Document XOMrvxk0B4wodjDY1GV5zDBG

VOLUME 24 NUMBER 19 JULY 1 2006 JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT From the Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston; Millennium Pharmaceuticals Inc, Cambridge, MA; St Vincent's Cancer Center; York Presbyterian Hospital, New York, NY; University of Arkansas, Little Rock, AR; Institute for Myeloma and Bone Cancer Research, West Hollywood; Alta Bates Cancer Center, Berkley, CA; Robert H. Lurie Cancer Center, Chicago, IL; Hackensack University Medical Center, Hackensack, NJ; New Sparrow Regional Cancer Center, Lansing, MI; M.D. Anderson Cancer Center, Houston, TX; Mayo Clinic, Rochester, MN; Carolinas Hematology-Oncology Association, Charlotte, NC; H. Lee Moffitt Cancer Center Research Institute, Tampa, FL; and University of North Carolina at Chapel Hill, Chapel Hill, NC. Submitted November 3, 2005; accepted April 13, 2006. Supported in part by Millennium Pharmaceuticals Inc and Johnson & Johnson Pharmaceutical Research & Development LLC. P.G.R. and H.B. are both first authors. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. Address reprint requests to Paul G. Richardson, MD, Dana-Farber Cancer Institute, 44 Binney St, Dana 1B02, Boston, MA 02115; e-mail: paul_richardson@dfci.harvard.edu. 2006 by American Society of Clinical Oncology 0732-183X/06/2419-3113/$20.00 DOI: 10.1200/JCO.2005.04.7779 Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib Paul G. Richardson, Hannah Briemberg, Sundar Jagannath, Patrick Y. Wen, Bart Barlogie, James Berenson, Seema Singhal, David S. Siegel, David Irwin, Michael Schuster, Gordan Srkalovic, Raymond Alexanian, S. Vincent Rajkumar, Steven Limentani, Melissa Alsina, Robert Z. Orlowski, Kevin Najarian, Dixie Esseltine, Kenneth C. Anderson, and Anthony A. Amato ABSTRACT Purpose To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. Patients and Methods Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology GroupNeurotoxicity (FACT/ GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n 13). Results Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. Conclusion Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy. J Clin Oncol 24:3113-3120. 2006 by American Society of Clinical Oncology INTRODUCTION Peripheral neuropathy is a major dose-limiting adverse effect of many anticancer agents. In patients with multiple myeloma, peripheral neuropathy is not only associated with the agents used to treat the disease, such as bortezomib,1,2 thalidomide,3 and vincristine,4 but it is also associated with the disease itself.5 Bortezomib has demonstrated activity and safety in heavily pretreated patients with relapsed and/or refractory multiple myeloma in phase II and III trials.1,2,6 The most frequent adverse events re- ported with bortezomib include GI symptoms, fatigue, cyclical thrombocytopenia, and peripheral neuropathy.1,2,6,7 Peripheral neuropathy was first reported in phase I trials.8-10 In the development of the multi- center, prospective, phase II Study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy (SUMMIT)1 and Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST)2 trials, the Downloaded from jco.ascopubs.org on September 8, 2010. For personal use only. No other uses without permission. Copyright 2006 American Society of Clinical Oncology. All rights reserved. 3113 Richardson et al protocols incorporated special assessments for neuropathy and mandated the involvement of a neurologist at each study center. The objectives of this analysis were to evaluate the frequency, characteristics, and reversibility of peripheral neuropathy in patients with relapsed and/or refractory myeloma treated with bortezomib who participated in SUMMIT and CREST. To accomplish these objectives, multiple methods were used including patient-reported outcomes, examination by a neurologist, investigator assessments, and, at one center, nerve conduction studies. PATIENTS AND METHODS The eligibility criteria for the patients enrolled onto SUMMIT and CREST have been described previously.1,2 Eligible patients had relapsed and/or refractory myeloma; patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS) were excluded, but otherwise, there were no exclusions specified for the presence of peripheral neuropathy. All patients provided written informed consent before study enrollment. These studies were conducted in accordance with the Declaration of Helsinki; each participating study center obtained institutional review board approval. Treatment and Study Design The SUMMIT and CREST trials were open-label, multicenter studies in which patients received bortezomib 1.3 mg/m2 and 1.0 or 1.3 mg/m2, respectively, by intravenous bolus on days 1, 4, 8, and 11 of a 21-day cycle. If patients had progressive disease after two cycles or stable disease after the first four cycles, they were eligible to receive oral dexamethasone 20 mg on the day of and day after bortezomib treatment. Patients could receive up to eight cycles, and patients who continued to benefit from treatment or had the potential to benefit were eligible to receive treatment in an extension study.1,2,8 Adverse events were assessed and reported by the investigator at each visit. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria (NCI CTC), version 2.0. Any grade 3 or 4 nonhematologic toxicity required that bortezomib be held for up to 2 weeks until the toxicity returned to grade 1. When treatment was resumed, the bortezomib dose was reduced by 25%. Patients who developed signs and/or symptoms of peripheral neuropathy were treated symptomatically. There was no specific guidance for dose modification or treatment in the event of peripheral neuropathy given in these protocols. Neurologic Assessments Baseline status of the patients was obtained from a patient-completed questionnaire for neurologic toxicities (Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology GroupNeurotoxicity [FACT/GOGNtx]), neurologic questioning and examination by a consulting neurologist, and electrophysiologic testing at one participating center. The FACT/ GOG-Ntx questionnaire11 was administered at screening, on day 1 of cycles 3, 5, and 7, and at study end. Patients were assessed by a neurologist for neuropathic symptoms and signs during the study period using a modified version of a standard assessment used in some other studies.10,12 At the investigator's discretion, the neurologic evaluation could be repeated during therapy and at the end of the study. This evaluation included specific questions regarding symptoms (sensory, autonomic, motor, and changes) and functional impairment and was essentially a modification of the Neuropathy Symptom Score and Neuropathy Symptoms and Change Score used in other studies.13,14 Muscle strength, sensation (light touch, pain, vibration, and proprioception), deep tendon reflexes, and blood pressure were assessed. The sensory, motor symptom, and examination scores and the autonomic score were used to calculate a total neuropathy score. Treatment-emergent neuropathy was also evaluated by the investigator; however, baseline investigator assessments by NCI CTC grade were not collected. An algorithm using specific components of the FACT/GOG-Ntx questionnaire and neurologic examination was developed to derive the baseline NCI CTC grade. A subgroup of patients from the lead study center underwent motor and sensory nerve conduction studies and quantitative sensory testing of vibratory, heat, and cold perception at baseline; during cycles 3, 5, and 7; at study completion; and as needed in patients who developed signs or symptoms of neuropathy during the study.14,15 Statistical Analysis The number of observations, mean, standard deviation, median, mini- mum, and maximum for continuous variables and the number and percentage for categoric data were calculated. The estimated probability of first onset of peripheral neuropathy was determined using the Kaplan-Meier method. All analyses were produced using SAS software (Version 8.2; SAS Institute, Cary, NC). The Wilcoxon signed rank test was used to assess change in total neuropathy scores, subscores, FACT/GOG-Ntx scores, and the nerve conduction data from baseline to study completion. The Wilcoxon rank sum test was used to assess differences between patients who developed symptomatic neuropathy and patients who did not. RESULTS Baseline Peripheral Neuropathy Baseline characteristics of the 256 patients treated with bort- ezomib in the two phase II studies are listed in Table 1. The proportion of patients with symptoms of peripheral neuropathy at baseline was 81% (194 of 239 patients) by FACT/GOG-Ntx questionnaire and Table 1. Baseline Characteristics Characteristic No. of Patients (N 256) % Age, years Median Range Sex Female Male History of diabetes Baseline FACT/GOG-Ntx Symptoms of peripheral neuropathy Neurologic examination Sensory or motor symptoms and signs Functional impairment with sensory or motor symptoms and signs Peripheral neuropathy Stage 0: normal Stage 1: loss of deep tendon reflexes or paresthesias Stage 2: objective sensory loss or paresthesia interfering with function Stage 3: sensory loss or paresthesia interfering with ADL Prior neurotoxic therapy Vincristine based Thalidomide Platinum 60 30-84 112 44 144 56 29 11 239 194 81 244 203 83 116 48 252 60 24 60 24 110 44 22 9 256 192 75 184 72 92 36 Abbreviations: ADL, activities of daily living; FACT/GOG-Ntx, Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity. Baseline data for FACT/GOG-Ntx available from 239 of 256 patients. Defined as a score greater than 0 on questions Ntx 1 to Ntx 4, Ntx 8, or Ntx 9 on FACT/GOG-Ntx (version 4). Baseline neurologic evaluations performed by a neurologist in 244 of 256 patients. Based on a scoring method using specific components of the FACT/ GOG-Ntx questionnaire and neurologic examination; baseline data from both tools available for 252 of 256 patients. 3114 JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on September 8, 2010. For personal use only. No other uses without permission. Copyright 2006 American Society of Clinical Oncology. All rights reserved. Bortezomib-Associated Peripheral Neuropathy Table 2. Total Neuropathy Scores, Subscores of Its Major Individual Components As Graded by Examining Neurologists, and FACT/GOG-Ntx Summary Scores Neurologist Assessment of Patients FACT/GOG-Ntx Summary Score (Max 44) Motor Symptom Score Motor Examination Score Sensory Symptom Score (Max 20) (Max 34) (Max 24) Sensory Examination Score (Max 66) Autonomic Score (Max 6) Total Neuropathy Score (Max 150) Neuropathy No. of No. Median Range P* No. Median Range P* No. Median Range P* No. Median Range P * No. Median Range P* No. Median Range P* Patients Median Range P* Baseline All patients 237 0 No neuropathy 151 0 Treatment-emergent 86 1.1 neuropathy End of study All patients 104 4.0 No neuropathy 49 2.0 Treatment-emergent 55 5.0 neuropathy .1234 0-19 236 0 0-16 150 0 0-19 86 0 .0093 0-18 107 0 0-16 50 0 0-18 57 2.0 .8815 0-34 240 0 0-34 154 2.0 0-22 86 2.0 .0450 0-34 104 5.5 0-34 50 3.0 0-24 54 8.5 .2721 .0040 .8234 .0046 0-24 242 9.0 0-36 223 1.0 0-6 243 15.0 0-95.6 239 0-24 155 8.0 0-36 141 1.0 0-6 156 14.0 0-95.6 153 0-23 87 12.0 0-34 82 1.0 0-5 87 20.2 0-70 86 .0001 0-24 110 17.3 0-17 53 13.0 0-24 57 21.0 .0004 0-40 101 2.0 0-33 48 1.8 4-40 53 2.0 .4204 .0001 0-6 111 32.0 0-77 188 0-4.5 53 22.0 0-72 110 0-6 58 38.5 2.8-77 78 .1440 9.0 0-39 7.0 0-34 11.0 0-39 .0005 12.0 0-38 10.0 0-35 15.0 0-38 NOTE. Higher values denote poorer function. Abbreviations: FACT/GOG-Ntx, Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology GroupNeurotoxicity; Max, maximum score for each subscale; SD, standard deviation. *Comparison between values for patients with and without treatment-emergent neuropathy. Individual scores are tallied to arrive at a total neuropathy score. 83% (203 of 244 patients) by the neurologists' examinations. Table 2 lists the baseline and end-of-study neuropathy scores and subscores, as assessed by neurologists and by the FACT/GOG-Ntx questionnaire. The baseline FACT/GOG-Ntx scores were similar among patients who had treatment-emergent neuropathy and those who did not. However, there were statistically significant differences in the baseline total neuropathy and sensory examination scores from the neurologist among patients who developed treatment-emergent neuropathy and those who did not; the differences for other subscores were not statistically significant. Twenty-two patients (9%) had FACT/GOG-Ntx scores and neurologist scoring at baseline that were equivalent to NCI CTC grade 3 neuropathy. The mean baseline FACT/GOG-Ntx summary score for these patients was 21.3 compared with 10.3 for all patients (of a maximum score of 44 on this test). The mean sensory neurologic examination score for these 22 patients at baseline was 10.1 compared with 11.0 in all patients. Thus, there was an apparent dissociation between subjective symptom and objective examination scores for patients with significant baseline sensory neuropathy. Frequency and Severity of Peripheral Neuropathy During Treatment Overall, investigators reported that 35% of patients (90 of 256 patients) had evidence of treatment-emergent peripheral neuropathy of any NCI CTC grade or worsening of baseline neuropathy. Patients with and without neuropathy at baseline based on the FACT/GOGNtx questionnaire had similar frequencies of treatment-emergent neuropathy (36% for each patient group). Grade 3 peripheral neuropathy tended to be more frequent in patients with evidence of peripheral neuropathy at baseline by FACT/GOG-Ntx questionnaire compared with patients without baseline evidence of peripheral neuropathy (14% v 4%, respectively; P .08). After treatment, the median FACT/GOG-Ntx scores were significantly higher whether treatment-emergent neuropathy was reported (P .0001) or not (P .0002). In addition, from baseline to the study end, a statistically significant increase in the total neuropathy score by neurologist assessment (P .0001) and all subscores (range, P .0001 to .0207), was observed for the entire patient population and for patients with or without treatment-emergent neuropathy, except the motor examination score in patients without treatmentemergent neuropathy. Thus, increased neuropathy scores in patients not experiencing painful neuropathy suggest that some had a subclinically evolving neuropathy. Treatment-emergent peripheral neuropathy was 21% in patients receiving bortezomib 1.0 mg/m2 and 37% in patients receiving bortezomib 1.3 mg/m2 (Table 3). As the cumulative bortezomib dose increased, the prevalence of peripheral neuropathy increased, reaching a plateau at cycle 5 (approximately 30 mg/m2 cumulative dose) and remaining fairly consistent through cycle 8. There was a positive correlation between cumulative bortezomib dose and FACT/ GOG-Ntx summary score (r 0.108; P .0037) and total neuropathy score (r 0.297; P .0001). The analysis according to age or prior thalidomide, vincristine, or platinum treatment did not show any apparent relationship to the incidence of treatmentemergent peripheral neuropathy. Nerve conduction studies and quantitative sensory testing were available in 13 patients. Six of 13 patients had evidence of a generalized Table 3. Treatment-Emergent Peripheral Neuropathy by Dose and Grade Bortezomib 1.0 mg/m2 (n 28) Bortezomib 1.3 mg/m2 (n 228) Grade No. of Patients % No. of Patients % Grade 1 3 11 16 7 Grade 2 1 4 37 16 Grade 3 1 4 31 14 Grade 4 1 400 Total 6 21 84 37 NOTE. Grade assigned by the investigator according to National Cancer Institute Common Toxicity Criteria version 2.0. www.jco.org Downloaded from jco.ascopubs.org on September 8, 2010. For personal use only. No other uses without permission. Copyright 2006 American Society of Clinical Oncology. All rights reserved. 3115 Richardson et al axonal sensorimotor polyneuropathy at baseline. Consistent with other assessments, there was no significant difference at baseline between patients who developed treatment-emergent neuropathy or worsening neuropathy and patients who did not (Table 4). There was no significant difference in any nerve conduction study parameter at the end of the study compared with baseline examinations, although there was a trend toward reduced amplitudes of the sural sensory nerve action potentials in patients who developed treatmentemergent neuropathy and in the ulnar sensory nerve action potential but not in any motor action potentials (Fig 1, Table 4). Of the seven patients without electrophysiologic evidence of a large-fiber polyneuropathy at baseline, three developed symptomatic treatmentemergent small-fiber neuropathy (characterized by burning aching pain, paresthesia, and allodynia) during the study without significant changes seen on nerve conduction studies. Outcomes, Interventions, and Reversibility Of 90 patients with treatment-emergent peripheral neuropathy, 35 experienced 3 neuropathy and/or neuropathy leading to discontinuation. Peripheral neuropathy was the reason for discontinuing treatment in 5% of patients (14 of 256 patients), representing 16% of patients (14 of 90 patients) who developed new or worsening neuropathy. Of the 14 patients who discontinued treatment, eight experienced onset of neuropathy during the first three cycles. When treatment was discontinued, peripheral neuropathy was grade 4 in one patient, grade 3 in 11 patients, and grade 2 in two patients. Dose reduction was required in 12% of patients (31 of 256 patients) because of peripheral neuropathy, representing 34% of patients (31 of 90 patients) who developed new or worsening neuropathy. At least one dose of bortezomib was held because of peripheral neuropathy in 7% of patients (19 of 256 patients), representing 21% of patients (19 of 90 patients) with new or worsening neuropathy. Neuropathic pain and other symptoms resolved to baseline levels or improved in 71% of patients (25 of 35 patients) with clinically significant neuropathy based on data at last follow-up. Resolution or improvement occurred during treatment in 37% of patients (13 of 35 patients) and after treatment in 31% of patients (11 of 35 patients). In one patient, it was unclear whether improvement occurred during or after treatment. Ten patients did not experience improvement in painful peripheral neuropathy after the final dose of bortezomib, but follow-up was limited because of progressive myeloma that was rapidly fatal in five patients. The median duration from the last dose to resolution or improvement of peripheral neuropathy was 47 days (range, 1 to 529 days). Medications commonly administered for the treatment of peripheral neuropathy were recorded as gabapentin, vitamin and nutritional supplements (eg, vitamin B6, alpha lipoic acid, and glutamine), opioids (eg, oxycodone, hydrocodone, fentanyl, and morphine), antidepressants (eg, amitriptyline, nortriptyline, and desipramine), and nonsteroidal anti-inflammatory agents (eg, celecoxib, rofecoxib, and ibuprofen). DISCUSSION Bortezomib-associated peripheral sensory neuropathy was first observed in phase I studies.8-10 As a result, a concerted effort was made to accurately assess peripheral neuropathy in the phase II SUMMIT1 and CREST2 trials. Because there is no commonly accepted standard for assessment of peripheral neuropathy, multiple methods, including patient-reported outcomes, investigator assessments, and neurologists' examinations, were used. The patient questionnaire was easiest to use for assessment, and slightly more peripheral neuropathy events were reported using this method. This finding is aligned with improved sensitivity of patient versus investigator reporting of adverse events described in other studies.16 Results from this analysis demonstrated that peripheral neuropathy associated with bortezomib seems to be a cumulative, Table 4. Sensory Nerve and Compound Muscle Action Potential Amplitudes at Baseline Compared With End of Study All Patients (n 13) Treatment-Emergent Neuropathy (n 7) No Treatment-Emergent Neuropathy (n 6) Amplitude Baseline EOS Baseline EOS Baseline EOS Sural sensory, V Mean SD Range Ulnar sensory, V Mean SD Range Peroneal motor, V Mean SD Range Ulnar motor, V Mean SD Range 5.0 5.4 0-16 13.6 8.6 0-26 3.8 2.0 1-8 8.6 6.7 5.3-15.6 3.4 3.7 0-10.3 11.4 6.4 0-22 3.4 1.7 0.9-6.5 8.7 3.7 6-13.2 4.8 5.0 0-14.5 11.0 6.6 1.9-21.4 3.7 1.7 2.1-5.7 9.2 12.3 5.3-15.6 1.9 2.4 0-5.1 9.3 4.1 4.7-16.9 3.3 1.3 2.2-5.4 9.3 4.7 6.1-13.2 5.4 6.3 0-16 16.5 10.2 0-26 4.0 6.9 1-8 8.0 1.1 6.7-9.1 5.0 3.0 0-10.3 14.0 8.0 0-22 3.6 5.9 0.9-6.5 8.0 2.3 6-10.5 NOTE. No changes reached significance (P .05). Abbreviations: EOS, end of study; SD, standard deviation. Normal 5 V. Abnormal. Normal 10 V. Normal 2 V. 3116 JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on September 8, 2010. For personal use only. No other uses without permission. Copyright 2006 American Society of Clinical Oncology. All rights reserved. Bortezomib-Associated Peripheral Neuropathy Fig 1. Mean sural sensory action potential amplitudes at baseline and end of study among patients who (A) did or (B) did not develop treatment-emergent sensory neuropathy. dose-related adverse effect that increases in prevalence through the first five treatment cycles. Most patients (71%) with clinically significant neuropathy experienced resolution or improvement of neuropathic pain and other symptoms during treatment after dose modification or on completion of therapy. An additional 14% of patients died before first follow-up, indicating that the rate of resolution or improvement may have been higher. Importantly, among patients who were treated in an extension trial to the SUMMIT and CREST studies, prolonged bortezomib exposure did not seem to increase the incidence or severity of treatmentemergent peripheral neuropathy.11 In this study, there tended to be a higher incidence of grade 3 or 4 neuropathy in patients with baseline evidence of neuropathy by FACT/GOG-Ntx (P .08). However, the overall rate of treatmentemergent peripheral neuropathy during bortezomib treatment could not be predicted from baseline total neuropathy or FACT/GOG-Ntx questionnaire scores. Importantly, sensory neuropathic symptoms may be out of proportion to objectively measurable signs at baseline and were also noted during treatment in three patients in whom nerve conduction studies and quantitative sensory testing showed no change, a phenomenon which is typical of small-fiber involvement. Therefore, patient history and symptomatic enquiry may be especially helpful in not only predicting potential risk but also in assessing patients during therapy. In this analysis, the development of treatment-emergent peripheral neuropathy seemed to be independent of the type of prior neurotoxic therapy that the patient received. Recent reports illustrate that bortezomib can be combined with other agents that are neurotoxic such as thalidomide.17 In front-line myeloma trials of bortezomib at the same dose and schedule (but for fewer cycles) combined with dexamethasone and administered with or without doxorubicin, lowgrade neuropathy was reported in a comparable or higher proportion of patients, but high-grade neuropathy and neuropathy resulting in discontinuation of treatment were less common, with improvement or resolution reported in most patients.18,19 At present, dose modification guidelines are warranted (Table 5). Adherence to these recommendations in the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial6,20 may have contributed to a reduction in grade 3 peripheral neuropathy compared with the findings of SUMMIT1 and CREST,2 although this cannot be verified on these data alone. Given that bortezomib represents an active treatment providing durable responses and a survival advantage in relapsed myeloma, its benefits are clear.6 As alluded to earlier, patients should be monitored for emergence of new or worsening symptoms or signs of neuropathy during treatment. Patient-completed questionnaires, such as the FACT/GOG-Ntx, may be helpful tools to identify patients at risk early and to institute dose-modification guidelines. Future studies to better characterize peripheral neuropathy in newly diagnosed patients and prospective evaluations of potential interventions to improve patient outcome are ongoing. Reliable assessment and management of neuropathy, with its significant impact on quality of life, constitutes an increasingly important component in the care of patients with multiple myeloma. Table 5. Recommended Dose Modification for Peripheral Neuropathy Severity of Peripheral Neuropathy Modification of Dose and Schedule Grade 1 (paresthesias or loss of reflexes) without pain or loss of function Grade 1 with pain or grade 2 (interferes with function but not with ADL) Grade 2 with pain or grade 3 (interferes with ADL) Grade 4 (permanent sensory loss that interferes with function) No action Reduce to 1.0 mg/m2 Withhold treatment until toxicity resolves, then reinitiate at a dose of 0.7 mg/m2 once weekly Discontinue treatment Abbreviation: ADL, activities of daily living. www.jco.org Downloaded from jco.ascopubs.org on September 8, 2010. For personal use only. No other uses without permission. Copyright 2006 American Society of Clinical Oncology. All rights reserved. 3117 Richardson et al REFERENCES 1. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003 2. Jagannath S, Barlogie B, Berenson J, et al: A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165-172, 2004 3. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999 4. Pal PK: Clinical and electrophysiological studies in vincristine induced neuropathy. Electromyogr Clin Neurophysiol 39:323-330, 1999 5. Ropper AH, Gorson KC: Neuropathies associated with paraproteinemia. N Engl J Med 338:16011607, 1998 6. Richardson PG, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:24872498, 2005 7. Lonial S, Waller EK, Richardson PG, et al: Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106:3777-3784, 2005 8. Aghajanian C, Soignet S, Dizon DS, et al: A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505-2511, 2002 9. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al: Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420-4427, 2002 10. Papandreou CN, Daliani DD, Nix D, et al: Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22:2108-2121, 2004 11. Calhoun EA, Welshman EE, Chang CH, et al: Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 13:741-748, 2003 12. Berenson JR, Jagannath S, Barlogie B, et al: Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer 104:2141-2148, 2005 13. Dyck PJ, Davies JL, Litchy WJ, et al: Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort. Neurology 49:229-239, 1997 14. Apfel SC, Schwartz S, Adornato BT, et al: Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneurop- athy: A randomized controlled trial--rhNGF Clinical Investigator Group. JAMA 284:2215-2221, 2000 15. Dumitru D, Amato AA, Zwartz MJ: Nerve conduction studies, in Dumitru D, Amato AA, Zwartz MJ (eds): Electrodiagnostic Medicine (ed 2). Philadelphia, PA, Hanley & Belfus, 2002, pp 159-223 16. Fromme EK, Eilers KM, Mori M, et al: How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30. J Clin Oncol 22:3485-3490, 2004 17. Zangari M, Barlogie B, Hollmig K, et al: Marked activity of Velcade plus thalidomide (VT) in advanced and refractory multiple myeloma (MM). Blood 104:413a-414a, 2004 (abstr) 18. Jagannath S, Durie BG, Wolf J, et al: Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 129:776-783, 2005 19. Oakervee HE, Popat R, Curry N, et al: PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 129:755-762, 2005 20. San Miguel JF, Richardson P, Sonneveld P, et al: Frequency, characteristics, and reversibility of peripheral neuropathy (PN) in the APEX trial. Blood 106:366a, 2005 (abstr) Acknowledgment We acknowledge the contributions of Essa Kayd and Denise Collins in the conduct of the study and the contributions of the research nurses and coordination staff at the centers. We also acknowledge the participation of the patients and their families. 3118 JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on September 8, 2010. For personal use only. No other uses without permission. Copyright 2006 American Society of Clinical Oncology. All rights reserved. Bortezomib-Associated Peripheral Neuropathy Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Authors Paul G. Richardson Hannah Briemberg Sundar Jagannath Patrick Y. Wen Bart Barlogie James Berenson Seema Singhal Michael Schuster Gordan Srkalovic Raymond Alexanian S. Vincent Rajkumar Steven Limentani Melissa Alsina Robert Z. Orlowski Kevin Najarian Dixie Esseltine Kenneth C. Anderson Anthony A. Amato Employment Leadership Consultant Stock Honoraria Research Funds Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (B) Millennium Pharmaceuticals, Inc (C) Millennium Pharmaceuticals, Inc (A); Celgene (A) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (A); Celgene (A) Millennium Pharmaceuticals, Inc (C) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (B) Celgene (A) Millennium Pharmaceuticals, Inc (C) Celgene (B); Millennium Pharmaceuticals, Inc (B) Millennium Pharmaceuticals, Inc (B) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (C) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (N/R) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (N/R) Millennium Pharmaceuticals, Inc (B) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (B) Millennium Pharmaceuticals, Inc (A) Millennium Pharmaceuticals, Inc (B) Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required Testimony Other www.jco.org Downloaded from jco.ascopubs.org on September 8, 2010. For personal use only. No other uses without permission. Copyright 2006 American Society of Clinical Oncology. All rights reserved. 3119 Richardson et al Author Contributions Conception and design: Paul G. Richardson, Hannah Briemberg, Patrick Y. Wen, Bart Barlogie, James R. Berenson, Raymond Alexanian, Robert Z. Orlowski, Dixie Esseltine, Kenneth C. Anderson, Anthony A. Amato Provision of study materials or patients: Paul G. Richardson, Sundar Jagannath, Bart Barlogie, James R. Berenson, Seema Singhal, David S. Siegel, David Irwin, Michael Schuster, Gordan Srkalovic, Raymond Alexanian, S. Vincent Rajkumar, Steven Limentani, Melissa Alsina, Robert Z. Orlowski Collection and assembly of data: Paul Richardson, Hannah Briemberg, Patrick Y. Wen, James R. Berenson, Seema Singhal, David S. Siegel, Michael Schuster, S. Vincent Rajkumar, Steven Limentani, Melissa Alsina, Kevin Najarian, Dixie Esseltine, Anthony A. Amato Data analysis and interpretation: Paul G. Richardson, Hannah Briemberg, James R. Berenson, David S. Siegel, Steven Limentani, Robert Z. Orlowski, Kevin Najarian, Dixie Esseltine, Anthony A. Amato Manuscript writing: Paul G. Richardson, Hannah Briemberg, Patrick Y. Wen, Raymond Alexanian, Robert Z. Orlowski, Dixie Esseltine, Kenneth C. Anderson, Anthony A. Amato Final approval of manuscript: Paul G. Richardson, Hannah Briemberg, Patrick Y. Wen, Bart Barlogie, Seema Singhal, David S. Siegel, Michael Schuster, S. Vincent Rajkumar, Steven Limentani, Robert Z. Orlowski, Kevin Najarian, Dixie Esseltine, Anthony A. Amato 3120 JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on September 8, 2010. For personal use only. No other uses without permission. Copyright 2006 American Society of Clinical Oncology. All rights reserved.