Characteristics of bortezomib- and thalidomide-induced peripheral neuropathy

Abstract

Dose-limiting peripheral neuropathy (PN) is frequently reported with the use of thalidomide and bortezomib, novel proteasome inhibitors. While these two agents have significant activity in multiple myeloma (MM), the combination and the associated PN have not been fully examined in untreated patients. The objective of this study was to report the baseline prevalence and occurrence of PN in newly diagnosed MM patients treated with bortezomib and thalidomide. Twenty-seven patients (11 men and 16 women) with previously untreated MM were prospectively monitored for PN. Total neuropathy score reduced (TNSr) was calculated at baseline and after every two cycles of bortezomib treatment. The median cumulative dose of bortezomib was 35.6 mg/m(2) (median 8 cycles) and of thalidomide was 16.8 g. Only three subjects showed mild PN at baseline (whole group median TNSr 0). At the end of treatment, PN developed in 26 patients (median TNSr 8). PN was of mild to moderate severity (TNSr grade 1 = 11, grade 2 = 10, grade 3 = 5, and grade 4 = 0). Nerve conduction studies showed axonal physiology in all except three subjects in whom demyelinating physiology was noted. The median TNSr was 17 in the demyelinating group and 9 in the axonal group. There was no significant correlation of TNSr with cumulative bortezomib or thalidomide dose. At follow-up, 80% of patients had become asymptomatic after discontinuation of the chemotherapy. We conclude that bortezomib and thalidomide combination chemotherapy induces a reversible length-dependent sensory>motor, predominantly axonal, large-fiber>small-fiber polyneuropathy. In a subset, a more severe demyelinating polyneuropathy may develop.

Figure 1

Baseline TNSr and end of treatment TNSr in the 27 subjects depicting the worsening of TNSr after chemotherapy with bortezomib and thalidomide. TNSr, total neuropathy score reduced.

Figure 2

TNSr and its subcomponents in the two groups, those developing axonal with those developing demyelinating neuropathy. Subjects developing demyelinating neuropathy had higher TNSr and more changes in strength, vibration, and neurophysiological change. TNSr, total neuropathy score reduced.

Figure 3

Change in TNSr is plotted against the cumulative doses of bortezomib and thalidomide. Subjects receiving higher cumulative doses of both bortezomib and thalidomide did not have higher TNSr values. TNSr, total neuropathy score reduced.

Figure 4

Reversibility of toxic neuropathy in the two groups: (a) those who completely stopped bortezomib and thalidomide; the median TNSs for 10 patients who stopped the drug was 1 at follow-up and (b) those who continued on a lower dose; median TNSs was 3 for those who continued with bortezomib. TNS, total neuropathy score; TNSs, TNS symptom score.