Incidence Of Bortezomib-induced Peripheral Neuropathy Research Articles

Inhibitors of the Mechanistic Target of Rapamycin Can Ameliorate Bortezomib-Induced Peripheral Neuropathy.

Bortezomib, an anticancer drug for multiple myeloma and mantle cell lymphoma, causes severe adverse events and leads to peripheral neuropathy. The associated neuropathy limits the use of bortezomib and could lead to discontinuation of the treatment; therefore, effective intervention is crucial. In the present study, we statistically searched for a drug that could alleviate bortezomib-induced peripheral neuropathy using adverse event self-reports. We observed that specific inhibitors of the mechanistic target of rapamycin (mTOR) lowered the incidence of bortezomib-induced peripheral neuropathy. These findings were experimentally validated in mice, which exhibited long-lasting mechanical hypersensitivity after repeated bortezomib treatment. This effect was inhibited for hours after a systemic injection with rapamycin or everolimus in a dose-dependent manner. Bortezomib-induced allodynia was accompanied by the activation of spinal astrocytes, and intrathecal injection of mTOR inhibitors or an inhibitor of ribosomal protein S6 kinase 1, a downstream target of mTOR, exhibited considerable analgesic effects in a dose-dependent manner. These results suggest that mTOR inhibitors, which are readily available to patients prescribed bortezomib, are one of the most effective therapeutics for bortezomib-induced peripheral neuropathy.

Impact of Body Mass Index on the Incidence of Bortezomib-induced Peripheral Neuropathy in Patients With Newly Diagnosed Multiple Myeloma

BackgroundPeripheral neuropathy is one of the most common dose-limiting toxicities associated with bortezomib; it can lead to dose reductions or therapy discontinuation. Obesity has been identified as being a risk factor for the development of peripheral neuropathy with other neurotoxic anticancer agents. We aimed to evaluate the impact of obesity on the incidence and severity of bortezomib-induced peripheral neuropathy. Patients and MethodsThis is a retrospective, single-center study of patients treated with subcutaneous bortezomib between January 1, 2012 and June 1, 2017. Eligible patients received at least 1 full cycle of subcutaneous bortezomib and had previously untreated, newly diagnosed multiple myeloma. Patients who received intravenous bortezomib or concomitant thalidomide were excluded. Patients were divided into 3 groups based on their body mass index (BMI): normal/underweight (BMI < 25), overweight (BMI = 25-29.9), and obese (BMI ≥ 30). ResultsA total of 143 patients fitting the inclusion criteria were identified. Patients across the 3 groups received bortezomib at similar doses and schedules (weekly vs. biweekly). Obese patients had an increased incidence in developing bortezomib-induced peripheral neuropathy (56.4%) compared with normal/underweight (17.3%) and overweight patients (26.9%). Further analysis showed that, compared with normal/underweight and overweight patients, obesity was not found to be associated with an increased risk of grade 3 to 4 bortezomib-induced peripheral neuropathy (P = .451). ConclusionObese patients were found to be at higher risk for the development of bortezomib-induced peripheral neuropathy compared with non-obese patients.

Glutathione Ameliorates Bortezomib (Velcade) -Induced Neuronal Toxicity in N2a and SHSY5Y Cells

Bortezomib (Velcade, Millennium Pharmaceuticals, Inc.), a potent proteasome inhibitor, is a boronic acid dipeptide that induce cancer cell death. It is an effective drug for both newly diagnosed or relapsed multiple myeloma (MM) patients and is widely used in the treatment of various kinds of lymphomas and other diseases. Peripheral nerve damage is one of the most significant nonhematologic toxicities of bortezomib. The reported incidence of bortezomib-induced peripheral neuropathy (BIPN) ranges from 25 to 75 % . When it occurs, the painful sensory neuropathy can interfere with quality of life (QOL) and with performance of activities of daily living, and it may also adversely affect clinical outcomes by forcing dose modification and/or premature treatment discontinuation. Therefore there are many efforts to improve multiple symptoms associated with BIPN. But there are no reports on amelioration of neurotoxicity which occurred in patients with treatment of bortezomib .Therefore control of this toxicity by the concomitant use of other safe candidates can make it a better option for the cancer therapy with bortezomib.Glutathione (GSH) is a substance produced naturally by the liver and it is also found in fruits, vegetables, and meats. GSH is an important antioxidant and capable of preventing damage to important cellular components caused by reactive oxygen species (ROS) such as free radicals, peroxides, lipid peroxides, and heavy metals. Several small randomized trials have addressed the protective effect of GSH against chemotherapy induced peripheral neuropathy (CIPN )with a platinum agent .In this study we observed that treatment of GSH either in the pre-treatment or in the post treatment inhibited the bortezomib -induced neuronal cell death in both mouse neuronal cells (N2a) as well as dopaminergic neuron of human origin (SHSY5Y). Bortezomib treatment at the concentration of 100 and 200 µg/ml significantly increased the cell death with increased lactate dehydrogenase activity (LDH) and increased apoptotic proteins expressions in the 24 h of treatment of both cells. GSH treatment (1 mg/ml) not only inhibited the bortezomib -induced cell death but also inhibited the LDH activity, suggesting that GSH ameliorates bortezomib -induced neuronal toxicity. A clear activation of the autophagy was also observed in the bortezomib treatment that was lowered by the GSH treatment. In addition to this inhibition of the apoptotic proteins specially Cleaved caspase 3 was observed in the neuronal cells and also the increased Bcl2 and NRF2 protein which are responsible for the cell survival was upregulated with GSH treatment suggesting that GSH increase the cell survival against bortezomib -induced neurotoxicity. Inhibition of the cleaved caspase-3, Bax and LC3 protein are prominent in SHSY5Y cells while activation of the BCL2 and NRF2 is more significant in N2a cells. To elucidate the role of GSH in the development and maintenance of bortezomib -induced neurotoxicity, we will additionally assess ROS and antioxidant enzyme activity levels in the cellular system.This research suggests that GSH ameliorates BIPN and thus can improve the QOL and increase the survival rate of patients treated with bortezomib. DisclosuresNo relevant conflicts of interest to declare.

Prophylaxis of Bortezomib-Induced Peripheral Neuropathy in Patients with Multiple Myeloma by High-Dose Intravenous Mecobalamin

To evaluate the efficacy and safety of high-dose intravenous mecobalamin (HDIME) for the treatment of bortezomib-induced peripheral neuropathy(BIPN) in the patients with multiple myeloma (MM). A total of 65 newly diagonsed patients with multiple myeloma receiving bortezomib in Tianjin Medical University General Hospital were enrolled in this single-centre randomized clinical trial from July 2012 to May 2016. Out of 65 patients 38 in control group received bortezomib-based chemotherapy and 27 patients in HDIME group received the additional high-dose intravenous mecobalamin. The incidence of BIPN in HDIME group was lower than that in control group(29.63% vs 55.26%, χ2=4.197,P<0.05). Whether the BIPN rate of Grade 2 or 3 and above in HDIME group significantly decreased as compared with control group(18.52% vs 47.37%,χ2=5.746,P<0.05) (3.71% vs 21.05%, χ2=3.983,P<0.05). The BIPN rate of less than 5 cycles of bortezomib was not significantly different between HDIME and control groups(χ2=2.714,P>0.05). Overall effective rate of HDIME group and control group was 77.78% and 73.68%(P>0.05) respectively. Neither PFS nor OS was significantly different between HDIME group and control group(P>0.05). Treatment-related toxicity was only mild rash in 1 case. No other side-effects including nausea, abdominal pain, and hypotension occurred. HDIME has a good efficacy for the prophylaxis BIPN and and without serious side effects.

The positive effects of one-hour intravenous administration of bortezomib on peripheral neuropathy in multiple myeloma patients.

Bortezomib-induced peripheral neuropathy (BiPN) in multiple myeloma (MM) patients is a common and serious side effect. Currently, it has been reported that subcutaneous (SC) administration of bortezomib decreases the incidence of BiPN as compared to standard intravenous (IV) bolus injection without any differences in efficacy. However, there are reports of severe injection site reaction following SC administration of bortezomib. The aim of this study was to evaluate the response rate and incidence of BiPN following one-hour IV infusion of bortezomib. The data was retrospectively collected from MM patients who had been treated with IV administration of bortezomib for one hour. Twenty-three patients were evaluated (median age 72 years, 13 males). The median number of treatment cycles was 5 (range 2–10). The cumulative bortezomib dose was 26.0 mg/m2 (14.3–66.3) and percent of actual per expected cumulative dose was 90% (50–100). The overall response (complete response plus partial response) rate was 65%. The incidence of BiPN was 57% (n = 13) and incidence of severe neuropathy was 4% (n = 1). One-hour IV infusion of bortezomib was an effective regimen for MM with reduced incidence of severe BiPN. This route of administration of bortezomib could be an alternative mode of delivery for patients with severe injection site reactions following SC administration.

The Clinical Spectrum of Bortezomib-Induced Peripheral Neuropathy (P06.140)

Objective: We sought to investigate the incidence, risk factors for development and phenotype of peripheral neuropathy in patient9s treated with bortezomib. Background Bortezomib (Velcade®) is the first member of a new class of chemotherapeutic agents that inhibit the proteasome-ubiquitination pathway. It is FDA-approved for use in multiple myeloma and mantle cell lymphoma. Bortezomib causes a painful axonal sensory-predominant length-dependent peripheral neuropathy in 30-40% of patients. A small subgroup of patients treated with bortezomib develop a severe neuropathy soon after commencing bortezomib, the mechanism of which is unclear. Design/Methods: We searched the Mayo Clinic Hematology Chemotherapy database for patients treated with bortezomib. We reviewed the clinical information to determine if neuropathy occurred in relation to the initiation of bortezomib. We reviewed the clinical and electrophysiological features and long-term followup of patients evaluated by a neurologist. Subjects were included if they received bortezomib and had follow-up for at least one cycle of chemotherapy. Results: 589 patients were identified. 378 patients met inclusion criteria. 138 (36.5%) were determined to have treatment-emergent peripheral neuropathy. The typical pattern was a painful, sensory-predominant peripheral neuropathy involving the hands and feet. Three patients had evidence of a plexopathy or polyradiculoneuropathy. Two patients had nerve biopsies suggesting microvasculitis. A prior history of peripheral neuropathy was more common in patients with treatment-emergent peripheral neuropathy (22% vs 14%, p Conclusions: In our series the incidence of bortezomib-induced peripheral neuropathy is 36.5%, similar to previous reports. A prior history of peripheral neuropathy appears to be a risk factor for the development of bortezomib-induced peripheral neuropathy. The pattern is most commonly a painful, sensory-predominant length-dependent neuropathy. An inflammatory neuropathy or polyradiculoneuropathy can occur with bortezomib with biopsy features suggesting microvasculitis. Disclosure: Dr. Mauermann has nothing to disclose. Dr. Dispenzieri has received research support from Millennium. Dr. Staff has nothing to disclose.

A155 Neurologic Monitoring Reduces the Incidence of Bortezomib-Induced Peripheral Neuropathy in MM

A155 Neurologic Monitoring Reduces the Incidence of Bortezomib-Induced Peripheral Neuropathy in MM