TrkA abundance is increased in cutaneous nerves in bortezomib-induced neuropathy

Background and objectivesTropomyosin receptor kinase A (TrkA), a high-affinity receptor for nerve growth factor (NGF), is highly expressed in nociceptive neurons and plays a key role in nociception. Increased NGF levels have been related to local angiogenesis. This study investigates skin biopsies of multiple myeloma patients who developed peripheral neuropathy during bortezomib treatment for localization and abundance of TrkA. MethodsMultiple myeloma patients with bortezomib-induced peripheral neuropathy (BIPN) were recruited at the University Hospital Wurzburg between 2021 and 2024. Age-and sex-matched controls without neuropathy were enrolled for comparison. Skin biopsies from the distal leg were analyzed to determine intraepidermal nerve fiber density (IENFD) and area, TrkA mean fluorescence intensity (MFI) and gene expression levels of TrkA and NGF. Additionally, the proximity between nerve fibers and blood vessels was measured. ResultsWe enrolled 50 patients with BIPN (age 64.1 {+/-} 9.2 years; 76% male) and 27 controls (age 60.7 {+/-} 7.1 years; 81.5% male). Sensory abnormalities included reduced sural nerve action potential amplitude (63.3%), elevated cold (36%) and heat pain detection thresholds (44%) compared to normative population values (95% CI). IENFD was reduced in patients (median 2.6 [1.6-4.2] fibers/mm) compared to controls (4.7 [3.1-6.8] fibers/mm; p < 0.05). TrkA protein abundance in epidermal nerve fibers (normalized MFI) was higher in patients (0.93 [0.56-1.25]) than controls (0.13 [0.08-0.17]; p < 0.0001) and moderately correlated with the number of bortezomib treatment cycles (r = 0.36, p < 0.05). TrkA mRNA levels did not differ between groups, while NGF mRNA levels were lower in BIPN patients (p = 0.01). Among BIPN patients, those reporting pain had higher NGF mRNA levels than those without pain (p = 0.04). Dermal vascular area was increased in BIPN patients (926.0 [714.8-1710] {micro}m2) compared to controls (705.1 [496.5-1190] {micro}m2; p < 0.05). DiscussionThis study identifies reduced IENFD, increased TrkA abundance in remaining fibers, and enhanced dermal vascularization in multiple myeloma patients with BIPN. These findings raise the possibility that dysregulated NGF/TrkA signaling may contribute to small fiber pathology and the associated alterations in sensory function observed in BIPN.