Relapsed or refractory multiple myeloma (RRMM) remains a therapeutic challenge despite advances in proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. A transformative strategy in recent years has been bispecific antibodies (BsAbs), engineered to simultaneously engage a tumor-associated antigen on malignant plasma cells and CD3 on T cells, thereby redirecting T-cell cytotoxicity toward the cancer cell. Two prominent targets in myeloma are B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D). Currently, there are four FDA-approved BsAbs available in the fifth-line treatment setting (BCMA-directed: teclistamab, elranatamab, linvoseltamab; GPRC5D-directed: talquetamab). Collectively, these agents demonstrate overall response rates exceeding 60% in heavily pretreated populations, including triple-class-refractory disease.
Safety
Despite their potency, bispecific antibodies have distinct toxicity profiles, including cytokine release syndrome (CRS), infections, immune effector cell-associated neurotoxicity syndrome (ICANS), and other hematologic and nonhematologic toxicities. Therefore, it is essential to have protocol-driven monitoring, rapid recognition of complications, and coordinated multidisciplinary treatment management.
CRS is a systemic inflammatory response triggered by rapid T-cell activation. CRS can range from mild fever and rigors to more significant hypotension and hypoxia. Across pivotal trials, CRS rates range from 50% to 70%, though the majority are grade 1 or 2 per ASTCT criteria. Severe CRS (grade 3 or higher) occurs in fewer than 5% of patients in most studies. Most CRS events occur early in therapy, particularly around the first full dose after step-up priming. Effective management often includes antipyretics, intravenous fluids, corticosteroids and interleukin-6 blockade with tocilizumab when indicated.
Infection represents a major cause of morbidity. Systematic reviews show that more than half of patients receiving bispecific therapy experience infections of any grade, with grade 3 or higher infections occurring in 20% to 40% of patients in some series. BCMA-targeted therapy frequently induces hypogammaglobulinemia due to plasma cell depletion. Preventive strategies include herpes simplex/varicella zoster virus and Pneumocystis jirovecii pneumonia prophylaxis; consideration of antibacterial prophylaxis in selected high-risk patients; routine immunoglobulin monitoring; and intravenous immunoglobulin (IVIG) replacement when clinically indicated.
Neurotoxicity, particularly ICANS, appears relatively uncommon with BsAbs (occurring in fewer than 5% of treated patients) compared with CAR T-cell therapies, but its possibility requires baseline neurologic assessment and ongoing assessment throughout treatment. When present, it is typically low grade and reversible with corticosteroid intervention.
Neutropenia, anemia and thrombocytopenia are common across BsAbs, reflecting on-target effects on plasma cells and bystander immune cells. Cytopenias may reflect both disease burden and immune-mediated marrow suppression. Growth factor support, transfusions and dose modifications are often required. GPRC5D-directed agents are associated with unique nonhematologic effects, including dysgeusia, xerosis/keratoderma, nail dystrophy and oral mucosal changes. These toxicities are generally low grade but may affect quality of life and adherence.
Monitoring
With unique adverse events, a structured monitoring strategy is essential. Before treatment initiation and with each dose, clinicians should assess vital signs, complete blood counts, metabolic panels and infection markers. Early identification of fever, hypotension, hypoxia or neurologic changes should trigger standardized CRS and neurotoxicity protocols, including the rapid use of tocilizumab and corticosteroids when indicated. Given the infection risk, vigilance for new symptoms and low thresholds for cultures and imaging are vital, along with appropriate prophylaxis according to guidelines. Moreover, patient and caregiver education on adverse events and when to seek urgent care is a cornerstone of monitoring.
Outpatient implementation
Delivering bispecific antibody therapy outside the hospital requires multidisciplinary coordination. Many centers have adopted an outpatient “step-up dosing” protocol, with initial priming doses under closer observation, often in an infusion center with immediate access to supportive care (CRS prophylaxis with tocilizumab or corticosteroids is typically given), followed by transition to regular outpatient schedules once tolerance is confirmed. Outpatient units must be equipped with trained staff familiar with CRS grading and management algorithms. Rapid access to emergency care for severe events, clear communication pathways with hematology/oncology providers and caregiver education are crucial elements. Many programs use standardized order sets, checklists and patient handouts to ensure consistent safety practices and support patient self-monitoring between visits.
Conclusion
Bispecific antibodies targeting BCMA and GPRC5D have revolutionized the treatment landscape for relapsed and refractory multiple myeloma, offering effective immunotherapy that can be safely delivered in outpatient settings when adverse events are proactively managed. Their toxicity profiles, marked by CRS, cytopenias, infections and target-specific nonhematologic effects, necessitate structured monitoring, rapid recognition of complications and coordinated multidisciplinary care. As clinicians gain more experience and protocols mature, these therapies will continue to expand access to potent, customizable regimens for patients with advanced myeloma.
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References:
- National Comprehensive Cancer Network. Multiple Myeloma Guidelines. Current version.
- Lee, David W., et al. “ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity.” Biology of Blood and Marrow Transplantation 25, no. 4 (2019): 625–638.
- van de Donk, N. W. C. J., et al. “Management of Infections in Patients Receiving Bispecific Antibodies for Multiple Myeloma.” Blood Cancer Journal (2023).
- Usmani, S. Z., et al. “Practical Considerations for Bispecific Antibody Therapy in Multiple Myeloma.” Journal of Clinical Oncology (2023).
