Leukemia & Lymphoma, October 2014; 55(10): 2277–2283 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.873535
ORIGINAL ARTICLE: CLINICAL
Assessment of bortezomib induced peripheral neuropathy in multiple myeloma by the reduced Total Neuropathy Score
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Chrysothea K. Zaroulis1,2, Konstantinos Chairopoulos2, Sotirios P. Sachanas3, Dimitris Maltezas1, Tatiana Tzenou1, Ilias Pessach1, Efstathios Koulieris1, Eleni Koutra4, Konstantinos Kilindireas5, Gerasimos A. Pangalis3 & Marie-Christine Kyrtsonis1 1Hematology Section, First Department of Propedeutic Internal Medicine, Laikon University Hospital, Athens, Greece, 2Department of Neurology, 417 General Military Hospital, Athens, Greece, 3Department of Hematology, Athens Medical Center,
Psychikon Branch, Athens, Greece, 4Department of Neurology, Evangelismos Hospital, Athens, Greece and 5Department of Neurology, National and Kapodistrian University of Athens, Eginition Hospital, Athens, Greece
Bortezomib treatment of patients with MM results in high response rates. However, one of the most severe side effects is PN, which is reported to be moderate while reversible after dose reduction or discontinuation of the drug. Its early recognition is important for effective management [6,7]. However, its accurate assessment is not easy because of patient and treating physician subjectivity. Although it is important to avoid disabling neurological sequelae and cumulative PN with retreatment or subsequent therapies, it is also equally important to offer patients this valuable treatment modality in a safe way. The purpose of the present study was to evaluate the neurological characteristics of bortezomib induced peripheral neuropathy (BIPN) using the Total Neuropathy Score reduced version (TNSr), in an attempt to report as objectively as possible the type, grade, duration and reversibility of neuropathy [8,9]. The TNSr was developed for accurate grading of PN. It is a composite measure as it includes clinical and neurophysiological examination, such as sensory and motor function, as well as pin and vibration sensibility, strength, deep tendon reflexes and sural (sensory nerve) and common peroneal (motor nerve) conduction velocities. Furthermore, it seems to have a greater sensitivity than the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) [10,11]. We also attempted to investigate possible PN risk factors such as age, previous neurotoxic therapies and laboratory parameters, as well as determine the best way to manage it [12,13].
Abstract We evaluated bortezomib induced peripheral neuropathy (BIPN) characteristics in an attempt to better clarify the type, grade, duration and reversibility of neuropathy as well as investigate possible peripheral neuropathy (PN) risk factors and detect the best way to manage it. We calculated the grading of neuropathy using the Total Neuropathy Score reduced version (TNSr) in a series of 51 patients with relapsed/refractory multiple myeloma treated with bortezomib. Seventy percent developed clinical PN. BIPN, although manageable, is frequently underestimated in patients treated with bortezomib intravenously. Continuous follow-up and management of PN are needed to avoid quality of life impairment. Keywords: Drug induced peripheral neuropathy, multiple myeloma, bortezomib
Introduction Paraprotein related peripheral neuropathy (PN) is frequently associated with treatment administration. Vincristine, thalidomide and more recently bortezomib are common neurotoxic agents inducing PN [1–3]. Bortezomib, a synthetic, boronic acid dipeptide (N-pyrazinecarbonyl-l-phenylalanine-l-leucine boronic acid), trade name Velcade, is a selective, reversible proteasome inhibitor and is extremely active in patients with multiple myeloma (MM). It reduces drug resistance in myeloma cells and also modulates the secretion by bone marrow stroma cells of cytokines that mediate the growth, survival and migration of myeloma cells [4]. Bortezomib blocks nuclear factor-κB (NF-κB) with multiple effects on MM cells and other molecules, such as neurotrophins in neurons [5].
Patients and methods Patients’ characteristics We studied 51 patients with ΜΜ classified into three categories: (1) 16 patients without prior exposure to neurotoxic
Correspondence: Chrysothea K. Zaroulis, Hematology Section, First Department of Propedeutic Internal Medicine, Laikon University Hospital, Athens, Greece. E-mail: [email protected] Received 17 July 2013; revised 24 November 2013; accepted 1 December 2013
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chemotherapeutic agents (vincristine, thalidomide, cisplatin), (2) 35 patients with previous neurotoxic therapies before bortezomib and (3) 10 patients sequentially evaluated with the TNSr after bortezomib administration at different time points. Patients with comorbidities predisposing to peripheral neuropathy such as diabetes, metabolic syndromes or other malignancies were excluded from the study. There were 26 men and 25 women. The patients’ median age was 66 years (45–80 years). Myeloma type was immunoglobulin G (IgG) in 65%, IgA in 17%, IgD in 5% and light chain in 13%. Thirteen percent, 54% and 33% had Durie–Salmon stage I, II and III disease, respectively, while International Staging System (ISS) groups 1, 2 and 3 included 29%, 27% and 44% of the patients, respectively. All were at relapse or refractory to prior treatment. They received bortezomib intravenously on days 1, 4, 8 and 11 every 21 days, at an initial dose of 1.3 mg/m2 for a median of four cycles. Dexamethasone, 20 mg, was also administered on days 2, 5, 9 and 12 [14].
presented with neuropathy of grade 1, TNSr 9–16 of grade 2, TNSr 17–24 of grade 3 and TNSr 24–32 of grade 4. Neurophysiological studies comprised two peripheral nerve calculations: the compound muscle action potential amplitude of the peroneal nerve (CMAP) and the sensory nerve action potential amplitude of the sural nerve (SNAP). Normal values of SNAP and CMAP were considered as ⱖ 7 μV and ⱖ 3 mV, respectively. Motor and sensory nerve conduction studies were performed using standardized equipment and techniques. The study was approved by the local ethical committee and patients’ approval was obtained.
Statistical methods Statistical analysis was performed using the statistical software SPSS version 15.0. Univariate p-values were calculated using the χ2 test.
Results Clinical evaluation
Methods Patients’ files were reviewed, and neuropathy evaluation by the treating hematologist reported all neurological complaints. Neurologic assessment consisted of (a) a questionnaire regarding symptoms, thermoregulatory and functional disorders and (b) clinical and neurophysiological examination which was performed by a consulting neurologist using bedside clinical examination. Neurologic examination included mental and mood evaluation, gait examination, motor evaluation, testing of cranial nerves, tactile sensation and pain perception, evaluation of thermal sense, as well as of vibratory sense, proprioceptive sense, stereognosis and two-point discrimination sense. Deep tendon reflexes were evaluated by patellar, Achilles and plantar reflexes. Motor evaluation was performed using the Medical Research Council (MRC) sum score for muscle strength, with which motor muscle strength is measured in six muscle groups at the right side of the body and in six muscle groups at the left side of the body. In the upper extremities we evaluated shoulder abduction, elbow flexion and wrist extension, while in the lower extremities evaluation concerned hip flexion, knee extension and ankle dorsiflexion with a 0–5 range per group (0 ⫽ no movement, 5 ⫽ normal strength). The MRC sum score can range from 0 to an optimal total sum score of 60 [15]. We used an arbitrary cut-off score of 48 [16]. Vibration sensibility was measured with a 128 Hz tuning fork in fingers, wrists and elbows in the upper extremities, while in the lower extremities it was measured in toes, ankles and knees [17]. Neuropathy was graded using the TNS, which ranged from 0 to 32 points (TNSr). TNSr evaluation included sensory and motor symptoms, pin and vibration sensibility, strength evaluation, tendon reflex examination, and sural and peroneal amplitude evaluation (eight parameters). Quantitative sensory tests and autonomic symptoms were excluded. Evidence of neuropathy was considered when the score was equal to or greater than 2. Patients with TNSr 2–8
Twelve patients developed gait abnormalities, including sensory ataxic gait in eight patients and parkinsonian and foot-drop gait in three and one, respectively. Tactile sensation was abnormal in 19 patients while pain perception and thermal sensation were abnormal in 19 and nine patients, respectively. Loss of sense at the lower limbs was developed in eight patients while two patients presented with loss of sense at both upper and lower limbs. Moreover, impaired sense at the lower limbs was observed in 16 patients while three patients disclosed impaired sense at both extremities. Four patients presented with loss of proprioceptive sense at the lower limbs while two were found to have loss of proprioceptive sense at both upper and lower limbs. Further, three patients developed stereognosis disorder and three two-point discrimination abnormality. Finally, deep tendon reflex evaluation revealed that 30, 10 and 10 patients disclosed loss of Achilles, patellar and both Achilles and patellar reflexes, respectively, while plantar reflex was noted in six patients (Table I). Results of the overall TNSr per patient are shown in Figure I.
Quantitative assessment of PN The incidence of PN grade 0, 1, 2, 3 and 4 was 9.8%, 25.5%, 60.7%, 4% and 0%, respectively (Table II). The majority of patients developed grade 2 PN (TNS 9–16), as well as admixed sensory and motor symptoms, meaning sensory alteration or weakness interfering with activities of daily living and symptoms of gait disorders. Median time to PN onset of any grade was 60 days (range 4–126 days), while the majority of patients developed PN within the first three cycles after bortezomib initiation regardless of previous neurotoxic treatment.
Qualitative assessement of PN The predominant sensory PN symptoms were numbness (37%) and neuropathic pain (27%), whereas burning (8%), tingling (4%) and paresthesias (2%) were less common (Table III). Symptoms were developed in the toes, soles and
TNSr evaluation of BIPN in MM 2279 Table I. Results of neurological evaluation.
Gait Sensory ataxic Steppage (foot-drop gait) Parkinsonian and aging gait (marche à petit pas) Cranial nerves Abnormal Tactile sensation Abnormal Pain perception Abnormal Thermal sensation Abnormal Vibratory sense Loss of sense in lower limbs Below knees Below malleolus Hallux Loss of sense in both upper and lower limbs Impaired sense in lower limbs Below knees Below malleolus Hallux Impaired sense in both upper and lower limbs Proprioceptive sense Loss in lower limbs Loss in both upper and lower limbs Stereognosis Loss of sense Two point discrimination Loss of sense Reflexes Loss of Achilles Impaired Achilles Loss of patellar Impaired patellar Loss of both Achilles and patellar Impaired both Achilles and patellar Plantar (Babinski reflex)
%
8 1 3
16 2 6
0
0
19
37
19
37
9
17
8 1 3 4 2 16 1 7 8 3
16 2 6 8 4 31 2 14 16 6
4 2
8 4
3
6
3
6
30 6 10 16 10 11 6
59 12 20 31 20 21 12
20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
TNSr
Grade
0–1 2–8 9–16 17–24 25–32
0 1 2 3 4
No. of patients 5 13 31 2 0
% 9.8 25.5 60.7 4 0
TNSr, Total Neuropathy Score (reduced).
grade PN usually reported that the painful area expanded on their palms and wrists or above their ankles and below the knees. One patient complained of a specific torturous sensation resembling insects walking along his lower limbs. Notably, the main symptoms were reported in glabrous skin. PN onset was mostly sudden. In the majority of patients BIPN symptoms were gradually recovered after a median period of 2 months from their initiation, providing that there was either dose reduction or even drug cessation. In our study bortezomib dose reduction was needed in 30% of patients and 40% of them discontinued treatment because of PN, mostly during the fourth cycle. Twenty-four percent of patients presented gait disorders that consisted of unsteady, tentative, antalgic, uncoordinated walking due to their sensory deficit-related distal weakness or other neurological reasons (Table I). Weakness was evaluated with the MRC sum score (Table IV). The majority of patients (82%) presented with optimal muscle strength score, 14% with mild weakness, mainly in the lower extremities with no impact on their quality of life, and 2% with moderate muscular impairment; one patient (2%) presented with severe muscular deficit. There was a need for this patient to use walking sticks because of the severity of his weakness, and this inevitably had a dismal impact on his daily activity.
Neurophysiological findings Distal axonopathy was the most common form of BIPN. Thirty-eight patients (74.5%) presented with PN. The
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51
fingertips, with stocking and glove distribution. Suppression of ankle jerks was observed primarily. Symptoms were noted more often in feet compared to the same symptoms in the upper limbs in a time-dependent way. Pain was described as intense, with sharp characteristics, like cold or electric shocks, more annoying during the night. Patients with high
TNS reduced
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Parameter
Table II. Grade of neuropathy according to TNSr. No. of patients
Patients Figure 1. Total Neuropathy Score reduced version (TNSr) evaluation per patient.
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Table III. Sensory symptoms. Symptom
Table V. Neurophysiological findings. No. of patients
%
Type of neuropathy
19 14 4 2 1 11
37 27 8 4 2 22
SA SMA MA Sural nerve (SNAP) Normal Abnormal Absent Peroneal nerve (CMAP) Normal Abnormal Absent
nerve conduction study evaluation (Table V) showed a predominantly sensory axonal polyneuropathy (55%), followed by sensory motor of axonal type and pure motor axonal BIPN in 42% and 3% of patients, respectively. Because the myelin sheath was not affected, nerve conduction studies showed normal or a slight reduction in velocities and normal latencies. In 55% of the patients, sural nerve action potentials were not recorded, while they were reduced in 16% (Table V). As far as the peroneal nerve was concerned, abnormal CMAP findings in the extensor digitorum brevis were found: CMAP was reduced in 35% while in 2% was not recorded (Table V). In the majority of patients there was a concordance between patients’ symptoms and neurophysiological findings. However, in 20% of patients BIPN was detected by neurophysiological evaluation despite the absence of clinical symptoms and/or signs of PN. Moreover, neurological examination including both clinical and laboratory criteria revealed that there was an overestimation of PN by the physician in 16% of patients.
Neurophysiological BIPN follow-up TNSr sequential evaluation TNSr sequential assessment was performed in 10 patients. TNSr was assessed before bortezomib initiation and 6 months and 12 months after bortezomib administration. This analysis disclosed that eight patients presented with pre-existing PN of grade 1 before bortezomib administration (time point 1). All patients had a significantly increased TNSr score (maximum value 20) 6 months after bortezomib administration (time point 2), while 12 months later TNSr values were slightly reduced, but they were not normalized in any patient (Figure 2).
%
21 16 1
55 42 3
15 8 28
29 16 55
32 18 1
63 35 2
SA, sensory axonal; SMA, sensory motor axonal; MA, motor axonal; SNAP, sensory nerve action potential; CMAP, compound muscle action potential.
patients 12 months after bortezomib administration, while the remainder had normalized values (Figure 3).
CMAP sequential evaluation Fourteen patients underwent sequential CMAP evaluation of the peroneal nerve at three time points (0, 6, 12 months after bortezomib initiation, respectively). Analysis of this sequential evaluation revealed that all patients presented with normal CMAP values (ⱖ 3 mV) before treatment initiation, while the majority of them developed the lowest values 6 months after bortezomib initiation. Only three patients had low CMAP values 12 months after bortezomib administration (Figure 4).
Neuropathy risk factors PN incidence was not associated with age, sex, paraprotein level, renal function, hemoglobin levels, prior neurotoxic therapies or number of previous lines.
BIPN treatment BIPN treatment was symptomatic, including drugs for neuropathic pain relief such as analgesics, antidepressants, antiepileptic agents and vitamins. As soon as PN symptoms presented, gabapentin was used at doses ranging from 900 to 1800 mg maximum daily dose, as well as pregabalin that showed efficacy at a daily
25
SNAP sequential evaluation Fourteen patients underwent sequential SNAP evaluation of the sural nerve at three time points (0, 6, 12 months after bortezomib initiation, respectively). The majority of them presented with absent or reduced SNAP 6 months after bortezomib initiation, and none of them had a SNAP value ⬎ 11 μV at this time point. Low SNAP values remained in two
No. of patients
20 15 TNS
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Numbness Pain Burning Tingling Paresthesias No symptoms
10 5
Table IV. Muscle strength evaluation. MRC sum score 49–60 37–48 25–36 13–24 0–12 MRC, Medical Research Council.
No. of patients
%
42 7 2 0 0
82 14 4 0 0
0 point 1
point 2
point 3
Figure 2. TNS sequential evaluation. TNS sequential assessment was performed in 14 patients. TNS was assessed before bortezomib initiation (point 1) and at a period of 6 months (point 2) and 12 months (point 3) after bortezomib administration.
TNSr evaluation of BIPN in MM 2281
S N A P
35 30 25 20 15 10 5 0
point 1
point 2
point 3
dose administration ranging from 150 to 450 mg maximum. The most commonly used antidepressants were serotonin reuptake inhibitors and duloxetine [18,19]. The latter showed efficacy at doses ranging from 60 to 120 mg daily, resulting in sensory symptom improvement and mood stabilization. Further, patients with severe neuropathic pain received an opioid-type analgesic such as fentanyl, while six patients with severe pain were placed on intravenous polyclonal immunoglobulins.
Discussion MM in the vast majority of patients is an incurable disease, with a median survival of 3–5 years [20]. The introduction of new drugs such as the proteasome inhibitor bortezomib has considerably increased response rates as well as patient survival [21]. However, BIPN occurs frequently. Thus, monitoring, early recognition and effective management of PN is important, in order for patients with MM to benefit from this therapy and maintain their quality of life [22–24]. Bortezomib administration affects peripheral nerves and dorsal root ganglia (DRG) neurons, through proteasome inhibition. Possible mechanisms are chromatolysis of DRG neurons and cytoplasmic accumulation of eosinophilic material, as well as neuronal mitochondrial damage, dysregulation of Ca2⫹ homeostasis and reduced neurotrophin levels [25–28]. In addition, bortezomib blocks the transcription of nerve growth factor, causing impaired trophic support and
CMAP
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Figure 3. SNAP sequential evaluation. Fourteen patients underwent sequential SNAP evaluation of sural nerve at three time points: 0, 6, 12 months (point 1, 2, 3) after bortezomib initiation respectively.
18 16 14 12 10 8 6 4 2 0 point 1
point 2
point 3
Figure 4. Compound muscle action potential (CMAP) sequential evaluation. Fourteen patients underwent sequential CMAP evaluation of the peroneal nerve at three time points: 0, 6, 12 months (points 1, 2, 3) after bortezomib initiation, respectively.
regeneration of neurons, which leads to peripheral atrophy [29,30]. The peripheral nervous system seems to be more vulnerable to toxic agents compared to the central nervous system because it does not have the capability of autoregulation, and the peripheral blood–nerve barrier is less efficient than the brain–blood barrier [31]. The aforementioned factors allow easier access of potential neurotoxins into the peripheral nervous system. Furthermore, DRG lack an efficient vascular barrier, making the cell body a target for drugs. Endothelial cells in the epineurium are fenestrated, and allow escape of blood proteins into the extracellular space, while endoneural nerves have no lymphatic system to remove toxins. Peripheral nerves have nothing analogous to the sink action of cerebrospinal fluid [32]. This absence of a vascular barrier may play an essential role in BIPN development, by allowing the exposure of peripheral nerves and cell bodies to bortezomib directly from plasma. Nerves are composed of different types of axons with different morphology and function, such as large myelinated axons, including motor axons and sensory axons responsible for vibration, proprioception and light touch, as well as small myelinated axons, including autonomic fibers and sensory fibers that are responsible for pain, temperature and light touch, and small unmyelinated axons which are sensory too, and responsible for pain and temperature [33]. Bortezomib-induced vibration and proprioception disorders reflect large myelinated axon affection, and BIPN manifestations such as neuropathic pain, burning, lightning-like or lancing pain, aching or allodynia are associated with small axon damage [34,35]. The predominant symptoms of our patients were numbness and neuropathic pain, followed by burning, tingling and paresthesias (resembling crawling insects). BIPN is a time-dependent symmetric neuropathy with a stocking–glove pattern, with the lower extremities first affected [36]. Our finding that neuropathic pain was the initial reported symptom could be attributed to the fact that bortezomib causes primarily small axon damage. Statistical analysis of our data did not confirm any association among PN and age or previous neurotoxic therapies such as thalidomide and vincristine, as predisposing factors. Twenty-three percent of our patients developed gait disorders and motor symptoms such as weakness and loss of balance, findings that were attributed mainly to sensory tract impairment, while one patient presented with pure motor neuropathy. The observed BIPN in our study had a sub-acute onset, as the majority of patients presented with symptoms between the second and fourth cycles of therapy; this finding is in accordance with previous studies [37–39]. The relatively sudden development of BIPN clinical symptoms could reflect the acuteness of toxicity of this specific regimen in contrast to other chemotherapeutics with insidious onset such as thalidomide, which induces a slowly progressive neuropathy starting months after treatment [40]. Axonal type of peripheral neuropathy is characterized by reduced amplitudes of CMAP and SNAP, which represent the algebraic sum of all individual fiber action potentials of a mixed and a sensory nerve, respectively [41]. On this basis,
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our neurophysiological study was performed by measuring CMAP and SNAP of the peroneal nerve and sural nerve, respectively. The main finding in our study was loss of recording motor and sensory amplitudes, which is consistent with axonal damage, while nerve conduction velocities and latencies were normal or slightly reduced. The latter result could be explained by the fact that the myelin sheath remains unaffected [42]. The peroneal and sural nerves were most affected by bortezomib administration compared to other long axon nerves. The tibial nerve study showed normal CMAP, velocity and latency, while the peroneal nerve was affected in 37% of our patients. The majority of patients with peroneal nerve involvement presented with sensory loss, noted over the distribution of the deep and superficial peroneal nerve. Of note was a patient who presented with pure motor neuropathy attributed to peroneal nerve damage consisting of weakness of the dorsiflexors resulting in foot drop and a steppage gait. Moreover, patients with sural nerve affection complained of abnormal sensations to the lateral calf and foot. Neurophysiological examination also disclosed a number of patients (22%) with subclinical PN developing laboratory disorders, while clinical examination of the same patients revealed no symptoms or signs of PN. On the other hand, there were patients with severe subjective complaints in whom neurophysiological evaluation did not detect respective abnormalities. In the present study, a subset of patients were followed up with TNSr sequential evaluations, in order to better evaluate BIPN evolution after symptomatic treatment and bortezomib discontinuation. Despite the fact that BIPN is generally considered reversible [43,44], in our study 10 patients with sequential TNS evaluation presented with persistent abnormal values, while neurophysiological abnormalities remained 12 months after bortezomib discontinuation. In accordance with our study, Chen et al. reported that recovery from pain and other sensory neuropathic symptoms required up to 2 years after bortezomib discontinuation [45]. We would suggest TNSr neurological assessment to continue until complete PN reversal or best improvement, certified at least twice over 12 months. Indeed such a schedule is often impossible in the context of myeloma because of eventual disease relapse and subsequent new antimyeloma drug administration. Damage to peripheral axons causes a number of chemical changes in nerve cell bodies which contribute to axonal regeneration. Regeneration is a process lasting for a long period of months or sometimes years, while return in function is frequently incomplete. For this reason, supportive strategies to face disability are necessary. Since there is no prophylactic treatment against BIPN, regular neurological, clinical and laboratory evaluation and dose modification or therapy discontinuation, if required, are initial tools in order to avoid additional morbidity and schedule appropriate treatment at the time of eventual relapse. Recently, optimized bortezomib use leading to significantly reduced BIPN development was observed with subcutaneous or weekly administration, while response rates were equally satisfying [46–48].
In conclusion, it appears that the concomitant use of clinical and laboratory criteria according to the TNSr system could better recognize, estimate and classify patients with PN [49]. In general, rTNS offers an accurate measurement of a patient’s actual neuropathy without subjectivity, and thus allows appropriate treatment adaptation, including neuroanalgesic drug administration, dose reduction, schedule changes or even discontinuation, according to response status and neuropathy severity.
Acknowledgements We are grateful to Pr. Cornblath and the CI-PeriNomS Group for permitting us to use the Total Neuropathy Score (TNS) and its subtypes, for which John Hopkins University holds the copyright.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2005;64:199–207. [34] Carozzi VA , Canta A , Oggioni N, et al. Neurophysiological and neuropathological characterization of new murine models of chemotherapy-induced chronic peripheral neuropathies. Exp Neurol 2010;226:301–309. [35] Giannoccaro MP, Donadio V, Gomis Pèrez C, et al. Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study. Neurol Sci 2011;32:361–363. [36] Cata JP, Weng HR, Burton AW, et al. Quantitative sensory findings in patients with bortezomib-induced pain. J Pain 2007;8:296–306. [37] Richardson PG, Xie W, Mitsiades C, et al. Single-agent bortezomib in previously untreated multiple myeloma:efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol 2009;27:3518–3525. [38] Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica. 2010;95:311–319. [39] Chaudhry V, Cornblath DR, Polydefkis M, et al. Characteristics of bortezomib- and thalidomide-induced peripheral neuropathy. J Peripher Nerv Syst 2008;13:275–282. [40] Grover JK, Uppal G, Raina V. The adverse effects of thalidomide in relapsed and refractory patients of multiple myeloma. Ann Oncol 2002;13:1636–1640. [41] Huynh W, Kiernan MC. Nerve conduction studies. Aust Fam Physician 2011;40:693–697. [42] Rosenberg NR, Portegies P, de Visser M, et al. Diagnostic investigation of patients with chronic polyneuropathy: evaluation of a clinical guideline. J Neurol Neurosurg Psychiatry 2001;71:205–209. [43] Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 2006;24:3113–3120. [44] Dimopoulos MA , Mateos MV, Richardson PG, et al. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. Eur J Haematol 2011;86:23–31. [45] Chen CI, Kouroukis CT, White D, et al. Bortezomib is active in patients with untreated or relapsed Waldenstrom’s macroglobulinemia: a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1570–1575. [46] Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011;12:431–400. [47] Mateos MV. Subcutaneous bortezomib: a step towards optimised drug use. Lancet Oncol 2011;12:410–411. [48] Bringhen S, Larocca A , Rossi D, et al. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 2010; 116:4745–4753. [49] Velasco R, Petit J, Clapés V, et al. Neurological monitoring reduces the incidence of bortezomib-induced peripheral neuropathy in multiple myeloma patients. J Peripheral Nerv Syst 2010;15:17–25.
ORIGINAL ARTICLE: CLINICAL
Assessment of bortezomib induced peripheral neuropathy in multiple myeloma by the reduced Total Neuropathy Score
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Chrysothea K. Zaroulis1,2, Konstantinos Chairopoulos2, Sotirios P. Sachanas3, Dimitris Maltezas1, Tatiana Tzenou1, Ilias Pessach1, Efstathios Koulieris1, Eleni Koutra4, Konstantinos Kilindireas5, Gerasimos A. Pangalis3 & Marie-Christine Kyrtsonis1 1Hematology Section, First Department of Propedeutic Internal Medicine, Laikon University Hospital, Athens, Greece, 2Department of Neurology, 417 General Military Hospital, Athens, Greece, 3Department of Hematology, Athens Medical Center,
Psychikon Branch, Athens, Greece, 4Department of Neurology, Evangelismos Hospital, Athens, Greece and 5Department of Neurology, National and Kapodistrian University of Athens, Eginition Hospital, Athens, Greece
Bortezomib treatment of patients with MM results in high response rates. However, one of the most severe side effects is PN, which is reported to be moderate while reversible after dose reduction or discontinuation of the drug. Its early recognition is important for effective management [6,7]. However, its accurate assessment is not easy because of patient and treating physician subjectivity. Although it is important to avoid disabling neurological sequelae and cumulative PN with retreatment or subsequent therapies, it is also equally important to offer patients this valuable treatment modality in a safe way. The purpose of the present study was to evaluate the neurological characteristics of bortezomib induced peripheral neuropathy (BIPN) using the Total Neuropathy Score reduced version (TNSr), in an attempt to report as objectively as possible the type, grade, duration and reversibility of neuropathy [8,9]. The TNSr was developed for accurate grading of PN. It is a composite measure as it includes clinical and neurophysiological examination, such as sensory and motor function, as well as pin and vibration sensibility, strength, deep tendon reflexes and sural (sensory nerve) and common peroneal (motor nerve) conduction velocities. Furthermore, it seems to have a greater sensitivity than the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) [10,11]. We also attempted to investigate possible PN risk factors such as age, previous neurotoxic therapies and laboratory parameters, as well as determine the best way to manage it [12,13].
Abstract We evaluated bortezomib induced peripheral neuropathy (BIPN) characteristics in an attempt to better clarify the type, grade, duration and reversibility of neuropathy as well as investigate possible peripheral neuropathy (PN) risk factors and detect the best way to manage it. We calculated the grading of neuropathy using the Total Neuropathy Score reduced version (TNSr) in a series of 51 patients with relapsed/refractory multiple myeloma treated with bortezomib. Seventy percent developed clinical PN. BIPN, although manageable, is frequently underestimated in patients treated with bortezomib intravenously. Continuous follow-up and management of PN are needed to avoid quality of life impairment. Keywords: Drug induced peripheral neuropathy, multiple myeloma, bortezomib
Introduction Paraprotein related peripheral neuropathy (PN) is frequently associated with treatment administration. Vincristine, thalidomide and more recently bortezomib are common neurotoxic agents inducing PN [1–3]. Bortezomib, a synthetic, boronic acid dipeptide (N-pyrazinecarbonyl-l-phenylalanine-l-leucine boronic acid), trade name Velcade, is a selective, reversible proteasome inhibitor and is extremely active in patients with multiple myeloma (MM). It reduces drug resistance in myeloma cells and also modulates the secretion by bone marrow stroma cells of cytokines that mediate the growth, survival and migration of myeloma cells [4]. Bortezomib blocks nuclear factor-κB (NF-κB) with multiple effects on MM cells and other molecules, such as neurotrophins in neurons [5].
Patients and methods Patients’ characteristics We studied 51 patients with ΜΜ classified into three categories: (1) 16 patients without prior exposure to neurotoxic
Correspondence: Chrysothea K. Zaroulis, Hematology Section, First Department of Propedeutic Internal Medicine, Laikon University Hospital, Athens, Greece. E-mail: [email protected] Received 17 July 2013; revised 24 November 2013; accepted 1 December 2013
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chemotherapeutic agents (vincristine, thalidomide, cisplatin), (2) 35 patients with previous neurotoxic therapies before bortezomib and (3) 10 patients sequentially evaluated with the TNSr after bortezomib administration at different time points. Patients with comorbidities predisposing to peripheral neuropathy such as diabetes, metabolic syndromes or other malignancies were excluded from the study. There were 26 men and 25 women. The patients’ median age was 66 years (45–80 years). Myeloma type was immunoglobulin G (IgG) in 65%, IgA in 17%, IgD in 5% and light chain in 13%. Thirteen percent, 54% and 33% had Durie–Salmon stage I, II and III disease, respectively, while International Staging System (ISS) groups 1, 2 and 3 included 29%, 27% and 44% of the patients, respectively. All were at relapse or refractory to prior treatment. They received bortezomib intravenously on days 1, 4, 8 and 11 every 21 days, at an initial dose of 1.3 mg/m2 for a median of four cycles. Dexamethasone, 20 mg, was also administered on days 2, 5, 9 and 12 [14].
presented with neuropathy of grade 1, TNSr 9–16 of grade 2, TNSr 17–24 of grade 3 and TNSr 24–32 of grade 4. Neurophysiological studies comprised two peripheral nerve calculations: the compound muscle action potential amplitude of the peroneal nerve (CMAP) and the sensory nerve action potential amplitude of the sural nerve (SNAP). Normal values of SNAP and CMAP were considered as ⱖ 7 μV and ⱖ 3 mV, respectively. Motor and sensory nerve conduction studies were performed using standardized equipment and techniques. The study was approved by the local ethical committee and patients’ approval was obtained.
Statistical methods Statistical analysis was performed using the statistical software SPSS version 15.0. Univariate p-values were calculated using the χ2 test.
Results Clinical evaluation
Methods Patients’ files were reviewed, and neuropathy evaluation by the treating hematologist reported all neurological complaints. Neurologic assessment consisted of (a) a questionnaire regarding symptoms, thermoregulatory and functional disorders and (b) clinical and neurophysiological examination which was performed by a consulting neurologist using bedside clinical examination. Neurologic examination included mental and mood evaluation, gait examination, motor evaluation, testing of cranial nerves, tactile sensation and pain perception, evaluation of thermal sense, as well as of vibratory sense, proprioceptive sense, stereognosis and two-point discrimination sense. Deep tendon reflexes were evaluated by patellar, Achilles and plantar reflexes. Motor evaluation was performed using the Medical Research Council (MRC) sum score for muscle strength, with which motor muscle strength is measured in six muscle groups at the right side of the body and in six muscle groups at the left side of the body. In the upper extremities we evaluated shoulder abduction, elbow flexion and wrist extension, while in the lower extremities evaluation concerned hip flexion, knee extension and ankle dorsiflexion with a 0–5 range per group (0 ⫽ no movement, 5 ⫽ normal strength). The MRC sum score can range from 0 to an optimal total sum score of 60 [15]. We used an arbitrary cut-off score of 48 [16]. Vibration sensibility was measured with a 128 Hz tuning fork in fingers, wrists and elbows in the upper extremities, while in the lower extremities it was measured in toes, ankles and knees [17]. Neuropathy was graded using the TNS, which ranged from 0 to 32 points (TNSr). TNSr evaluation included sensory and motor symptoms, pin and vibration sensibility, strength evaluation, tendon reflex examination, and sural and peroneal amplitude evaluation (eight parameters). Quantitative sensory tests and autonomic symptoms were excluded. Evidence of neuropathy was considered when the score was equal to or greater than 2. Patients with TNSr 2–8
Twelve patients developed gait abnormalities, including sensory ataxic gait in eight patients and parkinsonian and foot-drop gait in three and one, respectively. Tactile sensation was abnormal in 19 patients while pain perception and thermal sensation were abnormal in 19 and nine patients, respectively. Loss of sense at the lower limbs was developed in eight patients while two patients presented with loss of sense at both upper and lower limbs. Moreover, impaired sense at the lower limbs was observed in 16 patients while three patients disclosed impaired sense at both extremities. Four patients presented with loss of proprioceptive sense at the lower limbs while two were found to have loss of proprioceptive sense at both upper and lower limbs. Further, three patients developed stereognosis disorder and three two-point discrimination abnormality. Finally, deep tendon reflex evaluation revealed that 30, 10 and 10 patients disclosed loss of Achilles, patellar and both Achilles and patellar reflexes, respectively, while plantar reflex was noted in six patients (Table I). Results of the overall TNSr per patient are shown in Figure I.
Quantitative assessment of PN The incidence of PN grade 0, 1, 2, 3 and 4 was 9.8%, 25.5%, 60.7%, 4% and 0%, respectively (Table II). The majority of patients developed grade 2 PN (TNS 9–16), as well as admixed sensory and motor symptoms, meaning sensory alteration or weakness interfering with activities of daily living and symptoms of gait disorders. Median time to PN onset of any grade was 60 days (range 4–126 days), while the majority of patients developed PN within the first three cycles after bortezomib initiation regardless of previous neurotoxic treatment.
Qualitative assessement of PN The predominant sensory PN symptoms were numbness (37%) and neuropathic pain (27%), whereas burning (8%), tingling (4%) and paresthesias (2%) were less common (Table III). Symptoms were developed in the toes, soles and
TNSr evaluation of BIPN in MM 2279 Table I. Results of neurological evaluation.
Gait Sensory ataxic Steppage (foot-drop gait) Parkinsonian and aging gait (marche à petit pas) Cranial nerves Abnormal Tactile sensation Abnormal Pain perception Abnormal Thermal sensation Abnormal Vibratory sense Loss of sense in lower limbs Below knees Below malleolus Hallux Loss of sense in both upper and lower limbs Impaired sense in lower limbs Below knees Below malleolus Hallux Impaired sense in both upper and lower limbs Proprioceptive sense Loss in lower limbs Loss in both upper and lower limbs Stereognosis Loss of sense Two point discrimination Loss of sense Reflexes Loss of Achilles Impaired Achilles Loss of patellar Impaired patellar Loss of both Achilles and patellar Impaired both Achilles and patellar Plantar (Babinski reflex)
%
8 1 3
16 2 6
0
0
19
37
19
37
9
17
8 1 3 4 2 16 1 7 8 3
16 2 6 8 4 31 2 14 16 6
4 2
8 4
3
6
3
6
30 6 10 16 10 11 6
59 12 20 31 20 21 12
20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
TNSr
Grade
0–1 2–8 9–16 17–24 25–32
0 1 2 3 4
No. of patients 5 13 31 2 0
% 9.8 25.5 60.7 4 0
TNSr, Total Neuropathy Score (reduced).
grade PN usually reported that the painful area expanded on their palms and wrists or above their ankles and below the knees. One patient complained of a specific torturous sensation resembling insects walking along his lower limbs. Notably, the main symptoms were reported in glabrous skin. PN onset was mostly sudden. In the majority of patients BIPN symptoms were gradually recovered after a median period of 2 months from their initiation, providing that there was either dose reduction or even drug cessation. In our study bortezomib dose reduction was needed in 30% of patients and 40% of them discontinued treatment because of PN, mostly during the fourth cycle. Twenty-four percent of patients presented gait disorders that consisted of unsteady, tentative, antalgic, uncoordinated walking due to their sensory deficit-related distal weakness or other neurological reasons (Table I). Weakness was evaluated with the MRC sum score (Table IV). The majority of patients (82%) presented with optimal muscle strength score, 14% with mild weakness, mainly in the lower extremities with no impact on their quality of life, and 2% with moderate muscular impairment; one patient (2%) presented with severe muscular deficit. There was a need for this patient to use walking sticks because of the severity of his weakness, and this inevitably had a dismal impact on his daily activity.
Neurophysiological findings Distal axonopathy was the most common form of BIPN. Thirty-eight patients (74.5%) presented with PN. The
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51
fingertips, with stocking and glove distribution. Suppression of ankle jerks was observed primarily. Symptoms were noted more often in feet compared to the same symptoms in the upper limbs in a time-dependent way. Pain was described as intense, with sharp characteristics, like cold or electric shocks, more annoying during the night. Patients with high
TNS reduced
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Parameter
Table II. Grade of neuropathy according to TNSr. No. of patients
Patients Figure 1. Total Neuropathy Score reduced version (TNSr) evaluation per patient.
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Table III. Sensory symptoms. Symptom
Table V. Neurophysiological findings. No. of patients
%
Type of neuropathy
19 14 4 2 1 11
37 27 8 4 2 22
SA SMA MA Sural nerve (SNAP) Normal Abnormal Absent Peroneal nerve (CMAP) Normal Abnormal Absent
nerve conduction study evaluation (Table V) showed a predominantly sensory axonal polyneuropathy (55%), followed by sensory motor of axonal type and pure motor axonal BIPN in 42% and 3% of patients, respectively. Because the myelin sheath was not affected, nerve conduction studies showed normal or a slight reduction in velocities and normal latencies. In 55% of the patients, sural nerve action potentials were not recorded, while they were reduced in 16% (Table V). As far as the peroneal nerve was concerned, abnormal CMAP findings in the extensor digitorum brevis were found: CMAP was reduced in 35% while in 2% was not recorded (Table V). In the majority of patients there was a concordance between patients’ symptoms and neurophysiological findings. However, in 20% of patients BIPN was detected by neurophysiological evaluation despite the absence of clinical symptoms and/or signs of PN. Moreover, neurological examination including both clinical and laboratory criteria revealed that there was an overestimation of PN by the physician in 16% of patients.
Neurophysiological BIPN follow-up TNSr sequential evaluation TNSr sequential assessment was performed in 10 patients. TNSr was assessed before bortezomib initiation and 6 months and 12 months after bortezomib administration. This analysis disclosed that eight patients presented with pre-existing PN of grade 1 before bortezomib administration (time point 1). All patients had a significantly increased TNSr score (maximum value 20) 6 months after bortezomib administration (time point 2), while 12 months later TNSr values were slightly reduced, but they were not normalized in any patient (Figure 2).
%
21 16 1
55 42 3
15 8 28
29 16 55
32 18 1
63 35 2
SA, sensory axonal; SMA, sensory motor axonal; MA, motor axonal; SNAP, sensory nerve action potential; CMAP, compound muscle action potential.
patients 12 months after bortezomib administration, while the remainder had normalized values (Figure 3).
CMAP sequential evaluation Fourteen patients underwent sequential CMAP evaluation of the peroneal nerve at three time points (0, 6, 12 months after bortezomib initiation, respectively). Analysis of this sequential evaluation revealed that all patients presented with normal CMAP values (ⱖ 3 mV) before treatment initiation, while the majority of them developed the lowest values 6 months after bortezomib initiation. Only three patients had low CMAP values 12 months after bortezomib administration (Figure 4).
Neuropathy risk factors PN incidence was not associated with age, sex, paraprotein level, renal function, hemoglobin levels, prior neurotoxic therapies or number of previous lines.
BIPN treatment BIPN treatment was symptomatic, including drugs for neuropathic pain relief such as analgesics, antidepressants, antiepileptic agents and vitamins. As soon as PN symptoms presented, gabapentin was used at doses ranging from 900 to 1800 mg maximum daily dose, as well as pregabalin that showed efficacy at a daily
25
SNAP sequential evaluation Fourteen patients underwent sequential SNAP evaluation of the sural nerve at three time points (0, 6, 12 months after bortezomib initiation, respectively). The majority of them presented with absent or reduced SNAP 6 months after bortezomib initiation, and none of them had a SNAP value ⬎ 11 μV at this time point. Low SNAP values remained in two
No. of patients
20 15 TNS
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Numbness Pain Burning Tingling Paresthesias No symptoms
10 5
Table IV. Muscle strength evaluation. MRC sum score 49–60 37–48 25–36 13–24 0–12 MRC, Medical Research Council.
No. of patients
%
42 7 2 0 0
82 14 4 0 0
0 point 1
point 2
point 3
Figure 2. TNS sequential evaluation. TNS sequential assessment was performed in 14 patients. TNS was assessed before bortezomib initiation (point 1) and at a period of 6 months (point 2) and 12 months (point 3) after bortezomib administration.
TNSr evaluation of BIPN in MM 2281
S N A P
35 30 25 20 15 10 5 0
point 1
point 2
point 3
dose administration ranging from 150 to 450 mg maximum. The most commonly used antidepressants were serotonin reuptake inhibitors and duloxetine [18,19]. The latter showed efficacy at doses ranging from 60 to 120 mg daily, resulting in sensory symptom improvement and mood stabilization. Further, patients with severe neuropathic pain received an opioid-type analgesic such as fentanyl, while six patients with severe pain were placed on intravenous polyclonal immunoglobulins.
Discussion MM in the vast majority of patients is an incurable disease, with a median survival of 3–5 years [20]. The introduction of new drugs such as the proteasome inhibitor bortezomib has considerably increased response rates as well as patient survival [21]. However, BIPN occurs frequently. Thus, monitoring, early recognition and effective management of PN is important, in order for patients with MM to benefit from this therapy and maintain their quality of life [22–24]. Bortezomib administration affects peripheral nerves and dorsal root ganglia (DRG) neurons, through proteasome inhibition. Possible mechanisms are chromatolysis of DRG neurons and cytoplasmic accumulation of eosinophilic material, as well as neuronal mitochondrial damage, dysregulation of Ca2⫹ homeostasis and reduced neurotrophin levels [25–28]. In addition, bortezomib blocks the transcription of nerve growth factor, causing impaired trophic support and
CMAP
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Figure 3. SNAP sequential evaluation. Fourteen patients underwent sequential SNAP evaluation of sural nerve at three time points: 0, 6, 12 months (point 1, 2, 3) after bortezomib initiation respectively.
18 16 14 12 10 8 6 4 2 0 point 1
point 2
point 3
Figure 4. Compound muscle action potential (CMAP) sequential evaluation. Fourteen patients underwent sequential CMAP evaluation of the peroneal nerve at three time points: 0, 6, 12 months (points 1, 2, 3) after bortezomib initiation, respectively.
regeneration of neurons, which leads to peripheral atrophy [29,30]. The peripheral nervous system seems to be more vulnerable to toxic agents compared to the central nervous system because it does not have the capability of autoregulation, and the peripheral blood–nerve barrier is less efficient than the brain–blood barrier [31]. The aforementioned factors allow easier access of potential neurotoxins into the peripheral nervous system. Furthermore, DRG lack an efficient vascular barrier, making the cell body a target for drugs. Endothelial cells in the epineurium are fenestrated, and allow escape of blood proteins into the extracellular space, while endoneural nerves have no lymphatic system to remove toxins. Peripheral nerves have nothing analogous to the sink action of cerebrospinal fluid [32]. This absence of a vascular barrier may play an essential role in BIPN development, by allowing the exposure of peripheral nerves and cell bodies to bortezomib directly from plasma. Nerves are composed of different types of axons with different morphology and function, such as large myelinated axons, including motor axons and sensory axons responsible for vibration, proprioception and light touch, as well as small myelinated axons, including autonomic fibers and sensory fibers that are responsible for pain, temperature and light touch, and small unmyelinated axons which are sensory too, and responsible for pain and temperature [33]. Bortezomib-induced vibration and proprioception disorders reflect large myelinated axon affection, and BIPN manifestations such as neuropathic pain, burning, lightning-like or lancing pain, aching or allodynia are associated with small axon damage [34,35]. The predominant symptoms of our patients were numbness and neuropathic pain, followed by burning, tingling and paresthesias (resembling crawling insects). BIPN is a time-dependent symmetric neuropathy with a stocking–glove pattern, with the lower extremities first affected [36]. Our finding that neuropathic pain was the initial reported symptom could be attributed to the fact that bortezomib causes primarily small axon damage. Statistical analysis of our data did not confirm any association among PN and age or previous neurotoxic therapies such as thalidomide and vincristine, as predisposing factors. Twenty-three percent of our patients developed gait disorders and motor symptoms such as weakness and loss of balance, findings that were attributed mainly to sensory tract impairment, while one patient presented with pure motor neuropathy. The observed BIPN in our study had a sub-acute onset, as the majority of patients presented with symptoms between the second and fourth cycles of therapy; this finding is in accordance with previous studies [37–39]. The relatively sudden development of BIPN clinical symptoms could reflect the acuteness of toxicity of this specific regimen in contrast to other chemotherapeutics with insidious onset such as thalidomide, which induces a slowly progressive neuropathy starting months after treatment [40]. Axonal type of peripheral neuropathy is characterized by reduced amplitudes of CMAP and SNAP, which represent the algebraic sum of all individual fiber action potentials of a mixed and a sensory nerve, respectively [41]. On this basis,
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our neurophysiological study was performed by measuring CMAP and SNAP of the peroneal nerve and sural nerve, respectively. The main finding in our study was loss of recording motor and sensory amplitudes, which is consistent with axonal damage, while nerve conduction velocities and latencies were normal or slightly reduced. The latter result could be explained by the fact that the myelin sheath remains unaffected [42]. The peroneal and sural nerves were most affected by bortezomib administration compared to other long axon nerves. The tibial nerve study showed normal CMAP, velocity and latency, while the peroneal nerve was affected in 37% of our patients. The majority of patients with peroneal nerve involvement presented with sensory loss, noted over the distribution of the deep and superficial peroneal nerve. Of note was a patient who presented with pure motor neuropathy attributed to peroneal nerve damage consisting of weakness of the dorsiflexors resulting in foot drop and a steppage gait. Moreover, patients with sural nerve affection complained of abnormal sensations to the lateral calf and foot. Neurophysiological examination also disclosed a number of patients (22%) with subclinical PN developing laboratory disorders, while clinical examination of the same patients revealed no symptoms or signs of PN. On the other hand, there were patients with severe subjective complaints in whom neurophysiological evaluation did not detect respective abnormalities. In the present study, a subset of patients were followed up with TNSr sequential evaluations, in order to better evaluate BIPN evolution after symptomatic treatment and bortezomib discontinuation. Despite the fact that BIPN is generally considered reversible [43,44], in our study 10 patients with sequential TNS evaluation presented with persistent abnormal values, while neurophysiological abnormalities remained 12 months after bortezomib discontinuation. In accordance with our study, Chen et al. reported that recovery from pain and other sensory neuropathic symptoms required up to 2 years after bortezomib discontinuation [45]. We would suggest TNSr neurological assessment to continue until complete PN reversal or best improvement, certified at least twice over 12 months. Indeed such a schedule is often impossible in the context of myeloma because of eventual disease relapse and subsequent new antimyeloma drug administration. Damage to peripheral axons causes a number of chemical changes in nerve cell bodies which contribute to axonal regeneration. Regeneration is a process lasting for a long period of months or sometimes years, while return in function is frequently incomplete. For this reason, supportive strategies to face disability are necessary. Since there is no prophylactic treatment against BIPN, regular neurological, clinical and laboratory evaluation and dose modification or therapy discontinuation, if required, are initial tools in order to avoid additional morbidity and schedule appropriate treatment at the time of eventual relapse. Recently, optimized bortezomib use leading to significantly reduced BIPN development was observed with subcutaneous or weekly administration, while response rates were equally satisfying [46–48].
In conclusion, it appears that the concomitant use of clinical and laboratory criteria according to the TNSr system could better recognize, estimate and classify patients with PN [49]. In general, rTNS offers an accurate measurement of a patient’s actual neuropathy without subjectivity, and thus allows appropriate treatment adaptation, including neuroanalgesic drug administration, dose reduction, schedule changes or even discontinuation, according to response status and neuropathy severity.
Acknowledgements We are grateful to Pr. Cornblath and the CI-PeriNomS Group for permitting us to use the Total Neuropathy Score (TNS) and its subtypes, for which John Hopkins University holds the copyright.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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