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

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.

Bortezomib and other proteosome inhibitors—induced peripheral neurotoxicity: From pathogenesis to treatment

“…In contrast, Acetyl‐Lcarnitine, a critical component in mitochondrial energetics and function, was investigated in 32 relapsing MM patients without baseline PN greater than 2. Despite a lower rate of severe (grade 3 or 4) PN observed in the ALCAR cohort (15% vs 32%), differences were not statistically different . Importantly, although this trial reported fewer cases of grade 3 or 4 neuropathy among patients receiving the intervention, as reported by the treating physicians, when PN was measured by validated instruments such as the FACIT‐GOG‐NTX and the Neuropathic Pain index (NPI) index, the subjects reported increasing levels of neuropathy as they continued on study, highlighting the need of objective measures such as TNS or NCS to be incorporated when assessing neuroprotection in clinical trials.…”

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

“…69,70 For example, acetyl-L-carnitine, despite demonstrating great promise in initial clinical studies, 71 was not found to be effective in later clinical trials and even exacerbated CIPN in some patients. 72,73 Likewise, in a recent study of 243 patients treated with a-lipoic acid while receiving platinum chemotherapy, the agent demonstrated no protective effects. 74 The failure of these antioxidants to alleviate CIPN might be attributed to their rapidly exhausted antioxidant activity.…”

“…Clinical trials using nutraceuticals with antioxidant properties, including vitamin E, acetyl‐L‐carnitine, glutamine, glutathione, vitamin B6, omega‐3 fatty acids, and α‐lipoic acid, have reported controversial results . For example, acetyl‐L‐carnitine, despite demonstrating great promise in initial clinical studies, was not found to be effective in later clinical trials and even exacerbated CIPN in some patients . Likewise, in a recent study of 243 patients treated with α‐lipoic acid while receiving platinum chemotherapy, the agent demonstrated no protective effects .…”

Mechanisms Involved in the Development of Chemotherapy-Induced Neuropathy

“…Acetyl l-carnitine (ALCAR) has been reported to improve mitochondrial function following chemotherapy and became a promising avenue of CIPN therapy, with several studies in animal models reporting resolution of chemotherapy-induced mechanical and thermal hyperalgesia [74–77]. Initial clinical trials showed promise with ALCAR [78,79] but, unfortunately, subsequent trials found that ALCAR not only fails to have a significant ameliorating effect [80], but can actually worsen CIPN [81]. Thus, it remains unclear whether the clinical trial results negate the hypothesis of a central role of mitotoxicity in the pathophysiology of CIPN.…”