General Aspects and Mechanisms of Peripheral Neuropathy Associated With Bortezomib in Patients With Newly Diagnosed Multiple Myeloma

General Aspects and Mechanisms of Peripheral Neuropathy Associated With Bortezomib in Patients With Newly Diagnosed Multiple Myeloma Annemiek Broyl, Joost L.M. Jongen, and Pieter Sonneveld Introduction of the proteasome inhibitor bortezomib (Velcade, Millennium Pharmaceuticals, The Takeda Oncology Company, Cambridge, MA) has substantially improved outcomes for patients with multiple myeloma (MM), and has become one of the cornerstones of current anti-myeloma treatment regimens. However, with the introduction of bortezomib it has become clear that peripheral neuropathy (PN) is one of the most frequent, potentially disabling, nonhematologic complications of bortezomib, often requiring dose modification or discontinuation, with a potential negative impact on clinical endpoints and quality of life. To find a balance between maximal benefit of bortezomib treatment, while maintaining quality of life, it is necessary to minimize toxicity. Here, we discuss all aspects of bortezomib-induced peripheral neuropathy (BiPN), and elaborate on the mechanisms underlying the development of BiPN. Semin Hematol 49:249 –257. © 2012 Elsevier Inc. All rights reserved.

M

ultiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow, the presence of a monoclonal protein in serum and/or urine, and the presence of related organ or tissue impairment. More than a decade ago, the treatment of MM patients under 65 years of age consisted of chemotherapy in combination with corticosteroids, followed by high-dose melphalan and autologous stem cell transplantation. Patients ineligible for autologous stem cell transplantation received treatment with melphalan and prednisone. Since the introduction of novel agents, such as thalidomide and bortezomib, complete response rates, progression-free survival, and overall survival have substantially improved. However, with these novel agents different adverse events were reported. From the time thalidomide and bortezomib entered clinical trials, a strikingly high percentage of patients were reported to develop polyneuropathy.

Erasmus MC, Rotterdam, The Netherlands. Conflicts of interest: A.B. declares no conflicts of interest; J.L.M.J. received personal compensation from Pfizer; P.S. has served on advisory boards for Johnson & Johnson and Millennium Pharmaceuticals. Address correspondence to Annemiek Broyl, MD, Department of Hematology, Erasmus MC, ’s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. E-mail: [email protected] 0037-1963/$ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminhematol.2012.04.001

Seminars in Hematology, Vol 49, No 3, July 2012, pp 249 –257

CLINICAL PRESENTATION Peripheral neuropathy (PN) is defined as any form of damage, inflammation, or degeneration of peripheral nerves, implying that it is not limited to sensory nerve damage. Patients can also present with symptoms or signs of motor or autonomic nervous system damage, or both, although sensory neuropathy and neuropathic pain are the dominant features of bortezomib-induced peripheral neuropathy (BiPN). Sensory neuropathy includes characteristic symptoms such as hyperesthesia, hypoesthesia, and paresthesias (tingling), usually in a distal stocking-and-glove distribution over the hands and feet. Neuropathic pain, which can be a sharp pain or burning sensation, may occur at rest, is usually localized in the soles of the feet, but occasionally also presents in the fingers and the palmar sides of the hands. It is mainly caused by small fiber damage and is associated with altered heat and cold sensation.1 Additionally, sensory BiPN can result in areflexia and loss of proprioception, placing patients at risk for injury through ataxia and gait disturbance.2 Motor symptoms are rare and, if present, they mostly occur in the context of severe sensory peripheral neuropathy. Symptoms include muscle cramps, muscle atrophy, or loss of strength in distal muscles. Autonomic symptoms, such as orthostatic hypotension, bradycardia, and constipation can occasionally occur and are induced by damage to small fibers.3,4 To illustrate BiPN, the differences with thalidomide-induced neuropathy are depicted in Table 1. This issue of Semi249

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Table 1. Presenting Symptoms of Thalidomide-Induced Peripheral Neuropathy and Bortezomib-In-

duced Peripheral Neuropathy Peripheral Neural Tract Involved Sensory

Motor Autonomic

Presenting Symptoms Hypoesthesia; paresthesia: numbness, tingling, pin-prick sensation; hyperesthesia Ataxia; gait disturbance Neuropathic pain Weakness Muscle cramps; fasciculations Gastrointestinal Others

Thalidomide

Bortezomib

Common

Common

Rare Rare Rare Common Constipation Impotence; bradycardia

Rare Common Rare Rare Constipation Orthostatic hypotension

Sonneveld P, Jongen JL. Dealing with neuropathy in plasma-cell dyscrasias. Hematology Am Soc Hematol Educ Program. 2010;2010:423–30.

nars in Hematology concerns different aspects in treatment with bortezomib; thalidomide will not be further discussed here.

INCIDENCE OF BiPN BiPN has been well documented from the time of the initial clinical introduction of bortezomib in (heavily) pretreated relapsed/refractory MM patients included in phase II (SUMMIT [Study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy] and CREST [Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma]) and phase III (APEX [Assessment of Proteasome Inhibition for Extending Remissions]) trials.5⫺7 A total of 587 patients in these trials receiving standard doses of bortezomib were assessed for PN. By contrast with the phase II studies, where 22 of 256 (9%) patients had National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 PN at baseline, patients with grade 2 or higher PN at baseline were excluded in the APEX trial. BiPN grades 1– 4 occurred in 84 of 228 (37%) and 124 of 331 (37%) patients receiving bortezomib 1.3 mg/m2, and in six of 28 (21%) patients receiving bortezomib 1.0 mg/m2, with grade 3 in 9%–13%, and grade 4 in less than 1% of patients (Table 2).8,9 In the Intergroupe Francophone du Myélome (IFM) trial for newly diagnosed patients treated with bortezomib in the induction regimen followed by autologous stem cell transplantation, BiPN occurred in 47% of patients, with up to 16% being grade 3 or 4.10 In the HOVON 65/GMMG-HD4 trial including newly diagnosed transplant candidates, in which bortezomib was given as induction treatment as well as during maintenance, BiPN was observed in 37% of patients during induction treatment, with 24% concerning grade 3– 4 BiPN.11

In elderly patients, bortezomib in combination with melphalan and prednisone (VMP) was associated with 13% grade 3– 4 and 44% overall BiPN.12 Interestingly, when bortezomib was combined with other potentially neurotoxic agents, such as thalidomide, this did not further increase the rate of treatment-induced PN. PN grade 3– 4 occurred in 23 of 236 (10%) newly diagnosed MM patients treated with bortezomib, thalidomide, and dexamethasone (VTD).13 In 14% of relapsed/refractory MM patients treated with bortezomib, Lenalidomide, and dexamethasone (VRD), grade 3 BiPN was observed.14 Grade 3– 4 sensory neuropathy was reported in 8% of untreated MM patients ineligible for autologous stem cell transplantation receiving VMPT-VT and in 5% of patients receiving VMP; neuralgia was reported in 4% of patients receiving VMPT-VT and 3% of patients receiving VMP.15

RISK FACTORS FOR BiPN Baseline PN is present in 10%–37% of patients with myeloma. This can be attributed to comorbidity (eg, diabetes mellitus [DM]), previous neurotoxic treatment, or MM-related PN.16⫺19 It is of major importance to identify predisposing factors for treatment induced PN. Baseline PN and comorbidities such as the presence of DM, alcohol abuse, vitamin deficiencies, and viral infections at baseline condition may elicit or aggravate symptomatic PN. Several studies addressed the question as to which predisposing factors could affect development of BiPN; however, conflicting results have been reported. In the APEX trial, age, number and/or type of prior therapies, baseline glycosylated hemoglobin level, or DM history did not increase BiPN incidence and severity.9 Another study found that the risk of bortezomib-related PN was greater in patients who had PN and DM at baseline.16 In the VISTA trial

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Table 2. Incidence of Bortezomib-Induced Peripheral Neuropathy

Trial SUMMIT, CREST APEX IFM 2005–01 HOVON65/ GMMG-HD4 VISTA M. Cavo M. Dimopoulos A. Palumbo

Schedule

All BiPN (%)

BiPN Grade 3–4 (%)

References

13 8 v ⬍1 7v2 24 vs 10

5,6,8 7,9 48 11

Bortezomib Bor v Dex Bor/Dex v VAD PAD v VAD

256 331 v 336 239 v 239 373 v 371

35 37 v 9 46 v 28 37 v 26

VMP v MP VTD v VD VRD v RD VMPT-VT v VMP

340 236 49 250

44 v 5 34 v 14

v v v v

337 238 50 253

NR

13 v 0 10 v 2 14 v NR* 8v5

12 13 14 15

Abbreviations: NR, not reported; dex, dexamethasone; bor, bortezomib; VAD, vincristine/doxorubicin/dexamethasone; PAD, bortezomib/doxorubicin/dexamethasone; VMP, bortezomib/melphalan/prednisone; MP, melphalan/prednisone; VTD, bortezomib/thalidomide/dexamethasone; VD, bortezomib/dexamethasone; VRD bortezomib/lenalidomide/dexamethasone; RD, lenalidomide/dexamethasone; VMPT-VT, bortezomib/melphalan/prednisone/thalidomide- bortezomib/thalidomide. *Patients with previous grade ⱖ2 PN received RD, whereas patients with previous PN grade ⱖ2 received VRD.

(Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone), baseline PN was the only consistent risk factor for any BiPN, for grade ’2 BiPN, and for grade ’3 BiPN.20 In this context, pharmacogenetic studies building on the newest technologies might become helpful for risk stratification of treatment-related neurotoxicity.18,21,22

MECHANISMS OF BiPN Although neurons are post-mitotic cells, they are highly susceptible to the toxic effects of anticancer drugs. The main targets for treatment-emergent neurotoxicity in MM are the neuronal cell bodies within the dorsal root ganglion (DRG) and their axons extending in the extremities (Figure 1). Bortezomib mainly causes direct DRG toxicity, and axonopathy to a lesser extent. Concerning the mechanism of BiPN, a multifactorial pathogenesis seems likely. Mitochondrial and endoplasmic reticulum damage in both Schwann and satellite cells has been observed in sciatic nerve and DRG of rats given bortezomib23; bortezomib is known to induce apoptosis in MM cells through activation of the mitochondrial-based (“intrinsic”) apoptotic pathway.1 Another mechanism by which bortezomib could contribute to PN is dysregulation of mitochondrial calcium homeostasis.24 Disruption of the intracellular calcium homeostasis in nerves can promote depolarization and spontaneous discharge, causing pain and other abnormal sensations.25 Other factors involved in BiPN include autoimmune factors and inflammation,26 and blockade of nerve growth factor–mediated neuronal survival through inhibition of the activation of nuclear factor ␬B (NF␬B).6 In addition, MM itself is associated with peripheral neuropathy. Approximately 54% to 67% of MM patients

show abnormalities on neurophysiological examination at baseline17,18; however, PN is a dominant feature in 10%–37% of patients and mainly concerns a sensory or sensorimotor PN.17⫺19 Furthermore, BiPN was noted at higher frequencies in patients with MM than in those with solid tumors.27 The role of myeloma-related factors in peripheral neuropathy related to treatment is not clear. Richardson and colleagues characterized the possible role of myeloma-related factors in BiPN using baseline gene expression profiles (GEPs) of plasma cells from 25 patients with MM, nine patients with and 16 patients without treatment-emergent PN. The GEPs that distinguish patients with treatment-emergent PN did not involve genes with a clear etiological link to PN development. Although not significant due to the small number of patients, they observed gene profiles involved in protein translation, ribosomal proteins, and cell-surface markers.18 We have addressed the role of both the myeloma plasma cell as well as constitutional genetic variability in BiPN development. GEPs of purified plasma cells obtained from 170 patients at baseline and single nucleotide polymorphisms (SNP) profiles of peripheral blood (PB) from 186 patients, all treated with bortezomib, were determined. Patients who developed BiPN grades 2– 4 or 3– 4 were compared to patients who did not develop BiPN. Although separately analyzed, both GEPs in plasma cells and SNP profiles in PB revealed genes and pathways involved in the etiology of PN. Genes involved in the development and function of the nervous system, SOD2, SNPs in genes involved in dorsal root ganglion neurons, SERPINB2, but also SNPs in DNA repair genes and proinflammatory genes were overrepresented in patients with BiPN.21 This study

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Figure 1. Potential targets for thalidomide-induced and bortezomib-induced peripheral neuropathy. Reprinted from Lancet Oncology, 2011, Delforge M, Blade J, Dimopoulos MA, et al. Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Pages 1086 –95, Copyright 2010, with permission from Elsevier.

emphasized the contribution of both the inherited genetic constitution of the host (patient) and the tumor (myeloma) to the development of BiPN. A pharmacogenomic analysis from the phase III HOVON65/GMMG-HD4 and IFM 2005–1 trials, which compared conventional treatment with bortezomibbased induction regimens, found one significant SNP in het CYP17A1 gen, involved in steroid biosynthesis. Although not significant after multiple testing correction, 56 SNPs were associated with BiPN; pathway analysis of these SNPs showed involvement of neurological disease (21 genes, including NEFL, PON1, PTGS2, and ABCG2).22 Similarly, an independent pharmacogenomic analysis of the VISTA trial identified an association between time to onset of PN and the immune gene CTLA4, and the same association was shown in a confirmatory analysis of data from the IFM trial mentioned above.28 Efforts are under way to investigate whether genomewide screening of single nucleotide polymorphisms can be used to identify patients at risk of developing BiPN.

DIAGNOSIS AND MEASUREMENT OF PN Awareness of BiPN is crucial for early detection and appropriate intervention, especially for a small subset

of patients who may develop severe PN shortly after start of treatment with bortezomib. In daily clinical practice, reliable, uniform, and simple methods for screening and grading of PN are needed. One of the most widely used grading systems for assessing neurotoxicity are the NCI-CTC. Most of the published data concerning BiPN were based on use of either the NCI-CTC version 2.0 or 3.0 criteria,29 or the 11-item functional Assessment of Cancer Therapy Neurotoxicity (Ntx-FACT/GOG) subscale,30 both of which are current standards of neurotoxicity assessment. Other widely used algorithms are the criteria of the Eastern Cooperative Oncology Group,31 Ajani et al,32 and the World Health Organization.33 A disadvantage of all these methods is that they do not include assessment of neuropathic pain, a key sign of BiPN. However, recently an update of the NCI-CTC criteria was released, NCI-CTC version 4.0, which now also includes the grading of neuralgia (Table 3).34 Another limitation in using the above algorithms is that the degree of PN is subjective and dependent on patients’ reporting, thereby resulting in variances in interpreting clinical aspects and poor reliability. Limitations also result from intra- and interobserver variation of scales.35 In addition to symptom assessment, a regular and focused clinical neurological examina-

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Table 3. Definition of Peripheral Neuropathy According to NCI-CTC Criteria Version 4.0

Adverse Event

1

2

3

Peripheral motor neuropathy

Asymptomatic; clinical or diagnostic observations only; intervention not indicated Asymptomatic; loss of deep tendon reflexes or paresthesia

Moderate symptoms; Limiting instrumental ADL Moderate symptoms; limiting instrumental ADL Moderate pain; limiting instrumental ADL

Severe symptoms; limiting self care ADL; assistive device indicated

Peripheral sensory neuropathy

Neuralgia

Mild pain

Severe symptoms; limiting self care ADL

Severe pain; limiting self care ADL

4

5

Life-threatening Death consequences; urgent intervention indicated Life-threatening Death consequences; urgent intervention indicated — —

Abbreviation: ADL, activities of daily living.

tion including the evaluation of sensation (touch, pain, temperature, vibration, proprioception), distal muscle strength, ankle reflexes, and supine versus upright blood pressure is recommended. More complex algorithms such as the Total Neuropathy Score (TNSr), which combines the assessment of symptoms with electrophysiological measurements such as nerve conduction studies (NCS) and needle electromyography, result in higher sensitivity for the detection and specification of neurological damage.36 The value of these electrophysiological measurements to detailed clinical examination for the detection and follow-up of treatment-related PN in MM is still a matter of debate. First, electrophysiological measurements are difficult to apply in routine clinical practice. Second, discrepancies between neurophysiological and clinical results in BiPN are common: sensory neuropathic symptoms may be out of proportion to objectively measurable signs at baseline, as was noted during treatment in three patients who developed symptomatic treatment-emergent small-fiber neuropathy (characterized by burning aching pain, paresthesia, and allodynia) during the study, in whom NCS and quantitative sensory testing showed no change, a phenomenon that is typical of small-fiber involvement.8 The explanation for the discrepancy between NCS and clinical observation is that in BiPN small diameter sensory fibers are preferentially affected and NCS is not very sensitive for detection of damage to these fibers.4,8

MANAGEMENT OF BiPN Currently, there is no curative treatment for BiPN; therefore, prevention is the preferred approach to maintain quality of life and preserve future options for

anti-myeloma treatment. All MM patients should be clinically assessed for signs and symptoms of peripheral neuropathy before initiation of a neurotoxic drug. Patients with pre-existing PN should be monitored closely during initial treatment and prompt dose modification according to guidelines is important to prevent development of more serious neurologic complications and aid reversibility. Careful clinical assessment at each visit, with neurologic examination in case of suspected PN and neurophysiological testing in specific situations, is the best approach for detection and follow-up of drug-induced peripheral neuropathy. This is a multidisciplinary task requiring the awareness of patients, nurses, hemato-oncologists, and neurologists. Dose-modification guidelines for the management of BiPN have been based on experience during the first trials with single-agent bortezomib: the CREST and SUMMIT trials.5,6 In these trials the effect of dose adjustment/discontinuation was well established. Ninety of 256 patients included in the SUMMIT or CREST trials experienced BiPN, of which 35 had BiPN grade 3– 4. In the 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy grade 3– 4 and/or neuropathy requiring discontinuation, resolution to baseline or improvement occurred in 71%. The median duration from the last dose to resolution or improvement of peripheral neuropathy was 47 days (range, 1 to 529 days).8 Guidelines for bortezomib dose modification and/or discontinuation were subsequently validated in the APEX and VISTA trials.9,20 Overall, 124 of 331 (37%) patients included in the APEX trial had treatment-emergent PN, including 30 (9%) with grade ’3 PN; of patients with grade ’2 PN, 58 of 91 (64%) experienced

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Table 4. Definition of Peripheral Neuropathy According to NCI-CTC Criteria Version 3.0

Adverse Event

1

2

3

4

5

Peripheral motor Asymptomatic, Symptomatic weakness Weakness interfering Life-threatening; Death neuropathy weakness on interfering with with ADL; bracing disabling (eg, exam/testing function, but not or assistance to paralysis) only interfering with ADL walk (eg, cane or walker) indicated Sensory alteration or Disabling Death Peripheral Asymptomatic; Sensory alteration or paresthesia sensory loss of deep paresthesia (including tingling), interfering with neuropathy tendon interfering with ADL reflexes or function, but not paresthesia interfering with ADL (including tingling) but not interfering with function

improvement or resolution to baseline at a median of 110 days, including 49 of 72 (68%) who had dose modification versus 9 of 19 (47%) who did not. Survival outcome did not appear adversely affected in patients who had dose modification due to PN.9 In the VISTA trial, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade ’3 (⬍1% grade 4). The BiPN incidence was dose-related and reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m2. Median time to onset of BiPN was 2.3 months. BiPN was reversible; 79% of events improved by at least one NCI-CTC grade within a median of 1.9 months and 60% completely resolved within a median of 5.7 months, with reversibility similar in responding and nonresponding patients.20 More recently, multi-agent studies have shown that, in addition to dose reduction, weekly dosing may prevent the progression of PN and reduce severe PN and did not appear to affect efficacy.37 Weekly bortezomib dosing is therefore considered to be an effective strategy to prevent further worsening of PN once patients have developed BiPN grade 1. Bortezomib dose-modification guidelines have recently been updated and are based on NCI-CTC version 3.0 (Tables 4 and 5).38 For elderly patients, who frequently have additional comorbidities, adjustment in dose and frequency of bortezomib administration is recommended, as shown in Table 6. Once PN has resolved, there is no increased risk for cumulative BiPN upon re-treatment with bortezomibcontaining regimens. Furthermore, a recent published trial randomized 222 relapsed MM patients to subcutaneous (SC) administration (n ⫽ 148) or intravenous (IV) administration

(n ⫽ 74) of bortezomib. Overall response rates after four cycles were identical in both arms, 42%, and after eight cycles, 52%, with complete response rates of 10% (SC) and 12% (IV). After a median follow-up of 11.8 months no significant difference was observed in time to progression (TTP) (median, 10.4 v 9.4 months), in overall survival (1-years overall survival, 72.6% v 76.7%) in SC versus IV bortezomib. More importantly, percentages of BiPN grades 1– 4 (38% v 53%), grade ’2 (24% v 41%), and grade ’3 (6% v 16%) were significantly lower with SC versus IV administration of bortezomib.39 Pharmacological interventions to prevent BiPN have been proposed based on theoretical models, extrapolation from trials of different diseases, and the assumption that they are non-toxic, including vitamin B, antioxidants such as vitamin E, alpha-lipoic acid, glutathione, and supplements with glutamine or acetyl-L-carnitine.2,40 However, there are no prospective randomized studies, and the general use of these compounds to prevent BiPN warrants caution. In fact, the administration of pyridoxine (vitamin B6) can cause additional sensory neuropathy in patients with impaired renal function and in association with a protein-deficient diet.41,42 Vitamin C may interfere with bortezomib metabolism and may also abrogate bortezomib-mediated inhibition of proteasome activity.43,44 Drugs to alleviate bortezomib induced neuropathic pain in MM include gabapentin or pregabalin, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, carbamazepine, and opioid-type analgesics.40 The efficacy of these drugs is mainly based on uncontrolled studies, case reports, personal experience, or, most often, on studies in other indications such as painful diabetic neuropathy and postherpetic

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Table 5. Dose-Modification Guidelines for Bortezomib-Induced Neuropathy

BiPN, NCI CTCAE Score

Bortezomib Dose-Modification Guidelines

Grade 1

If the patient is on a biweekly schedule: reduce current bortezomib dose by one level* or prolong dosing interval to once weekly If the patient is already on a weekly schedule: reduce current bortezomib dose by one level* If the patient is on a biweekly schedule: reduce current bortezomib dose by one level* or prolong dosing interval to once weekly If the patient is already on a weekly schedule: reduce current bortezomib dose by one level* or consider temporary discontinuation of bortezomib. If the neuropathy resolves to grade 1 or better, once-weekly treatment with reduced bortezomib dose may be restarted if the benefit-to-risk ratio is favorable Discontinue bortezomib, if the neuropathy resolves to grade 1 or better, once-weekly treatment with reduced bortezomib dose may be restarted if the benefit-to-risk ratio is favorable Discontinue bortezomib

Grade 1 with neuropathic pain or grade 2

Grade 2 with neuropathic pain or grade 3 Grade 4

NOTE. Summary of Product Characteristics (SPC) guidelines were modified according to expert opinion and clinical practice in reference centres. *Bortezomib dose reductions: standard dose ⫽ 1.3 mg/m2; dose reduced by one level ⫽ 1.0 mg/m2; dose reduced by two levels ⫽ 0.7 mg/m2.

neuralgia but not on studies in BiPN. Local application of lidocaine or menthol-containing analgesic cream can temporarily alleviate bortezomib-induced neuropathic pain,2,45 whereas other compounds, such as capsaicin, can be harmful and should be used with care. Simple emollients such as cocoa butter are non-toxic and might be helpful for symptom relief. Furthermore, patients may be advised to wear loose-fitting clothes and shoes and to keep feet uncovered in bed. Patients with autonomic dysfunction should rise cautiously and avoid demanding physical tasks. Patients suffering from severe PN are disabled in the execution of daily tasks and, in addition to pharmacological intervention, may benefit from physical exercise and physiotherapy.2 The only effective approach in BIPN is to adhere to dose-modification guidelines to prevent treatment-emergent BIPN and allow treatment to continue.

FUTURE PERSPECTIVES BiPN is one of the most frequent but also one of the most feared dose-limiting side effects of bortezomib. Yet, for many patients, the probability of prolonged remission depends on the treatment with bortezomib alone or combined with other (potentially neurotoxic) anti-myeloma agents. Repetitive use of the (potentially neurotoxic) anti-myeloma agents during successive stages of their disease is inevitable. It is therefore of major importance to prevent BiPN in order to allow the treatment to be continued and completed. The prevention of severe BiPN by close monitoring, use of uniform, simple, and clear scales for screening and grading of PN, such as the NCI-CTC or the Ntx-FACT/GOG systems and, most importantly, by using dose-reduction algorithms, defines the standard of care. Also novel measures to prevent drug-induced PN are being undertaken. Recently, SC administration of bort-

Table 6. Dose Guidelines for Bortezomib in Elderly Patients

<65 yr Bortezomib

mg/m2

1.3 twice weekly

65–75 yr mg/m2

First cycle: 1.3 twice weekly Next cycles: 1.3mg/m2 once weekly

>75 yr 1.3 mg/m2 once weekly

256

ezomib was reported to significantly decrease the percentage of BiPN, while showing almost identical response and survival outcomes; however, follow-up is short.39 Furthermore, second-generation proteasome inhibitors that are less likely to cause PN, such as carfilzomib, with almost no grade 3– 4 PN, and NPI-0052 (marizomib), are being evaluated in clinical trials.46,47 Besides PN at baseline, no consistent risk factors for the development of BiPN have been established. Therefore, pharmacogenomic studies are the future for better identification of patients with an increased risk of bortezomib-induced PN.

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14.

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