Bortezomib induced peripheral neuropathy: a multimodal, monocentric,

Bortezomib induced peripheral neuropathy: a multimodal, monocentric, non-randomised clinical study - SA53

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Day 3: 9:45 poster sessions

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Institution: Department of Neurology, University Hospital Würzburg - Bavaria, Germany

Bortezomib induced peripheral neuropathy: a multimodal, monocentric, non-randomised clinical study

Background and aims: Multiple myeloma (MM) is a plasma cell disorder, which accounts for 13% of all haematological malignancies. The first-line therapy for this specific disease is bortezomib (BTZ), a selective and reversible proteasome inhibitor. A side effect of BTZ treatment is BTZ-induced peripheral neuropathy (BIPN). Patients suffering from BIPN have sensory disturbances and pain, and in more severe cases, paresis. BIPN is a dose-limiting complication in up to 30% of treated patients. Symptoms regress in some but not all patients after dose reduction or after the end of the treatment. Here we asked whether systemic inflammatory mediators or neurofilament light chain (NfL) follow the temporal course of symptom improvement or worsening.

Methods: This is an interim analysis of a monocentric, non-randomised clinical trial with MM patients including measurement of serum NfL in 16 patients at Baseline (BL), when they were included into the study and were currently under or had just started their BTZ treatment. Furthermore, serum NfL was measured in 10 patients with ongoing BTZ treatment at follow-up (BTZ), 10 patients with discontinued BTZ treatment at follow-up (BTZ stopped) and 18 healthy controls (HC). For CC-chemokine ligand 2 (CCL2), Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), six patients at BL and 3-month follow up (3M) were analysed. CCL2, IL-6, TNF-α and NfL were measured using the ELLA device (ProteinSimple, CA, USA).

Results: Median BL NfL levels were higher than HC (BL: 84.2 pg/ml; HC: 14.8; p = < 0.0001). Furthermore, follow-up NfL levels in the group “BTZ” and in the group “BTZ stopped” were higher than HC, but with decreasing absolute values (BTZ: 64.3 pg/ml; HC: 14.8; p = < 0.001; BTZ stopped: 37.4 pg/ml; HC: 14.8; p = < 0.05) (Figure1). In the group 3M, there were 2 patients with new pain development, 2 patients with pain resolution and 2 stable patients without pain since BL. Patients who developed pain at 3M tended to have increased levels of CCL2, IL-6 and TNFα, whereas patients with resolved pain at 3M tended to have decreasing levels of CCL2 and stable levels of IL-6 and TNF-α (Table 1, n.s. due to small n-numbers).

Conclusion: NfL levels under BTZ treatment were the highest at BL and decreased at follow-up, even more so, if BTZ had been stopped. Increasing CCL2, IL-6 and TNFα levels over time were associated with new pain development, decreasing CCL2 and stable IL-6 and TNFα levels with pain resolution. Since this is an ongoing project, updated data will be presented at the Congress.

Source of financial support:
This study is part of KFO5001 ResolvePAIN, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project ID: 426503586.

References:
Kortüm, K., Engelhardt, M., Rasche, L. et al. Das multiple Myelom. Internist 54, 963–977 (2013). https://doi.org/10.1007/s00108-013-3336-2
Cebulla, Nadine et al. “Neurofilament light chain levels indicate acute axonal damage under bortezomib treatment.” Journal of neurology, 10.1007/s00415-023-11624-2. 18 Feb. 2023, doi:10.1007/s00415-023-11624-2
Zhao, Weiwei et al. “Peripheral neuropathy following bortezomib therapy in multiple myeloma patients: association with cumulative dose, heparanase, and TNF-α.” Annals of hematology vol. 98,12 (2019): 2793-2803. doi:10.1007/s00277-019-03816-6

Relevance for Patient Care:
By examining systemic inflammatory mediators and neurofilament light chain, we seek to uncover differences between patients who develop and/or resolve pain and thus find predictors of BIPN that can be translated into everyday clinical practice.

Ethical Permissions:
This study has been approved by the Ethics Committee of the Medical Faculty of the University of Würzburg (# 98/20).

Figure 1: Median baseline NfL levels (Baseline) N = 16, median NfL levels of follow-ups with ongoing BTZ treatment (BTZ) N = 10, median NfL levels of follow-ups with discontinued BTZ treatment since baseline (BZ stopped) N = 10, median NfL levels of Healthy Controls (HC) N = 18; significance levels: * < 0.05, *** < 0.001, **** < 0.0001

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Nadine Cebulla

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Nadine Cebulla - Department of Neurology, University Hospital Würzburg , Daniel Schirmer - Department of Neurology, University Hospital Würzburg , Eva Runau - Department of Neurology, University Hospital Würzburg , Leon Flamm - Department of Neurology, University Hospital Würzburg , Calvin Terhorst - Department of Neurology, University Hospital Würzburg , Laura Jähnel - Department of Neurology, University Hospital Würzburg , Dr. med. Xiang Zhou - Department of Internal Medicine II, University Hospital Würzburg , Dr. med. Ann-Kristin Reinhold - Department of Anesthesiology, Intensive Care, Emergency Medicine and Pain Medicine, Center for Interdisciplinary Medicine, University Hospital Würzburg , Bruno Rogalla von Bieberstein - Department of Anesthesiology, Intensive Care, Emergency Medicine and Pain Medicine, Center for Interdisciplinary Medicine, University Hospital Würzburg , Prof. Dr. med. Heike Rittner - Department of Anesthesiology, Intensive Care, Emergency Medicine and Pain Medicine, Center for Interdisciplinary Medicine, University Hospital Würzburg , Prof. Dr. med. Hermann Einsele - Department of Internal Medicine II, University Hospital Würzburg , Prof. Dr. med. Martin Kortüm - Department of Internal Medicine II, University Hospital Würzburg , Prof. Dr. med. Claudia Sommer - Department of Neurology, University Hospital Würzburg

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Bortezomib induced peripheral neuropathy: a multimodal, monocentric, non-randomised clinical study - SA53

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