Background & Aims

Multiple Myeloma (MM) is a plasma cell disorder that is commonly treated with the first in class proteasome inhibitor bortezomib (BTZ). Patients treated with BTZ are at risk to develop bortezomib-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. Most of the postulated pathomechanisms have been established in animal models or in very small cohorts of patients, which keeps the level of evidence for targets and mechanisms low. The aim of this study is to unravel pathomechanisms in a large cohort and uncover potential new targets via RNA sequencing.

Methods

In this interim analysis we included 109 MM patients. We divided patients into 3 groups. FC: first cycle of BTZ treatment (N=23), OT: ongoing BTZ treatment (N=40), PT: BTZ treatment in the past (N=46). In addition, we analyzed a subgroup of patients from FC and OT group in follow-up investigations after 3, 6, 12, or ? 18 months and assigned them to the appropriate subgroup: pain development (N=6), pain resolving (N=6), neuropathy development (N=9), no neuropathy development (N=3), stable neuropathy (N=2) and stable pain (N=5). We measured neurofilament light chain (NfL), CC-chemokine ligand 2 (CCL2) and tumor necrosis factor alpha (TNF-?) in blood using the ELLATM device (ProteinSimple, CA, USA). Results from ongoing RNA sequencing will be presented at the Congress.

Results

In the pain development subgroup, median CCL2 and TNF-? levels were higher at the follow-up examination (FU) compared to baseline (BL); (BL CCL2: 209 pg/ml, FU CCL2: 415 pg/ml, p < 0.01; BL TNF-?: 8.0 pg/ml, FU TNF-?: 15.7 pg/ml, p < 0.05. In the other subgroups, median CCL2 and TNF-? levels remained stable. Notably, the highest Neuropathic Pain Symptom Inventory (NPSI) score was found in the stable pain group at their BL investigation (Median = 51) and the highest median NfL level in the OT group (93.4 pg/ml; p < 0.0001).

Conclusions

Increasing CCL2 and TNF? levels over time were associated with pain development. NfL levels were highest under ongoing BTZ treatment, indicating axonal damage.

References

Cebulla N, Schirmer D, Runau E, Flamm L, Gommersbach S, Stengel H, Zhou X, Einsele H, Reinhold AK, Rogalla von Bieberstein B, Zeller D, Rittner H, Kortüm KM, Sommer C. Neurofilament light chain levels indicate acute axonal damage under bortezomib treatment. J Neurol. 2023 Jun;270(6):2997-3007. doi: 10.1007/s00415-023-11624-2. Epub 2023 Feb 18. PMID: 36802032; PMCID: PMC10188420.

Presenting Author

Nadine Cebulla

Poster Authors

Nadine Cebulla

OTHR

Department of Neurology University Hospital Würzburg

Lead Author

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Daniel Schirmer

Department of Neurology, University Hospital Würzburg

Lead Author

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Eva Runau

Department of Neurology, University Hospital Würzburg

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Leon Flamm

Department of Neurology, University Hospital Würzburg

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Calvin Terhorst

Department of Neurology, University Hospital Würzburg

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Laura Jähnel

Department of Neurology, University Hospital Würzburg

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Johanna Güse

Department of Neurology, University Hospital Würzburg

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Nicola Giordani

Department of Neurology, University Hospital Würzburg

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Annett Wieser

Department of Neurology, University Hospital Würzburg

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Aikaterini Papagianni Dr.

Department of Neurology, University Hospital Würzburg

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Xiang Zhou Dr.

Department of Internal Medicine II, University Hospital Würzburg

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Ann-Kristin Reinhold

Universitätsklinikum Würzburg

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Heike Rittner

University Hospital Wuerzburg

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Hermann Einsele Prof. Dr.

Department of Internal Medicine II, University Hospital Würzburg

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Martin Kortüm Prof. Dr.

Department of Internal Medicine II, University Hospital Würzburg

Lead Author

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Claudia Sommer

Prof. Dr. MD

Institute for neurology, university hospital Würzburg, Germany

Lead Author

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Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral