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Updated: May 29, 2025
Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis
Published on: May 1, 2015
Unveiling causal immune cell-gene associations in multiple myeloma: insights from systematic reviews and Mendelian
Hui Zhang1,2, Ling Zhang3, Jing-Xuan Lian4
1Department of Traditional Chinese Medicine, Tangdu Hospital, Air Force Medical University (Fourth Military Medical University), Xi'an, China.
Background:
The efficacy of novel chimeric antigen receptor T-cell (CAR-T) therapy is inconsistent, likely due to an incomplete understanding of the tumor microenvironment (TME). This study utilized meta-analysis to evaluate CAR-T-cell therapy efficacy and safety and employed two-sample Mendelian randomization (MR) analysis to investigate the causal links between immune cells and Multiple Myeloma (MM).
Method:
Our literature review, conducted from January 1, 2019, to August 30, 2024, across Medline/PubMed, Scopus, and Web of Science, identified 2,709 articles, 34 of which met our inclusion criteria. We utilized MR analysis of GWAS data to identify immune cells causally related to multiple myeloma, followed by SMR analysis to highlight associated pathogenic genes and colocalisation analysis for validation.
Results:
The meta-analysis revealed an 82.2% overall response rate to CAR-T-cell therapy, characterized by a safe profile with a grade 3 or higher CRS of 6.3% and neurotoxicity of 0.9%. BCMA, CD38, and GPRC5D CAR-T-cell therapies had superior response rates, whereas BCMA and CD3 CAR-T-cell therapy rates lagged at 61.8%. Post-adjustment for multiple testing, the levels of seven types of immune cells (two types of Treg, two types of TNBK, two types of B cells, and one type of Myeloid cell) were found to be elevated in association with an increased risk of multiple myeloma (MM), while the levels of another eight types of immune cells (one types of Treg, three types of TNBK, one type of MT cells, and two types of Myeloid cell and one type of cDC cells) were demonstrated to be associated with a decreased risk of MM. As supported by sensitivity analysis. SMR analysis pinpointed the risk genes VDR, VHL, POMC, and FANCD2, with VHL and POMC correlating at the methylation level. VDR was not significantly correlated with MM after correction for multiple tests. NCAM1 also exhibited a significant methylation-level association with disease.
Conclusion:
Our study supports the efficacy and safety of CAR-T-cell therapy in rrMM patients, with an 82.2% ORR and low rates of severe CRS (6.3%) and neurotoxicity (0.9%). This finding also suggests that BCMA/CD19 bispecific CAR-T cells have a superior ORR, pending clinical confirmation. MR analysis reveals links between immune cells, genes such as VDR and VHL, and MM, enhancing our understanding of its pathophysiology.
Insights
Chimeric antigen receptor T-cell (CAR-T) therapy shows an 82.2% response rate for multiple myeloma (MM). Mendelian randomization analysis identified causal links between specific immune cells and MM risk, offering new insights into disease pathophysiology.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Chimeric antigen receptor T-cell (CAR-T) therapy efficacy for multiple myeloma (MM) is variable, potentially due to incomplete understanding of the tumor microenvironment (TME).
- This study evaluates CAR-T therapy efficacy and safety using meta-analysis and investigates causal links between immune cells and MM via Mendelian randomization (MR).
Purpose of the Study:
- To assess the efficacy and safety of CAR-T-cell therapy in relapsed/refractory multiple myeloma (rrMM).
- To identify immune cell types causally associated with MM risk using MR analysis.
- To pinpoint pathogenic genes linked to MM and explore their methylation-level correlations.
Main Methods:
- A comprehensive literature review (Jan 2019-Aug 2024) identified 34 relevant studies from 2,709 initial articles.
- Meta-analysis was performed to determine overall response rates (ORR) and adverse events (CRS, neurotoxicity) of CAR-T therapies.
- Two-sample MR analysis of GWAS data was used to investigate causal relationships between immune cell levels and MM risk, followed by SMR and colocalisation analyses.
Main Results:
- Meta-analysis showed an 82.2% ORR for CAR-T therapy in rrMM, with low rates of severe CRS (6.3%) and neurotoxicity (0.9%).
- BCMA, CD38, and GPRC5D CAR-T therapies demonstrated superior response rates.
- MR analysis identified seven immune cell types associated with increased MM risk and eight with decreased risk. VDR, VHL, POMC, and FANCD2 were pinpointed as risk genes, with VHL and POMC showing methylation-level correlation.
Conclusions:
- CAR-T therapy is effective and safe for rrMM patients, with high ORR and manageable toxicity.
- BCMA/CD19 bispecific CAR-T cells may offer superior ORR, warranting further clinical validation.
- The study elucidates causal links between immune cells, specific genes (e.g., VDR, VHL), and MM, advancing the understanding of its pathophysiology.
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