In a large, longitudinal cohort study involving a diverse population of adults with longitudinal SARS‐CoV‐2 serological assays, infection surveillance data, and comprehensive cancer treatment evaluation, we observed that patients with hematologic cancers or exposed to B‐cell targeted therapy (anti‐CD20/anti‐CD38) had significantly reduced humoral immunity to SARS‐CoV‐2 in addition to more frequent and more severe Omicron and subvariant infections. Here, CD38 is linked to hematopoietic and lymphoid cell neoplasm.