Neuropathy In Multiple Myeloma Research Articles

Abstract 4908: Study on Ca 2+-mediated regulation mechanisms on chemotherapy-induced peripheral neuropathy in multiple myeloma and non-Hodgkin lymphoma

Abstract In general, when treating cancer patients, various anticancer drugs are used in combination to enhance the anticancer effect. However, most drugs exhibit side effects. Neurotoxicity, one of the side effects commonly accompanied, greatly affects the quality of life and also reduces compliance with treatment. Calcium signal transduction, which occupies a key position in cell signal transduction, has been found to be involved in various mechanisms including proliferation, differentiation, and death of cells, beyond the existing research direction that focuses on channels. To identify the mechanisms of calcium signal regulation that can reduce chemotherapy induced peripheral neuropathy (CIPN) while maintaining anticancer functions of drugs, we study with the two drugs frequently used in non-Hodgkin lymphoma and multiple myeloma, borteozomib (BTZ) and vincristine (VIN), whose main side effects are neurotoxicity. We used the human neuroblastoma cell line, SH-SY5Y cells, and performed MTT assay after treating them with N-Acetylcysteine ​​(NAC), an antioxidant, to determine whether the reduction in cell viability by BTZ and VIN was due to the increase in ROS. When BTZ and VIN were treated with NAC, cytotoxicity by BTZ was significantly reduced and cell viability decreased by VIN was significantly increased. From these results, we found that ROS are involved in BTZ and VIN -induced apoptosis. In addition, we performed MTT assay using calcium inhibitors to investigate whether intracellular calcium signaling is involved in BTZ and VIN-induced apoptosis, and 8-Br-cADPR, Ned-19, Xestospongin C, and Heparin were used as calcium inhibitors. To confirm that the cell viability reduced by BTZ and VIN is recovered by calcium inhibitors, BTZ and VIN were treated together with calcium inhibitors, respectively. Cell viability was found to increase significantly. These results suggest that intracellular calcium signaling is involved in cell death induced by BTZ and VIN. The increase in [ca2+]i in the cytoplasm when treated with BTZ and VIN was measured using a fluorescence spectrophotometer. It was shown that the treatment with BTZ and VIN increased the calcium concentration in the cytoplasm within 1 minute. To confirm that the concentration of intracellular calcium was reduced by the calcium inhibitor, BTZ and calcium inhibitor were treated together, and it was confirmed that the intracellular calcium concentration increased by BTZ was decreased in a concentration-dependent manner at 2uM and 3uM of the calcium inhibitor. In conclusion, this experiment suggests that intracellular calcium signaling is involved in the BTZ and VIN’s reduction of neuronal cell viability (CIPN) in multiple myeloma and non-Hodgkin lymphoma. This research was supported by NRF 2021R1A2C1091322 (J.-S.Kim) and 2021R1F1A1064120 (J. Park). Citation Format: Jinny Park, Jong-Suk Kim, Kwang-Hyun Park. Study on Ca 2+-mediated regulation mechanisms on chemotherapy-induced peripheral neuropathy in multiple myeloma and non-Hodgkin lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4908.

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 < 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 < 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 < 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 < 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.

Glutathione combined with mecobalamin in the treatment of chemotherapy-induced peripheral neuropathy in multiple myeloma: a retrospective clinical study.

This study sought to examine the use of glutathione combined with mecobalamin in the prevention and treatment peripheral neuropathy (PN) in multiple myeloma (MM) patients, observe its effectiveness and safety, and explore the risk factors and prognostic factors of chemotherapy-induced peripheral neuropathy (CIPN). Patients in the study group were administered 2.4 g of glutathione intravenously once daily 2-3 days before chemotherapy, combined with 500 µg of mecobalamin administered intravenously once every other day until the end of the chemotherapy cycle. Patients who did not use this regimen were selected as a control group. Differences in adverse reactions, treatment efficiency, progression-free survival (PFS), and overall survival (OS) between the two groups were retrospectively analyzed. PFS and OS curves were plotted using the Kaplan-Meier method. The univariate analysis rates were compared using the χ2 test. The multivariate analysis was performed by a logistic regression analysis. The proportional hazard regression model was used for the univariate and multivariate proportional hazards model analyses. The incidence of PN, especially grade 2 and 3 PN, was more decreased in the study group than the control group. The history of diabetes (P=0.032) and the method of bortezomib injection (P=0.043) was found to affect the PN grade. The multivariate logistic regression analysis showed that diabetes was an independent risk factor of PN in MM patients [odds ratio (OR) =3.484, P=0.020]. The Proportional hazards model multivariate analysis showed that extramedullary disease (EMD) [hazard ratio (HR) =2.373, P=0.006] and elevated lactic dehydrogenase (LDH) (HR =1.934, P=0.009) were independent prognostic factors for MM patients. Glutathione combined with mecobalamin significantly reduced the incidence and severity of CIPN in MM patients, and did not increase the adverse reactions of patients with MM. Diabetes and bortezomib intravenously increased the incidence and severity of PN in patients with MM.

Low-Intensive Electropulse Therapy for Correction of Clinical and Functional Manifestations of Neuropathy in Multiple Myeloma

Polychemotherapeutic drugs can affect neuros system in patients with myeloma, which can worsen their quality of life and promote disease progression. The authors studied the dynamics of pain syndrome, microcirculation status and parameters of quality of life in patients with multiple myeloma complicated by peripheral polyneuropathy under polychemotherapy. In the course of the present study 106 patients were examined and divided into the three groups: in group I the patients were indicated standard polychemotherapy supplemented with the course of dynamic electroneurostimulation, in group II the patients were treated with placebo procedures along with the basic treatment, and in group III the patients received standard treatment. It was established that by the end of the therapy pain syndrome intensity decreased in patients from group I by 1.8 times, initially elevated pain threshold decreased by 24.4% and basal microcirculatory parameters improved by 1.4 times, whereas in the comparison groups significant changes were not observed. The treatment influenced on the quality of life: in group I the score of physical functioning (SF-36 questionnaire) increased by 1.5 times in comparison with the baseline, the score of general health perception and vitality increased by 1.7 and 1.5 times, respectively, which significantly differed from analogue parameters score in the comparison groups. It was established that introduction of dynamic electroneurostimulation into the treatment plan of patients with multiple myeloma reduced pains intensity, decreased pain threshold, stimulated microhemocirculation and contributed to improvement of quality of life that allowed the patients to continue their specific polychemotherapy.

Impact of concomitant dexamethasone dosing schedule on bortezomib-induced peripheral neuropathy in multiple myeloma.

Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules.

Chemotherapy-induced neuropathy in multiple myeloma: influence on quality of life and development of a questionnaire to compose common toxicity criteria grading for use in daily clinical practice.

Chemotherapy-induced peripheral neuropathy (CIPN) may negatively influence multiple myeloma (MM) patients' health-related quality of life (HRQOL). Dose modification is the only way to minimize CIPN. To measure CIPN in daily practice, the Indication for Common Toxicity Criteria (CTC) Grading of Peripheral Neuropathy Questionnaire (ICPNQ) was developed which can be completed within five minutes by the patient. The aims of this study were to (1) perform a psychometric evaluation of the ICPNQ and (2) examine the prevalence of CIPN and its influence on HRQOL in population-based MM patients. One hundred fifty-six MM patients, diagnosed between 2000 and 2014, completed the ICPNQ, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20), and EORTC QLQ-C30 (65% response). The psychometric analyses showed a Cronbach's alpha of 0.84, 0.74, and 0.61 for, respectively, the sensory, motoric, and autonomic subscales of the ICPNQ. Test-retest reliability and construct validity were good for all subscales. Overall, 65% of patients reported grade 2-3 neuropathy according to the ICPNQ. Patients with the highest CTC grades (grade 2 with neuropathic pain and grade 3 (38%)) according to the ICPNQ reported significantly worse scores on all EORTC QLQ-CIPN20 subscales compared to patients with lower CTC grades (p≤0.002). In addition, they reported statistically significant and clinically relevant worse HRQOL scores on almost all EORTC QLQ-C30 subscales. CIPN is a common side effect in MM patients, which has a negative impact on HRQOL. The ICPNQ is a valid instrument to distinguish the highest CIPN CTC grades from the lower CTC grades necessary to decide on dose modifications of chemotherapy in daily clinical practice.

A Pilot Placebo Controlled Study to Estimate the Effect Size of Glutamine to Prevent Peripheral Neuropathy in Multiple Myeloma

e318 Introduction: ‘Complementary and alternative medicine’ (CAM) includes natural products, mind/body practices and ‘whole system’ interventions. CAM use is high among cancer patients (1,2) but little is known about use among blood cancer patients. This paper examines CAM use, attitudes and disclosure among multiple myeloma (MM) patients and their health professionals (HP). It is part of a broader study examining CAM in the haematological setting. Methods: Participants were Australian English-speaking cancer patients (18 years plus) recruited from a hospital and two national patient associations. HPs were recruited from the same hospital and the Haematology Society of Australia and New Zealand. Participants completed an online or paper survey. Results: Recruitment included 157 MM patients and 176 HP. Of the MM participants 66% currently use CAM. Reported reasons to use: cope with the cancer experience (53%), reduce symptoms (52%), decrease emotional stress (44%), prevent future health problems (37%) and/or treat their cancer (19%). Only 38% had discussed CAM with their haematologist and 28% did not discuss CAM with any HP, most commonly because the HP never asked (30%). Eleven percent were warned about CAM risks. Reasons for not using CAM: interference with conventional treatments (43%), unable to find good practitioners (40%) and concerns about side effects (33%). Of the HP, 91% supported mind/body therapies and 41% supported natural products. Forty eight percent always asked about CAM use but only 19% felt they could advise patients. Of the CAM listed, 41% were strongly against use of Chinese herbs. Only 30% were confident discussing CAM therapies and 77% wanted to learn more. Conclusion: CAM use is common among MM patients and aids coping with experience and symptoms of disease. Patient disclosure however is low. HP findings reveal a lack of confidence about how to advise patients but strong desire to improve knowledge. Given many patients use CAM alongside conventional treatments, improved understanding of benefits, risks and interactions could aid communication and decision making and improve outcomes for all.

A Genome Wide Association Study Reveals Genetic Predisposition for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma By Variation in the PREP1-Cbs Locus

Introduction: Bortezomib has become an important part of myeloma therapy, despite the occurrence of toxicities such as bortezomib induced peripheral neuropathy (BiPN). Since effective prophylactic treatment is lacking, onset of BiPN can only be remedied by dose reduction or stop of treatment. Here, using a genome-wide genotyping method, we investigated the potential genetic predisposition to BiPN in MM patients who received bortezomib-dexamethasone (VD) induction therapy prior to autologous stem-cell transplantation (ASCT).Methods: We performed a genome-wide association study using the Affymetrix SNP 6.0 platform. In total 469 cases from the IFM 2005-01, IFM2007-02 clinical trials or routine diagnostic were included as discovery cohort. Another 114 samples from the HOVON-65/GMMG-HD4 trial were used as validation. Patients with BiPN grade 2 or higher after initiation of bortezomib treatment were assigned as cases (n=155 in discovery, n=40 in validation) and the remaining patients that did not developed BiPN were considered controls (n=314 in discovery, n=74 in validation). Additional exclusion criteria were a minor allele frequency ≤ 5%, genotype frequency < 95% or Hardy Weinberg equilibrium p-value <1 x 10-5; 371,075 tagging SNPs were thus included for analysis. Association of SNPs to BiPN was tested using a Cochran-Armitage trend test. Six SNPs were found with parametric p-value < 1 x 10-5. These SNPs were validated using the validation cohort.Results: Of three loci identified by six SNPs in the discovery cohort, one previously unreported gene locus (rs2839629) remained associated to BiPN in the validation data set. This locus at 21q22.3 had odd ratios of 1.89 (p<1x10-6) and 2.02 (p = 0.02) in the discovery and validation cohorts, respectively. It is localized in the 3’ UTR of PBX/knotted 1 homeobox 1 (PKNOX1; alias PREP1), which encodes for a homeodomain transcription factor. Amongst others, PKNOX1 may modulate levels of chemokine monocyte chemoattractant protein-1 (MCP-1). MCP-1 is universally increased in different models of peripheral neuropathic pain and may be considered as a biomarker of chronic pain (Zhang and de Koninck, J. Neurochem. 97:772-783 (2006)). Haplotype analysis revealed a strong linkage disequilibrium (LD, r2 = 0.87) to the neighbouring gene CBS which encodes an endogenous H2S-producing enzyme. The CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models (Takahashi et al., Pain, 150, 183-191, 2010).Conclusions: Our data provides evidence for susceptibility to BiPN in MM by variation in the PREP1-CBS locus, and suggests a new potential target in neuro-protective strategies of treatment. Validation of this finding may allow for the identification of patients at increased risk of BiPN which may benefit alternative treatments such as carfilzomib and better clinical management of this toxicity. DisclosuresSonneveld:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Moreau:Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Bortezomib‐ and thalidomide‐induced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study

A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). A total of 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed in 120 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (P < 0.001). PN resolved in 88 and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis, and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.

Analysis of Incidence and Risk Factors for Bortezomib-induced Peripheral Neuropathy in Multiple Myeloma

Analysis of Incidence and Risk Factors for Bortezomib-induced Peripheral Neuropathy in Multiple Myeloma

Assessment of bortezomib induced peripheral neuropathy in multiple myeloma by the reduced Total Neuropathy Score

We evaluated bortezomib induced peripheral neuropathy (BIPN) characteristics in an attempt to better clarify the type, grade, duration and reversibility of neuropathy as well as investigate possible peripheral neuropathy (PN) risk factors and detect the best way to manage it. We calculated the grading of neuropathy using the Total Neuropathy Score reduced version (TNSr) in a series of 51 patients with relapsed/refractory multiple myeloma treated with bortezomib. Seventy percent developed clinical PN. BIPN, although manageable, is frequently underestimated in patients treated with bortezomib intravenously. Continuous follow-up and management of PN are needed to avoid quality of life impairment.

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.

Physician Competence in Common Terminology Criteria for Adverse Events (CTCAE) Grading of Peripheral Neuropathy in Multiple Myeloma

AbstractAbstract 4702Treatment-induced peripheral neuropathy (PN) remains a clinical challenge in the management of patients with multiple myeloma (MM). A number of strategies have been developed to prevent the condition including modifications to dose, schedule, or mode of administration of PN-causing agents or selection of alternative active agents with reduced PN risk. Given the increasing number of options to reduce or mitigate PN, recognition of symptoms and appropriate grading is important to manage the toxicity and prevent cumulative or irreversible PN. An independent certified education series focusing on proteasome inhibition in MM, including associated toxicities and management, was conducted at hospitals, medical centers, cancer centers, medical practices, and community dinner venues throughout the United States. From April 2011 to January 2012, 51 live 1-hour education activities presented by respected leaders in the MM field were implemented in accordance with the essential areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) and Accreditation Council for Pharmacy Education (ACPE). The target audience for this program was hematologists, hematologist-oncologists, medical oncologists, oncology specialty pharmacists, and allied healthcare professionals charged with the care of patients with MM. The program educated 999 healthcare professionals including 553 physicians. Of the 553 physicians, 309 (56%) listed specialties that fell within the target audience. Practitioner knowledge, competence, and confidence were assessed via case vignettes prior to and immediately following each educational activity using an audience response system. Case vignette surveys completed 6 weeks following each activity evaluated practitioner performance. Practice gaps were identified through comparison of current best practices versus actual participant responses. Competence in CTCAE grading was assessed with a case vignette containing PN symptoms. Participants were asked to select the grade of PN from multiple choice answers of grades 1 through 5. Participation by the target physician audience in the assessment included 177 prior to the education, 176 after the education, and 54 at 6-weeks following the activity. The baseline grading gap for the physician target audience was 45%. Immediately following the education, there was a 30% improvement yielding a remaining practice gap of only 15%. However, educational erosion for PN CTCAE grading at 6 weeks was 24%, yielding only a 6% improvement over baseline and suggesting the majority of practitioners did not retain PN grading competency. Baseline, knowledge and competence gaps for all other assessments ranged from 32% to 68% and were reduced immediately following the education and at 6 weeks following the activity. While some educational erosion did take place at 6-weeks in other areas, it only ranged from 9% to 10% compared to 24% erosion for PN grading. Overall, physician knowledge, competence, and confidence were improved by this educational series. However, for CTCAE grading of PN, there was increased educational erosion suggesting a need for serial education to reinforce physician awareness of current grading criteria. Disclosures:Fagerlie:Millennium: The Takeda Oncology Company: Research Funding; Celgene Corporation: Research Funding; Onyx Pharmaceuticals, Inc: Research Funding. Heintz:Millennium: The Takeda Oncology Company: Research Funding; Celgene Corporation: Research Funding; Onyx Pharmaceuticals, Inc: Research Funding. Haas:Millennium: The Takeda Oncology Company: Research Funding; Celgene Corporation: Research Funding; Onyx Pharmaceuticals, Inc: Research Funding. Stacy:Millennium: The Takeda Oncology Company: Research Funding; Celgene Corporation: Research Funding; Onyx Pharmaceuticals, Inc: Research Funding.

Management of treatment-emergent peripheral neuropathy in multiple myeloma.

Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.

Prevalence of peripheral neuropathy in multiple myeloma at initial diagnosis

To evaluate the presence of peripheral neuropathy (PN) in newly diagnosed treatment-naive patients with multiple myeloma (MM), 29 patients and 25 age and sex matched controls underwent electrophysiological studies. Patients with associated diabetes, alcoholism, peripheral vascular disease and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M component and skin changes) were excluded from the study. The median age of patients was 56 years (range 28–82) and the sex ratio was 2.6:1. Eighteen (62.1%) patients were found to have evidence of PN by history and clinical examination alone (two patients), both clinical and electrophysiological evidence (five patients) and only electrophysiological evidence (11 patients). Out of 25 healthy controls, only two patients had evidence of PN by electrophysiological studies (cases vs. controls, p < 0.002). The commonest nerve involvement was in the form of sensory-motor axonal neuropathy followed by sensory-motor demyelinating neuropathy. This information may impact therapeutic and prognostic decision-making in newly diagnosed patients with MM.

Genetic Predisposition for Chemotherapy-Induced Neuropathy in Multiple Myeloma

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Towards a better understanding of treatment-related peripheral neuropathy in multiple myeloma

In this issue of The Lancet Oncology, Annemeik Broyl and colleagues1 assessed the genetic susceptibility to treatment-emergent neuropathy in patients who were in a prospective, phase 3 trial of bortezomib-based therapy (bortezomib, doxorubicin, and dexamethasone) versus vincristine-based induction treatment (vincristine, doxorubicin, and dexamethasone). The comparison between vincristine-induced peripheral neuropathy and bortezomib-induced peripheral neuropathy using gene expression profiling suggests that the factors involved in the development of peripheral neuropathy are distinct and involve different molecular mechanisms.

Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues

Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.

Genetic Associations with Bortezomib Mediated Neuropathy in Multiple Myeloma.

Abstract 1794Poster Board I-820The proteasome inhibitor bortezomib has demonstrated high antitumor activity in multiple myeloma (MM). Peripheral neuropathy (PNP) is a dose-limiting toxicity of bortezomib, which typically occurs within the first cycles of bortezomib in 30-40% of MM patients. Although bortezomib induced PNP is manageable and reversible in most MM patients, no effective prophylactic treatment against PNP is available and bortezomib discontinuation is frequently required. Identifying patients at risk of neuropathy and understanding its pathogenesis is therefore of great importance.The mechanism underlying bortezomib induced PNP is unknown. To investigate whether genetic variation is associated with bortezomib induced PNP, a custom-built molecular inversion probe (MIP) based single nucleotide polymorphism (SNP) chip, designed by “Bank on a Cure” (BOAC)) was used, containing 3404 SNPs selected in “functional regions” within 983 genes representing cellular functions and pathways that may influence disease response, toxicities, complications, and survival. To explore SNP associations with bortezomib induced PNP we compared cases and controls in two phase 3 clinical trials. In the Dutch-German HOVON-65/GMMG-HD4 trial 3 cycles of Bortezomib/Doxorubicin/Dexamethason were given for induction, and 52 PNP grade 2,3,4 cases (37 %) were identified during this treatment against 84 controls. In the French IFM 2005-01 trial 4 cycles of Bortezomib/Dexamethasone were given, and 74 PNP grade 2,3,4 cases (34 %) versus 144 controls were identified. A Cochran-Armitage trend test was applied on the combined data set using the program PLINK. To account for multiple testing we carried out label swapping procedures. A set of SNPs was identified that was highly associated with bortezomib induced PNP. The 5 most significant SNPs are rs3136516 in F2 (thrombin) (p=2.0×10-4; Odds Ratio (OR)=0.53, 95% confidence interval (CI)=0.38-0.72), rs2686184 in FDFT1 (p=2.1×10-4; OR=1.6, 1.17-2.19), rs2137975 in DPYD (p=2.3×10-4; OR=1.60, 1.17-2.20), rs2857605 in TNF (p=3.0×10-3; OR=0.53, 0.35-0.79), rs12198787 in TNF (p=4.9×10-3; OR=0.48, 0.30-0.79). In addition, 3 significant SNPs (rs10979601, rs10759326 and rs838827) were located in IKBKAP, a gene involved in hereditary sensory neuropathies. Another interesting associated SNP, rs7096206 (p=8.5×10-3; OR=1.60, 1.10-2.32), is known to lead to reduced MBL2 serum levels. Significant associations were also seen in ADME genes (drug absorption, distribution, metabolism, and excretion) such as ABCC1, CYP2C9, CYP1A1, CYP1A2, CYP11B1, CYP17A1, CYP3A4, ABCB11, FMO2 and SLC22A4. Overall, the set of associated SNPs were enriched for genes in pathways involved in DNA replication, DNA repair, cell-to-cell signaling and drug metabolism. In conclusion, we identified a set of SNPs which are highly associated with bortezomib mediated PNP. Both ADME and critical biological pathways are implicated, which suggests a critical role for bortezomib metabolism and biological effects in PNP development. Our results open the way to develop a classifier predicting PNP in MM patients. DisclosuresOff Label Use: Use of Bortezomib in first line treatment of Multiple Myeloma. Goldschmidt:Johnson and Johnson: Research Funding, Speakers Bureau. Lokhorst:Celgene: Consultancy. Sonneveld:Johnson and Johnson: Research Funding, Speakers Bureau.

Bortezomib-induced peripheral neuropathy in multiple myeloma: A comparison between previously treated and untreated patients

Peripheral neuropathy (PN), with neuropathic pain as main symptom, represents the dose-limiting toxicity of the proteasome inhibitor bortezomib. Aim of this study was to compare the incidence, risk factors, severity and outcome of PN and neuropathic pain in patient treated with bortezomib up-front or at relapse. We studied 55 patients with multiple myeloma (MM) who received bortezomib as first line therapy and 70 pre-treated patients who received bortezomib in relapse or progression. Regarding PN, no differences were found among untreated and pre-treated patients in the incidence (55% vs 52%, p = 0.43), severity (NCI grade 3–4 9% vs 14%, p = 0.27), and outcome (improved/resolved 90% vs 91%, p = 0.58). Concerning neuropathic pain, the incidence was lower (50% vs 81%, p = 0.008) and solved earlier (35 days vs 91 days, p = 0.02) in untreated compared with pre-treated patients. Untreated patients needed dose modification less frequently (36% vs 73%, p = 0.012). No correlation was found between development of PN and prior exposure to potentially neurotoxic drugs such as thalidomide, vincristine, and cysplatin. Age represented the main risk factor for PN ( p = 0.036) with an increase in risk of PN amounting to 6% per year of age. In conclusion, incidence, severity and outcome of bortezomib-related PN are similar in untreated and pre-treated MM patients except for neuropathic pain which has lower incidence and shorter duration in untreated patients with less frequent need for bortezomib discontinuation. Age emerges as the most relevant risk factor for peripheral neuropathy, with a risk increase for PN of 6% per year of age.