Effect of CYP2C19 polymorphism on response to bortezomib-based therapy in multiple myeloma patients.

BACKGROUND: Bortezomib, a commonly used anti-myeloma drug, is metabolized by liver microsomal enzymes which may be polymorphic and responsible for lack of response in 30% patients. Hence, the association of CYP2C19 polymorphism with treatment response was explored in this study. METHODS: Treatment naive multiple myeloma (MM) patients, eligible for bortezomib-based induction treatment, were recruited as per the inclusion - exclusion criteria. The genotyping of CYP2C19 was done using polymerase chain reaction-restriction fragment length polymorphism for *2, *3 and *17 alleles. The incidence and severity of peripheral neuropathy were noted at follow-up visits and graded as per CTCAE criteria ver 5.0. RESULTS: Total 220 patients were recruited from August 2016 till May 2021; with a mean age of 55.6 (9.5) years and 65.9% males. Bortezomib+cyclophosphamide+dexamethasone (41.8%) and bortezomib+lenalidomide+dexamethasone (38.2%) were the most prescribed regimens. The CYP2C19 was polymorphic in 38.6%, 2.3% and 23.7% patients for *2, *3 and *17 allele respectively. There were 195 treatment responders and 25 non-responders, and CYP2C19*2 allele was different between responders and non-responders (p = 0.02). All extensive metabolisers (n = 54) were noted to be treatment responders. Peripheral neuropathy was reported by 23.2% patients. The frequency of peripheral neuropathy was somewhat lower in patients having either *2/*2 or *3/*3 allele pattern for CYP2C19 (p = 0.44). CONCLUSIONS: Polymorphism in CYP2C19 enzyme is likely to have an impact on bortezomib treatment response and peripheral neuropathy. The study suggests the role of pharmacogenetics in personalised treatment of MM.

Role of inflammation and oxidative stress in chemotherapy-induced neurotoxicity.

Chemotherapeutic agents may adversely affect the nervous system, including the neural precursor cells as well as the white matter. Although the mechanisms are not completely understood, several hypotheses connecting inflammation and oxidative stress with neurotoxicity are now emerging. The proposed mechanisms differ depending on the class of drug. For example, toxicity due to cisplatin occurs due to activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which alters hippocampal long-term potentiation. Free radical injury is also involved in the cisplatin-mediated neurotoxicity as dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been seen which protects against the free radical injury by regulating glutathione S-transferases and hemeoxygenase-1 (HO-1). Thus, correcting the imbalance between NF-κB and Nrf2/HO-1 pathways may alleviate cisplatin-induced neurotoxicity. With newer agents like bortezomib, peripheral neuropathy occurs due to up-regulation of TNF-α and IL-6 in the sensory neurons. Superoxide dismutase dysregulation is also involved in bortezomib-induced neuropathy. This article reviews the available literature on inflammation and oxidative stress in neurotoxicity caused by various classes of chemotherapeutic agents. It covers the conventional medicines like platinum compounds, vinca alkaloids, and methotrexate, as well as the newer therapeutic agents like immunomodulators and immune checkpoint inhibitors. A better understanding of the pathophysiology will lead to further advancement in strategies for management of chemotherapy-induced neurotoxicity.

Mechanistic Involvement of Inflammation in Bortezomib-induced Peripheral Neuropathy.

AIM: The aim of the study was to establish the role of inflammation in bortezomibinduced peripheral neuropathy (BIPN). BACKGROUND: Peripheral neuropathy is the dose-limiting toxicity of bortezomib that can lead to discontinuation of the treatment. There are multiple mechanisms involved in the disposition of BIPN. However, the role of inflammatory mediators is still under investigation. A complete understanding of inflammatory markers in relation to BIPN can lead to the development of effective therapy for prophylaxis and treatment of peripheral neuropathy. OBJECTIVE: Based on the available data, the role of inflammatory mediators in the development of peripheral neuropathy due to bortezomib has been postulated. METHODS: The "Pubmed" and "Google Scholar" were used as the search engines with terms like "peripheral neuropathy", "bortezomib-induced peripheral neuropathy" and "inflammation". Original research, case reports and review articles were considered. RESULTS: Bortezomib use is associated with the development of peripheral neuropathy. This effect is due to the damage to Schwann cells and dorsal root ganglion neurons, mitochondrial damage, increased ion channel susceptibility, and higher infiltration of macrophages in the spinal cord. All these factors collectively increase the secretion of inflammatory mediators and lead to the development of neuropathic pain. CONCLUSION: Targeting inflammatory mediators may be helpful in the treatment of bortezomibinduced peripheral neuropathy.

Evaluation of serum glucose-regulated protein 78 (GRP78) as a biomarker of treatment response to bortezomib-based induction regimen in multiple myeloma: A cross-sectional pilot study.

GRP78 overexpression in myeloma cells has been associated with bortezomib resistance in multiple myeloma (MM). However, serum GRP78 as a maker of bortezomib-based treatment response remains unexplored. The objective of the study was to evaluate serum GRP78 levels in MM patients who underwent a bortezomib-based induction regimen. This cross-sectional study included adult MM patients (n=30) who completed at least four cycles of bortezomib-based induction therapy. Healthy volunteers (n=30) and newly diagnosed MM patients (n=19) were also recruited to identify the disease-associated change in GRP78 levels. Serum GRP78 was estimated by ELISA. Surface and intracellular expression of GRP78 in bone marrow plasma cells was evaluated in ten MM patients by flow cytometry. Among 30 MM patients [median (range): 52 (38-68) years; 20 males] who completed at least four cycles of bortezomib-based induction therapy, 20 were responders and 10 were non-responders. Serum GRP78 levels were not significantly different between responders [median (IQR): 5.2 (3.1, 8.0) µg/ml] and non-responders [median (IQR): 4.3 (0.1, 7.1) µg/ml] (p=0.4). Although non-significant (p=0.3), median serum GRP78 was higher in newly diagnosed patients when compared to healthy volunteers. Bone marrow plasma cells ranged from 0.2 to 57.8% in the analyzed samples. Intracellular GRP78 expression in bone marrow plasma cells was higher (1.6 to 5 times) when compared to surface expression. To conclude, serum GRP78 levels vary widely in different MM patient groups but did not correlate with response to a bortezomib-based induction regimen.