Although administration by the subcutaneous route has been shown to reduce the risk of bortezomib-induced peripheral neuropathy (PN), the incidence remains high at 38%, with 25% of patients experiencing grade ≥2 and 6% experiencing grade ≥3 neuropathy.
Risk factors for bortezomib-induced PN include:
•Total exposure (up to cumulative dose of 26 mg/m2)
•Baseline neuropathy (increases risk of grade ≥3)
•Single nucleotide polymorphisms in drug metabolism, nervous system function, immune modulation
Race as a potential risk factor:
•The patient population of clinical trials is largely homogeneous in race. Phase II and III trials consisted of 80-98% Caucasian subjects.
•Race as a risk factor for bortezomib-induced PN has only been investigated in one single-center study assessing intravenous bortezomib, and no association was found.
•Race is a predictor variable for diabetic neuropathy.
•The pathophysiology of bortezomib-induced PN may have a genetic basis.
•Racial differences in oncology therapeutics have been attributed to pharmacogenetics. Socioeconomic status also correlates to racial differences in outcomes.
Single-center descriptive retrospective cohort study
•Age ≥18 years
•Subcutaneous bortezomib between 01/23/12 and 07/31/16
•Zuckerberg San Francisco General Hospital medical record with past medical history and diagnoses
•Fewer than 5 cycles of bortezomib due to reasons other than PN
A total of 27 subjects met study criteria and were included in the final analysis. 47 patients met inclusion criteria. 20 patients were excluded (13 due to intravenous bortezomib and 10 due to fewer than 5 bortezomib cycles for reasons other than PN, with 2 patients having ongoing treatment, 2 patients experiencing disease progression, 2 patients with other severe illness, 3 patients ttransferred to an outside facility, and 1 patient lost to follow-up.)
Patients were representative of real-world patients with respect to baseline characteristics, including age, sex, and indication for bortezomib. Confounding is unlikely, as a very low number of subjects exhibited conditions potentially contributing to peripheral neuropathy (1 patient had baseline neuropathy due to prior thalidomide, and 1 patient had a concomitant medication with a risk of PN i.e. amiodarone.)
Different races were well represented, including 10 black or African American (37.0%), 6 Asian or Pacific Islander (22.2%), 4 Caucasian (14.8%), 6 Latino (22.2%), and 1 Middle Eastern (3.70%).
•A smaller proportion of Caucasian patients developed PN (25%, vs other races 80-83%).
•The incidence of bortezomib-induced PN may thus be under-reported in clinical trials.
•Of subjects developing PN, the lowest proportion of black or African American subjects obtained dose reduction (50%, vs other races 80-100%).
•The severity of PN at dose reduction for black or African American and Asian or Pacific Islander subjects was highest (mean severity grade 2.5, vs other races 1-1.5).
•The incidence of bortezomib-induced peripheral neuropathy may be higher in non-Caucasian patients.
•Black or African American patients appear less likely to receive bortezomib dose reduction, potentially reflecting a disparity that warrants further study.
•Future studies elucidating risk factors of bortezomib-induced peripheral neuropathy enable a more precise assessment of risk versus benefit for optimal bortezomib treatment.
•First study to date investigating the impact of race on treatment-emergent peripheral neuropathy with subcutaneous bortezomib
•Low potential for confounding
•Baseline characteristics representative of typical patient population receiving bortezomib treatment
•Potential misclassification bias from retrospective nature
•Limited generalizability due to single-center data
•Underpowered due to limited sample size
•Mixed race not documented in medical record
•Sample size estimation to detect statistical significance
•More robust subgroup analyses
•Multi-center design for broader generalizability