Advancing T Cell Engagers in Multiple Myeloma: Structural Design and Clinical Optimization to Address Current Limitations

T cell engagers (TCEs) have emerged as transformative agents in multiple myeloma, driving a paradigm shift through advances in molecular engineering and clinical application. This review examines these developments across structural design and clinical optimization. Structurally, the field has evolved from IgG-like formats enabling subcutaneous administration toward multi-specific architectures designed to circumvent antigen escape and enhance tumor selectivity. Clinically, strategies have been refined by early TCE integration to leverage preserved immune fitness, step-up dosing to mitigate cytokine release syndrome, and combinations with gamma-secretase inhibitors or immunomodulatory drugs to overcome resistance. However, key limitations persist: antigen loss and lineage plasticity; on-target/off-tumor depletion of normal plasma cells with hypogammaglobulinemia and infection; T-cell exhaustion under continuous exposure; and the absence of predictive biomarkers for response, toxicity, and sequencing. Future efforts should prioritize conditional or logic-gated formats that decouple potency from systemic exposure, target rotation to preempt escape, biomarker-driven selection with minimal residual disease-guided duration, and home-based subcutaneous delivery. Integrating bioengineering innovation with optimized clinical protocols while confronting these constraints will be essential for TCEs to deliver durable remissions and advance the prospect of a functional cure for MM.