P-377: Impact of weekly versus twice weekly bortezomib on rates of peripheral neuropathy in combination with lenalidomide, dexamethasone and daratumumab

Introduction: Daratumumab in combination with bortezomib, lenalidomide and dexamethasone (D-VRd) is standard of care for newly diagnosed multiple myeloma (MM). This is based on results from the phase II GRIFFIN and phase III PERSEUS trials. In these trials, bortezomib, a proteasome inhibitor, was administered twice weekly on days 1, 4, 8 and 11 of each 21-day or 28-day cycle respectively. A common side effect of bortezomib is peripheral neuropathy (PN) which was seen in 59.6-72.5% of patients in the GRIFFIN trial and 51.6-53.6% in the PERSEUS trial. Single-center studies and real-world data have shown similar efficacy and lower rates of PN with weekly verses twice weekly bortezomib in various bortezomib-containing regimens, but none evaluated this exclusively in D-VRd. As clinical guidelines cite the aforementioned trials, some patients still receive twice weekly bortezomib. This study will analyze the tolerability of weekly versus twice weekly bortezomib in 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. MM patients ≥18 years of age who were treated with D-VRd and received at least two 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, 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. The primary objective is to assess rates of PN in patients with MM receiving D-VRd in once weekly versus twice weekly bortezomib. 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: 21 of 58 patients (36%) receiving weekly bortezomib developed PN, which was significantly lower than the 17 of 24 patients (74%) on twice weekly dosing (p< 0.001). The observed incidence of PN in the twice weekly group is similar to that reported 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< 0.001) and treatment for PN (p< 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 77 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 were similar between groups.

Conclusions: This study continues to demonstrate clinically relevant reduction in PN for patients receiving once weekly versus twice weekly bortezomib, extending the data to the D-VRd regimen. Further analysis is needed in this context to prospectively evaluate weekly versus twice weekly bortezomib. It is important to advocate for intensity modification in future clinical trials.