OAB-048: Suboptimal humoral immune response to SARS-CoV-2 mRNA vaccination in myeloma patients is associated with anti-CD38 mAb and BCMA-targeted treatment

BACKGROUND: Multiple myeloma (MM) patients are immunocompromised due to defects in humoral/cellular immunity and immunosuppressive therapy. Reports indicate that the antibody (Ab) response in MM after 1 dose of SARS-CoV-2 RNA vaccine is attenuated. Vaccine response kinetics in patients with prior COVID-19 and impact of treatment remain unknown. METHODS: We analyzed SARS-CoV-2 spike-binding (anti-S) IgG level in 320 MM patients receiving COVID-19 vaccination. Blood and saliva were taken at multiple time points. 69 age-matched healthcare workers were used as controls. RESULTS: The 320 MM patients (median age 68 years) received two-dose mRNA vaccines (69.1% BNT162b2, 27.2% mRNA-1273). Median time to diagnosis was 60 months with a median of 2 prior treatment lines (range 0-16). We included 23 patients with smoldering MM. 59 patients (18.4%) were not on active treatment; 148 (43.8%) received anti-CD38 mAb-containing treatment and 36 (11.3%) were on BCMA-targeted therapy. 131 patients (40.9%) exhibited a complete response at last evaluation. 260 patients (81.3%) had anti-S IgG measured >10 days after the second vaccine (median 51 days). Of these, 84.2% mounted measurable anti-S IgG levels (median 149 AU/mL). In the control group, Ab levels were significantly higher (median 300 AU/mL). Ab levels in the 38 vaccinated MM patients with prior COVID-19 were 10-fold higher than those of patients without prior COVID-19 (median 801 vs 69 AU/mL, p<0.001). MM patients on active treatment had lower anti-S IgG levels (p=0.004) compared to patients not on therapy (median 70 vs 183 AU/mL). Notably, 41 patients (15.8%) failed to develop detectable anti-S IgG: 24/41 (58.5%) were on anti-CD38 mAb, 13/41 (31.7%) on anti-BCMA bispecific Ab therapy and 4/41 (9.8%) >3 months after CAR T. Multivariate analysis (corrected for age, vaccine type, lines of treatment, time since diagnosis, response status and lymphopenia) confirmed that anti-CD38-containing (p=0.005) and BCMA-targeted treatment (p<0.001) are associated with not developing detectable anti-S IgG. Clinical relevance is emphasized by 10 cases of COVID-19 after 1 (n=7) or 2 vaccine doses (n=3, all without anti-S IgG) with 1 patient passing due to respiratory failure. CONCLUSION: MM patients mount a suboptimal IgG response after SARS-CoV-2 vaccination with 15.8% developing no detectable anti-S IgG. Ongoing analyses will show kinetics of patients with low-normal Ab levels in comparison to healthy controls. SARS-CoV-2-specific T cell responses and extensive immunophenotyping of >40 patients in the context of vaccination will be reported at the meeting. Immediate implications are the continuation of non-pharmacological interventions, e.g. masking and social distancing, for vulnerable patients. The findings underscore a need for serological monitoring of MM patients following COVID-19 vaccination and for clinical trials assessing use of prophylactic strategies or studies exploring additional immunization strategies.