title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: University of Wisconsin Carbone Cancer Center, 600 Highland Ave, Madison, WI, 53792, USA, nsc@medicine.wisc.edu.
authors.forename: Natalie
authors.initials: N
authors.lastname: Callander
authors.forename: Stephanie
authors.initials: S
authors.lastname: Markovina
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Paul
authors.initials: P
authors.lastname: Hutson
authors.forename: Toby
authors.initials: T
authors.lastname: Campbell
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
authors.forename: Ronald
authors.initials: R
authors.lastname: Go
authors.forename: Robert
authors.initials: R
authors.lastname: Hegeman
authors.forename: Walter
authors.initials: W
authors.lastname: Longo
authors.forename: Eliot
authors.initials: E
authors.lastname: Williams
authors.forename: Fotis
authors.initials: F
authors.lastname: Asimakopoulos
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
mesh_terms: D000108:Acetylcarnitine / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism*; D009460:Neurologic Examination / Q000379:methods; D018697:Nootropic Agents / Q000009:adverse effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D012008:Recurrence; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D018697:Nootropic Agents; D011719:Pyrazines; D000069286:Bortezomib; D000108:Acetylcarnitine; D003907:Dexamethasone; D004317:Doxorubicin