Treatment-induced Peripheral Neuropathy Research Articles

P07.15.B NEUROMUSCULAR HIGH-RESOLUTION ULTRASOUND IN PERIPHERAL NEUROTOXICITY OF SYSTEMICALLY TREATED CANCER PATIENTS

Abstract BACKGROUND Up to 40 % of cancer patients treated with neurotoxic cytostatic chemotherapies develop treatment-induced peripheral neuropathy. Furthermore, in patients treated with immune checkpoint inhibitors neuromuscular immune-related adverse events (irAEs) are the most common neurological complication. The differentiation between various types of peripheral neurotoxicity, neurological comorbidities and (para-)neoplastic conditions requires experienced clinical and neurophysiological diagnostics within an interdisciplinary team of experts. High-resolution ultrasound (HRUS) is a widely used diagnostic tool for peripheral neuropathies. As there are no generally approved biomarkers of treatment-related neurotoxicity so far, HRUS might extend the repertoire of diagnostic and neuromonitoring methods in patients with neuropathies induced by cytostatic agents, immunotherapy, and targeted therapy. MATERIAL AND METHODS We present the integration of HRUS into a standardized algorithm for suspected peripheral neurotoxicity by characterizing a case series from our neuro-oncological center. We show representative HRUS findings of seven cancer patients (diagnosed with breast cancer, cholangiocarcinoma, colorectal carcinoma, or multiple myeloma) treated with platinum derivates, immune checkpoint inhibitors, bortezomib, or lenalidomide. RESULTS We describe the potential of HRUS independently of a certain cancer treatment regimen and beyond that in patients with both neurological co-morbidities and concomitant neoplastic infiltration of the nervous system. In our retrospective cohort, HRUS revealed partly continuous and partly discontinuous nerve swelling as well as compression syndromes. Moreover, we detected enlargements of dorsal roots and vagus nerve in cancer patients with treatment-induced neuropathies for the first time. In addition, we identified significant discordance between clinical, electrophysiological and HRUS findings and discuss how peripheral neurotoxicity may be amenable to complementary HRUS assessment and neuromonitoring. CONCLUSION At our institution, neuromuscular ultrasound is an integral part of the interdisciplinary algorithm for peripheral neuropathies in systemically treated cancer patients. HRUS expands the neurological tool inventory for cancer patients and accelerates the differentiation of peripheral neurotoxicity, neurological comorbidities, and neoplastic affection of the nervous system in a non-invasive and cost-sparing manner. Our data may help to detect distinct patterns of nerve enlargement as new biomarkers of peripheral neurotoxicity. Thus, we employed our data to conduct a prospective, cross-sectional trial (PARTICIPATE), which has the potential to define the diagnostic relevance of HRUS for patients treated with agents affecting the PNS and its impact on cancer patient care.

Abstract 4397: Chemotherapy-induced peripheral neuropathy and falls in cancer survivors relate to digital balance and gait impairments

Abstract Background and Aim: Standing postural sway and gait tests with body-worn inertial sensors provide a multitude of objective, digital balance, and gait measures that represent several different domains controlling mobility. However, it is not clear which domains of balance or gait best reflect the impact of treatment-induced peripheral neuropathy on mobility or differentiate fall risk in cancer survivors. This study aimed to determine which domains of balance and gait differed between cancer survivors who reported 1) symptoms of peripheral neuropathy versus asymptomatic survivors and 2) falls in the previous six months versus non-fallers. Methods: Both postural sway during 30 seconds of quiet stance and gait characteristics from the Instrumented Time-Up-and-Go test (ITUG) were recorded with six synchronous inertial sensors (Opals by APDM Wearable Technology, a Clario company). The sensors were placed on both shanks and wrists, and one on the lumbar spine and sternum in 425 female cancer survivors (age: 62 ± 6 years). A principal component analysis (PCA) approach was used first to identify independent domains of mobility from 14 balance and gait measures for subsequent analysis. Results: PCA analysis revealed 5 independent domains (PC1: Sway amplitude, PC2: Gait pace; PC3: Sway frequency; PC4: Gait spatial-temporal and PC5: Turning) that accounted for 81% of the variance of performance across the participants. Cancer survivors who reported neuropathy showed a significantly higher sway frequency (PC3) than asymptomatic survivors. Cancer survivors who reported falls showed a significantly larger sway area (PC1) and slower gait pace (PC2) than non-fallers. Conclusions: Wearable sensor instrumentation from short balance and gait tests capture objective digital gait and balance outcomes reflective of treatment-related neuropathy and fall risk in women treated with chemotherapy for cancer. Wearable sensors could be used for oncology clinical trials to assess the impact of cancer treatment and symptom mitigation strategies to limit changes in mobility that might lead to excess falls in people with cancer. Citation Format: Vrutangkumar Shah, Daniel Muzyka, Carolyn Guidarelli, Kristen Sowalsky, Kerri M. Winters-Stone, Fay B. Horak. Chemotherapy-induced peripheral neuropathy and falls in cancer survivors relate to digital balance and gait impairments. [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 4397.

Burden of Treatment-Induced Peripheral Neuropathy in Patients with Multiple Myeloma in Sweden

Introduction: Treatment-induced peripheral neuropathy (TIPN) is a complication of multiple myeloma (MM) treatment. Objective: This real-world, retrospective study used electronic medical record (EMR) data from 3 Swedish clinics to assess the occurrence and economic burden of TIPN in patients with MM. Methods: Eligible patients had an MM diagnosis in the Swedish Cancer Registry between 2006 and 2015 and initiated treatment during that period. Follow-up was until last EMR visit, death, or study end (April 2017). The current analyses included patients receiving bortezomib, lenalidomide, carfilzomib, or thalidomide at any treatment line. To discern healthcare resource utilization (HCRU) and costs associated with TIPN from other causes, patients with TIPN were matched with those without on baseline characteristics, treatment, and line of therapy. All analyses were descriptive. Results: Overall, 457 patients were included; 102 (22%) experienced TIPN. Patients experiencing TIPN during first-line treatment mostly received bortezomib-based regimens (n = 48/57 [84%]); those with TIPN during second- and third/fourth-line treatment mostly received lenalidomide/thalidomide-based regimens (19/31 [61%], 8/14 [57%], respectively). Patients with TIPN had higher HCRU/costs than those without TIPN (mean differences in hospital outpatient visits: 5.2, p = 0.0031; total costs per patient-year: EUR 17,183, p = 0.0007). Conclusions: Effective MM treatments associated with a reduced incidence of TIPN could result in decreased healthcare expenditure.

The Treatment-induced Neuropathy Assessment Scale (TNAS): a psychometric update following qualitative enrichment

BackgroundThe validation of the Treatment-induced Neuropathy Assessment Scale (TNAS v2.0), a patient-reported outcome measure of symptoms associated with cancer treatment-induced peripheral neuropathy (TIPN), was previously reported. Further patient input (qualitative interviewing, cognitive debriefing) suggested that the measure should be modified to better reflect the TIPN experience. We report the performance of a revised version (TNAS v3.0) for assessing TIPN across cancer treatments. This TNAS version incorporates extensive patient input, in accordance with FDA guidance on the development of patient-reported outcomes measures. Patients with multiple myeloma, colorectal cancer, or gynecological cancer treated with bortezomib, oxaliplatin, or taxane–platinum combination therapy, respectively, completed the TNAS v3.0, European Organization for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy (EORTC-CIPN20), and a cognitive debriefing survey during a scheduled clinic visit. Patients also participated in in-depth qualitative interviews about their TIPN symptoms. The psychometric properties of the TNAS v3.0 were evaluated.ResultsCognitive debriefing survey results were summarized and showed that most patients found the items easy to complete, comprehensible, acceptable, and not redundant. A notable change from TNAS v2.0 was the separation of “numbness” from “tingling,” although these 2 items remained the most severe, followed by a new “pain” item. The Cronbach coefficient alphas for the 9-item TNAS were 0.88 and 0.90 at the first and second administrations, respectively, indicating good reliability. The test–retest reliability of the TNAS was 0.97. The correlation coefficients for the 9-item TNAS and the EORTC-CIPN20 were 0.69 for the sensory subscale, 0.70 for the motor subscale, and 0.32 for the autonomic subscale, indicating good validity.ConclusionThis psychometric evaluation showed that the TNAS v3.0 is valid and reliable. Further research is needed to determine clinically meaningful differences in TNAS v3.0 scores and demonstrate its responsiveness over time.

Concept domain validation and item generation for the Treatment-Induced Neuropathy Assessment Scale (TNAS).

Treatment-induced peripheral neuropathy (TIPN) is a difficult problem experienced by patients with cancer that can interfere with their ability to receive optimal therapy. The Treatment-Induced Peripheral Neuropathy Scale (TNAS) is a patient-reported outcome (PRO) measure developed to assess TIPN symptom burden. However, PRO validation is an ongoing process. The aim of this qualitative study was to define the conceptual model, establish content domain validity, and refine items for the TNAS based on patient input. Patients who received bortezomib, oxaliplatin, or platinum-taxane combination therapy reported their experience of TIPN in single qualitative audiotaped interviews. Themes of the TIPN experience were identified by descriptive analysis of the transcribed interviews. Three groups of 10 patients each who had received bortezomib, oxaliplatin, or platinum-taxane combination therapy, for a total of 30 patients, reported their experiences. Two themes reported by patients were TIPN sensations and functional interference. Five sensations (numbness, tingling, pain, heat or burning, and coldness) and five functional impacts (using hands, walking, maintaining balance or falling, wearing shoes, and sleeping) were reported by at least 20% of patients and were selected for inclusion in the TNAS v3.0 for additional psychometric testing. The assessment of TIPN must be convenient, reliable, and practical for patients, who are the most reliable source of information about symptoms. The TNAS, developed with direct patient input, provides an easily administered and conceptually valid method of patient report of TIPN burden for use in research and practice.

Costs Associated with Treatment Induced Peripheral Neuropathy in Patients with Multiple Myeloma By Lines of Therapy

Background: Recent introductions of multiple myeloma (MM) chemotherapy agents have improved response and survival rates, yet substantial unmet treatment needs persist. Treatment-induced peripheral neuropathy (TIPN) is a common toxicity associated with anti-myeloma treatments. This study evaluated the economic burden attributable to TIPN for MM patients in real-world practice settings in the US.Methods: Adult patients with ≥1 inpatient or 2 outpatient claims (within 30 - 365 days) with a diagnosis of MM (ICD-9-CM code 203.0x) and ≥1 claim indicating the administration or prescription of a MM therapy (bendamustine, bortezomib, carfilzomib, cisplatin, cyclophosphamide, doxorubicin, doxorubicin liposomal, lenalidomide, melphalan, pomalidomide, thalidomide) on or after the date of the first found MM diagnosis in 7/1/2006 - 3/31/2015 were extracted from MarketScan claims databases. The initiation of the first MM treatment was the index date. All patients had ≥12-month continuous enrollment (baseline) before index date, and were followed for ≥3 months from index date until the earliest of inpatient death, end of continuous enrollment in health plans, or end of the study period (i.e., 6/30/2015). To ensure that patients were newly diagnosed and newly treated, a 12-month period with no diagnosis of MM prior to the first observed MM diagnosis and a 12-month period with no MM therapy during baseline was required. Lines of therapy (LOT) were designated starting on the date of the first MM chemotherapy and/or immunotherapy treatment. A LOT ended at the earliest occurrence of a 90-day gap in all MM treatments comprising the line of therapy, initiation of a different MM treatment >90 days after the current line of therapy start (even if the current regimen did not discontinue), inpatient death, or end of data. All subsequent lines of therapy were identified using the same approach. For every LOT, TIPN was considered as being present when a medical claim code indicating a diagnosis for PN (ICD-9-CM diagnosis codes 337.2x; 353.0x-353.4x; 355.7x; 355.9x; 357.xx; 377.34; 729.2x; 782.0x) was observed. Eligible claims were those observed within 9 months from the start date of the LOT, and without evidence of PN during the 12-month pre-period through the 7 days following the start date of the line. Non-TIPN controls had no PN medical claims any time during the LOT. Controls were propensity score matched to TIPN patients in a ratio of up to 3:1 based on demographic and clinical characteristics. Medical costs per patient per month (PPPM, in 2015 $) during each line were reported.Results: A total of 1,145 TIPN patients and 7,468 non-TIPN patients met study criteria (15.3% TIPN); and 1,120 TIPN patients were matched to 3,265 non-TIPN patients. Among them, 1018 TIPN and 3346 non-TIPN 1st lines, 231 TIPN and 1718 non-TIPN 2nd lines, and 52 TIPN and 1074 non-TIPN 3rd and subsequent lines were identified. Baseline characteristics in the two groups after matching were similar (mean age: 64; male: 61%; renal disease: 23-24%; duration of LOT: 187-233 days). PPPM total costs were significantly higher for TIPN patients compared to non-TIPN controls in the 1st ($2377, p<0.001) and 2nd LOT ($6974, p=0.031). Incremental costs among TIPN patients were driven by significantly higher inpatient admissions and outpatient medical costs in both the 1st and 2nd LOTs. Costs between TIPN and non-TIPN controls were not significantly different in 3rd LOT.Conclusions: TIPN is prevalent (15.3%) in patients with MM; it adds to the cost of MM treatment in earlier lines of therapy. Effective novel treatments that do not add to the economic burden associated with TIPN are needed to manage MM. [Display omitted] DisclosuresPanjabi:Amgen, Inc.: Employment, Equity Ownership. Song:Truven Health Analytics: Employment; Amgen: Other: This study was funded by Amgen..

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.

Measuring treatment-induced peripheral neuropathy in patients with cancer.

e21674Background: Peripheral neuropathy (PN) is a common complication of cancer treatment. Measurement of PN is necessary for prevention and effective management. An important aspect of PN measurem...

European Myeloma Network guidelines for the management of multiple myeloma-related complications.

The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A).

Real world impact of treatment-induced peripheral neuropathy (TIPN) on patient reported outcomes (PROs) in patients with multiple myeloma (MM) in the United States.

e19531 Background: Some MM treatments can cause TIPN, which is associated with pain, burning, tingling and can impact multiple aspects of patients’ lives. This study examined the PRO impact of TIPN...

Association Of Treatment Induced Peripheral Neuropathy (TIPN) With Treatment Patterns and Outcomes In Patients (pts) With Newly Diagnosed Multiple Myeloma (NDMM)

BackgroundPeripheral neuropathy (PN) is associated with multiple myeloma (MM) and often exacerbated by anti-MM treatments. TIPN poses significant morbidity and may result in therapy modifications. The impact of TIPN on treatment patterns and outcomes is not well studied in “real world” settings. We examined the association between TIPN in NDMM with treatment changes and efficacy outcomes in community oncology practices. MethodsThis was a retrospective review of clinical practice data from 12 US practices. Included pts had NDMM between 1/1/2008 and 7/1/2010, received anti-MM therapy and were ≥ 18 years of age at initiation of front line therapy. Inclusion was stratified with approximately half of the sample having TIPN from initial therapy (i.e. before 1stdocumented disease progression), as confirmed through review of medical records. Front line therapies were classified as those that included: 1) Lenalidomide (L), 2) Thalidomide (T), 3) Bortezomib ± Thalidomide (B), 4) Lenalidomide + Bortezomib (LB), and 5) Other regimens (O). Multivariate Cox regression models were used to identify pt level risk factors for TIPN, including regimen. Cox models with time varying covariates were used to predict: a) time to dose reduction; b) time to delay, discontinuation or switch; c) time to progression (TTP), and d) overall survival (OS). TIPN was modeled as a binary, time varying predictor of each outcome (pt observation split by non-TIPN and TIPN intervals), controlling for demographic and clinical characteristics, and treatment regimen. ResultsMean age of sampled patients (n=229) was 66.6 years (range 40-91), 49.3% were female, 58.5% Caucasian, and 34.9% African American. Of 229 pts, 112 experienced TIPN during front line therapy. Of the 117 without TIPN, 23 (19.7%) experienced PN during front line that was not attributed to treatment. Relevant comorbidities were higher in the TIPN than non-TIPN pts but not significantly different; diabetes (26.8% v 21.4%, p =0.360) and renal disease (26.8% v 20.5%, p=0.28). TIPN severity during front line treatment was reported as severe (22.3%), moderate (25.9%), mild (25.0%), and unknown (26.8%). Front line treatment included B: 110 (48.0%), L: 36 (15.7%), O: 31 (13.5%), T: 30 (13.1%) and LB: 22 (9.6%), with B uniformly administered IV rather than SC. TIPN occurred in 69.6% of B containing vs. 30.4% of non-B containing regimens.Median duration of front line treatment ranged from 5.1 (O) to 6.74 months (R). Overall, 94 pts (41.0%) had dose reductions, and 117 pts (51.1%) had a delay, discontinuation or switch in therapy. Of the 117, 62 continued with front line therapy after the delay, discontinuation or switch. Overall median TTP was 27.7 months, and median OS was 47.9 months. Median time to TIPN in TIPN patients was 4.52 months. Regimen was a significant predictor of time to TIPN (p = .0056), with L (HR = .323, p = .0009) and O (HR = .455, p = .037) at lower risk than B. Table 1 shows that time varying TIPN was associated with dose reduction and treatment delay, discontinuation, or switch. Each analysis controlled for gender, age, presence of any relevant comorbidity, performance status, stage of disease, and regimen.Table 1Cox Regression Results for Analysis of Time Varying TIPNEndpointp-valueHR for Time Varying TIPNHR 95% CIDose Reduction.0012.3591.414-3.936Treatment Delay, Discontinuation or Switch.0061.8241.186-2.806Time to Progression.3411.2010.823-1.753Overall Survival.1760.7340.469-1.149For analysis of dose reduction, the only other significant pt level predictor was comorbid disease (HR = 1.903, p = .006). Other pt level covariates were not associated with predicting delay, discontinuation or switch. Gender was a significant predictor of TTP (HR = .643, p = .017), indicating lower risk for males. For analysis of OS, comorbid disease and age were significant (HR = 1.7, p = .02; 1 year HR = 1.035, p = .002, respectively), as was stage (p = .0038), with more advanced stage tending to be associated with higher risk. ConclusionsThis retrospective study of TIPN in MM showed that occurrence of TIPN was associated with increased risk of dose reduction, and of treatment delay, discontinuation or switch. TIPN was not significantly associated with TTP or OS, likely because most treatment modifications (including dose reduction) did not involve complete treatment discontinuation. Regimen combinations with a lower neurotoxicity burden should be considered in NDMM patients. Disclosures:Panjabi:Onyx Pharmaceuticals, Inc.: Employment, Equity Ownership.

Retrospective analysis of treatment-induced peripheral neuropathy (TIPN) in multiple myeloma (MM).

e19530 Background: Peripheral neuropathy (PN) is commonly present at MM diagnosis and exacerbated or induced by MM treatments. TIPN poses significant morbidity, and may result in therapy modifications (TM). We examined the “real-life” onset and severity of TIPN in newly diagnosed patients (pt) receiving anti-MM therapies. Methods: Medical records from a US community oncology network were reviewed. Newly diagnosed MM pt treated between 1/1/08 and 7/1/10, ≥18 years, and followed for ≥24 months were eligible. The protocol pre-defined inclusion of an equal number of TIPN and non-TIPN cases. Regimen-related TIPN was based on clinician judgment and/or correspondence of TIPN with regimen start/end dates. Uni- and multi-variate (MV) analyses examined association of demographic and regimen characteristics with TIPN, TIPN severity, and TM. Results: In all, 716 MM records were screened; 367 were deemed ineligible or incomplete. Of 349 eligible records, 229 were abstracted, 10 had unusable data, and 219 formed the analytic set; 120 records were excluded since the accrual target (N=225) had been met. Average age of pts was 67.0 years, 49.3% were female, 57.5% Caucasian, and 36.0% African-American (AA). A majority (56.6%) had 1 regimen prior to 1st disease progression, 26.0% had 2 and 17.4% had &gt;2 regimens. Overall, 138/219 (63.0%) developed PN, 123/219 (53.7%) with documented TIPN. TIPN developed during 1st line therapy in the majority 110/123 (89.4%). Univariate analysis revealed that TIPN pt were younger, more likely to be AA, and treated more frequently with bortezomib-based regimens BTZ-BR (63.3 v 9.3%). MV analysis showed TIPN was associated with BTZ-BR (OR=14.5, 95% CI=6.5-32.2), but not age, race, gender, and diabetes. BTZ-BR compared to non BTZ-BR were associated with severe and grade 3/4 TIPN (79.3 v 20.7%; χ2=5.36, p=0.02), and TM (65.7 v 34.3%, χ2=5.57, p=0.02). Notable TM included dose reductions (66.7 v 33.3%) and delays (83.3 v 16.7%). Conclusions: In this study of newly diagnosed MM pt, TIPN developed frequently during 1st line therapy. BTZ-BR were associated with TIPN that was severe and resulted in greater TM. While this analysis represents a small pt population, the results are provocative and warrant further study.

Baseline Peripheral Neuropathy Does Not Impact the Efficacy and Tolerability of the Novel Proteasome Inhibitor Carfilzomib (CFZ): Results of a Subset Analysis of a Phase 2 Trial In Patients with Relapsed and Refractory Multiple Myeloma (R/R MM)

Baseline Peripheral Neuropathy Does Not Impact the Efficacy and Tolerability of the Novel Proteasome Inhibitor Carfilzomib (CFZ): Results of a Subset Analysis of a Phase 2 Trial In Patients with Relapsed and Refractory Multiple Myeloma (R/R MM)

Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial

Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity in patients with multiple myeloma, often requiring adjustment of treatment and affecting quality of life. We investigated the molecular profiles of early-onset (within one treatment cycle) versus late-onset (after two or three treatment cycles) bortezomib-induced peripheral neuropathy and compared them with those of vincristine-induced peripheral neuropathy during the induction phase of a prospective phase 3 trial. In the induction phase of the HOVON-65/GMMG-HD4 trial, patients (aged 18-65 years) with newly diagnosed Salmon and Durie stage 2 or 3 multiple myeloma were randomly assigned to three cycles of bortezomib-based or vincristine-based induction treatment. We analysed the gene expression profiles and single-nucleotide polymorphisms (SNPs) of pretreatment samples of myeloma plasma cells and peripheral blood, respectively. This study is registered, number ISRCTN64455289. We analysed gene expression profiles of myeloma plasma cells from 329 (39%) of 833 patients at diagnosis, and SNPs in DNA samples from 369 (44%) patients. Early-onset bortezomib-induced peripheral neuropathy was noted in 20 (8%) patients, and 63 (25%) developed the late-onset type. Early-onset and late-onset vincristine-induced peripheral neuropathy was noted in 11 (4%) and 17 (7%) patients, respectively. Significant genes in myeloma plasma cells from patients that were associated with early-onset bortezomib-induced peripheral neuropathy were the enzyme coding genes RHOBTB2 (upregulated by 1·59 times; p=4·5×10(-5)), involved in drug-induced apoptosis, CPT1C (1·44 times; p=2·9×10(-7)), involved in mitochondrial dysfunction, and SOX8 (1·68 times; p=4·28×10(-13)), involved in development of peripheral nervous system. Significant SNPs in the same patients included those located in the apoptosis gene caspase 9 (odds ratio [OR] 3·59, 95% CI 1·59-8·14; p=2·9×10(-3)), ALOX12 (3·50, 1·47-8·32; p=3·8×10(-3)), and IGF1R (0·22, 0·07-0·77; p=8·3×10(-3)). In late-onset bortezomib-induced peripheral neuropathy, the significant genes were SOD2 (upregulated by 1·18 times; p=9·6×10(-3)) and MYO5A (1·93 times; p=3·2×10(-2)), involved in development and function of the nervous system. Significant SNPs were noted in inflammatory genes MBL2 (OR 0·49, 95% CI 0·26-0·94; p=3·0×10(-2)) and PPARD (0·35, 0·15-0·83; p=9·1×10(-3)), and DNA repair genes ERCC4 (2·74, 1·56-4·84; p=1·0×10(-3)) and ERCC3 (1·26, 0·75-2·12; p=3·3×10(-3)). By contrast, early-onset vincristine-induced peripheral neuropathy was characterised by upregulation of genes involved in cell cycle and proliferation, including AURKA (3·31 times; p=1·04×10(-2)) and MKI67 (3·66 times; p=1·82×10(-3)), and the presence of SNPs in genes involved in these processes-eg, GLI1 (rs2228224 [0·13, 0·02-0·97, p=1·18×10(-2)] and rs2242578 [0·14, 0·02-1·12, p=3·00×10(-2)]). Late-onset vincristine-induced peripheral neuropathy was associated with the presence of SNPs in genes involved in absorption, distribution, metabolism, and excretion-eg, rs1413239 in DPYD (3·29, 1·47-7·37, 5·40×10(-3)) and rs3887412 in ABCC1 (3·36, 1·47-7·67, p=5·70×10(-3)). Our results strongly suggest an interaction between myeloma-related factors and the patient's genetic background in the development of treatment-induced peripheral neuropathy, with different molecular pathways being implicated in bortezomib-induced and vincristine-induced peripheral neuropathy.

Neurotoxic and peripheral neuropathic effects in preclinical and clinical studies of carfilzomib (CFZ), a novel proteasome inhibitor (PI).

8135 Background: Treatment-induced peripheral neuropathy (TIPN) is a common, frequently debilitating, therapy-limiting complication in multiple myeloma (MM). Chemotherapies associated with TIPN in MM include thalidomide and bortezomib (BTZ). CFZ, a novel, highly selective PI, is structurally and mechanistically distinct from BTZ. In Ph I-II trials single-agent CFZ is active without dose-limiting PN in pts with relapsed and/or refractory (R/R) MM. Here we compare CFZ and BTZ in a neurotoxicity model and report clinical experience with CFZ in R/R MM. Methods: An in vitro neurotoxicity model established with differentiated SH-SY5Y neuroblastoma cells was used to investigate PI effects on neurite degeneration. A possible mechanism was pursued by bioinformatic and biochemical methods. Data were pooled from 2, ongoing Ph II trials of single-agent CFZ in pts with R/R MM, including neuropathy history, baseline neuropathic symptoms and neurological exam findings, prospective neurological exams, and FACT-GOG/NTx pt survey scores. PN adverse event data were also included. Results: Following 24 hrs of exposure to 10 nM BTZ, SH-SY5Y cells showed 40% reduction in neurite length/cell compared to CFZ- or vehicle-treated cells. Both agents induced equivalent proteasomal inhibition suggesting off-target effects induce neurodegeneration. HtrA2/Omi, a mitochondrial serine protease with a role in neuron survival was identified in databases and confirmed as a target of BTZ (IC50 = 3 nM), but not of CFZ (>10 μ M). At screening, 72% of 135 pts had active Grade (G) 1/2 PN; 81% had a history of TIPN. Pts received a mean of 30.4 CFZ doses (range 2–72) and 17% received >10 mo of therapy. New onset PN or PN worsening from baseline was reported in 16% of pts. There were no reports of G4 PN, missed doses, or treatment discontinuations. Only 1 pt was dose-reduced due to PN. Conclusions: In contrast to BTZ TIPN, CFZ-related PN is uncommon and not dose-limiting. In vitro, BTZ induces neurotoxicity in a proteasome-independent manner and potently inhibits a neuronal cell survival factor, HtrA2. These in vitro and clinical data suggest that severe PN is not a PI class effect. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Bristol-Myers Squibb, Celgene, Facet, Millennium, Novartis, Onyx Onyx Celgene, Johnson & Johnson, Merck, Millennium, Onyx, Ortho, Takeda Bristol-Myers Squibb, Celgene, Facet, Gloucester Pharmaceuticals, Millennium, Novartis, Onyx

Clinical evaluation and patterns of chemotherapy-induced peripheral neuropathy.

To determine the pattern of change in peripheral nerve function (as measured by vision, hearing, deep tendon reflexes, vibratory sense, cutaneous sensation, gait and balance, muscle strength, and orthostatic blood pressure) occurring among individuals receiving cancer treatment with known neurotoxic agents. A convenience sample of 16 participants with cancer who were receiving chemotherapy had their peripheral nerve function assessed at baseline and at 4 weeks and 12 weeks of treatment. Data were analyzed using plots and regression slopes to determine change over time in clinical measures of peripheral nerve function. Outcome variables were vision, hearing, deep tendon reflexes, vibratory sense, cutaneous sensation, gait and balance, muscle strength, and changes in orthostatic blood pressure. This is the first prospective study to use comprehensive clinical measures of peripheral nerve and muscle changes resulting from combination chemotherapy or a biotherapy regimen. Alterations in vision, hearing, deep tendon reflexes, vibratory sense, cutaneous sensation, balance, muscle strength, and orthostatic blood pressure were noted, but gait remained unchanged. This study provides beginning evidence of the need for careful, ongoing assessment of treatment-induced peripheral neuropathy. Standardized clinical practice procedures that incorporate patient evaluation for peripheral neuropathy must still be developed. In addition, we must educate our patients about the functional changes they may expect, and we must develop strategies to assist them in managing limitations that they experience as a result of peripheral neuropathy.