P59 active treatment and low igm are associated with inferior sars-cov-2 spike antibody response to three doses of covid-19 rna vaccination in patients with multiple myeloma

Introduction: Patients with multiple myeloma (MM) frequently present with substantial immune impairment and an increased risk for infection-related mortality. From the end of January 2020, infection by SARS-CoV-2 has radically changed our lives. Since the COVID-19 (COronaVIrus Disease-2019) pandemic is still ongoing, counting more than 514 million confirmed cases and 6.24 millions deaths, it is still to clarify why the response to infection differs from person to person and which immunopathological mechanisms lead to severe disease. Concerning this, it is well documented that patients with impairment of the immune system are more at risk of developing severe COVID-19 with reduced survival. In this setting, the development of vaccines against SARS-CoV-2 represented a central point in the fight against the pandemic. Regarding this, we aimed to evaluate the immune response in MM patients vaccinated for SARS-CoV-2 during their active anti-MM treatment. Methods: This study included 158 patients affected by active MM or smoldering MM (SMM) and 40 healthy subjects. All subjects received 2 or 3 doses of the BNT162b2 (Pfizer/BioNTech) vaccine. A serology sample was collected before the first vaccination, 30 days after the second, and 60 days after the third dose. Results: At 30 days from the double dose, the median anti-spike IgG levels in MM was 25.2 (IQR, 3-135 AU/mL), significantly lower than those in SMM (360.2 IQR, 245-424 AU/mL, p<0.0001), and in the control group (704 IQR, 390-1340 AU/mL, p<0.0001). At 60 days from the third dose, the median anti-spike IgG levels in MM was 38 IQR (8-248 AU/mL), significantly lower than those in SMM (650 IQR, 419-1370 AU/mL, p<0.0001) and in the control group (995 IQR, 455-1502 AU/mL, p<0.0001). Our results indicate that continuous treatment (p=0.0003), therapy with monoclonal antibodies alone (p=0.006) or associated to immunomodulatory agents (p=0.02), high-dose of dexamethasone (p=0.002), and IgM <50 mg/dL (p=0.003), are associated with an inadequate response to COVID-19 vaccination and a not stable anti-SARS-CoV-2 titer. Moreover, in our series of 40 patients undergoing prophylaxis with tixagevimab/cilgavimab, 9 (22.5%) experienced COVID-19, with a practically asymptomatic course, underlining the effectiveness of this therapy in preventing serious infection and ensuring the best clinical management (Figure 1). Conclusions: A third mRNA vaccine failed to warrant long-term humoral immune responses against SARS-CoV-2, in the setting of patients undergoing continuous MM treatment and reporting a low value of IgM. After two months from the third dose, most non-responder patients at two doses did not show a stable anti-SARS-CoV-2 titer. These patients should be addressed to receive passive immunization with tixagevimab/cilgavimab instead of a further dose of vaccine to warrant long-term protection.