Cytokine Dynamics in Bortezomib-Induced Peripheral Neuropathy: Challenges in Translating Preclinical Findings to Humans

Abstract

Background and Aims

Bortezomib-induced peripheral neuropathy (BIPN) remains a common treatment side effect in patients with multiple myeloma (MM). Data from rodent models indicate a role of proinflammatory cytokines in BIPN pathophysiology, making them potential therapeutic targets. We therefore tested cytokine levels throughout the course of BIPN in a cohort of MM patients.

Methods

We performed an interim analysis of a monocentric, non-randomized, observational study including 113 patients with MM. Three groups of patients—within their first cycle of BTZ treatment (FC), with ongoing BTZ treatment at the time of recruiting (OT), and with BTZ treatment in the past (PT)—were compared to controls. Sixteen FC patients were followed up for a median of 6 months. Serum TNF-α, IL-6, and CCL2, the cytokines most often implied in the animal models, were analyzed via the ELLA device.

Results

CCL2 levels were not different among our patient groups or in comparison with healthy controls. Compared to healthy controls, the FC group had the highest IL-6 levels, followed by the PT and then the OT group. The FC group also had higher TNF-α levels compared to all other groups. Six months after inclusion, patients showed a decrease in TNF-α levels compared to their baseline. There was no correlation between TNF-α levels and neuropathy severity or impairment in daily life.

Interpretation

Factors related to MM may influence systemic cytokine levels in BIPN patients, limiting conclusions on their role in BIPN pathophysiology and their utility as drug targets.