Real-world analysis of infections after bispecific antibodies targeting anti-B-cell maturation antigen (BCMA) and protective impact of intravenous immunoglobulin (IVIG) in patients with multiple myeloma

Abstract Introduction: Elranatamab and teclistamab are bispecific antibodies (BsAb) directed against B-cell maturation antigen (BCMA) and are highly effective in treatment of multiple myeloma (MM) with responses seen in over 60% of the patients (Moreau et al, NEJM 2022 & Lesokhin et al, Nature Medicine 2023). Toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are usually limited to the initial ramp-up phase but due to long-lasting depletion of normal B- and plasma cells, infections including opportunistic ones, are exceedingly common in patients receiving anti-BCMA BsAb both during and after treatment (60-70% of patients had infections on MAJESTEC-1 and MagnetisMM-3). Intravenous Immunoglobulin (IVIG) is recommended as prophylaxis against infections during the duration of treatment with BsAb. Despite consensus and national guidelines, application of these supportive care strategies remains inconsistent and when used, their impact has not been well studied in real-world patients. Here, we report the incidence of infections, utilization patterns and effect of IVIG use among patients with MM receiving elranatamab and teclistamab using large-scale real-world data. Methods: We conducted a retrospective analysis of de-identified electronic health records from Epic Cosmos, which covers more than 1700 hospitals and 40000 clinics in the United States. Adult patients (>18 years old) diagnosed with MM, have received >2 doses of elranatamab or teclistamab and with >6 months of data collected in Epic Cosmos were included. Patients were followed from first to last administration of BsAb. International Classification of Disease-Clinical Modification (ICD-CM)-10 codes were used to identify episodes of treatment toxicity, specifically infections. Infection episodes were considered distinct if consecutive ICD codes indicating infection were more than 56 days apart or ICD codes suggested a different etiology. Proportion of patients with each type of toxicity, rate of toxicity episodes and time to first toxicity episode were quantified. Among patients who received IVIG while on BsAb, the rate of infections before and after IVIG initiation was compared using paired t-test. Results: A total of 1646 MM patients (1491 received teclistamab and 155 received elranatamab) met study eligibility and had a median follow-up of 7.1 months (interquartile range [IQR], 1.8-13.0). Median age at the time of initiation of BsAb was 70 years (IQR, 63-76) and 881 (53.5%) were male. Majority (n=1402, 86%) lived in urban areas, 1042 (63.3%) identified as white and 808 (49.1%) were anti-CD38 exposed. Median time from diagnosis to BsAb initiation was 4.7 years (IQR, 2.3-7.5). Common comorbidities included hypertension (n = 881, 53.5%), hyperlipidemia (n = 621, 37.7%), chronic renal disease (n = 445, 27.0%) and type 2 diabetes mellitus (n = 365, 22.2%). During treatment with BsAb, 493 patients (30%) were documented to have at least 1 infection with an infection rate of 0.06 (standard deviation [SD], 0.27) episode/patient-month and median time to first infection was 2 months (IQR, 0.7-5.1). Bacterial sepsis was the most common type of infection (n = 200, 12.2%), followed by febrile neutropenia (n = 126, 7.7%), viral pneumonia (n = 89, 5.4%) and CMV (n=70, 4.3%). The risk of infection was higher amongst those who received teclistamab (n = 458, 30.7%) compared to those who received elranatamab (n = 35, 22.6%), p = 0.03. Only half of the patients (n = 826, 50.2%) received IVIG while on BsAb and among these patients, infection rate decreased from 0.09 (SD, 0.27) episode/patient-month prior to IVIG use to 0.03 (SD, 0.15) episode/patient-month after IVIG use (p <0.001). Conclusion: We report the incidence of infections along with the protective effect of IVIG on the risk of infections in the largest nationwide cohort of MM patients treated with anti-BCMA BsAb. Risk of infections was lower with elranatamab than teclistamab. Only half of the patients on BsAb received IVIG, though the use of IVIG was associated with a 67% decrease in infections. More awareness is needed to expand the use of IVIG to prevent infections in patients receiving BsAbs and prospective studies would be crucial to establish optimal dosing schedules and fully understand the impact of IVIG on clinical outcomes.