Patients with Monoclonal Gammopathy Have a High Rate of Second Symptomatic COVID-19 Infection Even after a Prior COVID-19 Infection and Vaccination

Background: Patients with hematologic malignancies, including multiple myeloma (MM), light chain (AL) amyloidosis, smoldering MM (SMM) and monoclonal gammopathy of undetermined significance (MGUS), have disproportionately high rates of COVID-19 infection and associated mortality. While inferior immune response to COVID-19 vaccination have been described in patients with monoclonal gammopathy, information on the rate and severity of COVID-19 infections in patients who do demonstrate immunogenicity after a prior infection or vaccination is limited. Additionally, the prevalence and clinical course of second symptomatic COVID-19 infections in patients with monoclonal gammopathy is not known.

Methods: Patients with MGUS, SMM, MM or AL amyloidosis evaluated at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 were screened. Patients with a positive polymerase chain reaction test for SARS-CoV-2 and either a spike Ab (Ab) or a nucleocapsid Ab tested were included. Spike Ab was reported quantitatively (positive result >0.8 IU/mL per laboratory standard) and nucleocapsid Ab testing was reported as either positive or negative. For this study, we defined “fully vaccinated” as 2 doses of Pfizer or Moderna mRNA vaccine or 1 dose of the Janssen vaccine based on the prevalent CDC recommendation during the study period. Patients with a 2^nd symptomatic COVID-19 infection had an interim negative COVID-19 test result with complete clinical recovery.

Results: Out of 19,943 patients with an underlying monoclonal gammopathy, 483 patients (2.4%) had a documented positive COVID-19 PCR test and 101 patients had COVID-19 antibody testing performed [spike Ab=54, nucleocapsid Ab=47]. The baseline characteristics of these 101 patients are depicted in Table 1. Out of the 101 patients, 13 (13%) developed a 2^nd symptomatic COVID-19 infection. Details of the timeline for second infections in relation to vaccination, antibody testing and ongoing treatment are depicted in Figure 1. The majority of 2^nd COVID-19 were mild (11/13, 85%) and the 2 patients (15%) with a severe 2^nd infection were both unvaccinated. The median time to 2^nd infection was 6.3 months (range 1-19 months) from the 1^st COVID-19 infection. Of the 42 patients with MM/AL, 25 patients were in remission and 1 out of these 25 (4%) patients developed a 2^nd COVID-19 infection. Compared to patients in remission, 5 (29%) of the 17 patients with MM/AL not in remission developed a 2nd infection (p=0.03). Rate of 2^nd infection was 21% (6/28) in unvaccinated patients compared to 10% (7/73) in patients after completion of initial vaccination series (p=0.11). Six out of the 7 vaccinated patients had received a third dose of vaccination prior to the 2^nd infection. Among the 382 patients in whom an antibody test was not performed, 22 (6%) patients developed a second infection out of which 3 (14%) were severe.

Out of 101 patients, 85 patients were unvaccinated at the time of first infection and 63 (74%) developed a positive COVID-19 Ab after the 1^st symptomatic infection (spike Ab n=38, nucleocapsid Ab n=25). Out of these 63 patients with seropositivity, 7 (11%) developed a second symptomatic COVID-19 infection at a median time of 9.9 months (range 2.9–19.6) from first COVID-19 infection and 6 (range 2–18.7) months from the time of antibody testing. To assess seropositivity after vaccination, spike Ab was used as nucleocapsid Ab can be negative after mRNA vaccination. Among the vaccinated patients at the time of first infection (n=16), 6 had a spike Ab tested before 1^st COVID-19 infection at a median of 65 (range 16–109) days from vaccination. Of these, 5 (83%) demonstrated a positive spike Ab response to the vaccination. Despite seropositivity, all 5 developed COVID-19 and 2 patients with positive spike Ab developed a severe 1^st COVID-19 infection (without mortality) at 84 days and 99 days from vaccination, respectively [spike Ab level was 145 IU/mL and > 250 IU/mL, respectively]. None of the vaccinated and seropositive patients (n=10) developed a 2^nd symptomatic COVID-19 infection.

Conclusion: Patients with an underlying MM, AL or MGUS demonstrate a substantial risk for second symptomatic COVID-19 infections suggesting a rapidly waning immunity. Most of the 2^nd COVID-19 infections were mild, with severe infections restricted to the unvaccinated population. Patients in whom underlying MM or AL was in remission was protective against a 2^nd infection.