P-400: An immune atlas of the dysfunctional cellular and antibody response to COVID-19 vaccination in patients with multiple myeloma

Introduction: Infection is the leading cause of death in patients with multiple myeloma (MM). However, the cell-specific extent of baseline immune dysfunction and of the weakened response to vaccination is poorly described. Thus, we aimed to identify the hallmarks of impaired immunity in MM using the COVID-19 mRNA vaccines as a case study.

Methods: Twenty-eight MM patients and two control groups were studied: 53 patients with a B-cell lymphoproliferative disorder (B-CLPD) and 96 age-matched health care practitioners (HCP). A total of 1,099 peripheral blood and serum samples were collected at baseline, at days 7 and 14 after the first dose, at days 7 and 62 after the second dose, as well as before and after the booster. Immune profiling was performed using multidimensional and computational flow cytometry that systematically analyzed 56 immune cell-types per sample and time point. Serum levels of IgM, IgG and IgA against the receptor-binding domain (RBD) of the spike (S) glycoprotein, S glycoprotein, nucleocapsid (N) and main protease were quantified using a multiplex-microsphere-based flow cytometry assay. SARS-CoV-2-specific CD8 T cells were quantified using a dextramer panel of S, N, membrane, and ORF3 proteins.

Results: When compared to HCP and B-CLPD, MM patients showed abnormal distribution at baseline and impaired expansion during vaccination of nearly all the 17 B-cell subsets analyzed in this study. Accordingly, anti-RBD IgM, IgA and IgG titers after the second dose were lower in patients with MM vs B-CLPD (P≤.002). When compared to HCP, both MM and B-CLPD patients showed significantly reduced anti-RBD and anti-S antibody levels over time. Significant deviations at baseline and longitudinally were also observed in classical monocytes, and 6 of 30 T-cell subsets. In contrast to HCP, the percentage of virus-specific CD8 T cells after the second dose did not increase in patients with MM and B-CLPD. Importantly, the booster increased anti-RBD IgG levels (20,184 to 186,629 IU/mL, P<.001) and virus-specific cells (0.08 to 0.14% among CD8 T cells, P=.02) in HCP, but not in MM and B-CLPD (P≥.14). Furthermore, the booster induced virus-specific CD8 T cell differentiation into an effector memory phenotype in HCP, whereas no antigen-dependent differentiation was observed in patients with MM and B-CLPD.
Based on differences in immune-cell distribution using HCP as a reference, we calculated an immune dysregulation longitudinal cumulative score in each individual that included 48,496 parameters. Up to 34% MM and 17% B-CLPD patients showed notable immune dysregulation. Among them, 75% and 33%, respectively, had low seroconversion after the second dose.

Conclusions: We provide an atlas of the immune dysfunction in MM patients and how it affects the efficacy of vaccination strategies such as for COVID-19. The schedule of vaccine doses may thus benefit from individualization according to patients’ immune status, which could act as a surrogate of host, tumor and treatment-related immune dysfunction.