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Originally published as JCO Early Release 10.1200/JCO.2006.05.6689 on August 28 2006 © 2006 American Society of Clinical Oncology. Development of Neuropathy in Patients With Myeloma Treated With Thalidomide: Patterns of Occurrence and the Role of Electrophysiologic Monitoring
From the Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne; Department of Medicine, University of Melbourne, Melbourne; Department of Neurology, Alfred Hospital, Prahran; Department of Medicine, Monash University, Clayton, Australia; and the Celgene Corp, Warren, NJ Address reprint requests to Linda Mileshkin, MBBS, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria 3002, Australia; e-mail: Linda.Mileshkin{at}petermac.org
PURPOSE: Peripheral neuropathy frequently limits the duration of treatment with thalidomide for patients with multiple myeloma. We assessed the time course of occurrence, possible predictive factors, and the utility of serial nerve electrophysiological studies (NES) for detecting onset of neuropathy. PATIENTS AND METHODS: Seventy-five patients with relapsed/refractory myeloma were enrolled onto a multicenter trial of dose-escalating thalidomide with or without interferon. Patients underwent clinical assessment plus NES at baseline and every 3 months. Time to development of neuropathy according to clinical or NES criteria was compared. Patient and treatment-related factors were compared as predictors of neuropathy. RESULTS: Thirty-nine percent had some NES abnormalities at baseline. Patients received thalidomide at a median dose-intensity of 373 mg/d. Thirty-one of 75 patients (41%) developed neuropathy during thalidomide treatment; 11 patients (15%) discontinued treatment with thalidomide due to neuropathy. The actuarial incidence of neuropathy increased from 38% at 6 months to 73% at 12 months, with 81% of responding patients developing this complication. Serial NES did not reliably predict the imminent development of clinical neuropathy requiring thalidomide cessation, nor were patient age, sex, or prior therapy predictive. Patients who developed neuropathy had a longer duration of thalidomide exposure (median, 268 v 89 days; P = .0001). Cumulative dose or dose-intensity received was not predictive. CONCLUSION: The majority of patients will develop peripheral neuropathy given sufficient length of treatment with thalidomide. To minimize the risk of neurotoxicity, therapy should be limited to less than 6 months. Electrophysiologic monitoring provides no clear benefit versus careful clinical evaluation for the development of clinically significant neuropathy.
Within the last 6 years, several novel, biologically derived treatment options for patients with multiple myeloma have emerged: thalidomide, its derivative lenalidomide, and the proteasome inhibitor, bortezomib.1 Physicians are now faced with the dilemma of how best to sequence these drugs to optimize efficacy and toxicity. Thalidomide's major toxicities are constipation, somnolence, and neurotoxicity.2 Neuropathy, in particular, may limit the ability to continue effective treatment and has been documented to affect quality of life.3,4 Bortezomib is highly active but also has problematic neuropathy in up to 35% of patients, which is grade 3 or higher in 8% to 17%, but reversible in the majority.5,6 The reported incidence of thalidomide neuropathy varies from 25% to 75% in most series that use serial nerve electrophysiologic studies (NES) in addition to clinical assessment.7-26 The cardinal sign on NES is a 50% decrease in the sensory nerve action potential (SNAP) amplitude, with relative conservation of nerve conduction velocities.10,17,27 The relationship between the development of neuropathy and the duration of exposure, cumulative dose, and dose-intensity of thalidomide is controversial. Because of a perceived correlation between cumulative dose and severity of neuropathy,28,8,12,13,19 some clinicians use as low a dose as possible of thalidomide (possibly risking efficacy) or cease thalidomide at the first sign of neuropathy. Conversely, others report successfully continued treatment using a reduced dose without progression of neuropathy.9 Although the use of NES for monitoring the development of neuropathy has been recommended, its usefulness remains unproven. In this study, we assessed the utility of NES performed once every 3 months in 75 patients with relapsed or refractory myeloma on a prospective study using thalidomide.29 We also assessed the pattern of occurrence of neuropathy and its relationship with potential patient- and treatment-related predictive factors.
In brief, patients commenced treatment with thalidomide (Thalomid; Celgene Corp, Warren, NJ) at a dose of 200 mg/d, with planned dose escalation during the first 8 weeks to 800 mg/d. Ethics committees of participating institutions approved the trial. Patients with peripheral neuropathy of grade 2 or greater (Table 1) were excluded. Dose escalation was ceased or the dose reduced if patients developed adverse effects reported to be intolerable. At week 12, patients with stable or responsive disease continued thalidomide, and commenced subcutaneous interferon alfa-2b (Intron, Shering-Plough, Sydney, Australia). Thalidomide (n = 75) with (n = 19) or without (n = 56) interferon was continued until progressive disease or patient intolerance, including development of clinically significant neuropathy.
Patients were assessed clinically for neurotoxicity weekly for 24 weeks and then monthly using history and neurologic examination, plus grading of toxicity (Table 1). Patients underwent NES once every 3 months, including measurement of F-wave latency, motor nerve conduction amplitude, and velocity in the posterior tibial nerve, plus measurement of the peak-to-peak SNAP and conduction velocity in the sural nerve. For patients who developed neuropathy, the median cumulative dose was calculated as the dose of thalidomide received up until the time of development of neuropathy. Peripheral neuropathy was defined as cessation of thalidomide due to neurotoxicity, more than grade 1 sensory neuropathy attributed to thalidomide, decrease in SNAP of more than 50% on serial NES, or development of additional neuropathic changes on serial NES if the baseline SNAP was absent. Differences between baseline patient and treatment variables were compared using a Mann-Whitney U test or a Fisher's exact test, with a P = .05 considered statistically significant. Times to development of neuropathy according to clinical or NES criteria were compared using Kaplan-Meier analysis.
As reported previously, characteristics of the 75 patients are listed in Table 2 and the treatment outcomes are listed in Table 3. 29
Development of Neuropathy Sixty-six of the patients completed a baseline NES and 38 had two or more serial studies (range, two to nine NES studies). Twenty-six (39%) of the 66 patients had evidence of sensory neuropathy with or without motor neuropathy on their baseline NES, with seven patients having an absent SNAP. No patients had clinical neuropathy more than grade 1 at enrollment. Thirty-one of the 75 patients (41%) developed evidence of peripheral neuropathy by clinical and/or electrophysiologic criteria, with 24 patients (32%) developing clinical evidence of more than grade 1 neuropathy (Table 4).
Of the 38 patients who completed serial NES, 20 (53%) developed electrophysiologic criteria for neuropathy. The predominant neurophysiologic change was loss of the SNAP with preservation of sensory velocity. However, motor changes including decreases in compound muscle action potential amplitude and conduction velocity were also seen in 15 of these 20 patients (75%). Increased F-wave latencies were seen in 21% of patients. In the majority, any motor changes occurred after a decline in the SNAP. However, in 40% of the 38 patients who completed serial NES, the sensory and motor changes occurred concurrently. For those 31 patients who developed neuropathy, the median time to onset was 24 weeks (range, 2 to 60 weeks). The actuarial incidence of peripheral neuropathy for the entire 75-patient cohort increased with time on treatment (38% ± 14% at 6 months and 73% ± 16% at 12 months), as shown in Figure 1. Seventeen (81%) of the 21 responding patients developed neuropathy. Of the 11 patients (15%) who discontinued thalidomide because of neurotoxicity, four of these discontinued early (< 8 weeks) and the remaining seven discontinued after 4 to 31 months (Table 5).
Predictors of Neuropathy Baseline NES. The positive predictive value of an abnormal baseline NES for the subsequently developing neuropathy was only 46%, but 73% of the patients with neuropathy severe enough to necessitate cessation of thalidomide (n = 11) had abnormal baseline studies. Of those patients who developed early neuropathy within 8 weeks of commencing thalidomide (n = 7), five had abnormal baseline NES. Four of these seven patients had to discontinue thalidomide early; all four had abnormal baseline NES. In comparison, only 15 of 55 patients who did not develop early neuropathy had an abnormal baseline NES (P = .03). However, the negative predictive value of a normal baseline NES for the entire cohort was only 53%.
Serial NES.
The first sign of neuropathy was clinical in 45% of patients and detected on NES testing in 45% of patients. The results of the clinical evaluation and serial NES were concordant in 28 (74%) of 38 patients. In 10 patients (26%) the clinical findings and NES results were discordant; three patients ceased thalidomide due to clinical grade
To explore the possible value of early detection of clinical neuropathy using NES, we analyzed the time to neuropathy after the detection of a 50% reduction in the SNAP in the 17 patients who had not manifested clinical neuropathy before that time. The SNAP reduction was first observed after a median of 24 weeks treatment (range, 12 to 60 weeks). Ten of these 17 patients did develop clinical grade
Clinical parameters. Of the baseline patient variables, the only significant predictor of the development of peripheral neuropathy was a lower baseline serum level of beta2-microglobulin (ß2-microglobulin; Table 2). However, a landmark analysis of only patients who received more than 3 months of thalidomide showed no significant difference in the baseline ß2-microglobulin level of patients who developed neuropathy compared with those who did not, suggesting that the lower serum ß2-microglobulin was seen in patients with a better prognosis who received a longer duration of thalidomide (median treatment time, 218 days for ß2-microglobulin  median level v 84 days for ß2-microglobulin > median level; P = .007). The measurement of vitamin B12 and folate levels was not mandated in the study, and was not performed in any patients before thalidomide treatment began. However, in a medical record review of 47 patients from our center, three were folate deficient and three were B12 deficient when levels were measured because neuropathy was developing during thalidomide treatment. Duration of thalidomide. In general, patients who developed neuropathy received thalidomide for longer. Patients who developed neuropathy received a median of 268 days thalidomide compared with 89 days in those who did not (P = .0001). Of note, patients who developed neuropathy continued to take thalidomide for a median of 19 weeks (range, 0 to 86 weeks) after the neuropathy was first manifest, before symptoms became intolerable (n = 11), or they discontinued taking it for other reasons such as progressive disease (n = 20; Fig 3). Interferon was administered to 14 of the 31 patients who developed neuropathy compared with five of the 44 patients who did not. However, this primarily reflected the fact that those who received interferon tended to be patients with responsive disease who continued taking thalidomide for longer, with no difference in the median time to development of neuropathy between those who received interferon and those who did not (median, 252 v 224 days; P = not significant), suggesting that the addition of interferon did not increase the likelihood of developing neuropathy.
Cumulative dose of thalidomide. Figure 4 shows that a larger proportion of patients developed neuropathy with higher cumulative doses, but this does not explain whether the increase is due to the cumulative dose itself or prolonged drug exposure. We found that the median cumulative dose received up until the time of development of neuropathy was not significantly different from the median cumulative dose received by those who did not develop neuropathy (60 v 40 g; P = not significant). Moreover, neuropathy was still seen in patients who received lower cumulative doses, with eight of 23 patients (35%) developing neuropathy at a cumulative dose of less than 20 g.
Dose-intensity of thalidomide. Excluding those patients who received less than 8 weeks thalidomide (during dose escalation; n = 15), there was no significant difference in the dose-intensity of thalidomide received by those who developed neuropathy (up until the time of neuropathy) and those who did not (median dose-intensity 345 v 482 mg/d; P = .08). In fact, those who developed neuropathy tended to receive a lower dose-intensity of thalidomide, reflecting the fact that investigators tended to decrease the dose in those developing neuropathy. Although Figure 5 demonstrates that the majority of patients developing neuropathy received a dose-intensity of more than 200 mg/d, it also demonstrates that a substantial number of patients receiving more than 200 mg/d did not develop neuropathy. Only six patients in our trial received less than 200 mg/d, with five developing evidence of neuropathy, which was clinically evident in four but did not require cessation of thalidomide.
We could not describe accurately whether neuropathy due to thalidomide was reversible, given that patients were not assessed formally regarding neuropathy after thalidomide was discontinued.
This study confirms that neuropathy is common in patients with relapsed or refractory multiple myeloma. Even though all patients had less than grade 2 clinical neuropathy at study enrollment, 39% had some neuropathic changes on a baseline NES before thalidomide. Subsequently, 53% of patients had deterioration of NES, with almost 40% developing evidence of grade  2 clinical neuropathy and 15% ceasing treatment because of this complication. Thalidomide is most frequently reported to cause a length-dependent axonal neuropathy.27 Typical clinical features are tingling or painful distal paraesthesia, or sensory loss affecting the feet and sometimes the hands.2,10 Motor involvement and proprioceptive failure has been reported occasionally.27 However, in our study motor NES changes were seen commonly and frequently developed concurrently with sensory changes, suggesting that thalidomide frequently causes a sensorimotor axonal neuropathy, in contrast to bortezomib, which causes a predominantly sensory neuropathy.7
The major predictor of developing neuropathy was the duration of exposure to thalidomide. Other studies have described that adverse events attributable to thalidomide increase with dose and duration of therapy.30,31 Richardson et al31 reported neuropathy in 37% of 30 myeloma patients treated with thalidomide for relapse after autograft; the frequency and severity of treatment-related adverse events, including neuropathy, increased with longer duration of therapy and/or thalidomide dose In our study, the risk of developing neuropathy in patients who were able to continue taking thalidomide for a prolonged period (ie, responders) was 81%. Two other studies have focused specifically on the development of peripheral neuropathy in thalidomide-treated myeloma patients and reported results consistent with ours. Offidani et al21 reported results from 59 myeloma patients treated with thalidomide with and without oral melphalan; peripheral neuropathy developed in 39%. Tosi et al22 described long-term toxicity results in a group of 40 patients who had received more than 1 year of treatment with thalidomide with or without dexamethasone; 75% ultimately developed evidence of neuropathy. Given that duration of thalidomide treatment is important, the next issues are to determine the relative importance of cumulative dose and dose-intensity. We found in this study that the median cumulative dose received up until the time of development of neuropathy was not statistically different from the median cumulative dose received by those who did not develop neuropathy. Moreover, 35% of patients developed neuropathy at a cumulative dose of less than 20 g. Review of the literature identified 12 other studies that attempted to examine the relationship between the cumulative dose and neuropathy (Table 6). No association was found in eight of these studies, with a range of median cumulative doses from 17.6 to 58 g. Four studies suggested neuropathy was more likely with a higher cumulative dose, and that severity of neuropathy worsened with cumulative dose. A study by Cavaletti et al8 in 65 patients suggested such a correlation. However, they reported no correlation in patients who were treated with less than 20 g of thalidomide. As mentioned, this was not reproducible in our study.
Methodological problems in some of these studies may have accounted for some of these discrepancies; none of the studies that found an association between the cumulative dose and neuropathy specified whether the cumulative dose was the total cumulative dose taken by the patient or the cumulative dose taken up until the time neuropathy developed. This is important, given that patients often continue treatment with neuropathy, potentially confounding any analysis of an impact of cumulative dose. We found no significant difference in the dose-intensity of thalidomide treatment received by those who developed neuropathy and those who did not. However, because our study involved intrapatient dose escalation of thalidomide, with 75% of patients receiving more than 400 mg/d, we could not adequately assess the risk of neuropathy with low-dose thalidomide (< 200 mg/d) or completely separate out the relative contributions of cumulative dose and dose-intensity to the neuropathy risk. In study by Offidani et al,21 patients received a mean dose of 150 mg/d, and a median dose of more than 150 mg/d was associated significantly with a higher risk of developing neuropathy. Two other nonmyeloma studies, in which the majority of the patients received low-dose thalidomide (up to 125 mg/d), have also suggested a higher risk of neuropathy with higher dose-intensity treatment.10,13 However, some studies have not shown a correlation with dose-intensity (Table 6). This issue needs to be put into context of the ongoing debate of the importance of dose and disease response in myeloma.29,32-36 We were unable to define reliable clinical predictors for the development of neuropathy, although patients with a lower baseline level of serum ß2-microglobulin were more at risk (which may reflect a better prognosis in patients who received a longer duration of thalidomide). The lack of identifiable clinical risk factors is frustrating, but in keeping with other larger studies in which neither age, sex, nor the length or type of prior treatments (including vincristine) were predictive (Table 6).10,11,21,22 Overall, we found that abnormalities on a baseline NES were not predictive for the development of neuropathy; the positive predictive value of a patient with an abnormal baseline NES subsequently developing neuropathy was 46%. Nonetheless, the majority (73%) of the patients with more severe neuropathy, which necessitated cessation of thalidomide, had abnormal baseline studies. This finding in itself would support performance of a baseline study before thalidomide treatment is begun. Conversely, the negative predictive value of a normal baseline NES is not that reassuring at only 53%. However, a baseline study may help predict for a higher risk of clinically relevant neuropathy and possibly identify patients at risk of early-onset neuropathy. A baseline study may also be useful for comparison if an additional study is required because an unclear clinical diagnosis. However, in myeloma patients there may be technical difficulties due to an absent SNAP or peripheral edema due to thalidomide.19 Regarding monitoring for the development of neuropathy, our results demonstrate that careful clinical monitoring is just as useful as performance of serial NES; for the most part, NES changes did not reliably predict imminent clinical neuropathy severe enough to warrant cessation of thalidomide, and in some patients did not correlate with clinical findings. Other investigators have also reported nonmyeloma patients treated with thalidomide in whom the clinical and electrophysiologic findings are not correlated.14,19 Our findings need to be placed into the context of modern management of myeloma. Combination thalidomide plus dexamethasone recently has been reported to be highly active in patients with newly diagnosed myeloma when compared with dexamethasone along; however, increased toxicities including neuropathy are seen with the combination.37 Because any neuropathy may preclude the use of other potentially neurotoxic treatment options such as bortezomib at relapse, it is important that patients be monitored for the development of neuropathy during thalidomide therapy. Alternatively, for patients with existing neuropathy, lenalidomide is a highly active and less neurotoxic treatment alternative. We conclude that the development of neuropathy relates primarily to the duration of exposure to thalidomide; dose-intensity and total cumulative dose are less important. To minimize the risk of neurotoxicty, thalidomide as used in the current study should be limited to less than 6 months. This finding may be particularly important for patients who are having induction therapy with thalidomide before high-dose chemotherapy. Given the sudden increase in neurotoxicity from approximately 40% to almost 75% between 6 and 12 months, we would recommend short exposure with optimum doses to maximize response. For patients for whom prolonged therapy is being considered (ie, elderly patients) long-term therapy is likely to be difficult, and it is in this setting that low-dose thalidomide combinations, which maybe tolerated for longer, should be explored. In this study the use of baseline electrophysiological studies had some, but limited, use to predict early neurotoxicity and warrants additional study.
Although all authors completed the disclosure declaration, the following author or 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C)
We thank the Rotary Club of Camberwell, Australia, and Myeloma Foundation of Australia for assistance in patient education through the activities of the myeloma nurse.
published online ahead of print at www.jco.org on August 28, 2006. Supported by Celgene Corp, Warren, NJ, and by the Medical Oncology Group (Australia)/Novartis Clinical Research Fellowship (L.M.). Presented in part at the 42nd Annual Meeting of the Americal Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Richardson P, Schlossman R, Jagannath S, et al: Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: Results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin Proc 79:875-882, 2004 32. Barlogie B, Desikan R, Eddlemon P, et al: Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: Identification of prognostic factors in a phase 2 study of 169 patients. Blood 98:492-494, 2001 33. Neben K, Moehler T, Benner A, et al: Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma. Clin Cancer Res 8:3377-3382, 2002 34. Johnston RE, Abdalla SH: Thalidomide in low doses is effective for the treatment of resistant or relapsed multiple myeloma and for plasma cell leukaemia. Leuk Lymphoma 43:351-354, 2002[CrossRef][Medline] 35. Pini M, Baraldi A, Pietrasanta D, et al: Low-dose of thalidomide in the treatment of refractory myeloma. Haematologica 85:1111-1112, 2000 36. Palumbo A, Giaccone L, Bertola A, et al: Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 86:399-403, 2001 37. Rajkumar SV, Blood E, Vesole D, et al: Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 24:431-436, 2006 Submitted January 18, 2006; accepted July 20, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
