Increased COVID-19 Breakthrough Infection Risk after Sars-Cov-2 Vaccine Boosting in Patients with Plasma Cell Disorders: A Large Nationwide Veterans Affairs Study

Abstract

Introduction Coronavirus disease 2019 (COVID-19) is particularly serious in patients with multiple myeloma (MM), with estimated mortality of over 30% in early studies in unvaccinated patients. SARS-CoV-2 vaccination and boosting is an effective approach to preventing infection in the general population. We previously showed that patients with MM experience significantly higher rates of breakthrough infection and severe COVID-19 after SARS-CoV-2 vaccination, consistent with other studies showing that patients with compromised immune systems exhibit reduced antibody response to SARS-CoV-2 vaccination. Thus, the objective of this retrospective cohort study in the national Veterans Affairs (VA) healthcare system was to evaluate risk of breakthrough infections after SARS-CoV-2 vaccine boosting in patients with MM and monoclonal gammopathy of undetermined significance (MGUS) compared to matched patients without plasma cell disorders during the 322-day period following initial booster availability. Methods We used a matched cohort design to measure risk of breakthrough infection after vaccine boosting among patients with MM or MGUS relative to those without, using the same matching procedure as in our recent study of breakthrough infections after initial vaccination (La et al., Blood, 2022). Full boosting was defined to start 7 days after receipt of the 3rd dose of BNT162b2 or mRNA-1273 vaccine. Patients vaccinated with Janssen Ad26.COV2.S or prior SARS-CoV-2 infection were excluded. We did not evaluate second booster series. Boosted patients with MM or MGUS were matched 1:1 with boosted controls on factors potentially associated with SARS-CoV-2 exposure: age, race, VA facility, and rurality of home address. For each day of the study period, each new fully-boosted patient with MM or MGUS was matched with a control patient without MM or MGUS. The primary outcome was laboratory-confirmed SARS-CoV-2 infection. The secondary outcome of severe COVID-19 was defined as in our previous work. Each pair was followed until SARS-CoV-2 infection, death or end of study. The Fine-Gray subdistribution hazard was used to measure risk of infection with the competing risk of death. Results Between 8/1/2021 and 6/22/2022 we identified 1822 patients with MM (median age 73, Non-Hispanic white 57%) and 6971 with MGUS (median age 75, Non-Hispanic white 55%) who were fully boosted from a mRNA-based vaccine prior to the end of study. 1706 MM and 6503 MGUS patients were matched to non-MM/MGUS controls. The median follow-up time for the matched boosted cohort was 260 days among MM and 225 days among MGUS, reflecting an earlier median date of boosting among MM (9/23/2021) than MGUS (11/5/2021) patients. Compared to controls, patients with MM had an increased risk of breakthrough infection after boosting, (hazard ratio [HR] 2.60, 95% confidence interval [CI] 1.96-3.45, p<0.001), and MGUS (HR 1.90, 95% CI 1.60-2.25, p<0.001) (Figure). Risk for severe COVID-19 following vaccination and boosting in patients with MM was also observed (HR 2.39, 95% CI 1.33-4.29, p=0.003) but not among MGUS (HR 1.06, 95% CI 0.75-1.51, p=0.74). Patients with last therapy within 90 days of receiving a booster tended to experience more breakthrough infections (11.3%, p<0.001), especially those receiving anti CD38 therapy in that timeframe (16.3% experienced breakthrough infections, p<0.001). Breakthrough incidence increased further in all groups approximately 3½ after booster, possibly due to waning immunity, increasing prevalence of vaccine-resistant SARS-CoV-2 variants, or a combination thereof. Conclusion Vaccination and boosting are effective for preventing SARS-CoV-2 infection and severe COVID-19. Effectiveness may be reduced in patients with plasma cell disorders, likely owing to a co-existing immunosuppression due to disease process as well as associated therapy, which impacts humoral immune response. Patients with MM are at higher risk than patients with MGUS, especially for severe COVID-19. Relative to our previous study, patients with MM and MGUS have lower or equal estimated HR of both SARS-CoV-2 infection and severe COVID-19 post-booster compared to post-vaccination, but CIs overlap so further study is needed for a definitive comparison. Our findings suggest these vulnerable populations should be considered for additional mitigation strategies, such as pre-exposure prophylaxis, even after vaccination and boosting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal