Acetyl-L-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone: a study from the Wisconsin Oncology Network.

Natalie Callander,Eliot Williams,Jens Eickhoff,Toby Campbell,Walter Longo,Fotis Asimakopoulos,Peiman Hematti,Ronald Go,Shigeki Miyamoto,Stephanie Markovina,Robert Hegeman,Paul Hutson

doi:10.1007/s00280-014-2550-5

Abstract

PurposeRetreatment with bortezomib (B) is often considered for patients with relapsed multiple myeloma (MM), but this strategy is hindered by uncertainty of response and emergence of B-induced peripheral neuropathy (PN). We incorporated acetyl-l-carnitine (ALCAR) to prevent PN and allow for adequate dosing. We also investigated the correlation between B-inducible NF-κB activation and response to therapy.MethodsNineteen patients with relapsed/refractory MM received up to 8 cycles of intravenous bortezomib, doxorubicin and oral low-dose dexamethasone (BDD) to evaluate response and toxicity. Thirteen additional patients received prophylactic ALCAR (BDD-A). Patients receiving BDD-A were evaluated by FACT-GOG-TX, FACIT-Fatigue, Neuropathic Pain index (NPI) and Grooved Pegboard (GP) testing. Primary MM cells from 11 patients were tested for B-inducible NF-κB activation.ResultsSeventy-six percent of subjects were refractory to previous treatment, 39 % refractory to bortezomib. Median cycles received were 5. CR + PR for the entire group were 53 % and did not differ between groups. Incidence of ≥3 PN was 32 % in the BDD group versus 15 % in the BDD-A group (p = ns). Patient-reported fatigue and PN measured by FACT-GOG-TX increased throughout the treatment period in the BDD-A group, although time to complete GP testing declined. In a sub-study examining constitutive bortezomib-inducible NF-κB activity in primary subject-specific MM cells, the presence of NF-κB activation correlated with lower likelihood of response.ConclusionsAddition of ALCAR to BDD did not alter the incidence or severity of PN in relapsed MM patients receiving a B-based regimen. Bortezomib-inducible NF-κB activation in patient-derived primary MM cells may be associated with poorer response.

Highlights

Multiple myeloma is an incurable plasma cell malignancy with a course characterized by initial responsiveness to treatment, followed by the appearance of increasingly refractory disease and death due to infection, renal failure and cytopenias [1]
We have demonstrated that the combination of doxorubicin, low-dose dexamethasone and bortezomib is associated with a high response rate of 53 % (CR and Partial response (PR)), even in very refractory patients
Our study suggests that the addition of ALCAR did not eliminate treatment-related peripheral neuropathy (PN), there appeared to be fewer cases of grade 3 or 4 neuropathy among patients receiving the prophylaxis as reported by the treating physicians

Summary

Introduction

Multiple myeloma is an incurable plasma cell malignancy with a course characterized by initial responsiveness to treatment, followed by the appearance of increasingly refractory disease and death due to infection, renal failure and cytopenias [1]. Initial trials of single agent bortezomib for relapsed MM resulted in response rates of 30–35 % [3, 4]. MM patients rapidly acquire resistance to bortezomib when used as a single agent, and it is apparent that this resistance may in part be modified through combination with other existing chemotherapy agents, including steroids, Cancer Chemother Pharmacol (2014) 74:875–882 alkylating agents, anthracyclines and immunomodulatory drugs [5,6,7]. As more experience has been gained with these combinations, it is apparent that some patients who have previously received bortezomib can be retreated at the time of relapse with excellent results [8]. Predicting which relapsed patients will respond to retreatment with bortezomib remains essentially a “trial and error” process

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