Features and Risk Factors of Peripheral Neuropathy during Treatment of Advanced Multiple Myeloma with Bortezomib.
Authors: El-Cheikh Jean , Stoppa Anne Marie , Duran Segolene , Bouabdallah Reda , Vey Norbert , Coso Diane , Ivanov Vadim , Charbonnier Aude , Faucher Catherine , de Collela Jean Marc Schiano , Camerlo Jacques , Gastaut Jean-Albert , Blaise Didier , Mohty Mohamad 
Published: April 2020

Abstract
Bortezomib has demonstrated activity and safety in heavily pretreated patients with relapsed and/or refractory multiple myeloma (MM). Peripheral neuropathy (PN) is among the most frequent adverse events reported with bortezomib, requiring dose-adjustment and careful patient-clinical monitoring. The aim of this retrospective single centre study was to determine the frequency, characteristics, and reversibility of PN from bortezomib treatment of 100 consecutive advanced MM patients treated with bortezomib 1.0 or 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11, every 21 days. PN was evaluated by investigator neurological examination at baseline, during the study, and at last follow-up. Patients characteristics at baseline prior to bortezomib initiation were as follow: median age: 60 (range, 27–77), prior history of diabetes: n=8 (8%), prior autologous transplantation: n=76 (76%), prior treatment with thalidomide: n=75 (75%) with a median dose of 200 (range, 50–600) mg for a median duration of 8 (range, 1–61) months. Median duration between thalidomide discontinuation and bortezomib initiation was 5 (range, 0–43) months. Before treatment with bortezomib, 48 patients (48%) already had some form of PN [grade 1, n=27 (56%); grade 2, n=16 (33%); grade 3, n=5 (11%)]. With a median follow-up of 8 (range, 0.1–32) months from bortezomib initiation, patients from this series received a median of 4 (range, 1–12) cycles of bortezomib. Bortezomib-related emergent PN was observed in 38 patients (38%; 95%CI, 28–47%), with grade 1, 2, 3, and 4 PN occurring in 17 (45%), 15 (39%), 5 (13%) and 1 (3%) patients respectively. Median time to onset of bortezomib-related PN was 53 (range, 11–182) days after bortezomib initiation. In most cases (n=30; 79%), patients had sensory symptoms, while 8 patients (21%) experienced both sensory and motor symptoms. Bortezomib-related PN led to dose reduction or discontinuation in 18 patients. Of the 38 patients with bortezomib-related PN, resolution to baseline or improvement occurred in 20 (53%) patients, at a median time of 3 (range, 1–8) months. In univariate analysis, comparing patients with and without bortezomib-related PN, prior history of treatment with thalidomide (P=0.009), patient baseline grade of PN at bortezomib initiation (P=0.04), number of bortezomib cycles administered (P=0.0005), and cumulative dose (mg) of bortezomib received by patients (P=0.001), were found to be significantly associated with the risk of emergence of bortezomib-related PN. In multivariate analysis, the total number of cycles of bortezomib (less or more than 4 cycles), and a prior history of treatment with thalidomide were the strongest parameters significantly associated with an increased incidence of bortezomib-related PN (P=0.03; OR=2.6; 95%CI, 1.1–6.1 and P=0.02; OR=3.9; 95%CI, 1.2–12.6 respectively). In all, we conclude that, though relatively frequent, bortezomib-associated PN seemed reversible in a majority of patients and manageable after dose reduction or discontinuation. However, the finding that the development of bortezomib-related PN seems to be dependent of the patient history of prior neurotoxic therapy (mainly thalidomide), raises the question of the optimal sequence and schedule of administration of these anti-MM effective drugs as single agents, but also in combination.