A Retrospective Study to Evaluate the Incidence and Severity of Peripheral Neuropathy for Relapsed/Refractory Multiple Myeloma Patients upon Retreatment with Bortezomib
Authors: Berenson James R. , Bitran Jacob D. , Tabbara Imad , Lutzky Jose , Stampleman Laura V. , Ailawadhi Sikander , Steis Ronald , Moezi Mehdi M. 
Published: October 2019

Abstract
Background: Peripheral neuropathy (PN) is associated with multiple myeloma (MM) and often worsened with thalidomide (THAL) and vincristine (VCR) therapy. Bortezomib (BTZ) is a proteasome inhibitor approved for the treatment of MM that has been also shown to cause PN. An increased risk of BTZ-induced PN has been associated with the presence of both PN and diabetes mellitus (DM) before treatment. However, the incidence and characteristics of BTZ-induced PN among MM patients (pts) retreated with another BTZ-containing regimen is unknown. We analyzed the incidence, severity and risk factors for PN after treatment of MM pts with a second BTZ-containing regimen.
Methods: Retrospective chart analysis. MM pts that had progressed from at least one prior BTZ-containing regimen and had received treatment with another BTZ-containing regimen were eligible. Pts had to have experienced PN during the course of the first BTZ regimen and could not have received therapy with THAL or VCR. The protocol was later amended to allow inclusion of pts without PN during their first BTZ treatment and those who had received THAL or VCR. Statistical significance was assessed using Fisher’s or McNemar’s tests as appropriate. The relationship between comorbidities, prior THAL or VCR treatment and PN grade after BTZ treatment and re-treatment was analyzed using a multivariate logistics regression model. All statistical analyses were two-sided and were performed at the 0.05 level of significance.
Results: As of July 3, 2014, 83 pts have been accrued to the retrospective analysis, and 58 chart reviews have been completed. The median age of pts included in the analysis was 64 years (range: 31-84 years); 57% of the pts were male and 69% were Caucasian. Pts had received a median of 2 prior regimens (range: 2-10); 43% of the pts had received prior regimens containing THAL and 15% of those had also received therapy with VCR. Prior to the protocol amendment, the eligibility criteria required pts to have experienced PN after the first BTZ treatment; therefore, most pts included in this analysis (88%) had PN.During their first BTZ treatment, the most severe grade of PN experienced by the majority of the pts was grade 1 (N=34), followed by grade 2 (N=13) and grade 3 (N=4). A comparison of the symptoms assessed when pts had their most severe grade of PN during this treatment and the severity reported at its onset showed that PN worsened in only 16% of pts. Nearly half (48%) of pts showed no change in PN whereas symptoms improved or resolved in 15% and 9% of the pts, respectively. During treatment with the second BTZ-containing regimen, a comparable proportion of pts (N=44; 76%) reported having experienced PN. Among those experiencing PN upon re-treatment, the most severe grade of PN experienced by the majority of the pts (N=29) was also grade 1, followed by grade 2 (N=12) and grade 3 (N=3). During the second BTZ treatment, a comparison of the symptoms that pts had when PN was at its worst and those recorded at its onset demonstrated that PN worsened in only 7% of the pts. PN showed no change in 47%, improved in 15%, or resolved in 7% of the pts.Interestingly, 17% of the pts (N=10) who had reported PN while receiving their first BTZ-containing regimen did not report this complication during their second BTZ treatment, while 7% of the pts (N=4) experienced PN only upon re-exposure. There was no association between the incidence of PN during the first BTZ treatment and its incidence during re-treatment (p=0.1213) or between the severity of PN (defined as worsening vs. not worsening) after first BTZ treatment and its severity after BTZ re-exposure (p=0.1306).
Fifty-four percent of the pts presented with comorbidities, including DM (26%), hypertension (HTN, 22%) and peripheral vascular disease (PVD, 13%). There were no associations between PN grade after BTZ treatment and prior THAL or VCR exposure (p=0.5569) or between PN grade and comorbidities (DM, p=0.6657; HTN, p=0.9966; PVD, p=0.9966). Similar results were found for BTZ re-exposure (THAL or VCR, p=0.8672; DM, p=0.4137; HTN, p=0.2033; PVD, p=0.9954).
Conclusions: Results from this retrospective study show that the severity and incidence of PN did not change with a second BTZ-containing regimen. Comorbidities or prior therapy with other PN-inducing agents such as THAL or VCR did not significantly increase the risk of PN after BTZ re-treatment. Enrollment into the study continues and updated results will be presented at the meeting.

Disclosures
Berenson: Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tabbara:Millennium: Speakers Bureau. Lutzky:Millennium: Speakers Bureau. Ailawadhi:Millennium: Consultancy. Moezi:Millennium: Speakers Bureau.