Serum lipidomics for exploring biomarkers of bortezomib therapy in patients with multiple myeloma

Abstract

Although the proteasome inhibitor bortezomib (BTZ) shows excellent efficacy in multiple myeloma (MM), a fraction of patients has a suboptimal or no response to this agent. In addition, BTZ‐induced peripheral neuropathy (BiPN), a frequent side‐effect of this therapy, limits its use in some patients. This study aimed to explore serum lipid biomarker candidates to predict the response to BTZ and the severity of BiPN. Fifty‐nine serum samples were collected from patients with MM prior to receiving BTZ plus low‐dose dexamethasone therapy. Serum levels of phospholipids, sphingolipids, neutral lipids, and polyunsaturated fatty acids and their oxidation products were measured by a comprehensive lipidomic study. Overall, 385 lipid metabolites were identified in patients’ sera; lower levels of several glycerophospholipids, sphingolipids, and cholesteryl esters were associated with a poor treatment response. Metabolites related to platelet‐activating factor biosynthesis and cholesterol metabolism appeared particularly relevant. Furthermore, several lysophosphatidylcholines, phosphatidylcholines, ceramides, neutral lipids, and oxidative fatty acids were significantly increased or decreased in patients with BiPN grades ranging from G0 to G3. Among these compounds, mediators reportedly inducing myelin breakdown and stimulating inflammatory responses were prominent. Although further study is necessary to validate these biomarker candidates, our results contribute to the development of predictive biomarkers for response to BTZ treatment, or ensuing severe BiPN, in patients with MM.

Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy

“…A biomarker reflecting the severity of pain is strongly desired for both diagnostics in clinical practice and validation of the efficacy of novel analgesic drugs in clinical trials. Recently, lipidomics analysis of serum from 59 patients identified certain lipid species as biomarker candidates of BIPN symptoms [ 89 ]. Although further validation is necessary, several species of phosphatidylcholines, ceramides, neutral lipids, and oxidative fatty acids seem to be related to the severity of BIPN [ 89 ].…”

“…Recently, lipidomics analysis of serum from 59 patients identified certain lipid species as biomarker candidates of BIPN symptoms [ 89 ]. Although further validation is necessary, several species of phosphatidylcholines, ceramides, neutral lipids, and oxidative fatty acids seem to be related to the severity of BIPN [ 89 ]. These approaches exploring symptom-reflecting biomarkers will not only facilitate objective visualization of the severities of symptoms, such as pain, but also improve our understanding of the pathological mechanisms of BIPN.…”

A new prediction model integrated serum lipid profile for patients with multiple myeloma

“…Abnormal lipid metabolism is an important feature of tumor cells and is also a potential target for tumor treatment [30,31]. Studies have shown that compared with healthy controls, patients with myeloma have abnormal lipid levels [15,28,32]. In addition, in vivo and in vitro studies have found that statins, which are HMG-CoA reductase inhibitors used for the treatment of hyperlipidemia, may increase the susceptibility of myeloma cells to apoptosis through a variety of ways.…”

Neuromuscular complications of cancer therapy

“…A recent study longitudinally tested early and late metabolite profiles as predictive biomarkers of patients’ susceptibility to vincristine-induced peripheral neurotoxicity, and documented several statistically significant metabolomic changes, including lysine degradation, sphingolipid, glutathione, and glycerophospholipid metabolism, but none of them survived correction for multiple testing [32 ▪ ]. Another recent study added to this topic, by showing changes in the levels of lysophosphatidylcholines, phosphatidylcholines, ceramides, neutral lipids, and oxidative fatty acids in patients with multiple myeloma and bortezomib neurotoxicity [33]. Further studies are warranted to confirm if the results of metabolomic and lipidiomic studies can have true value in early predicting severe CIPN.…”