Introduction: Bortezomib (Bz, VELCADE) is a proteasome inhibitor proven safe and effective for patients (pts) with relapsed and/or refractory multiple myeloma (MM). Pts in SUMMIT (

NEJM 2003;348:2609
) and CREST (
BJH 2004;127:165
) underwent rigorous testing (neurologic evaluations, FACT/GOG-Ntx questionnaires, nerve conduction studies) to determine the incidence, characteristics and reversibility of PN. In these phase 2 trials, the PN rate was 31–41% (grade [G] ≥ 3 in 11–12%). Specific dose modification (DM) guidelines for PN were not incorporated into the phase 2 trials but were developed for subsequent studies. The objective of this report was to evaluate the frequency, characteristics and reversibility of PN in an updated analysis of the randomized phase 3 APEX trial (
NEJM 2005;352:2487
), in which specific DM guidelines for PN were implemented.

Methods: Pts with relapsed MM were randomized to Bz 1.3 mg/m2 IV on d 1, 4, 8, 11 q3wk for 8 cycles then 3 cycles on d 1, 8, 15, 22 q5wk, or dexamethasone (Dex) 40 mg PO on d 1–4, 9–12, 17–20 q5wk for 4 cycles, then 5 cycles on d 1–4 q4wk. Pts with G ≥ 2 PN were excluded. Data were collected on incidence, severity and reversibility of PN.

Results: Of 331 pts safety evaluable enrolled on Bz, 120 (36%) developed PN, including 30 (9%) with G ≥ 3. PN was classified as sensory or not specified in the vast majority of cases; motor neuropathies were rare. Of 91 pts with G ≥ 2 PN, 68 had DM, including 37 with doses reduced, held or schedule modification and 31 with Bz discontinuation (DC); 23 pts not following DM protocol. The majority (58 pts; 64%) of the 91 pts improved (9%) or had complete resolution (55%) of symptoms. Of 37 pts with DM without Bz DC, the majority (26 pts; 70%) had improvement, all with complete resolution of PN to baseline, with a median time to resolution of 78 d. Of 31 pts requiring Bz DC, 2 (6%) improved and 17 (55%) had complete resolution of PN with a median time to improvement/resolution of 121 d. Of 23 pts who did not follow the DM protocol, 12 (52%) had complete resolution with a median time to resolution of 106 d. The rates of PN (any G, G ≥ 3) were similar regardless of pt age or number/type of prior therapies (Table). The median TTP of 91 pts with G ≥ 2 PN, 68 pts with DM, and the Bz arm overall were 6.2, 6.9 and 6.2 months, respectively.

Conclusion: The overall rate of PN in APEX was similar to that of SUMMIT and CREST, but the rate of G ≥ 3 PN was lower, perhaps because of specific DM guidelines. PN was reversible in the majority of pts, and DM did not compromise efficacy. Pt age or number/type of prior therapies did not appear to affect the rate or severity of PN.

PN
Bz SubgroupAny G*, %G ≥3, %
*Bz related 
ge; 65 y 35 9 
< 65 y 37 9 
> 1 prior therapy 36 10 
1 prior therapy 37 8 
Steroids 38 7 
Alkylating agent 35 7 
Anthracycline 39 7 
Vinca alkaloid 38 8 
Thalidomide 44 8 
Transplantation 37 7 
PN
Bz SubgroupAny G*, %G ≥3, %
*Bz related 
ge; 65 y 35 9 
< 65 y 37 9 
> 1 prior therapy 36 10 
1 prior therapy 37 8 
Steroids 38 7 
Alkylating agent 35 7 
Anthracycline 39 7 
Vinca alkaloid 38 8 
Thalidomide 44 8 
Transplantation 37 7 
View Large

Topics:
apex trial, peripheral neuropathy, brachial plexus neuritis, bortezomib, alkylating agents, anthracycline antibiotics, dexamethasone, multiple myeloma, nerve conduction study, neuritis, motor

Author notes

Corresponding author

2005, The American Society of Hematology
2005
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