Prospective study of immunogenicity to SARS-CoV-2 booster vaccines in multiple myeloma and Waldenström macroglobulinemia Open Access

• We show for the first time that 2 SARS-CoV-2 booster vaccinations can overcome ineffective responses in nearly 90% of MM and WM patients.

• Despite eliciting SARS-CoV-2 antibodies, we show that MM and WM patients have decreased antibody-mediated effector functions.

Patients with multiple myeloma (MM) and Waldenström macroglobulinemia (WM) have increased risk of severe COVID-19. Impaired humoral responses to the primary vaccination series against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in MM and WM patients, but impact of booster vaccinations and functional status of the elicited antibodies is unknown. We performed a prospective cohort study investigating SARS-CoV-2 vaccination in MM (n=93) and WM (n=48) patients. The primary endpoint was effective immune response (EIR) at 28 days after the primary vaccination series (i.e., anti-spike SARS-CoV-2 antibody titer >250 U/mL). The EIR rate after the primary vaccination series was 47% and 25% in MM and WM patients, respectively. Following the first and second booster vaccinations, the EIR rates increased to 84% and 91% in MM patients, respectively, and 60% and 89% in WM patients, respectively. Factors associated with lower EIR in MM patients were hypogammaglobulinemia, lymphopenia, and treatment with anti-CD38 monoclonal antibody or corticosteroid. Treatment with a BTK inhibitor or rituximab was associated with a lower EIR in WM patients, while asymptomatic and treatment naïve WM patients had a higher EIR. Functional profiling identified reduced antibody-dependent cellular phagocytosis (ADCP), neutrophil phagocytosis (ADNP), and NK cell activity (ADNKA) against wild-type and variant SARS-CoV-2 (a, b, and g) in both MM and WM patients compared to healthy donors. Our data demonstrate that although MM and WM patients have impaired humoral responses to the primary SARS-CoV-2 vaccination series, repeated booster vaccines significantly improve immunogenicity. The study was registered at ClinicalTrials.gov (#NCT04830046).