Kai Rejeski, Rahul Banerjee, Joshua A. Hill
T-cell engaging bispecific antibodies (BsAbs) have transformed the treatment landscape for multiple hematologic malignancies and are under investigation in the frontline setting, within combination regimens, and for non-malignant diseases. However, their increasing use has revealed new patterns of immune suppression and infectious complications that differ from other treatment modalities including chimeric antigen receptor T-cell therapy. Notably, infections are frequent and represent the principal cause of non-relapse mortality. These risks with repeated BsAb dosing arise from multifactorial mechanisms, including B-cell or plasma-cell aplasia, hypogammaglobulinemia, and early cytopenias. Additional contributors such as T-cell exhaustion, cytokine-directed immune modulation, and disease-related immunodeficiency further compound infection risk. The result is a dynamic and cumulative impairment of host immunity that evolves over the course of therapy. In this "How I Treat" article, we provide a practical, phase-based framework for preventing and managing infections in patients receiving BsAbs for non-Hodgkin lymphoma or multiple myeloma. Our review includes pre-treatment evaluation, the period of active therapy, and long-term follow-up. Using representative cases, we highlight strategies for infectious disease screening, antimicrobial prophylaxis, immunoglobulin supplementation, vaccination, and other supportive care practices. Our aim is to equip clinicians with an evidence-informed and pragmatic framework for mitigating BsAb-related infection risks.