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

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 4; pp. 875 - 882
• Main Authors: Callander, Natalie, Markovina, Stephanie, Eickhoff, Jens, Hutson, Paul, Campbell, Toby, Hematti, Peiman, Go, Ronald, Hegeman, Robert, Longo, Walter, Williams, Eliot, Asimakopoulos, Fotis, Miyamoto, Shigeki
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2014; Springer; Springer Nature B.V
• Subjects: Acetylcarnitine - administration & dosage; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Biological and medical sciences; Boronic Acids - administration & dosage; Boronic Acids - adverse effects; Bortezomib; Cancer Research; Clinical Trial Report; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Dexamethasone - administration & dosage; Dexamethasone - adverse effects; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Drug Resistance, Neoplasm; Female; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Multiple Myeloma - physiopathology; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nervous system (semeiology, syndromes); Neurologic Examination - methods; Neurology; NF-kappa B - metabolism; Nootropic Agents - adverse effects; Oncology; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - diagnosis; Peripheral Nervous System Diseases - prevention & control; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pyrazines - administration & dosage; Pyrazines - adverse effects; Recurrence; Severity of Illness Index; Treatment Outcome; Tumors; United States; North America; Wisconsin; America; Acetyl; carnitine; Bortezomib; Neuropathy; Multiple myeloma; NF-kB; Antineoplastic agent; Relapse; Myeloma; Doxorubicin; Prevention; Signal transduction; Isomerases; Cancerology; Immunoglobulinopathy; Lymphoproliferative syndrome; Network; Transcription factor NFκB; Peripheral nerve disease; Human; Corticosteroid; DNA topoisomerase (ATP-hydrolysing); Immunopathology; Nervous system diseases; Treatment resistance; Dexamethasone; Enzyme; Steroid hormone; Low dose; Enzyme inhibitor; Acetyl-L-carnitine; Malignant hemopathy; Topoisomerase II inhibitor; Malignant tumor; Chemotherapy; Treatment; Analog; Proteasome inhibitor; Dipeptides; Anthracyclins; Cancer
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-014-2550-5

Purpose Retreatment 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. Methods Nineteen 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. Results Seventy-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. Conclusions Addition 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.