Rethinking mechanisms of neurotoxicity with BCMA directed therapy
Ghulam Rehman Mohyuddin1, Rahul Banerjee2, Zakariya Alam3
1Department of Hematology and Hematological Malignancies, Huntsman Cancer Center, University of Utah, United States.
Abstract:
B-cell maturation antigen (BCMA) has become a key target for antibody-drug conjugates, bispecific antibodies, chimeric antigen receptor T-cell therapies, and other immunotherapies in multiple myeloma. Some of these agents such as belantamab mafodotin and idecabtagene vicleucel have already received regulatory approval in the United States. Although BCMA has generally been considered to be expressed almost exclusively in plasma cells with a low likelihood of on-target off-tumor toxicity, there has been a range of unusual neurotoxicity observed across the spectrum of BCMA immunotherapies. In certain cases, these unusual neurotoxicity presentations have led to patient death or withdrawal of agents from further development. Our review summarizes the literature in this field and highlights the possibility of on-target toxicities due to neural expression of BCMA. We draw attention to the need for further investigation of these toxicities. This risk becomes increasingly important as BCMA targeted therapies are brought to earlier lines of treatment.
Insights
B-cell maturation antigen (BCMA) immunotherapies show unusual neurotoxicity, possibly due to neural BCMA expression. Further research is crucial as these treatments advance.
Area of Science:
- Oncology
- Immunotherapy
- Neuroscience
Background:
- B-cell maturation antigen (BCMA) is a primary target for multiple myeloma immunotherapies, including antibody-drug conjugates and CAR T-cell therapies.
- Approved BCMA-targeted agents like belantamab mafodotin and idecabtagene vicleucel are transforming treatment paradigms.
- BCMA was historically considered exclusively expressed on plasma cells, suggesting minimal on-target, off-tumor toxicity.
Purpose of the Study:
- To review the literature on neurotoxicity associated with BCMA-targeted immunotherapies.
- To investigate the potential link between unusual neurotoxicity and neural expression of BCMA.
- To emphasize the need for further research into BCMA-related toxicities.
Main Methods:
- Comprehensive literature review of studies reporting neurotoxicity in patients treated with BCMA-targeted therapies.
- Analysis of clinical data and case reports to identify patterns of neurotoxicity.
- Evaluation of existing evidence regarding BCMA expression in neural tissues.
Main Results:
- A spectrum of unusual neurotoxicity has been observed across various BCMA immunotherapies.
- Some cases of neurotoxicity have been severe, leading to patient death or discontinuation of therapy.
- Emerging evidence suggests potential on-target toxicity due to BCMA expression in the nervous system.
Conclusions:
- The observed neurotoxicity raises concerns about the safety profile of BCMA-targeted therapies.
- Neural expression of BCMA may contribute to these adverse events, necessitating further investigation.
- Understanding and mitigating these risks are critical as BCMA therapies are considered for earlier lines of treatment in multiple myeloma.
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