The Role of Microenvironment in Bispecific Antibodies Treatment in Multiple Myeloma

ABSTRACT Multiple myeloma (MM) is a clonal plasma cell malignancy that remains largely incurable despite major therapeutic advances. T‐cell‐redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T (CAR‐T) cells have recently emerged as highly effective therapies in relapsed/refractory MM, inducing deep responses even in heavily pretreated patients. However, disease relapse, limited durability of response, and treatment‐related toxicities remain frequent, underscoring the need to better understand mechanisms of resistance. Accumulating evidence indicates that the tumor microenvironment (TME) plays a central role in shaping BsAb efficacy in MM. Immunosuppressive cellular components, including regulatory T‐cells, myeloid‐derived suppressor cells, and dysfunctional antigen‐presenting cells, as well as inhibitory cytokines, hypoxia, and metabolic constraints within the TME, profoundly impair T‐cell activation, expansion, and persistence following BsAb engagement. In addition, chronic CD3 stimulation within the TME may promote T‐cell exhaustion, contributing to suboptimal responses and disease progression. This review focuses on the dynamic interplay between BsAbs and the MM TME, highlighting how microenvironment‐driven immune suppression, antigen escape, and impaired T‐cell fitness influence clinical outcomes. We further discuss emerging strategies designed to overcome these barriers, including rational combination approaches, immunomodulatory agents, and next‐generation trispecific antibodies that enhance co‐stimulation or dual‐antigen targeting. Understanding and therapeutically modulating the TME represents a critical step toward improving the depth, durability, and safety of BsAb‐based therapies in MM.