P-378: Longitudinal antibody and T-cell kinetics over four doses of COVID-19 vaccination and predictors of poor response in patients with multiple myeloma.

Introduction: Patients with multiple myeloma (MM) have been a highly vulnerable population during the COVID-19 pandemic, with an attenuated response to initial vaccinations. Whilst studies have reported the immune response to COVID-19 vaccination in MM patients at isolated time points, little is known about how immunity evolves over successive doses, the effect of the fourth dose and the predictors of poor response. Here, we report results of a longitudinal study that aimed to understand the dynamics of immune responses to doses 2-4 of COVID-19 vaccination in MM.

Methods: We conducted a national prospective study to investigate COVID-19 immunity acquired by infection or vaccination in patients with MM. The study was open from December 2020 to October 2022 to any UK resident with a diagnosis of MM. The online Rare UK Diseases Study (RUDY) digital platform was used to obtain informed consent and patient-reported clinical details. Patients provided up to three longitudinal serum samples taken ≥3 weeks following doses 2-4. COVID-19 spike (S) and nucleocapsid (N) IgG antibodies were measured by turbidimetry (Abbott), with positive values taken as >1.4 IU/mL and >50 IU/mL, respectively. Collected heparin samples were used to isolate peripheral blood mononuclear cells (PBMCs) and perform a S-protein interferon gamma release assay (IGRA) (Oxford Immunotec T IGRA) to quantify COVID-19-specific effector T cells, with positive results defined as >8 interferon gamma-releasing cells/1 million PBMCs.

Results: In total, 141 MM patients (median age 66.6 years, 45% female) provided three longitudinal samples following doses 2-4, which were assayed for humoral (n=138) and T-cell (n=61) immune responses. Median Anti-S titres increased from post-2nd (1,065 IU/mL; 93% positive) to post-3rd (6,024 IU/mL; 96% positive) to post-4th (11,179 IU/mL; 98% positive) doses [p < 0.0001]. Longitudinal Anti-S responses were greater in those with a positive T-spot [p < 0.05] or previous natural COVID-19 infection [p < 0.001] and positively correlated with serum IgM [r=0.39-0.44, p< 0.0001]. In comparison, positive T-cell IGRA responses to S-antigen were observed in 62%, 56% and 70% of patients following doses 2-4, respectively. IGRA responses were stronger in patients who had received a mix of recombinant protein and mRNA-based vaccines (compared to mRNA-based alone) [p < 0.01] and positively correlated with lymphocyte count after four doses [r=0.35, p=0.0014]. Both poor myeloma disease status (as defined by International Myeloma Working Group response group) and concurrent anti-CD38/BCMA therapy predicted lower Anti-S and IGRA responses.

Conclusions: In summary, our data support a robust humoral and cellular immune response to COVID-19 booster doses, including in those with an initial poor response. Our data establish the laboratory and clinical profile of poor vaccine responders, that could be targeted for more intensive COVID-19 risk management, and provide insights to interrogate the biological basis of variable immunity in MM.