Impact of Genetic Polymorphisms on Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma: A Systematic Review and Bioinformatics Analysis.

BACKGROUND

Bortezomib, a 26S proteasome inhibitor, has become a cornerstone in the treatment of multiple myeloma. However, its use is limited by a common and potentially serious adverse effect, bortezomib-induced peripheral neuropathy (BIPN), which manifests in 30-60% of multiple myeloma patients primarily as a sensory, distal, axonal neuropathy, often with pain, numbness, tingling, and in some cases, motor involvement, which can lead to dose reductions, therapy discontinuation, or long-term morbidity. BIPN is associated with genetic predisposition, and several studies suggest that single-nucleotide polymorphisms (SNPs) may contribute to the protective or increased risk effects of BIPN. This study aimed to investigate the genetic basis of BIPN in multiple myeloma.

METHODS

A qualitative systematic review was conducted to determine unique SNPs with significant association with BIPN. The search was performed using PubMed, Embase, Scopus, Web of Science, Google Scholar, Cochrane Library, ScienceDirect, and ClinicalTrials.gov. The risk of bias analysis was conducted following the Q-Genie protocol. The included SNPs were computationally analyzed using Gene Ontology enrichment, KEGG, and PPI network analyses to determine pathways implicated in BIPN. SNPnexus analysis was applied, including SIFT and PolyPhen-2 functional prediction, evolutionary conservation, epigenetic regulatory mapping, significant biological pathways, and population allele frequencies.

RESULTS

From a total of 9 studies, 48 SNPs increase the risk of BIPN, while 21 are protective. Computational analyses revealed that SNP-associated BIPN genes are implicated in xenobiotic response, detoxification, signal transduction, and inflammatory pathways. SIFT and PolyPhen-2 identified some variants with a potential impact on protein function. Several SNPs are conserved, which reflects their functional roles. Allele frequencies are distinct, with some SNPs being rare and others showing uneven distribution across populations.

CONCLUSIONS

Genetic variants probably play a significant role in the development of BIPN. The findings provide a mechanistic framework for predictive genotyping and personalized therapeutic strategies to mitigate BIPN in multiple myeloma patients.