Bortezomib-induced Neuropathy Research Articles

Bortezomib-induced neuropathy is in part mediated by the sensitization of TRPV1 channels

TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin nerve terminals. Tissue injury and inflammation result in the sensitization of TRPV1 and sustained activation of TRPV1 can lead to cellular toxicity though calcium influx. To identify signals that trigger TRPV1 sensitization after a 24-h exposure, we developed a phenotypic assay in mouse primary sensory neurons and performed an unbiased screen with a compound library of 480 diverse bioactive compounds. Chemotherapeutic agents, calcium ion deregulators and protein synthesis inhibitors were long-acting TRPV1 sensitizers. Amongst the strongest TRPV1 sensitizers were proteasome inhibitors, a class that includes bortezomib, a chemotherapeutic agent that causes small fiber neuropathy in 30–50% of patients. Prolonged exposure of bortezomib produced a TRPV1 sensitization that lasted several days and neurite retraction in vitro and histological and behavioral changes in male mice in vivo. TRPV1 knockout mice were protected from epidermal nerve fiber loss and a loss of sensory discrimination after bortezomib treatment. We conclude that long-term TRPV1 sensitization contributes to the development of bortezomib-induced neuropathy and the consequent loss of sensation, major deficits experienced by patients under this chemotherapeutic agent.

Bortezomib-induced neurotoxicity in human neurons is the consequence of nicotinamide adenine dinucleotide depletion.

The proteosome inhibitor bortezomib has revolutionized the treatment of multiple hematologic malignancies, but in many cases, its efficacy is limited by a dose-dependent peripheral neuropathy. We show that human induced pluripotent stem cell (hiPSC)-derived motor neurons and sensory neurons provide a model system for the study of bortezomib-induced peripheral neuropathy, with promising implications for furthering the mechanistic understanding of and developing treatments for preventing axonal damage. Human neurons in tissue culture displayed distal-to-proximal neurite degeneration when exposed to bortezomib. This process coincided with disruptions in mitochondrial function and energy homeostasis, similar to those described in rodent models of bortezomib-induced neuropathy. Moreover, although the degenerative process was unaffected by inhibition of caspases, it was completely blocked by exogenous nicotinamide adenine dinucleotide (NAD+), a mediator of the SARM1-dependent axon degeneration pathway. We demonstrate that bortezomib-induced neurotoxicity in relevant human neurons proceeds through mitochondrial dysfunction and NAD+ depletion-mediated axon degeneration, raising the possibility that targeting these changes might provide effective therapeutics for the prevention of bortezomib-induced neuropathy and that modeling chemotherapy-induced neuropathy in human neurons has utility.

Role of inflammation and oxidative stress in chemotherapy-induced neurotoxicity.

Chemotherapeutic agents may adversely affect the nervous system, including the neural precursor cells as well as the white matter. Although the mechanisms are not completely understood, several hypotheses connecting inflammation and oxidative stress with neurotoxicity are now emerging. The proposed mechanisms differ depending on the class of drug. For example, toxicity due to cisplatin occurs due to activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which alters hippocampal long-term potentiation. Free radical injury is also involved in the cisplatin-mediated neurotoxicity as dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been seen which protects against the free radical injury by regulating glutathione S-transferases and hemeoxygenase-1 (HO-1). Thus, correcting the imbalance between NF-κB and Nrf2/HO-1 pathways may alleviate cisplatin-induced neurotoxicity. With newer agents like bortezomib, peripheral neuropathy occurs due to up-regulation of TNF-α and IL-6 in the sensory neurons. Superoxide dismutase dysregulation is also involved in bortezomib-induced neuropathy. This article reviews the available literature on inflammation and oxidative stress in neurotoxicity caused by various classes of chemotherapeutic agents. It covers the conventional medicines like platinum compounds, vinca alkaloids, and methotrexate, as well as the newer therapeutic agents like immunomodulators and immune checkpoint inhibitors. A better understanding of the pathophysiology will lead to further advancement in strategies for management of chemotherapy-induced neurotoxicity.

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy.

Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

Dose-dependent immunomodulatory effects of bortezomib in experimental autoimmune neuritis.

Proteasome inhibition with bortezomib has been reported to exert an immunomodulatory action in chronic autoimmune neuropathies. However, bortezomib used for the treatment of multiple myeloma induces a painful toxic polyneuropathy at a higher concentration. Therefore, we addressed this controversial effect and evaluated the neurotoxic and immunomodulatory mode of action of bortezomib in experimental autoimmune neuritis. Bortezomib-induced neuropathy was investigated in Lewis rats using the von Frey hair test, electrophysiological, qPCR and histological analyses of the sciatic nerve as well as dorsal root ganglia outgrowth studies. The immunomodulatory potential of bortezomib was characterized in Lewis rats after experimental autoimmune neuritis induction with P253-78 peptide. Clinical, electrophysiological, histological evaluation, von Frey hair test, flow cytometric and mRNA analyses were used to unravel the underlying mechanisms. We defined the toxic concentration of 0.2 mg/kg bortezomib applied intraperitoneally at Days 0, 4, 8 and 12. This dosage induces a painful toxic neuropathy but preserves axonal regeneration in vitro. Bortezomib at a concentration of 0.05 mg/kg significantly ameliorated experimental autoimmune neuritis symptoms, improved experimental autoimmune neuritis-induced hyperalgesia and nerve conduction studies, and reduced immune cell infiltration. Furthermore, proteasome inhibition induced a transcriptional downregulation of Nfkb in the sciatic nerve, while its inhibitor Ikba (also known as Nfkbia) was upregulated. Histological analyses of bone marrow tissue revealed a compensatory increase of CD138+ plasma cells. Our data suggest that low dose bortezomib (0.05 mg/kg intraperitoneally) has an immunomodulatory effect in the context of experimental autoimmune neuritis through proteasome inhibition and downregulation of nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFKB). Higher bortezomib concentrations (0.2 mg/kg intraperitoneally) induce sensory neuropathy; however, the regeneration potential remains unaffected. Our data empathizes that bortezomib may serve as an attractive treatment option for inflammatory neuropathies in lower concentrations.

Weekly Dosing of Bortezomib in RVD Achieves Minimal Toxicity with No Reduction in Efficacy in a Diverse Cohort of Multiple Myeloma Patients

Introduction: Lenalidomide, bortezomib, and dexamethasone is a standard of care in the treatment of fit multiple myeloma patients due to high efficacy, with ORR exceeding 90% in the first-line setting (Richardson et al. 2010). The initial RVD regimen utilized a 21-day cycle with bortezomib administered IV 1.3 mg/m2 days 1, 4, 8, and 11; lenalidomide 25 mg administered days 1-14; and dexamethasone administered 160 to 320 mg per cycle. However, toxicity may be treatment-limiting, with bortezomib-induced neuropathy affecting up to 80% of patients. Modifications to RVD to optimize tolerance include reducing the bortezomib dose to a weekly schedule (1.6 mg/m2 IV or 1.3 mg/m2SC) and extending the cycle to 28 or 35 days (Broijl et al. 2016; O'Donnell et al. 2014). Notably, those regimens were studied in transplant-ineligible or relapsed/refractory patients. Based on regimens like CyBorD (which utilize weekly SC administration of bortezomib, are well-tolerated and are efficacious), we modified the standard 21-day RVD regimen to include 3 doses of weekly bortezomib in an attempt to preserve efficacy while minimizing toxicity. We present a retrospective analysis of both fit and transplant-ineligible patients treated at our institution using “Louisville RVD.”Methods: We identified the charts of patients who received RVD over a 21-day cycle at the following starting doses: lenalidomide 25 mg orally days 1-14; bortezomib 1.5 mg/m2 SC days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, and 15. Autologous stem cell harvest took place after 4 cycles of lenalidomide-based therapy when feasible, in appropriate candidates. We noted demographic factors, ISS stage, performance status, cytogenetic risk stratification, line of therapy (initial, later-line, and consolidation), history of autologous transplant, degree of response (PD, SD, PR, VGPR, and CR based on International Myeloma Working Group criteria), EFS, OS, and toxicities.Results: We identified 23 patients who received Louisville RVD between 2009 and 2017. Median age was 59 years (range 37-77) at treatment start; 9 (39%) were 65 or older; 12 (52%) were male; 11 (48%) were African-American; ISS stages were I in 6 (26%), II in 7 (30%), III in 9 (39%), and missing in 1 patient; ECOG status was 0 in 7 (30%), 1 in 11 (48%), and 2 in 5 (21%). Line of therapy was 1 in 13 (56%) and 2 or later in 10 (44%); RVD was used as post-transplant consolidation in 4 (14%). Line of therapy ranged from 1 to 8. 16 patients (57%) were treated with intent to transplant. The median number of cycles given was 4 (range 1-64). Dose reductions and discontinuation occurred in 5 (22%) patients and 1 (4%) patient after 1 cycle, respectively. Response was assessable in 22 patients. 21 (95%) of patients achieved PR or better; 3 patients (14%) achieved CR, 7 (32%) VGPR; and 11 (50%) PR. OS and EFS at 1 year were 90% and 60%, respectively; median duration of follow-up was 15.5 months (range 1.2-95.1); follow-up time was limited for a significant fraction of our patients. There was no association of relapse with ISS stage (p=0.357), ECOG score (p=0.088), or cytogenetic risk (p=1.00). Treatment-related toxicities were reported for 11 patients. Treatment-emergent neuropathy was seen in 5 patients (22%); 4 patients experienced grade 1 neuropathy (17%), and 1 patient experienced grade 3 neuropathy (4%). 1 patient underwent dose-reduction of bortezomib to 1.3 mg/m2 after 18 cycles. 6 patients had treatment related cytopenias (26%), of which 1 (4%) was grade 3.Conclusions: Retrospective analysis of 21-day “Louisville RVD” with weekly subcutaneous bortezomib demonstrates efficacy comparable to previously published RVD regimens. Toxicity, especially peripheral neuropathy, favors the weekly SC administration schedule. Dose reductions were uncommon and treatment discontinuations were rare. Patients may ultimately achieve superior bortezomib dosing due to rarity of dose reductions. Our cohort was well-balanced with regard to ethnicity, gender, age, and performance status. Treatment was efficacious and well-tolerated in both transplant and non-transplant candidates. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

MO232BORTEZOMIB INDUCED PERIPHERAL AND CENTRAL NEUROPATHY : ABOUT 3 CASE REPORTS

Abstract Background and Aims Bortezomib is a proteasome inhibitor, whose efficacy in the treatment of multiple myeloma has been proven over the last years. However, its side effects may cause concern for patients as well as physicians. We focused in this study on Bortezomib-induced neuropathy, one of the most frequent complications. We present 2 cases of peripheral sensory neuropathy and one intriguing case of central neurological manifestation, all caused by Bortezomib administration. Case 1 A 62-year-old man, with a history of diabetes and hypertension, was diagnosed with multiple myeloma in 2019. He received 2 cycles of Bortezamib (2,5 mg), Dexamethasone , and Cyclophosphamide. Each cycle included 4 doses of Bortezomib, and the cycles were 21 days apart. At the end of the second cycle the patient developed posterior cord syndrome with balance disorder and lower extremities paresthesia. Axonal sensitivo-motor polyneuropathy was confirmed by electromyography. A pharmacology investigation was conducted, and the symptoms were attributed to Bortezomib toxicity. Evolution was favourable after change in protocol to Revlimide. No recurrence was noted. Case 2 A 64-year-old man with no prior history was diagnosed with multiple myeloma in 2020. She received a protocol of 4 cycles, 21 days apart, of Bortezomib (2.1 mg) ,Dexamethasone and Thalidomide . Three weeks after the first cycle, the patient presented with confusion, gait disturbance and four-limb pyramidal deficiency syndrome. Electromyography showed axonal sensitivo-motor polyneuropathy .In the absence of other causes, Bortezomib toxicity was suspected and the patient underwent an emergency epurative hemodialysis session, after which symptoms completely disappeared. Bortezomib doses were then reduced. The evolution was favourable. Case 3 A 50-year-old woman was diagnosed with multiple myeloma in 2018 with Randall's disease and quadri-pyramidal syndrome. She was put on 4 courses of Bortezomib 2.4mg Cyclophosphamide and Dexamethasone, 21 days apart. After 2 coursess, she presented a generalized tonic-clonic seizure preceded by headache, dizziness and followed by speech disturbances. Biological screening for metabolic disorders and toxins was unremarkable. Cerebral MRI showed no abnormalities. Doses of Bortezomib were reduced during the following course. We then witnessed an improvement in speech and no recurrence of seizures. Conclusion Bortezomib induced neuropathy is a serious and debilitating complication to which physicians must pay special attention. This side effect can be managed by dose reduction or change of molecules. Outcomes are often favourable.

Diagnostic utility of Sudoscan for detecting bortezomib-induced painful neuropathy: a study on 18 patients with multiple myeloma.

IntroductionIn the past few years, treatment of multiple myeloma has undergone a deep change for the employment of novel treatment comprising proteasome inhibitors. Bortezomib is a first-line drug in therapy of multiple myeloma. The onset of peripheral neuropathy is a dose-limiting collateral effect of the drug. This neuropathy is a distal symmetric neuropathy that affects both large and small fibers. Nerve conduction study (NCS) can be used for the diagnosis of bortezomib neuropathy, but this technique demonstrates alterations of the large nerve fibers. Sudoscan is a novel technique utilized to offer an evaluation of sudomotor function. The main objective of this study was to compare the sensitivity and diagnostic specificity of Sudoscan with respect to the nerve conduction study after bortezomib treatment.Material and methodsA total of 18 multiple myeloma patients were studied, 10 (55.5%) men and 8 (44.5%) women. Patients were analyzed at baseline and after 6 months of treatment with bortezomib. Subjects were submitted to nerve conduction study and electrochemical skin conductance evaluation with the Sudoscan device. Patients were also submitted to a clinical measure of pain and neuropathy.ResultsAt baseline NCS showed that only the mean sural SAP amplitude was below the 2SD lower limit of normal in 3 (16.7%) patients, while at same time we found an alteration of Sudoscan profiles in 2 (11.1%) patients. After 6 months of treatment, the NCS profiles were altered in 13 (72.2%) patients, and the Sudoscan profiles were modified in 11 (61.1%) subjects.ConclusionsOur results suggest that Sudoscan can be considered for the diagnosis of bortezomib-induced neuropathy. It is objective, reproducible, and surely easier than the traditional nerve conduction study. Sudoscan may be a useful help to manage the therapeutic interventions in multiple myeloma.

Alpha-lipoic acid alters the antitumor effect of bortezomib in melanoma cells in vitro

Bortezomib (BOZ) is a proteasome inhibitor chemotherapeutic agent utilized to treat multiple myeloma and recently offered to cure melanoma. Bortezomib-induced neuropathy is one of the dose-limiting side-effects, which can be treated with antioxidants (e.g. alpha-lipoic acid—ALA and Vitamin B1—vit B1). We hypothesized that these antioxidants may counteract the antitumor activity by disrupting the BOZ-induced pathways (e.g. proteasome inhibition or reactive oxygen species generation). The objectives were: (i) to verify the anti-proliferative effect of BOZ; (ii) to compare the influence of the antioxidants on the antitumor effect of BOZ in melanoma (A2058) and myeloma (U266) cells. At first, the reduction in the anti-proliferative effect of BOZ by ALA was proved in melanoma cells. Analysis of p53 phosphorylation and the cell cycle progression revealed that ALA failed to counteract these effects of BOZ. Nevertheless, a good correlation was found between the inhibition of the anti-proliferative effect, the anti-proteasome activity and the oxidative stress level after the co-treatment with 20 ng/mL BOZ + 100 μg/mL ALA. Downregulation of apoptotic proteins such as HO-1 and Claspin along with the inhibition of the cleavage of Caspase-3 indicated the proteomic background of the altered responsiveness of the melanoma cells exposed to BOZ + ALA. This phenomenon draws attention to the proper application of cancer supportive care to avoid possible interactions.

MOLECULAR FEATURES OF BORTEZOMIB-INDUCED NEUROPATHY IN PATIENTS WITH MULTIPLE MYELOMA

Background. The regimens of therapy with bortezomib have significantly improved the survival among patients with multiple myeloma (MM). However, the development of peripheral polyneuropathy (PP) resulting from treatment using proteasome inhibitors is still an undesirable event. Risk factors for PP in MM patients include old age, previous neuropathy and use of neurotoxic drugs. Recent studies have established the presence of a genetic component in the mechanism of developing bortezomib-induced neurotoxicity. However, there are conflicting opinions on the role of genetic characteristics in predicting the risk of treatment-induced neuropathy development.Aim. To identify the risk group of bortezomib-induced PP based on the analysis of gene polymorphism of the immune response in patients with newly-diagnosed MM.Materials and methods. A study of the association of 20 polymorphic loci of 14 immune response genes in 46 MM patients was conducted using a candidate gene identification approach. All the patietns were receiving VCD therapy with bortezomib.Results. The distribution of single nucleotide polymorphisms was compared in groups of patients with the presence and absence of PP. It is found that homozygous carriers of the wild type allele of the genes TLR6 (Ser249Pro) (p = 0.006), IL1β (G-1473C) (p = 0.04), IL4 (C-589T) (p = 0.04), as well as haplotype carriers with the mutant allele of the gene IL10 (G-1082A) (p = 0.04) and with the wild type allele gene IL2 (T-330G) (p = 0.01) were significantly more frequent among PP patients.Сonclusion. Our results have confirmed the contribution of the genetic component to the risk of developing bortezomibinduced neuropathy. These findings can be used for individualization of therapeutic approaches to the treatment of MM patients.

Tamoxifen suppresses paclitaxel-, vincristine-, and bortezomib-induced neuropathy via inhibition of the protein kinase C/extracellular signal-regulated kinase pathway.

Chemotherapy-induced neuropathy is a highly problematic, dose-limiting effect of potentially curative regimens of cancer chemotherapy. When neuropathic pain is severe, patients often either switch to less-effective chemotherapy agents or choose to discontinue chemotherapy entirely. Conventional chemotherapy drugs used to treat lung and breast cancer, multiple myeloma, and lymphoma include paclitaxel, vincristine, and bortezomib. Approximately 68% of patients receiving these anticancer drugs develop neuropathy within the first month of treatment, and while strategies to prevent chemotherapy-induced neuropathy have been investigated, none have yet been proven as effective. Recent reports suggest that chemotherapy-induced neuropathy is associated with signal transduction molecules, including protein kinase C and mitogen-activated protein kinases. It is currently unclear whether protein kinase C inhibition can prevent chemotherapy-induced neuropathy. In this study, we found that tamoxifen, a protein kinase C inhibitor, suppressed paclitaxel-, vincristine-, and bortezomib-induced cold and mechanical allodynia in mice. In addition, chemotherapy drugs induce neuropathy via the protein kinase C/extracellular signal-regulated kinase pathway in the spinal cord in lumbar segments 4-6 and dorsal root ganglions. In addition, tamoxifen was shown to act synergistically with paclitaxel to inhibit tumor-growth in mice injected with tumor cells. Our results indicated that paclitaxel-, vincristine-, and bortezomib-induced neuropathies were associated with the protein kinase C/extracellular signal-regulated kinase pathway in the lumbar spinal cord and dorsal root ganglions, which suggest that protein kinase C inhibitors may be therapeutically effective for the prevention of chemotherapy-induced neuropathy when administered with standard chemotherapy agents.

Evaluation of Bortezomib-Induced Neuropathy Using Total Neuropathy Score (Reduced and Clinical Versions) and NCI CTCAE v4.0 in Newly Diagnosed Patients With Multiple Myeloma Receiving Bortezomib-Based Induction.

Bortezomib-induced peripheral neuropathy (BiPN) is a dose-limiting adverse effect of bortezomib-based therapy for multiple myeloma (MM). The reporting of BiPN is variable because of the use of different neuropathy scales. Most investigators use the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). We prospectively evaluated the incidence of BiPN in treatment-naive patients with MM receiving weekly cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in 28-day cycles using 3 neuropathy scores: Total Neuropathy Score-reduced (TNSr) and -clinical (TNSc), and NCI CTCAE v4.0. Twenty-six patients received CyBorD. Twenty patients completed follow-up. The rates of occurrence of BiPN were as follows: TNSr- 55% (n= 11), TNSc- 40% (n= 8), and NCI CTCAE- 45% (n= 9). All 3 scales showed worsening after treatment (P< .01). When compared to BiPN by TNSr, sensitivities for NCI CTCAE and TNSc were 77.8% and 88.9%, respectively. Specificity was 63.3% for both NCI CTCAE and TNSc. Among 12 patients who did not have BiPN by NCI CTCAE scale, 41.7% (n= 5) and 16.7% (n= 2) patients satisfied the criteria for BiPN by TNSr and TNSc, respectively. The higher detection rate of neuropathy by TNSr and TNSc is probably due to increment in scores that are allotted for increase in anatomic extent of sensorimotor involvement, unlike the NCI CTCAE scale, which requires functional limitation for increase in grade. NCI CTCAE may be suboptimal in comparison to TNSr and TNSc in assessment of BiPN because it may miss worsening neuropathy without functional limitation.

Inhibition of the neuronal NFκB pathway attenuates bortezomib-induced neuropathy in a mouse model

Bortezomib is a proteasome inhibitor with a remarkable antitumor activity, used in the clinic as first line treatment for multiple myeloma. One hallmark of bortezomib mechanism of action in neoplastic cells is the inhibition of nuclear factor kappa B (NFκB), a transcription factor involved in cell survival and proliferation. Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity that often requires adjustment of treatment and affects patient’s prognosis and quality of life. Since disruption of NFκB pathway can also affect neuronal survival, we assessed the role of NFκB in bortezomib-induced neuropathy by using a transgenic mouse that selectively provides blockage of the NFκB pathway in neurons. Interestingly, we observed that animals with impaired NFκB activation developed significantly less severe neuropathy than wild type animals, with particular preservation of large myelinated fibers, thus suggesting that neuronal NFκB activation plays a positive role in bortezomib induced neuropathy and that bortezomib treatment might induce neuropathy by inhibiting NFκΒ in non-neuronal cell types or by targeting other signaling pathways. Therefore, inhibition of NFκB might be a promising strategy for the cotreatment of cancer and neuropathy.

An Overview of Bortezomib-Induced Neurotoxicity.

The boronic acid dipeptide bortezomib, able to induce tumor cell death by degradation of key proteins, is the first proteasome inhibitor drug to enter clinical practice. It is employed as first-line treatment in relapsed or resistant multiple myeloma (MM) patients. However, bortezomib often induces a dose-limiting toxicity in the form of painful sensory neuropathy, which can mainly be reduced by subcutaneous administration or dose modification. In this review we focus on the current understanding of the pathophysiological mechanisms of bortezomib-induced neuropathy to allow further studies in animal models and humans, including analysis of clinical and pharmacogenetic aspects, to optimize the treatment regimens.

Neurotoxicity of stem cell mobilization chemotherapy with vinorelbine in myeloma patients after bortezomib treatment

Vinorelbine chemotherapy with G-CSF stimulation is the standard mobilization regimen in Switzerland for multiple myeloma patients. However, with the increasing use of bortezomib during induction treatment, adding the neurotoxic compound vinorelbine for mobilization may aggravate bortezomib-induced polyneuropathy. In this retrospective single-center study, we aimed to explore vinorelbine mediated neuropathy in 106 consecutive bortezomib pretreated myeloma patients. We confirmed that vinorelbine with G-CSF represents a reliable and effective regimen for mobilization of autologous stem cells. However, the single administration of 35mg/m2 vinorelbine added significant neurotoxicity. We found that 24 patients (24%) reported vinorelbine mediated neurotoxicity: Aggravation of bortezomib-induced neuropathy was observed in 17 patients (17%), and vinorelbine mobilization induced first occurrence of polyneuropathy in additional 7 patients (7%). We observed that development of polyneuropathy was not associated with differing survival rates. Finally, affected patients reported polyneuropathy associated disease burden as “very high” in 13% and “high” in 50%. Our data indicate that a single administration of vinorelbine to mobilize autologous stem cells is associated with significant additional polyneuropathy in bortezomib pretreated myeloma patients. The efficacy of vinorelbine mobilization should be balanced against its neurotoxic potential.

Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice.

Polyneuropathy is a frequent and potentially severe side effect of clinical tumor chemotherapy. The goal of this study was to characterize paclitaxel-, cisplatin-, vincristine- and bortezomib-induced neuropathy in C57BL/6 mice with a comparative approach. The phenotype of the animals was evaluated at four time points with behavioral and electrophysiological tests, followed by histology. Treatment protocols used in this study were well tolerated and induced a sensory and predominantly axonal polyneuropathy. Behavioral testing revealed normal motor coordination, whereas all mice receiving verum treatment developed mechanical allodynia and distinct gait alterations. Electrophysiological evaluation showed a significant decrease of the caudal sensory nerve action potential amplitude for all cytostatic agents and a moderate reduction of nerve conduction velocity for cisplatin and paclitaxel. This finding was confirmed by histological analysis of the sciatic nerve which showed predominantly axonal damage: Paclitaxel and vincristine affected mostly large myelinated fibers, bortezomib small myelinated fibers and cisplatin damaged all types of myelinated fibers to a similar degree. Neuropathic symptoms developed faster in paclitaxel and vincristine treated animals compared to cisplatin and bortezomib treatment. The animal models in this study can be used to elucidate pathomechanisms underlying chemotherapy-induced polyneuropathy and for the development of novel therapeutic and preventative strategies.

Impact of dose modification on intravenous bortezomib-induced peripheral neuropathy in multiple myeloma patients.

Patients discontinue bortezomib treatment despite good response to the therapy because of bortezomib-induced neuropathy. Early and active dose reduction is recommended for efficacy of treatment. This study evaluates patterns of bortezomib-associated neuropathy and examines the effectiveness of dose modification on symptom management and treatment compliance. This is a retrospective cohort study of multiple myeloma patients who received bortezomib intravenously from 2009 to 2012 at Samsung Medical Center, Seoul, Korea. Peripheral neuropathy was assessed using neurotoxicity subscale of the FACT/GOG-Ntx at daily clinical practice; physicians modified the dosage and schedule of bortezomib treatment. Mixed-effect models were used for evaluating changes of neuropathy symptoms over time. Linear spline models and multivariate logistic regression were used for testing the effectiveness of interventions. There were 1,060 visits of 55 multiple myeloma patients during the study period. Patients were most likely to have numbness of feet, painful burning in feet, muscle weakness, and the symptoms worsened over time (P < 0.05). For patients who received intervention (n = 32, 58.1 %), neuropathy symptoms were significantly decreased after the intervention (coefficient, -0.1 (95 % confidence interval (CI), -0.8, 0.6)). The intervention group had on average 5.19 (95 % CI, 3.79, 6.59) more bortezomib administrations and was 1.4 times more likely to complete the treatment (odds ratio, 1.40 (95 % CI, 0.31, 6.32)) than the nonintervention group. Close monitoring of peripheral neuropathy in patients receiving bortezomib is a feasible and useful way to manage neuropathy in the real world.

The Addition Of Bortezomib (Velcade®) To The Combination Of Mitoxantrone and Etoposide For Relapsed Or Refractory Acute Leukemia Does Not Appear To Improve The Likelihood Of Response: Results Of a Phase II Trial

IntroductionRefractory and relapsed acute leukemias are defined by their resistance to chemotherapeutic agents. Resistance in leukemia cells is thought to be at least in part mediated by the upregulation of nuclear factor- κB (NF-κB). It has been speculated that inhibition of NF-κB activity would render chemotherapy-resistant leukemic cells more susceptible to standard salvage regimens.Bortezomib, whose mechanism of action involves rescuing malignant cells' pro-apoptotic pathway through proteasome inhibition, is thought to indirectly inhibit NF-κB. The combination of mitoxantrone and etoposide has an acceptable, albeit moderate, frequency of inducing complete responses in relapsed/refractory acute myeloid leukemia with 35–45% CR rate of 4–5 month median duration. In this phase II trial, our group utilized bortezomib in an effort to potentiate the cytotoxic effects of mitoxantrone and etoposide in patients with relapsed or refractory acute leukemias. MethodsPatients with relapsed or refractory acute myeloid or lymphoid leukemia (AML or ALL) were enrolled on a phase I-II dose escalation study of bortezomib (0.7, 1.0, or 1.3 mg/m2) on days 1 and 4 in combination with mitoxantrone 10 mg/m2 days 1–5 and etoposide 100 mg/m2 days 1–5. The phase 1 portion of the study was completed in late 2007. The phase 2 dose of bortezomib was 1.3 mg/m2. The primary endpoint was frequency of CR at count recovery with secondary endpoints including safety and tolerability. A Simon two-staged design was utilized and a preplanned interim analysis allowed the trial to proceed. ResultsForty-four evaluable subjects were enrolled in the phase II portion of the trial. There were 18 men (41%) and 26 (59%) women. The median age was 51 (range 19-71). Seventeen patients (38%) had received 2 or more prior therapies and 5 patients (11%) had relapsed following allogeneic transplants prior to study initiation. The majority of subjects had AML (80%). The CR rate was 0.27 (90% CI: 0.24, 0.50). The regimen was generally well tolerated with grade 3/4 febrile neutropenia in 17 patients (38%). Non-hematologic serious adverse events included: congestive heart failure (n=3, 7%), grade 3 mucositis (n=2, 5%), tracheal stenosis (n=1, 2%), and interstitial pneumonitis (n=1, 2%). Despite concerns about bortezomib-induced neuropathy, only one patient (2%) developed this complaint. Median survival for those who responded (n = 12) was 14.4 months (95% CI: 5.1, 25.7) and for non-responders (n=32) was 6.2 months (95% CI: 4.2, 10.0). The likelihood of achieving a CR was similar for patients with AML or ALL; 0.26 (95% CI: 0.13, 0.43) for AML and 0.33 (95% CI: 0.08, 0.70) for ALL. Sixteen of 44 patients underwent allogeneic stem cell transplant (7 in CR, 9 with residual disease) with 3 still alive at the conclusion of the study. ConclusionsThe addition of bortezomib to mitoxantrone and etoposide does not appear to improve CR rates over the standard salvage regimen alone, and outside the context of clinical investigation, we cannot recommend its routine use in acute leukemias. The use of other novel agents to enhance the efficacy of combination chemotherapy regimens is being explored, including the use of mTOR inhibitors. Further analysis including pharmacodynamic study of NF-κB inhibition may prove informative. Disclosures:Off Label Use: The use of bortezomib in acute leukemias is off label but is studied in the presented research as a way to potentiate the other therapeutic agents. Mookerjee:AstraZeneca: Equity Ownership; Incyte: Employment, Equity Ownership. Kasner:Roche: Research Funding.

Bortezomib-induced neuropathy: Axonal membrane depolarization precedes development of neuropathy

ObjectiveBortezomib is a proteasome inhibitor with high efficacy for multiple myeloma but with severe peripheral neurotoxicity, leading to dose modification and severe neurological disability. This study aimed to investigate the pathophysiology of bortezomib-induced neuropathy. MethodsThreshold tracking was used to assess the excitability of sensory and motor axons. Measurements were sequentially performed before and after bortezomib treatment in nine patients with newly diagnosed multiple myeloma. ResultsIn total, 67% of patients finally developed symptomatic neuropathy. Changes in sensory axonal excitability indices readily occurred after the first course of administration. Patterns of changes in excitability indices suggest membrane depolarization (decreased superexcitability, P<0.001; decreased depolarizing threshold electrotonus 90–100ms, P=0.02). Abnormalities in nerve conduction parameters suggestive of axonal degeneration appeared after the second course of treatment. ConclusionsBortezomib induces a depolarizing shift in resting membrane potential prior to the development of neuropathy. Membrane depolarization could be associated with impairment of electrogenic Na+–K+-ATPase-dependent pump caused by toxic effects of bortezomib on mitochondria. SignificanceAxonal depolarization and hyperexcitability might enhance neurodegeneration in bortezomib-induced neuropathy.

Immune modulation therapy in the management of bortezomib-induced peripheral neuropathy

Peripheral neuropathy (PN) is one of the most common side effects of bortezomib therapy. The majority of bortezomib-related PN is a sensory neuropathy of mild to moderate degree, and is reversible after dose reduction or discontinuation. However, occasionally bortezomib-induced neuropathy can be severe and affects motor and/or autonomic nerves, and may be mediated by immune process. The role of immune modulation therapy in the management of bortezomib-induced PN was not well established. Here, we reported a case of bortezomib-induced severe PN that responded well to plasma exchange and steroid treatment.