Sars-Cov-2 Antibody Decay Monitoring in mRNA Vaccinated Multiple Myeloma Patients

Introduction: Amid the current COVID-19 pandemic, the highest mortality rates are among the elderly and immunocompromised. Multiple myeloma (MM) patients are immunocompromised and often are elderly. Not only do MM patients develop more frequent infections, but it is one of the leading causes of death for these patients. This population develops more severe COVID-19 due to various mechanisms that impair their ability to fight infection. This also reduces their ability to generate immunity from vaccination, as has been demonstrated by their diminished responses to vaccines for various respiratory illnesses. It follows that while phase III trial results for mRNA1273 and BNT162b2 COVID-19 vaccines showed an efficacy of 94-95% against even mild infection with this virus, the efficacy has been shown to be lower among MM patients. We recently evaluated patients' antibody responses to vaccination for COVID-19 by measuring anti-spike IgG levels in patient serum from before vaccination (baseline) and two weeks after dose 2 (D2W2) of vaccination with mRNA-1273 or BNT162b2, and found that most MM patients have impaired responses (Stampfer et al., Leukemia 2021). Patients who received mRNA-1273 vaccine had higher antibody levels than those who were vaccinated with BNT162b2, and specific clinical and myeloma-related characteristics predicted vaccine responsiveness. In the current study, we are monitoring anti-spike IgG antibody levels at Dose 2 Week 8 (D2W8) and Dose 2 Week 16 (D2W16) post-mRNA vaccination among these patients and in age-matched healthy controls to investigate antibody decay.

Methods: Participants in the trial included MM patients (n=91) at the Berenson Cancer Center, and age-matched healthy controls (n=27). Healthy subjects were not known to be immunocompromised or currently receiving immunosuppressive therapy. Vaccination was done outside of the clinic and subjects provided copies of their CDC-issued COVID-19 vaccination cards to confirm dosing dates. Sera from vaccinated individuals were drawn at baseline (0-60 days prior to first vaccine dose) and at intervals following their second dose (14-21, 56-70, and 112-126 days post-vaccination). Background levels were determined from the clinic's serum bank of healthy subjects drawn pre-April 2019. Using an ELISA-based assay that detects IgG antibodies to SARS-CoV-2 spike protein, we determined Anti-SARS-CoV-2 spike ectodomain serum antibody levels and quantified them in IU/mL based on the WHO International Standard 20/136.

Results: We analyzed the patient and control populations, and specifically for those classified as responders from our original published study (D2W2 >50 IU/mL). All controls but only 70% of patients (64/91) were classified as responders, so this responder-specific analysis was only relevant for patients. There was a significant decline in anti-SARS-CoV-2 spike antibodies from D2W2 to D2W8 for both patients and controls; D2W16 results are pending. Median values dropped from 283.1 IU/mL to 90.9 IU/mL among patients, and 893.6 IU/mL to 354.4 IU/mL among controls. Median antibody levels among patients classified as responders dropped from 482.9 IU/mL to 145.5 IU/mL (p <0.0001). We also found that the D2W8 value for patients was significantly lower than that of controls (90.9 IU/mL vs 354.4 IU/mL, p<0.0001), as well as among the responder group (145.5 IU/mL vs 354.4 IU/mL, p=0.0005). A cutoff of <147 IU/mL has previously been associated with an increased risk for breakthrough infections. Spike antibody levels of 50% of patients who responded and 64.8% of all patients were <147 IU/mL at D2W8, whereas only 7.4% of controls were <147 IU/mL (p<0.0001).

Conclusions: The markedly lower anti-spike antibody levels among MM patients compared to healthy controls at week 8 post-vaccination indicate that they remain at high risk for breakthrough infections. Combined with their rapid decline in anti-spike antibody levels over only a 6-week period, this indicates that even MM patients who responded initially to vaccination are likely to require boosters sooner than healthy individuals. This immunocompromised population remains at high risk even following vaccination and should continue to maintain social distancing precautions during periods of high local SARS-CoV-2 transmission.