Dysregulated Humoral and Cellular Response to Sars-Cov-2 Vaccination in Patients with MGUS and SMM

Introduction Patients with hematological malignancies, including multiple myeloma (MM), experience sub-optimal responses to SARS-CoV-2 vaccination. Monoclonal Gammopathy of Undetermined Signi fi cance (MGUS) and Smoldering Multiple Myeloma (SMM) are precursors to MM and are associated with immune dysregulation. MGUS and SMM affect approximately 5% of individuals over 50 years of age, who remain largely undiagnosed. Here, we present the results from a prospective observational cohort study which we launched in November 2020 to characterize the effect of plasma cell pre-malignancies on response to SARS-CoV-2 vaccination. To assess in cellular immune response between patients and we performed 2,025,611 peripheral blood immune cells from 224 samples of healthy donors and patients with MGUS, SMM, MM before and after vaccination for SARS-CoV-2. By comparing immune cell abundance between pre- and post-vaccination samples, we observed a signi fi cant increase in the abundance of Th2, Th17 cells, and Tregs post-vaccination in patients with MGUS and SMM, an effect which we did not observe in healthy donors. This fi nding may potentially indicate a dysregulated T-cell response to SARS-CoV-2 vaccines in patients with plasma cell premalignancy. Additional analyses are ongoing to determine whether these helper T-cell responses are speci fi c to SARS-CoV-2 antigens or perhaps occur in response to general changes in the cytokine milieu. Conclusion Taken together, our results indicate that antibody titers decline signi fi cantly faster in patients with MGUS and SMM, a defect that may persist following a third dose of vaccination, and that patients with MGUS and SMM may have altered cellular responses to vaccination. These fi ndings highlight that despite the absence of symptoms, plasma cell premalignancy may represent an immunocompromised state. Additional analyses of our large single-cell sequencing dataset, coupled with antigen stimulation experiments in vitro may provide further insights into the dysregulation of cellular immune responses to SARS-CoV-2 vaccination in patients with plasma cell premalignancy. study.