Neuropathy In Multiple Myeloma Patients Research Articles

Neuropathy as an adverse effect of proteasomal inhibitors in multiple myeloma treatment: a network meta-analysis (P11-8.004)

<h3>Objective:</h3> To determine the comparative risk of incidence of neuropathy associated with proteasomal inhibitors (PIs) in multiple myeloma (MM) patients. <h3>Background:</h3> PIs (bortezomib, carfilzomib, ixazomib) are commonly used in treating MM. Bortezomib is traditionally associated with peripheral neuropathy, but it remains unclear whether its adverse effects also mirror the class-specific neurotoxic profile of PIs. Newer oral proteasome inhibitor, ixazomib, has fewer incidences of neuropathy. However, a direct comparison of neuropathy as a side effect of individual PIs has not been performed. <h3>Design/Methods:</h3> Published randomized control trials (RCTs) reporting neuropathy in MM patients (newly diagnosed and/or relapsed) treated with PI were searched up to May 2021. Studies where PIs were used along with chemotherapy vs. placebo, or no additional drugs (control) in the other arm were included. The primary outcome was the presence of neuropathy after follow-up. Pair-wise meta-analysis and network meta-analysis were performed using the frequentist’s approach to estimate the odds ratio (OR). <h3>Results:</h3> Eleven randomized clinical trials with a total of 3576 MM patients were evaluated in the analysis, which reported the incidence of neuropathic events. A total of nine studies on bortezomib(6), ixazomib(2), and carfilzomib(1) reported neuropathic events against a control group. Two studies compared bortezomib to carfilzomib. There was a significant increase in all grade (OR = 2.51, 95% CI 1.54–4.09) and high-grade neuropathy (based on CTCAE criteria) (OR = 3.37, 95% CI 2.36–4.81) among patients treated with any PI compared to control. Among the PIs, bortezomib was associated with a maximum risk of all-grade neuropathy (OR 4.00; 95% CI 3.30–4.85). <h3>Conclusions:</h3> Our results showed that treatment with bortezomib is associated with the highest risk of neuropathy among PIs in MM patients. This may warrant increased awareness among treating physicians and close monitoring of patients treated with these agents. <b>Disclosure:</b> Dr. Garg has nothing to disclose. Avash Das has nothing to disclose. Mr. GUPTA has nothing to disclose. Prof. KUMAR has nothing to disclose. Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion Pharmaceuticals. Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda Pharmaceuticals. Dr. Roy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for argenx. Dr. Roy has stock in Cabaletta bio. . The institution of Dr. Roy has received research support from Martin Shubik Fund for IBM at Yale University.

Repetitive transcranial magnetic stimulation for chemotherapy-induced peripheral neuropathy in multiple myeloma: A pilot study

Objective: Chemotherapy-induced peripheral neuropathy is one of the major toxicities in multiple myeloma patients, often resulting in dose reductions or treatment interruptions. Repetitive transcranial magnetic stimulation is a safe non-invasive neuromodulation therapy with potential benefits for chemotherapy-induced peripheral neuropathy. The objective of this study was to investigate the efficacy of repetitive transcranial magnetic stimulation treatment on chemotherapy-induced peripheral neuropathy in multiple myeloma patients. Materials and methods: We screened 30 multiple myeloma patients with chemotherapy-induced peripheral neuropathy who underwent repetitive transcranial magnetic stimulation treatment in this study. Prior to and following repetitive transcranial magnetic stimulation treatment, patients were assessed with nerve conduction velocity, visual analog scale and the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-CIPN 20-item scale (EORTC QLQ-CIPN20). Categorical and continuous variables were analyzed using Fisher’s exact test and Mann-Whitney U test respectively. A p-value &lt; 0.05 (2-tailed) was considered statistically significant. Results: Following repetitive transcranial magnetic stimulation treatment, 24/30 (80.0%) patients reported a reduction in chemotherapy-induced peripheral neuropathy symptoms. Meanwhile, all 15 patients with grade 2 chemotherapy-induced peripheral neuropathy experienced improvements about themselves, compared to 8/10 patient with grade 3 chemotherapy-induced peripheral neuropathy and 1/5 with grade 4 chemotherapy-induced peripheral neuropathy. Visual analog scale scores decreased after repetitive transcranial magnetic stimulation treatment (5.40 ± 1.94 vs 3.10 ± 1.60, p &lt; 0.001). We also observed enhancements in both motor conduction velocity and sensory conduction velocity of patients in bilateral median nerves, posterior tibial nerves, common ulnar nerves and peroneal nerves following repetitive transcranial magnetic stimulation treatment. Analysis of the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-CIPN 20-item scale data (17.68 ± 8.14 vs 10.50 ± 9.55, p &lt; 0.001) revealed significant reductions in scores. Patients with grade 2–3 ( n = 25) exhibited a mean reduction of 8.89 ± 4.24 points, while those with grade 4 ( n = 5) showed a difference value of 3.54 ± 3.45, p &lt; 0.001. No adverse events were observed. Conclusion: Our findings suggest that repetitive transcranial magnetic stimulation is a safe and effective therapeutic approach for ameliorating peripheral nerve injury and alleviating the chemotherapy-induced peripheral neuropathy symptoms in multiple myeloma patients. Early initiation of repetitive transcranial magnetic stimulation treatment may yield more favorable outcomes for these patients.

High prevalence of peripheral neuropathy in multiple myeloma patients and the impact of vitamin D levels, a cross-sectional study

PurposePeripheral neuropathy (PN) is common in patients with multiple myeloma (MM). We hypothesized that the relationship between hypovitaminosis D and PN described in diabetes mellitus patients may also be present in MM patients.MethodsTo study this potential association, we assessed the incidence of hypovitaminosis D (vitamin D < 75 nmol/L [= 30 ng/mL]) in smouldering and active MM patients in two Dutch hospitals. Furthermore, a validated questionnaire was used to distinguish different PN grades.ResultsOf the 120 patients included between January 2017 and August 2018, 84% had an inadequate vitamin D level (median vitamin D level 49.5 nmol/L [IQR 34–65 nmol/L]; mean age: 68 years [SD ± 7.7]; males: 58%). PN was reported by 69% of patients (n = 83); however, of these 83 patients, PN was not documented in the medical records of 52%. An association was found between lower vitamin D levels and higher incidence of PN in the total population (P = 0.035), and in the active MM patients (P = 0.016).ConclusionThis multi-centre cohort study showed that PN and hypovitaminosis D are common in MM patients, and addressing low vitamin D levels in the treatment of MM patients might be beneficial in reducing the risk of PN. More attention for PN is warranted, as PN is underreported by clinicians. Further research is needed to fully understand the implications of vitamin D in the development of PN in patients with MM.Clinical trial registrationNetherland Trial Register NL5835, date of registration July 28, 2016

Prevalence of Chemotherapy-Induced Peripheral Neuropathy in Multiple Myeloma Patients and its Impact on Quality of Life: A Single Center Cross-Sectional Study.

Bortezomib is a pivotal drug for the management of multiple myeloma. However, bortezomib is a neurotoxic anticancer drug responsible for chemotherapy-induced peripheral neuropathy (CIPN). CIPN is associated with psychological distress and a decrease of health-related quality of life (HRQoL), but little is known regarding bortezomib-related CIPN. This single center, cross-sectional study assessed the prevalence and severity of sensory/motor CIPN, neuropathic pain and ongoing pain medications, anxiety, depression, and HRQoL, in multiple myeloma patients after the end of bortezomib treatment. Paper questionnaires were sent to patients to record the scores of sensory and motor CIPNs (QLQ-CIPN20), neuropathic pain (visual analogue scale and DN4 interview), anxiety and depression (HADS), the scores of HRQoL (QLQ-C30 and QLQ-MY20) and ongoing pain medications. Oncological data were recorded using chemotherapy prescription software and patient medical records. The prevalence of sensory CIPN was 26.9% (95% CI 16.7; 39.1) among the 67 patients analyzed and for a mean time of 2.9 ± 2.8 years since the last bortezomib administration. The proportion of sensory CIPN was higher among patients treated by intravenous and subcutaneous routes than intravenous or subcutaneous routes (p = 0.003). QLQ-CIPN20 motor scores were higher for patients with a sensory CIPN than those without (p < 0.001) and were correlated with the duration of treatment and the cumulative dose of bortezomib (coefficient: 0.31 and 0.24, p = 0.01 and 0.0475, respectively), but not sensory scores. Neuropathic pain was screened in 44.4% of patients with sensory CIPN and 66.7% of them had ongoing pain medications, but none were treated with duloxetine (recommended drug). Multivariable analysis revealed that thalidomide treatment (odds-ratio: 6.7, 95% CI 1.3; 35.5, p = 0.03) and both routes of bortezomib administration (odds-ratio: 13.4, 95% CI 1.3; 139.1, p = 0.03) were associated with sensory CIPN. Sensory and motor CIPNs were associated with anxiety, depression, and deterioration of HRQoL. Sensory CIPN was identified in a quarter of patients after bortezomib treatment and associated with psychological distress that was far from being treated optimally. There is a need to improve the management of patients with CIPN, which may include better training of oncologists regarding its diagnosis and pharmacological treatment.

Effect Evaluation of Strychnos nux-vomica L. with Integrative Methods for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma Patients: A Self-Controlled Clinical Trial

To explore the clinical effect and adverse reactions of Strychnos nux-vomica in bortezomib-induced peripheral neuropathy (BIPN) of patients with multiple myeloma (MM). A total of 19 MM patients with BIPN were enrolled and Nux Vomica Capsule (NVC, 0.4 g, thrice daily) were orally administrated for 30 days. Comparative analysis on parameters between pre- and post-therapy, including peripheral neuropathy (PN) grade, neurotoxicity score, Chinese medicine (CM) syndrome score, total neuropathy score (TNS), coagulation function, and serum nerve growth factor (NGF) levels were conducted. The adverse events were monitored. In BIPN of MM patients who received NVC, PN grade was lowered, neurotoxicity score was obviously decreased (P⩽0.01), and both CM syndrome score and TNS were remarkably decreased (P<0.01). After the therapy, activated partial thromboplastin time was prolonged (P<0.01) and fibrinogen was declined (P<0.05), showing improvement in the hypercoagulable state of patients. No significant difference of NGF recovery degrees was detected between pre- and post-therapy (P>0.05). No evident adverse reactions were observed during the course of treatment. Strychnos nux-vomica L. has significantly effect with a good safety in treatment of BIPN in MM patients.

The effect of rat nerve growth factor combined with vitamin B on peripheral neuropathy in multiple myeloma patients

ABSTRACT Background: Peripheral neuropathy can induce marked disability and negative effects on quality of life and is the most common therapy-related complication in multiple myeloma patients treated with bortezomib. Currently, there is no useful method to prevent or treat it. So, it is necessary to study the clinical efficacy of rat nerve growth factor combined with vitamin B for the treatment of peripheral neuropathy in multiple myeloma patients. Methods: Sixty multiple myeloma patients who developed peripheral neuropathy after bortezomib-based chemotherapy in Jiaxing First Hospital from October 2015 to May 2018 were randomly divided into treatment and control groups. Changes in serum NGF level and electromyograms before and after treatment were analyzed, and the effects were evaluated via a FACT/GOG-Ntx questionnaire score. Results: After treatment, the NGF level in the treatment group (13.2 ± 3.73 pg/ml) was higher than that in the control group (9.22 ± 2.93 pg/ml, P < 0.05). Improvements in the electromyograms were more pronounced in treatment group than those in the control group, with statistical significance. The FACT/GOG-Ntx questionnaire scores, both in the treatment group and the control group, were decreased (4.00 ± 1.58 vs. 5.20 ± 2.33; P < 0.05), and the alleviation of the symptoms in the treatment group were more obvious. Conclusion: Rat nerve growth factor combined with vitamin B is a safe and effective method for treating peripheral neuropathy in multiple myeloma patients.

Prevention of Bortezomib-Related Peripheral Neuropathy With Docosahexaenoic Acid and α-Lipoic Acid in Patients With Multiple Myeloma: Preliminary Data.

Background and Aims: Peripheral neuropathy is a common complication of chemotherapy that can induce marked disability that negatively affects the quality of life in patients with multiple myeloma (MM). The aim of this study was to prevent the onset or the worsening of peripheral neuropathy in MM patients treated with bortezomib (BTZ), using a new nutritional neuroprotective compound. We report preliminary results of 18 out of 33 patients who completed the study. Methods: We administered a tablet of Neuronorm to patients, containing docosahexaenoic acid 400 mg, α-lipoic acid 600 mg, vitamin C 60 mg, and vitamin E 10 mg bid for the whole follow-up period. Neurological visit assessment, electroneurography, and evaluation scales were performed at baseline and after 6 months. Results: At 6 months, 8 patients had no chemotherapy-induced peripheral neuropathy, while 10 patients experienced chemotherapy-induced peripheral neuropathy of grade 1 according to the Common Terminology Criteria for Adverse Events, one of them with pain. Seventeen patients did not report painful symptoms; no limitation of functional autonomy and stability in quality of life domains explored was observed. Conclusions: Our results seem to indicate that early introduction of a neuroprotective agent in our patients with MM treated with BTZ could prevent the onset or the worsening of neuropathic pain, avoiding the interruption of the therapy with BTZ, and maintaining a good functional autonomy to allow normal daily activities. Despite the limitations due to the fact that this is a preliminary study, in a small population, with short follow-up, our data seem to indicate that the nutraceutical may have some potential to be considered for a future trial.

Long-term Reversibility Analysis of Peripheral Neuropathy in Multiple Myeloma Patients Treated with Bortezomib

Long-term Reversibility Analysis of Peripheral Neuropathy in Multiple Myeloma Patients Treated with Bortezomib

Prediction of peripheral neuropathy in multiple myeloma patients receiving bortezomib and thalidomide: a genetic study based on a single nucleotide polymorphism array.

Bortezomib- and thalidomide-based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment-induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome-wide association study based on more than 300000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MAS65, NCT00443235). The highest-ranking single nucleotide polymorphism was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P=.1708). Prediction analyses, cytoband enrichment, and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment.

Bortezomib-induced peripheral neuropathy in multiple myeloma patients

To describe the side effects of bortezomib in treatment of multiple myeloma (MM), especially the incidence of peripheral neuropathy (PN). Information of 107 patients with MM who were treated with bortezomib in the First Affiliated Hospital of Zhejiang University from 2009 to 2014, were collected and analyzed retrospectively, to analyze the occurrence of adverse events during the treatment, especially the incidences of PN in each cycle and in different patients. A total of 40 (37%) patients suffered from PN, among which 13 patients were grade 3 PN and no patients reported grade 4 PN. Other common treatment-related side effects were thrombocytopenia, gastrointestinal reactions, fatigue, lung infection, herpes zoster in turn. In 44 MM patients treated strictly with bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11) of each 3-week cycle, 20(45%) patients suffered from PN, of which 6 (14%) patients got grade 3 PN. In other 63 patients who received bortezomib less than 1.3 mg/m(2), 20 (32%) patients got PN and 7(11%) patients were grade 3 PN. There was no significant difference in the incidence of PN between the two groups of MM patients mentioned above (P=0.149), as well as the incidence of grade 3 PN (P=0.694). Univariate and multivariate analyse revealed that gender, age, a history of hypertensive disease, diabetes or hepatitis B virus infection, baseline PN symptoms and a history of neurotoxicity drug therapy were all not risk factors for PN (all P>0.05). The reduction of bortezomib do not decrease the incidence of PN in bortezomib treatment of MM. Age, a history of diabetes and baseline PN symptoms are not risk factors for PN in bortezomib treatment of MM.

Primary Systemic Amyloidosis Associated With Multiple Myeloma. Our Experience

e206 to 33%/75% (grades 3/4: 30%/18%) of patients with newly diagnosed or recurrent multiple myeloma (MM) under intravenous (IV) bortezomib therapy, respectively. Currently, the introduction of subcutaneous (SC) administration has reduced this toxicity. Patients and Methods: We analysed the incidence of peripheral neuropathy in MM patients (pts) treated with SC bortezomib with different regimens in two different haematological units. Results: 47 patients with MM were included. Median age was 64(34-83) years, 20(43%) were male. Myeloma subtypes were: 55% IgG, 26% IgA, 17% Bence-Jones and 2% non-secretor. At diagnose, 49% ISS 2 and 25% ISS 3. 38 (81%), 4(8%) and 5 (11%) pts were treated at diagnose, at first and second, or subsequent relapse, respectively. The regimens of treatment were: 30% VMP, 32% VTD, 9% VCD, 6% VRD and 23% VD. Median cycles of bortezomib received were 5(1-9). All but one patients initially received bortezomib at 1,3 mg/m2 dose. Seven pts (15%) received IV bortezomib previously, 2 pts (6%) had presented previous neuropathy being symptomatic at initial treatment in one patient. In patients who received bortezomib at first line, 14 pts (37%) developed PN during treatment (VMP:43%, VTD:43%, VRD:33%, VCD:0%, VD:17%): in 9 pts (24%) the PN was grade 1(VMP:29%, VTD:29%, VD:17%); in 4 pts (11%) grade 2 (VMP:7% VTD:14%, VRD:33%), and 1 patient (3%) grade 3 (VMP:7%). None patient developed grade 4 PN. 12 pts (92%) pts developed PN in first 4 cycles, 7(50%) in first two cycles. PN was reversible in 10 pts (71%) and in 8(57%) was totally reversible. Of 9 patients who received bortezomib at first or subsequent relapse, 7 pts (78%) had received IV bortezomib previously. Three pts (33%) developed PN (VD:2 pts grade 1; VTD:1 patient grade 2). All three patients had received bortezomib previously. PN was reversible in all patients, partially in 2(66%) and totally in the other patient (33%). Conclusion: Although SC administration of bortezomib shows a lower incidence of PN, in current analyses we observe that PN is a common adverse effect of patients treated with this proteasome inhibitor. Regimens combining three drugs (with thalidomide or lenalidomide) show an increase in incidence with respect combination of two drugs. However, the majority of patients had grade 1 PN, being reversible in the majority of cases.

Therapy-related peripheral neuropathy in multiple myeloma patients.

This review discusses the most common issues concerning multiple myeloma (MM)-related peripheral neuropathy (PN). This is an important MM complication, observed in up to 54% of newly diagnosed patients, caused by the disease itself or its treatment. Although its aetiology is largely unknown, a number of mechanisms are suspected. It is important to know the neurological status of a patient, as many new antimyeloma medicines can trigger or exacerbate any pre-existing neuropathy. Examples include thalidomide-induced and bortezomib-induced PN (TiPN and BiTN, respectively), which are key MM treatment options. TiPN is usually sensory and sensorimotor, whereas BiPN is typically sensory. The mechanisms of chemotherapy-induced neurotoxicity in MM are well known; thalidomide seems to induce PN through its antiangiogenic properties, whereas bortezomib neurotoxicity is connected with disrupted calcium homeostasis. TiPN incidence ranges from 25% to 75%, and its prevalence and severity appears to be dose-dependent. BiPN incidence is almost 40% and is dose-related as well. Poor (25%) reversibility of TiPN prompted the recommendations for dose and exposure reduction, whereas BiPN cases are mostly reversible (64%). Peripheral sensory neuropathy is very rare in patients receiving bendamustine monotherapy. Because of this favourable toxicity profile, bendamustine may be considered a promising option for combination therapies in pre-existing PN in myeloma patients. Considering the lack of curative therapy for treatment-emergent PN, prevention is a key management strategy in MM patients. All patients should be evaluated for PN before the administration of a neurotoxic drug, and those under treatment should be closely monitored by a neurologist.

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 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.

Chemotherapy-induced peripheral neuropathy in multiple myeloma patients undergoing maintenance therapy.

9646 Background: After 3-months autologous stem cell transplant (AuSCT), a percentage of multiple myeloma (MM) patients during maintenance therapy continue to experience a complex of symptoms related to peripheral neuropathy. This longitudinal study examined these self-reported neuropathy symptoms and identified circulating inflammatory markers associated with high neuropathy-related symptoms. Methods: MM patients (N=51) rated symptom severity on 0-10 scale via the M. D. Anderson symptom Inventory (MDASI) weekly from 3 to 9 months post AuSCT during maintenance therapy. Patient also rated pain on hand or foot in routine clinic visit. A panel of pro- and anti-inflammatory cytokines, receptors, chemokines was evaluated on serum samples by Luminex. Mixed effect analysis was used to describe the changes on cytokines and symptom outcomes across time. Trajectory analysis identified patients that persistently reported higher or lower symptom severity overtime. Results: During the study period, there was no significant reduction on pain in general or on hand/foot, or change in neuropathic symptoms such as numbness/tingling and muscle weakness. Among a third (33%) of patients who was consistently in high pain (mean 5.5), MIP-1a (p=.001) and MCP-1 (p=.032) showed significant decrease. Approximately 40 % had persistently high numbness/tingling (mean 5.2) across the observation period. Compared to low symptom group patients, this high numbness group had significantly higher IL-6 (p=.019) and TNF-alpha (p=.006). High muscle weakness (mean 3.1) was for 69% of the sample. This group had significantly higher CRP (p=.005) and TNF-alpha (p=.001). Conclusions: This is the first longitudinal study that tracked persistent neuropathy-related symptoms for MM patients post AuSCT. Approximately one third reported painful neuropathy, either from induction therapy or ongoing maintenance therapy. High levels of these neuropathy symptoms were associated with higher levels of specific pro-inflammatory markers. This study provided rationale for examining the effectiveness of anti-inflammation as mechanism driven intervention on peripheral neuropathy in this cohort of MM patients.

A case of peripheral nerve microvasculitis associated with multiple myeloma and bortezomib treatment

Bortezomib-induced peripheral neuropathy typically presents as a painful, length-dependent sensory predominant neuropathy. A case report, including nerve pathology, is presented of a man with multiple myeloma who developed a severe motor predominant polyradiculoneuropathy in the setting of bortezomib treatment. We also review the Mayo Clinic Hematology Dysproteinemia database for patients treated with bortezomib. A 53-year-old man with Stage III multiple myeloma developed a severe motor predominant polyradiculoneuropathy following bortezomib treatment with electrophysiological features of multiple conduction blocks and pathological evidence of peripheral nerve microvasculitis. Our institutional experience is that 36.5% of dysproteinemia patients treated with bortezomib develop treatment-emergent peripheral neuropathy, and the most common pattern is a painful sensory predominant peripheral neuropathy. A motor predominant polyradiculoneuropathy is a rare presentation of bortezomib-associated peripheral neuropathy in multiple myeloma patients which may progress despite treatment withdrawal and may be due to microvasculitis.

Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients

Bortezomib induced peripheral neuropathy is a dose-limiting side effect and a major concern in the treatment of multiple myeloma. To identify genetic risk factors associated with the development of this side effect in bortezomib treated multiple myeloma patients, a pharmacogenetic association study was performed using a discovery set (IFM 2005-01; n = 238) and a validation set (HOVON65/GMMG-HD4 and a Czech dataset; n = 231). After multiplicity correction, none of the 2,149 single nucleotide polymorphisms tested revealed any significant association with bortezomib induced peripheral neuropathy. However, 56 single nucleotide polymorphisms demonstrated an association with bortezomib induced peripheral neuropathy with pointwise, uncorrected significance. Pathway analysis of these polymorphisms demonstrated involvement of neurological disease (FDR <20%). Also a clear enrichment of major bortezomib metabolizing genes was found. Univariate evaluation of these 56 polymorphisms in the validation set demonstrated one single nucleotide polymorphism with pointwise significance: rs619824 in CYP17A1. (IFM 2005-01 clinicaltrials.gov identifier: NCT00200681; HOVON-65/GMMG-HD4 isrctn.org identifier: ISRCTN64455289).

Peripheral Neuropathy In Multiple Myeloma Patients Treated with Lenalidomide

AbstractAbstract 5024 Background:Lenalidomide is an oral IMiD® immunomodulatory compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity. As demonstrated by 2 randomized, double-blind, placebo-controlled pivotal phase III registration trials, lenalidomide plus dexamethasone (Len/Dex) was well tolerated and achieved significant clinical efficacy and survival outcomes vs placebo plus Dex (PBO/Dex) in patients (pts) with relapsed/refractory multiple myeloma (MM) (Weber 2007; Dimopoulos 2007). In MM, the rate of symptomatic peripheral neuropathy (PN) is 3–13%, although the rate of subclinical neuropathy detected by electrophysiological studies or histopathological evaluation is estimated to be much higher (40-60%; Kwan 2007). Published incidence of PN has been notable with thalidomide (Thal) ranging from 0 to 90%, depending on pt characteristics, concomitant treatments, dose/exposure duration, and techniques for identifying PN. We present the result of our analysis of PN adverse events (AEs) reported with Len. Methods:Reports of PN from the 2 registration studies (MM-009, MM-010; data cutoff June and August 2005, respectively), and postmarketing safety reports (Dec 2005 to Dec 2009) were retrieved from Celgene clinical and safety databases utilizing the Preferred Terms for PN AEs within the PN Standardized MedDRA (v13.0) Query (SMQ) to obtain all possible cases. Severity grades were according to the NCI CTCAE (V3).Results: Clinical Studies703 pts (353 Len/Dex; 350 PBO/Dex) from the 2 registration studies were included in this analysis. The proportion of pts with ≥1 Grade (G) 1–4 PN AEs and ≥1 serious adverse event (SAE) was similar between the Len/Dex and PBO/Dex arm (45.6% vs 44.9% and 1.1% vs 1.1%, respectively). However, the proportion of pts with ≥1 G3/4 PN was slightly higher with Len/Dex vs PBO/Dex (9.3% vs 5.1%). Among the Len/Dex pts with PN AEs, prior Thal or vincristine was reported in 39.1% and 60.9% of pts, respectively and 24.8% of pts had history of PN. Among the PBO/Dex pts with PN AEs, prior Thal or vincristine was reported in 46.5% and 58.0% of pts, respectively and 29.3% of pts had a history of PN. Within this SMQ analysis, the PN AEs reported in ≥5% of the pts were peripheral neuropathy, hypoaesthesia, paraesthesia, and muscle weakness in both treatment arms. 98.3% of PN AEs were not SAEs and 83.2% were G1/2 in the Len/Dex arm. Among pts in the Len/Dex arm and with PN AEs, PN resolved in 61.5% and study drug was continued in 78.9% of pts. Study drug was reduced due to PN in 12.4% and interrupted in 5.0% of pts in the Len/Dex arm. The median time to onset of PN event was longer in the Len/Dex arm compared with the PBO/Dex arm (41 vs 31 days). PostmarketingA total of 2857 PN AEs were reported in 2329 of an estimated 73,592 MM pts. The reporting rate of PN AEs is 3.2% in the MM indication. Within this SMQ analysis, the PN AEs reported in ≥0.5% of the pts were peripheral neuropathy, hypoaesthesia, and paraesthesia. 93.8% of PN AEs were not SAEs. Most pts were males and elderly with a median age of 66 yrs (range: 29–95). Among MM pts with PN AEs and available information, 13% had prior Thal, 5% had prior bortezomib, and 11% had a history of PN. In the majority of reports, outcome was unknown and Len was continued. The median time to onset of PN event was 60 days (range: 1–1460). Conclusion:In 2 pivotal phase III registration trials, the incidence rate of peripheral neuropathy adverse events was similar between the Len/Dex and PBO/Dex arms. Most pts had prior anti-myeloma therapies associated with PN and a quarter of the pts had a history of PN. Limited information in postmarketing reports on prior therapies and medical history may have underestimated pre-existing PN and exposure to prior anti-myeloma therapies associated with PN. PN AEs occurred within a median of 60 days of starting Len. In conclusion, peripheral neuropathy adverse events in MM pts treated with Len are generally not SAEs and did not commonly require dose modification or interruption.ReferencesDimopoulos et al. NEJM 2007;357(21):2123-2132.Kwan JY. Neurol Clin 2007;25(1):47-69.Weber et al. NEJM 2007;357(21):2133-2142. Disclosures:Castaneda:Celgene: Employment. Weiss:Celgene: Employment. Minton:Celgene: Employment. Kim:Celgene: Employment. Freeman:Celgene: Employment. Yu:Celgene: Employment. Knight:Celgene: Employment.

Neurological monitoring reduces the incidence of bortezomib‐induced peripheral neuropathy in multiple myeloma patients

Bortezomib (BTZ) is a proteasome inhibitor approved in the treatment of multiple myeloma (MM). Bortezomib-induced peripheral neuropathy (BIPN) is an unpredictable dose-limiting adverse event in one-third of patients. In the present study, 58 relapsed/refractory MM patients treated with BTZ were analyzed. The study's aim was to compare BIPN incidence and severity between both groups and to identify risk factors of BIPN. Twenty-four MM patients were evaluated by a neurologist periodically during BTZ treatment in order to prevent high-grade BIPN. Thirty-five MM patients previously treated with BTZ were reviewed. Seven (29%) patients in the monitored group and 19 (56%) in the historical cohort developed BIPN (p = 0.044). In the univariate analysis, factors related to BIPN in the whole series were age, number of vincristine and BTZ cycles, lactate dehydrogenase and neurological monitoring. Multivariate analysis revealed that absence of neurological monitoring (Hazard Ratio [HR]: 4.94 IC 95% [1.31-18.68], p = 0.019) and prior treatment with vincristine (HR: 1.34 IC 95% [1.04-1.74], p = 0.026) were associated with greater risk of BIPN. Baseline total neuropathy score-clinical version (TNSc) was a good predictor of BIPN, with higher risk for patients with TNSc >2 (p = 0.038). Neurological monitoring is useful for diminishing BIPN. Neurological monitoring of patients with baseline TNSc >2 should be considered.

Genetic Variation in ADME Genes Is Associated with Thalidomide Related Peripheral Neuropathy in Multiple Myeloma Patients.

Peripheral neuropathy is a major adverse effect seen in multiple myeloma (MM) patients treated with thalidomide, with rates varying between trials from 15% to 70%. Peripheral neuropathy can often lead to ongoing impairment of quality of life and can lead to discontinuation of treatment. Identifying patients at risk of neuropathy and understanding its pathogenesis would be a significant step forward in the management of thalidomide based therapy. Proposed mechanisms have included: Anti-angiogeneic properties of thalidomide leading to a reduction in nerve blood supply; direct toxic effects of thalidomide on neurons of the posterior root ganglia and dysregulation of neurotrophin activity through effects of thalidomide on NFkB. Genetic variation in genes important in the mechanism of thalidomide neurotoxicity are likely to impact on whether an individual patient develops this adverse effect. Taking a nested case control approach we used peripheral blood DNA from 388 Caucasian MM patients all who had received induction thalidomide (200mg) as part of the Myeloma IX trial. Samples from 80 patients that developed sensory-motor peripheral neuropathy in response to thalidomide therapy were available for this analysis, these were age and sex matched with a ratio of one case to 4 controls. We assayed 3403 SNPs in coding and predicted regulatory regions selected in 1266 genes previously shown to be involved in the pathogenesis, treatment response and side effects associated with myeloma and its therapy. SNPs were present on a custom-built Affymetrix® targeted genotyping chip (designed by “Bank on a Cure” (BOAC)), which utilizes molecular inversion probe technologies. We carried out a univariate analysis by Fischer exact tests. Due to the large number of SNPs and relatively small number of samples, we chose to correct for multiple testing using label swapping permutation using the program PLINK. The most significant SNPs associated with thalidomide related peripheral neuropathy are listed with p=permutated empirical p-value and OR=Odds Ratio: ABCC2-Ile1324Ile (p<9.71×10−5;OR=1.972,1.39−2.8); DGKH-Ala1201Val (p<1.05×10−3;OR =4.267,1.85−9.87); EXO1-Arg354His (p<1.4×10−3;OR=1.79,1.25−2.55) and NPC2-3′UTR (p<1.6×10−3, OR=0.42,0.24−0.75). DGKH, EXO and NPC2 are genes previously reported to play a role in peripheral neurotoxicity. The ABCC2-Ile1324Ile SNP forms part of previously reported functional haplotype. Significant associations were also seen in a number of other ADME genes (drug absorption, distribution, metabolism, and excretion): ABCB1, ABCB11, ABCC1, CYP1A1, CYP20A1, CYP20A1, CYP2C9, CYP3A7, CYP4F2, FMO2, FMO3, FMO6, SLC12A6, SLC22A3 and SLC7A7. Significant associations were also seen in genes important in neurological system processes and central nervous system development: ERBB2, NQO1, MY03A, PPARD, DBH, NGFR, GSTP1, TCF8 and ICF1R. Our results indicate the importance of thalidomide dose and cumulative exposure, and highlight the metabolism of thalidomide as playing a pivotal role in dictating neuropathy events and open the way for predictive testing and dose adjustment. The results also implicate a direct toxicity mechanism for thalidomide related peripheral neuropathy, as we see a number of associations with SNPs in genes with known importance in peripheral neuron function.