Visualization of Bortezomib Induced Peripheral Neuropathy By Dorsal Root Ganglion MRI in Patients with Multiple Myeloma

Background:

Whereas most treatments in multiple myeloma (MM) are stopped due to their inefficiency over time and the development of drug resistance, the use of the proteasome inhibitor bortezomib (BTZ) is mainly limited by its neurotoxic effects and the induction of BTZ induced neuropathy (BIPN). Of particular pathophysiological importance is the dorsal root ganglion (DRG), which plays a central role in the development of BIPN (Argyriou et al. Blood 2008). As early BIPN diagnosis and treatment adjustment is critical, we here investigated the predictive potential of DRG MRI and measured the DRG T2 signal intensity as a biomarker of inflammation in BTZ treated MM patients.

Methods: We recruited a total of 112 MM patients receiving BTZ either currently or in the past. Of these, 92 (82 %) had BIPN, which was painful in 37% (n=41) and mild and only detectable by sophisticated clinical-neurological diagnostics in 52% of patients (n = 58, severity Grade 1 with/without pain). DRG MRI was performed in a subset of 54 patients, including 45 of them with detectable BIPN (all grades), and additionally in 12 healthy controls. Using high-resolution three-dimensional T2-weighted fast spin-echo DRG MRI, we evaluated the lumbosacral DRG Th12-S2 bilaterally in all patients. Comparative analyses were performed using one-way ANOVA with Bonferroni correction. Pearson's Rho was used for the correlation analyses.

Results: Analysis revealed a significant increase in DRG T2 signal intensity in MM patients with BIPN compared to MM patients without BIPN (p= 0.005) and healthy controls (p= 0.003). Furthermore, an inverse correlation was found between DRG T2 signal intensity and intraepidermal nerve fiber density (IENFD) (p= 0.035). The mean DRG volume on L5+S1 level (in mm³) did not differ significantly between the groups, however, IENFD was significantly decreased in BIPN MM patients (n=26; 3.41 fibers/mm) compared to the healthy controls (n=12, 5.28 fibers/mm; p = 0.031), MM patients without BIPN showed no difference in IENFD (4.45 fibers/mm) compared to healthy controls.

Conclusion:

DRG T2 signal intensity is a surrogate marker of inflammation, and our observations suggest that inflammatory changes at the DRG level underlie BIPN in MM patients. Our imaging holds potential to be used as a non-invasive biomarker for early BIPN detection and to define patients at risk. This is an ongoing study, and imaging from the full cohort and from additional longitudinal assessment will be presented at the meeting.

Rasche:Pfizer: Honoraria; Skyline Dx: Research Funding; Janssen: Honoraria; GSK: Honoraria; BMS: Honoraria; Amgen: Honoraria. Waldschmidt:Oncopeptides: Consultancy; Pharmamar: Honoraria; Stemline Menarini: Consultancy; Beigene: Honoraria; Pfizer: Honoraria; GSK: Honoraria; Sanofi: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Einsele:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria. Kortüm:GSK: Honoraria; BMS: Honoraria; Menarini Stemline: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Skyline Dx: Research Funding; Amgen: Honoraria.