Neurotoxicity of bortezomib therapy in multiple myeloma: A single‐center experience and review of the literature

Abstract

BACKGROUND. Bortezomib is active in heavily pretreated multiple myeloma patients; the dose‐limiting toxicity is peripheral neuropathy (PN). METHODS. The authors retrospectively reviewed the incidence, severity, and risk factors for PN in 78 patients who received bortezomib. The median age was 57 years (range, 33–80 years), 62% of patients were men, and 37% of patients were African Americans. Seventeen patients (22%) had diabetes mellitus (DM), and 66 patients (85%) had received thalidomide. Before bortezomib treatment, 37% of the patients reported subjective, grade 1 or 2 PN. Patients received bortezomib alone (n = 10 patients) plus dexamethasone (n = 36 patients) and thalidomide (n = 20 patients) or chemotherapy (n = 12 patients). PN affected 52% of patients, including grade 3 and 4 PN in 15% and 7%, respectively. RESULTS. Twelve patients stopped bortezomib because of side effects that included PN (n = 9 patients), diarrhea (n = 2 patients) and cytomegalovirus pneumonia (n = 1 patient); 11 patients had dose reductions because of PN. Grade 4 PN affected 6 patients (sensory, n = 4 patients; motor/sensory, n = 2 patients). The onset of grade 4 PN was sudden rather than cumulative. Factors that were predictive of PN grade were baseline PN (P = .002), prior thalidomide use (P = .03), and the presence of DM (P = .03). Multiple myeloma responses included complete, near complete, and partial responses in 5% of patients, 10% of patients, and 27% of patients, respectively. Responses were independent of PN and of whether bortezomib was combined with chemotherapy or thalidomide. Patients remained on therapy longer for a median of 5 cycles (range, 2–36 cycles) when they received bortezomib plus thalidomide versus 3 cycles (range, 1–19 cycles) for the other combinations. PN therapy was mostly supportive. It was noteworthy that 6 of 9 patients with PN who received lenalidomide as salvage therapy after bortezomib had significant improvement in their symptoms. CONCLUSIONS. The risk of bortezomib‐related PN was greater in patients who had PN and DM at baseline. The authors concluded that an unexpected, symptomatic improvement of PN on lenalidomide is worth further investigation. Cancer 2007. © 2007 American Cancer Society.

Effect of CYP2C19 and CYP3A4 gene polymorphisms on the efficacy of bortezomib-based regimens in patients with multiple myeloma

“…PN is the main dose-limiting toxicity associated with bortezomib therapy (18). The results of the present study indicated that no differences were found between the occurrence of PN in patients with the CYP2C19 genotype and those with the CYP3A4 genotypes.…”

“…CYP3A4 * 1 was considered to be the wild type genotype. In a previous study, * 18 was only reported in Asian populations, and had a frequency of 2% (12). The frequency of the CYP3A4 * 18 allele in the present study was 0.9%.…”

Complications of Multiple Myeloma Therapy, Part 1: Risk Reduction and Management of Peripheral Neuropathy and Asthenia

“…The reported incidence is 1% to 20% in untreated patients with MM and 37% to 83% in previously treated individuals; neurophysiologic evidence of neuropathy may be detected in 11% to 52% and 39% to 46% of these populations, respectively. [1][2][3][4][5][6] Risk factors for PN include treatment-specific characteristics, such as therapy duration, dose intensity, and cumulative dose, and patient-specific factors, such as age, comorbidities (e.g., diabetes mellitus, alcoholism), and the presence of preexisting neuropathy. The incidence of thalidomide-induced PN varies among different patient populations, treatment regimens, and diagnostic criteria, but estimates range from 37% to 83%.…”

“…Therapeutic Intervention: Nonpharmacologic management of sensory PN symptoms or neuropathic pain may involve the use of daily vitamins and nutritional supplements (e.g., multi-B complex vitamins [B 1 , B 6 , B 12 ], folic acid, magnesium, potassium, vitamin E, acetyl l-carnitine, α-lipoic acid, l-glutamine; see Table 3 for dosing), emollient creams (e.g., cocoa butter, menthol, and eucalyptus-based creams), and physical therapy, as well as therapeutic massage.…”

Relationship between Chemotherapy-induced Peripheral Neuropathy and Quality of Life in Patients with Hematologic Malignancies

“…When used after exposure to thalidomide, bortezomib, or vincristine, lenalidomide can cause mild to severe CIPN [6]. The incidence rate of bortezomib-induced CIPN in patients with newly diagnosed MM ranged from 11% to 81% [7][8][9], and rigorous measures are required to control bortezomib-induced CIPN as demonstrated by its severity-dependent dosimetry guidelines [10]. Given the risks involved, it is crucial to assess the relevance of CIPN, identify high-risk factors for CIPN prior to administering known neurotoxic agents, and conduct routine CIPN monitoring and medical interventions to alleviate CIPN symptoms in accordance with therapy plans.…”