yet whether these patients can mount effective immune responses remains unknown. In this prospective observational study of 731 individuals recruited nationwide through Dana-Farber Cancer Institute, we used SARS-CoV-2 vaccination as a standardized immunological challenge alongside childhood vaccine serology. We show that precursor myeloma is associated with broad dysfunction across innate and adaptive immunity, including accelerated antibody waning, erosion of childhood vaccine titers, impaired antigen-specific T cell expansion, and blunted innate activation. Mechanistically, we link these defects to tumor burden-dependent APRIL depletion and downregulation of APRIL-responsive pathways in normal plasma cells, validated in an independent cohort. These findings have direct implications for cancer vaccine development, immunotherapy, and infection management in early-stage hematologic malignancies.