Weekly Bortezomib Decreases Rates of Peripheral Neuropathy without Diminishing Efficacy As Compared to Twice Weekly Bortezomib in Combination with Lenalidomide, Dexamethasone and Daratumumab
Authors: Yi Irvin , Gaspar Eleni , Eighmy William , Roeder Heidi , Bar Noffar 
Published: December 2024

Background: Bortezomib-induced peripheral neuropathy (PN) is a significant cause of dose delay and discontinuation in multiple myeloma (MM) therapy, with significant symptom burden on patients. Bortezomib is used in combination with daratumumab, lenalidomide and dexamethasone (D-VRd) as standard of care for frontline treatment in MM. This combination is based on results from the phase II GRIFFIN and phase III PERSEUS trials. PN was seen in 59.6-72.5% of patients in the GRIFFIN trial and 51.6-53.6% in the PERSEUS trial. In these trials, bortezomib was administered twice-weekly on days 1, 4, 8 and 11 of each 21-day cycle. Given bortezomib-induced PN is dose-dependent (Carozzi et al., 2013), many physicians prefer to adminster bortezomib once-weekly on days 1, 8, 15 and 22 over a 28-day cycle in D-VRd. This schedule delivers the same cumulative dosage as twice-weekly, but is theorized to reduce PN. Single-center studies and real-world data have demonstrated lower rates of PN and similar efficacy on this type of schedule in various bortezomib-containing regimens (Cook et al., 2021), but none evaluated this exclusively in D-VRd. As the GRIFFIN and PERSEUS trials are cited in clinical guidelines and their treatment schedules are incorporated in health system pathways and chemotherapy builds, some patients still receive twice-weekly bortezomib. This study will analyze the efficacy and tolerability of weekly versus twice-weekly bortezomib exclusively in patients receiving D-VRd.

Methods:This is a single-center, retrospective cohort study performed on eligible patients treated at Yale Cancer Center including network sites from January 1, 2017, to November 1, 2023. Patients ≥18 years of age with a diagnosis of MM who were treated with D-VRd and received at least 2 doses of bortezomib were included. Patients were excluded if they had a diagnosis of PN prior to starting D-VRd, received anti-neuropathic medications prior to D-VRd treatment, if they had received bortezomib in a regimen prior to D-VRd or if they switched from twice-weekly to once weekly regimen for reasons other than PN. There are two primary objectives: first, to assess rates of PN in patients with MM receiving D-VRd in once weekly versus twice-weekly bortezomib. Second, to evaluate treatment efficacy at the end of induction using overall response rate, as defined by IMWG criteria, and progression rate. Secondary objectives include number of bortezomib dose reductions and/or dose discontinuations due to PN, rate of PN stratified by grade and use of anti-neuropathic pain agents.

Results: 17 of 50 patients (34%) receiving weekly bortezomib developed PN, significantly lower than the 17 of 21 patients (81%) who developed PN on twice-weekly dosing (P&lt;0.001). The observed incidence of PN in the twice-weekly group is similar to that measured in the GRIFFIN and PERSEUS trials. While there was no difference in the severity of PN as graded by the CTCAE version 5.0, significantly fewer patients required dose reductions due to PN (P&lt;0.013) and treatment for PN (P&lt;0.001) in the weekly group compared to the twice-weekly group. The median number of days from starting bortezomib to diagnosis of PN was 60 days in the weekly group and 63 days for the twice-weekly group. The number of bortezomib doses and D-VRd cycles prior to diagnosis of PN were similar between groups. Importantly, there was no difference in efficacy on D-VRd between the two groups. The overall response rate (ORR) for weekly bortezomib was 48 of 49 patients (98%), compared to all 21 of 21 patients (100%) for twice-weekly (P&gt;0.999). There was also no difference in disease progression for weekly (10%) and twice-weekly (5%) dosing (P=0.666), at a median follow-up time of 23.3 months for weekly and 23.6 months for twice-weekly.

Discussion: This study continues to demonstrate once weekly bortezomib dosing leads to a clinically relevant reduction in PN as compared to twice-weekly dosing, without impacting treatment efficacy. It is the first study to extend the data specifically to D-VRd, the current frontline treatment for MM. Further alignment between real-world data and health system pathways is needed.