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`Bortezomib-induced peripheral neurotoxicity:
`an update.
`
`ARTICLE in ARCHIVE FÜR TOXIKOLOGIE · JULY 2014
`
`Impact Factor: 5.08 · DOI: 10.1007/s00204-014-1316-5 · Source: PubMed
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`Arch Toxicol (2014) 88:1669–1679
`DOI 10.1007/s00204-014-1316-5
`
`Rev Iew A RTIcle
`
`Bortezomib‑induced peripheral neurotoxicity: an update
`
`Andreas A. Argyriou · Guido Cavaletti · Jordi Bruna ·
`Athanasios P. Kyritsis · Haralabos P. Kalofonos
`
`Received: 17 May 2014 / Accepted: 17 July 2014 / Published online: 29 July 2014
`© Springer-verlag Berlin Heidelberg 2014
`
`Abstract This review paper provides a critical explo-
`ration of updates concerning the spectrum of charac-
`teristics and treatment options of bortezomib-induced
`peripheral neuropathy (BIPN). e mphasis is given on patho-
`genesis issues. Although the mechanism underlying BIPN
`still remains elusive, it is increasingly acknowledged that
`the inhibition of proteasome activity in dorsal root ganglia
`and peripheral nerves, the mitochondrial-mediated disrup-
`tion of c a++ intracellular homeostasis and the disregula-
`tion in nuclear factor κB and brain-derived neurotrophic
`factor play a significant pathogenic role. Assessment of
`BIPN is based on comprehensive grading scales, using a
`combination of “subjective” and “objective” parameters,
`which turn out to be ambiguously interpreted, thus leading
`to both under- and misreporting of its true incidence and
`severity. BIPN is clinically defined as a typical example of
`
`A. A. Argyriou (*)
`Department of Neurology, “Saint Andrew’s” State General
`Hospital of Patras, 26335 Patras, Greece
`e-mail: andargyriou@yahoo.gr
`
`A. A. Argyriou · H. P. Kalofonos
`Division of Oncology, Department of Medicine, University
`of Patras Medical School, Rion, Patras, Greece
`
`G. c avaletti
`e xperimental Neurology Unit, Department of Surgery
`and Translational Medicine, University of Milan-Bicocca,
`Monza, Italy
`
`J. Bruna
`Unit of Neuro-Oncology, Hospital Universitari de Bellvitge-Ic O
`Duran i Reynals, Barcelona, Spain
`
`A. P. Kyritsis
`Department of Neurology, University of Ioannina Medical
`School, Ioannina, Greece
`
`a dose-dependent, distally attenuated painful, sensory neu-
`ronopathy. Patients pre-treated with neurotoxic regimens
`and those with pre-existing neuropathy are more likely to
`develop severe neurotoxicity. To date, there is no effective
`pharmacological treatment to prevent BIPN, and therefore,
`interventions remain merely symptomatic to focus on the
`alleviation of neuropathic pain. Hence, strict adherence to
`the dose reduction and schedule change algorithm is rec-
`ommended in order to prevent treatment-emergent BIPN
`and allow the continuation of treatment. Further studies in
`animal models and humans, including experimental, clini-
`cal, neurophysiological and pharmacogenetic approaches,
`are needed to allow the identification of the true spectrum
`of BIPN pathogenesis and characteristics. It is expected
`that such comprehensive approaches would be the starting
`point for the development of early preventive and therapeu-
`tic interventions against BIPN.
`
`Keywords Bortezomib · Peripheral neuropathy ·
`Neurotoxicity · Pathogenesis · Diagnosis · Incidence ·
`Treatment
`
`Introduction
`
`The ubiquitin proteasome system (UPS) is the principal
`cellular pathway to regulate intracellular protein degrada-
`tion, and this task is performed by a complex proteolytic
`machine, composed of several components. Soon after
`the identification of the characteristics of UPS in the early
`1980s, there were several attempts to selectively induce
`apoptosis in tumour cells with the development of novel
`proteasome inhibitors (Shen et al. 2013).
`Bortezomib (BTZ), a boronic acid dipeptide 20S protea-
`some complex inhibitor, was approved in 2004 by both US
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`and e uropean authorities for the treatment of multiple mye-
`loma (MM) and mantle cell non-Hodgkin’s lymphoma. The
`antitumour action of BTZ is based on its ability to induce
`G2-M cell cycle arrest, apoptosis by causing Bcl-2 phos-
`phorylation, inhibition of NF-κB and eventually inhibition
`of angiogenesis (Piperdi et al. 2011).
`c hemotherapy-induced peripheral neurotoxicity (c IPN)
`ranks among the most common non-haematological and
`dose-limiting toxicities of a number of effective chemo-
`therapeutic agents, including taxanes, platinum compounds
`and proteasome inhibitors such as BTZ, administered either
`alone or in combination regimens (Argyriou et al. 2007;
`Sioka and Kyritsis 2009). In this context, bortezomib-
`induced peripheral neuropathy (BIPN) is considered to be
`one of the most severe, unpredictable and potentially per-
`manent non-haematological side effects of chemotherapy
`against MM, thus also having a detrimental effect on the
`quality of life (Qol ) of survivors (Argyriou et al. 2008,
`2010). This is because patients with pre-existing peripheral
`neuropathy or those at high risk might be treated with sub-
`cutaneous BTZ as it appears to be less neurotoxic than BTZ
`when administered intravenously (Argyriou et al. 2012,
`2014). This review study provides a critical exploration of
`updates relating to the pathogenesis, clinical characteristics
`and management of BIPN.
`
`The ubiquitin proteasome system (UPS)
`
`The cytosolic 26S proteasome (approximately 2,000 kDa
`in molecular mass) is composed by one 20S protein subu-
`nit and two 19S regulatory cap subunits. The core where
`protein degradation is eventually completed is hollow with
`openings at the two ends, which are associates with a 19S
`regulatory subunit each, containing multiple ATPase active
`sites and ubiquitin-binding sites. This structure recognizes
`polyubiquitinated proteins and transfers them to the cata-
`lytic core. Although both 26S and 20S proteasomes have
`proteolytic activity (Finley 2009), 26S proteasome activ-
`ity is required for normal neuronal homeostasis, while 20S
`proteasome is insufficient for neuronal survival (Bedford
`et al. 2008). In mammals, 20S core particle is formed by
`α and β subunits, divided into 4 concentric rings. The outer
`two rings in the stack consist of seven α subunits each,
`which serve as docking domains for the regulatory activ-
`ity. The inner two rings each consist of seven β subunits
`each and contain the protease active sites that perform
`the proteolysis reactions. The β1, β2 and β5 subunits are
`catalytic, with three distinct substrate specificities consid-
`ered chymotrypsin-like, trypsin-like and peptidyl-glutamyl
`peptide-hydrolyzing.
`BTZ primarily targets the β5 and, to a lesser extent, the
`β1 proteasome subunits (Adams 2004; Richardson et al.
`
`2006a). The mechanism of BTZ anticancer activity has
`been extensively investigated, and it has been demonstrated
`that its main signalling pathways include the up-regulation
`of genes involved in pro-apoptotic pathways, inhibition
`of NF-κB activation, induction of endoplasmic reticulum
`stress and activation of the mitochondrial-based (“intrin-
`sic”) apoptotic pathway, which lead to cell cycle arrest and
`apoptosis (Mcc onkey and Zhu 2008).
`
`Pathogenesis of peripheral neuropathy
`
`In well-characterized animal models of BIPN, it has been
`demonstrated that the administration of BTZ using neuro-
`toxic schedules remarkably inhibits proteasome activity in
`dorsal root ganglia (DRG) and peripheral nerves, although
`the dynamics and extent of this inhibition are different,
`while it is confirmed that no effect is present in the brain
`(Meregalli et al. 2014). However, given the important dif-
`ferences in the biology of cancer cells and neurons, it is not
`established whether the same mechanisms at the basis of
`BTZ anticancer activity are also responsible for its neuro-
`toxicity, although mitochondrial and endoplasmic reticu-
`lum damage in both Schwann and satellite cells (Fig. 1a,
`b) has been observed in the sciatic nerve and DRG of mice
`and rats treated with BTZ (c avaletti et al. 2007; Bruna
`et al. 2010, 2011).
`Moreover, the observation that BIPN is more severe in
`patients affected by multiple myeloma (MM) than in sub-
`jects treated with BTZ due to solid cancers (Roccaro et al.
`2006) increases the possibility that MM itself plays a role
`in the genesis of BIPN. In fact, it is well recognized that
`more than 50 % of MM patients have neurophysiologi-
`cally evident abnormalities at baseline and this comorbid-
`ity might enhance the neurotoxicity of BTZ through still
`unknown mechanisms (Richardson et al. 2009a).
`On this background, several experimental studies have
`been performed and suggested events and mechanisms
`which are likely to be relevant to the onset and course of
`BIPN besides cytoplasmic proteasome inhibition (Broyl
`et al. 2012). Intracellular calcium homeostasis disruption in
`BTZ-treated subjects can have detrimental effects on mito-
`chondrial activity (l andowski et al. 2005), but also induce
`changes in nerve activity, promoting depolarization and
`spontaneous discharge, which might be at the basis of the
`typical neuropathic pain reported by BTZ-treated patients
`(Siau and Bennett 2006).
`Axonal excitability has been tested in patients treated
`with BTZ using the threshold tracking technique (Bostock
`et al. 1998; Kiernan and Bostock 2000), a sophisticated
`neurophysiological method able to detect aberrant axonal
`function prior to the development of pathological changes
`detected using conventional techniques. In a small cohort
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`excitability, no significant differences between the mag-
`nitude of excitability changes and the severity of chronic
`BIPN could be evidenced (Nasu et al. 2014). The observed
`axonal membrane depolarization suggests plasma mem-
`brane ion flow dysfunction, possibly related to decreased
`Na+–K+-ATPase-dependent pump function, or altered Na+
`or K+ conductance (Han et al. 2008; Kiernan and Bostock
`2000; Kiernan et al. 2000) and a continuous and abnormal
`influx of Na + ions can cause overload of the Na+–K+-
`ATPase-dependent pump, resulting in the initiation of
`mitochondrial energy conversion failure, as well as in other
`alterations in intracellular ion concentrations (Nodera et al.
`2011; w axman 2008). Given several methodological limi-
`tations (firstly, the very small cohort of patients investi-
`gated), the intriguing results of this clinical study need fur-
`ther confirmation.
`Recent studies evidenced another intracellular target
`of BTZ activity that might be relevant to BIPN, i.e. tubu-
`lin. In in vitro experiments, Poruchynsky and colleagues
`(Poruchynsky et al. 2008) demonstrated that BTZ is able
`to increase the amount of polymerized tubulin polymeriza-
`tion and to induce microtubule stabilization in several cell
`types. Interestingly, not only cancer cells (e.g. neuroblas-
`toma, MM cells) but also neurons are sensitive to this BTZ,
`although the extent of the effect was different. To investi-
`gate in vivo the relevance of BTZ-induced tubulin polym-
`erization in the pathogenesis of BIPN, this phenomenon
`was analysed using a well-characterized chronic rat model
`(Meregalli et al. 2010, 2012). In this model, the kinetics
`and extent of proteasome inhibition and of tubulin polym-
`erization were evaluated and correlated with different BIPN
`features. It showed that BTZ induced tubulin polymeriza-
`tion in the sciatic nerves (Fig. 1c) and DRG, while this
`effect was not evident in the brain, and that it was closely
`with BIPN severity. Similar results were confirmed in vitro
`in different experimental settings (Staff et al. 2013; Mere-
`galli et al. 2014).
`Besides its effects in the cytoplasm, BTZ also has
`marked effects at the nuclear level, where nuclear processes
`are organized in structural and functional compartments
`(Palanca et al. 2014). w ithin the nucleus, proteasomal pro-
`teolysis is involved in quality control mechanisms and in
`the turnover and activity of nuclear proteins such as tran-
`scription regulators and splicing factors (Desterro et al.
`2000; l afarga et al. 2002; von Mikecz 2006), all events
`that might be affected by BTZ activity. In fact, it has been
`demonstrated in DRG neurons of BTZ-treated rats (c asa-
`font et al. 2010) that the inhibition of proteasome activity
`induces accumulation of ubiquitinated proteins, reduction
`of extranucleolar transcription and nuclear retention of pol-
`yadenylated RNAs in nuclear bodies called poly(A) gran-
`ules. These results were subsequently expanded, also dem-
`onstrating changes in the geometry, position and polarity of
`
`Fig. 1 Dorsal root ganglion light micrograph obtained from a borte-
`zomib-treated rat. Neurons have a normal aspect, while satellite cells
`show mild intracytoplasmic vacuolations (arrows). e lectron micro-
`graph showing severe vacuolation (asterisks) in the cytoplasm of a
`satellite cell (sc) surrounding a neuron (n) of normal aspect. Repre-
`sentative immunoblot demonstrating a marked shift from the soluble
`(S) to the polymerized (P) form of α-tubulin in the sciatic nerve of a
`bortezomib-treated (BTZ) rats vs a control animal (c TRl )
`
`of patients treated with BTZ sensory axonal, excitability
`indices, superexcitability and depolarizing threshold elec-
`trotonus significantly decreased immediately after the first
`cycle of treatment, and these changes persisted until com-
`pletion of the third cycle. On the motor side, excitability
`testing showed significantly decreased depolarizing thresh-
`old electrotonus after the second cycle of treatment. How-
`ever, despite the recognition of these changes in nerve fibre
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`
`the neuronal nucleus, associated with disruption of the pro-
`tein synthesis mechanism and DNA damage (Palanca et al.
`2014). However, these marked changes were not associated
`with DRG neuronal death, in agreement with previously
`reported in vivo observations (c arozzi et al. 2010; Mere-
`galli et al. 2010; Bruna et al. 2010; c arozzi et al. 2013;
`c hiorazzi et al. 2013).
`e xtracellular factors possibly involved in BIPN include
`autoimmune factors and inflammation (Ravaglia et
` al.
`2008; Alé et al. 2014) and blockade of nerve growth factor-
`mediated neuronal survival secondary to BTZ-mediated
`inhibition of the activation of nuclear factor κB (NF-κB)
`(Richardson et al. 2003). c hanges in brain-derived neuro-
`trophic factor (BDNF) levels have recently been proposed
`as a candidate mechanism underlying BIPN (Broyl et al.
`2010). In this context, it should be considered that plate-
`lets play an important role in the homeostasis of BDNF in
`the blood, since BDNF is stored and transported in human
`platelets and released by agonist stimulation (Fujimura
`et al. 2002).
`A clinical study tested the hypothesis that decreased
`BDNF levels in the plasma of patients with BIPN may
`result from a lack of secretion of the growth factor from
`the platelets, even in patients without a decrease in their
`blood count (Azoulay et al. 2014). In this study, flow cyto-
`metric analysis evidenced an increase of BDNF content
`in the platelets of patients with BIPN compared to plate-
`lets of patients without BIPN. Although altered peripheral
`blood levels of BDNF were associated with neurological
`impairment (Azoulay et al. 2005), these results suggest that
`mechanisms involving BDNF release might act in BTZ-
`treated patients. In fact, platelet aggregation is inhibited
`by exposure to BTZ (Avcu et al. 2008) and platelets from
`MM patients treated with BTZ have diminished aggrega-
`tion in response to several agonists (Zangari et al. 2008).
`By reducing platelet activation, BTZ might inhibit BDNF
`release from its main storage compartment, therefore
`depriving nerve fibres and neurons of its trophic support
`during the onset of BIPN and limiting the possibility of
`effective repair.
`Although the neurotoxicity mechanism of BTZ remains
`to be elucidated, the results obtained so far indicate that
`investigation is still necessary to understand the pathogen-
`esis of BIPN, also considering intracellular targets other
`than the proteasome.
`
`Diagnosis
`
`The diagnosis of BIPN is established in most of the rele-
`vant studies with the use of standard clinical grading scales,
`such as the National c ancer Institute c ommon Terminol-
`ogy c riteria for Adverse e vents (Nc I-c Tc Ae v3 or v4 for
`
`sensory and motor neuropathy) and the 11-item neurotox-
`icity subscale [FAc T/GOG-Ntx (Functional Assessment of
`c ancer Therapy/Gynaecologic Oncology Group-Neurotox-
`icity)] that was developed by the Gynaecologic Oncology
`Group (c avaletti et al. 2010).
`To overcome limitations in accurately grading BIPN
`with those scales resulting from intra- and interobserver
`variation (Postma et al. 1998), some recently published
`studies have also employed either the Total Neuropa-
`thy Score (TNS) or shorter variants, such as the reduced
`(TNSr) or clinical (TNSc) version of TNS (l anzani et al.
`2008; velasco et al. 2010; Zaroulis et al. 2014). Recent
`evidence from our group showed that the TNSc appears
`superior to Nc I-c Tc Ae in terms of sensitivity in estimat-
`ing the severity of c IPN, including BIPN (c avaletti et al.
`2013). As such, we recommend the use of TNSc to assess
`BIPN, but for a comprehensive evaluation, patients should
`also be tested with the pain v isual Analogue Scale (vAS)
`or the 11-point pain intensity numerical scale (PI-NRS), to
`capture the intensity of neuropathic pain in the context of
`BIPN.
`
`Incidence and severity of BIPN
`
`According to the results of major phase 2/3 clinical trials,
`as outlined in Table 1, the incidence of BIPN ranges from
`31 to 45 %. First-line BTZ treatment administered in the
`usual manner (intravenous administration of bortezomib
`1.3 mg/m2, twice a week for 2 weeks, followed by 1 week
`without treatment) is able to induce grade 1 or 2 BIPN in
`14 and 17 % of treated patients, respectively, when assessed
`with the Nc I-c Tc Ae scale.
`Pre-treatment with other neurotoxic antineoplastic
`drugs, such as vincristine and thalidomide, is associated
`with even higher percentages (18–37 %) of clinically
`significant (grades 1 and 2) BIPN. In those pre-treated
`patients, included in Table 1 (n = 2,174 patients), the inci-
`dence rate of treatment emergent, severe (grades 3 and
`4) neurotoxicity following administration of intravenous
`(iv) BTZ at 1.3 mg/m2 per dose and at weighted arithme-
`tic cumulative received mean dose of 28.5 mg/m2 is about
`7 %. These severe BIPN incidence estimates are compara-
`ble (9 %) to those observed in patients (n = 855 patients)
`receiving first-line BTZ treatment, although those newly
`treated MM patients had received a higher weighted arith-
`metic cumulative mean dose of 40.5 mg/m2. Dose reduc-
`tion or treatment discontinuation occurs in up to 12 % of
`BTZ-treated patients due to treatment-emergent BIPN,
`mostly occurring in those with pre-existing neuropathy
`due to exposure to other neurotoxic chemotherapies (Rich-
`ardson et al. 2006b; Garderet et al. 2012; Dimopoulos
`et al. 2011).
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`
`Table 1 Neuropathy incidence, clinical, and treatment schedules characteristics of phase 3 trials using BTZ adding the phase 2 (SUMMIT) trial
`that conducted the accelerated approval of BTZ by FDA
`
`Author
`
`Size arm
`
`Age
`(median)
`
`Planned total dose
`(mg/m2)
`
`Median cycles
`(planned)
`
`Neuropathy grade
`
`c omments
`
`Multiple myeloma
`Newly diagnosed
` Palumbo et al.
`(2010)
` San Miguel et al.
`(2008a, b)
`
`n = 254
`n = 257
`n = 344
`
`71 y
`71 y
`71 y
`
`67.3 (40.1a)
`67.3 (39.4a)
`52
`
`9b
`
`8 (9)
`
`Thalidomide containing
`regimens
`
`G 3–4: 8 %
`G 3–4: 5 %
`G 1: 14 %
`G 2: 17 %
`G 3–4: 13.3 %
`
`Thalidomide containing
`regimen
`30 % dose reductions
`
`5 % discontinued
`
`Phase 2
`
`Induction with vincristine
`containing agent
`25 % dose reductions and
`2 % discontinued
`
`4 % discontinued
`Thalidomide containing
`regimen
`
`v incristine and cisplatin
`containing regimens
`Toxicity not reported by
`separate treatment arms
`1 % discontinuation
`
`Refractory or relapsing
` Garderet et al.
`n = 135
`(2012)
` Hjorth et al. (2012) n = 54
` Dimopoulos et al.
`n = 317
`(2013)
`n = 320
` Moreau et al.
`n = 148 sc
`(2011a, b)
`n = 74
`
`60 y
`
`71 y
`
`61 y
`63 y
`64.5 y
`64.5 y
`
`62.4
`
`7.5 (12)
`
`5.2 per cycle until
`prog or tox
`5.2 per cycle until
`prog or tox
`41.6 (33.76a)
`41.6 (31.46a)
`
`4
`
`76
`
`8 (8)
`8 (8)
`
`5 (8)
`
`5 (8)
`5 (8)
`
`G 1–2: 17.7 %
`G 3–4: 23.3 %
`G 2: 18.8 %
`G 3–4: 22.2 %
`G 3–4: 7.6 %
`G 3–4: 7.3 %
`G 1–2: 32 %
`G 3–4: 6 %
`G 1–2: 37 %
`G 3–4: 16 %
`G 1–2: 19.1 %
`G 3–4: 5.9 %
`G 1–2: 9.7 %
`G 3–4: 1.3 %
`G 1–2: 9.5 %
`G 3–4: 2.8 %
`G 1–2: 28 %
`G 3–4: 8 %
`
`29 % completed
`41.6 mg and 5 % all
`cycles (11)
`39 % completed (8) G 1–2: 19 %
`G 3–4: 12 %
`
`5(6)
`
`2 (2)
`6 (6)
`
`G 1–2: 52 %
`G 3–4: 5 %
`47 % completed (3b) G 1–2: 35 %
`G 3–4: 5 %
`G 2: 15 %
`G 3–4: 9 %
`G 2: 46 %
`G 3–4: 14 %
`G 2: 8.1 %
`G 3–4: 8.1 %
`G 1–2: 59.6 %
`G 3–4: 11.1 %
`G 1–2: 50 %
`G 3–4: 3 %
`G 1: 21.3 %
`G 2: 15.5 %
`G 3–4: 7.1 %
`
`93 % completed
`
`91 % completed
`95 % completed
`
`100 % completed
`
` Mikhael et al.
`(2009)
` Orlowski et al.
`(2007)
`
`n = 638
`n = 318
`n = 318
`
`62.7 y
`
`41.6
`
`61 y
`62 y
`
`41.6 (23.2a)
`41.6 (24.4a)
`
` Richardson et al.
`(2005)
`
`n = 331
`
`62 y
`
`57.2
`
`60 y
`
`41.6
`
` Richardson et al.
`n = 202
`(2003)
`Induction pre-transplant and consolidation regimens
` Mellqvist et al.
`59 y
`41.6
`n = 187
`(2013)
` Sonneveld et al.
`n = 221
`(2012)
` Rosiñol et al.
`n = 129
`(2012)
`n = 130
`
`57 y
`
`57 y
`56 y
`
`15.6b
`
`10.4
`31.2
`
`c avo et al. (2012)
`
` Moreau et al.
`(2011a, b)
`
` Harousseau et al.
`(2010)
`
`n = 160
`n = 99
`n = 100
`
`n = 121
`n = 119
`
`57.4 y
`
`26
`
`57 y
`58 y
`
`57.2 y
`57.2 y
`
`15.6
`12
`
`15.6
`15.6
`
` c avo et al. (2010) n = 236
`
`58 y
`
`26
`
`94 % completed
`
`G 1: 18 %
`G 2: 6 %
`G 3–4: 10 %
`
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`Table 1 continued
`
`Author
`
`Size arm
`
`Follicular lymphoma
`c oiffier et al. (2011) n = 334
`
`Arch Toxicol (2014) 88:1669–1679
`
`Age
`(median)
`
`Planned total dose
`(mg/m2)
`
`Median cycles
`(planned)
`
`Neuropathy grade
`
`c omments
`
`58 y
`
`32
`
`5 (5)
`
`G 1–2: 13 %
`G 3–4: 3 %
`
`0.3 % patients discontinued
`BTZ dose 1.6 mg/m2
`
`Y years, G neuropathy grade by Nc I-c Tc Ae , prog progression, tox toxicity, sc subcutaneous
`a Total administered dose of BTZ
`b Plus BTZ 1.3 mg/m2 every 14 days during 2 years as maintenance. e very cycle usually contain four doses of BTZ 1.3 mg/m2. Discontinua-
`tions and reduction doses reported are due to BIPN
`
`On the other hand, and as shown in Table 1, BTZ used as
`induction pre-transplant or consolidation therapy is associ-
`ated with significantly varying estimates of incidence and
`severity of BIPN, because of the variability of planned
`total dosages and the difficulty in extrapolating the final
`delivered cumulative BTZ dose from the reports. Moreo-
`ver, results from a small (n = 28) phase 2 trial showed that
`21 % of patients treated with lower dose BTZ schedules
`(1 mg/m2) developed BIPN, whereas 15 % of them pre-
`sented clinically significant (grades 1/2) and 8 % treatment-
`emergent (grade 3/4) neurotoxicity (Jagannath et al. 2004).
`The subcutaneous BTZ formulation and the reduced
`schedules of 1.3 mg/m2 once a week instead of the clas-
`sical twice-a-week regimen merit attention. A phase 3
`trial tested the subcutaneous (sc) formulation, as an alter-
`native to the traditional iv route, and the results, as out-
`lined in Table 1, suggested similar efficac y but, impor-
`tantly enough, a lower incidence of neurotoxicity (Moreau
`et al. 2011a). Both arms were well balanced for the risk of
`developing peripheral neuropathy, and the median cumu-
`lative dose as well as dose intensity was similar between
`arms (sc arm: 33.75 and 5.13 mg/m2 vs iv arm: 31.46 and
`4.89 mg/m2). However, the results of this trial should be
`interpreted with caution because of some methodologi-
`cal issues, including the trial’s end point, which was set
`to efficacy rather than safety and the 2:1 randomization,
`resulting in a smaller size of the iv arm. Another issue
`worth mentioning was that although the incidence of clini-
`cally significant BIPN (grades 1 and 2) was comparable
`between arms, there was evidence in this trial of signifi-
`cantly increased high-grade (grades 3 and 4) neurotoxic-
`ity in patients allocated in the iv arm, compared to older
`results from large trials, which report a lower incidence of
`severe BIPN (Table 1).
`Another phase 3 trial compared the efficacy of a chemo-
`therapeutic regimen comprising BTZ–melphalan–pred-
`nisone plus thalidomide against the same schedule with-
`out thalidomide. In this trial, the protocol was amended
`after start, to evaluate whether dose reduction from twice-
`weekly to once-weekly BTZ infusions was able to main-
`tain the efficacy and reduce toxicity (Palumbo et al. 2010).
`
`Despite differences in the planned dose, both groups
`received similar median cumulative BTZ doses (39.4 vs
`40.1 mg/m2), because of a significant increase in both dose
`reductions and incidence of withdrawals in patients allo-
`cated to the twice-weekly group (n = 134), compared to
`the once-weekly group (n = 369). In any case, a signifi-
`cantly reduced overall incidence of grade 3/4 neurotoxicity
`was observed (8 vs 28 %) in the once-weekly vs the twice-
`weekly group (Palumbo et al. 2010). However, it should be
`mentioned that although these findings appear interesting,
`they are not obtained from a pre-planned phase 3 trial, and
`this issue might have induced bias.
`Neuropathic pain ranks among the cardinal symptoms
`of BIPN and results from large trials show that the pres-
`ence of severe neuropathic pain (grade 3–4) is reported by
`5–16 % of patients (San Miguel et al. 2008a; Palumbo et al.
`2010; Hjorth et al. 2012; Mellqvist et al. 2013). Moreover,
`it is evidence that neuropathic pain of any severity develops
`more frequently in pre-treated patients with antineoplastic
`therapy (39 vs 15 %), compared to those chemotherapy-
`naïve (Jagannath et al. 2005; Richardson et al. 2006a).
`Finally, BTZ therapy can also evoke autonomic dysfunc-
`tion in 12–50 % of patients, with constipation (12 %) and
`orthostatic hypotension (50 %) being the most frequent
`symptoms (Richardson et al. 2006b; Palumbo et al. 2010;
`velasco et al. 2010; Mellqvist et al. 2013).
`
`Risk factors of BIPN
`
`l ike almost any neurotoxic antineoplastic drug, the cumula-
`tive BTZ dose is the most significant risk factor for BIPN
`development. Neurotoxicity, in both pre-treated and newly
`diagnosed MM patients, usually appears within the first 5
`cycles of treatment, being closely linked to the delivered
`cumulative dose. After the 5th cycle (at a cumulative dose of
`approximately 30 mg/m2), its incidence slowly increases to
`reach a plateau at 42–45 mg/m2 and does not increase there-
`after (Richardson et al. 2009b; Dimopoulos et al. 2011).
`However, the evidence of pre-existing neuropathy prior
`to the initiation of BTZ-based chemotherapy represents the
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`1675
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`strongest clinical risk factor for BIPN development (l an-
`zani et al. 2008; Dimopoulos et al. 2011). Advanced age
`was considered another significant risk factor for BIPN in
`some small series (Mateos et al. 2006; c orso et al. 2010).
`However, this association was not confirmed by the results
`of larger trials on the incidence or severity of neurotoxic-
`ity (Richardson et al. 2006b; Dimopoulos et al. 2011),
`thereby suggesting that elderly patients without any sig-
`nificant comorbidities are not more liable to develop BIPN
`and should be treated with the optimal BTZ dose. w e also
`believe that advanced age per se is not a risk factor for
`c IPN and both its incidence and severity remain compa-
`rable between elderly and younger patients (Argyriou et al.
`2006, 2013).
`Other clinical factors, such as creatinine clearance (San
`Miguel et al. 2008b; Morabito et al. 2011), International
`Staging System Myeloma, excessive weight/obesity and
`diabetes have also not been identified as risk factors (Dimo-
`poulos et al. 2011). Finally, it is suggested that BIPN might
`also be a proteasome inhibitor class effect, as up to 20 %
`of patients may have sensory polyneuropathy prior to BTZ
`therapy initiation (Richardson et al. 2009a).
`
`Clinical and electrophysiological characteristics
`of BIPN
`
`There are no major updates in the clinical and electro-
`physiological spectrum of BIPN. It is widely acknowl-
`edged that patients usually complain of neuropathic pain,
`mainly located in the fingertips and toes, sensory loss to all
`modalities, distally attenuated, suppression or even abolish-
`ment of deep tendon reflexes in proportion to sensory loss
`and proprioception changes. Those cardinal symptoms and
`signs of BIPN are in line with a painful neuropathy due to
`dysfunction in all three major fibre (Aβ, Aδ and c ) types of
`sensory nerves (Argyriou et al. 2012).
`From the electrophysiological point of view, nerve con-
`duction studies usually reveal the typical findings of a toxic
`c IPN, consistent with distal, sensory, axonal neuronopathy.
`Findings of sensorimotor peripheral neuropathy can occa-
`sionally be seen (Park et al. 2013). Quantitative sensory
`testing confirms a persistent and severe impairment of Aβ,
`Aδ and c fibres in BTZ-treated patients with chronic BIPN,
`due to loss of both epidermal nerve fibres and Meissner’s
`corpuscles (c ata et al. 2007; Boyette-Davis et al. 2011).
`
`Reversibility and long‑term course of BIPN
`
`The improvement or resolution of BIPN is normally
`observed in up to 85 % of patients between 2 and
`3.5 months after discontinuation of BTZ
`treatment
`
`(Richardson et al. 2005, 2006b, 2009a; Dimopoulos et al.
`2011). Although the outcome appears similar between
`newly and pre-treated patients with other cytostatics, the
`neuropathy in this last group is resolved more slowly and
`neurotoxicity improves by at least one Nc I-c Tc Ae grade
`within a median of 1.9 months in newly MM treated com-
`pared to 3.6 months in pre-treated patients (Dimopoulos
`et al. 2011). c ompared to chemotherapy naïve, a much
`higher ratio (36 vs 73 %) of reduction or discontinuation of
`treatment is observed in those patients (c orso et al. 2010).
`Finally, up to 30 % of patients do not experience any
`recovery and neurotoxicity remains indefinitely in some
`cases (Richardson et al. 2006b; Dimopoulos et al. 2011;
`Argyriou et al. 2014) and, to our knowledge, the literature
`still contains no report of delayed de novo appearance of
`BIPN after BTZ therapy discontinuation.
`
`Options for neuroprotection
`
`To date, several agents, including various opioids, tricyclic
`antidepressants, anticonvulsants, serotonin–norepinephrine
`reuptake inhibitors, non-steroidal anti-inflammatory agents,
`vitamins and nutritional supplements, have been tested for
`their efficacy to symptomatically treat the neuropathic pain
`component in the context of BIPN (Argyriou et al. 2012).
`However, based on results from randomized controlled
`trials (Rc Ts), only duloxetine appears effective and well
`tolerated enough to alleviate BTZ-associated neuropathic
`pain.
`A recently published Rc T sought to determine the effect
`of a 5-week treatment with duloxetine, 60 mg daily, on
`average pain severity in chemotherapy-treated patients with
`various neurotoxic agents such as taxanes and platinum
`compounds. This study concluded that the use of duloxe-
`tine compared to placebo for 5 weeks resulted in a greater
`reduction in average pain (Smith et al. 2013). It is acknowl-
`edged that no BTZ-treated patients were included in the lat-
`ter trial, but in our opinion taking into account the major
`similarities among painful c IPN, duloxetine might also be
`effectively used against painful BIPN.
`Similar to the case of symptomatic treatment, one can-
`not recommend based on Rc Ts the use of any neuropro-
`tectants tested to date for prophylaxis from BIPN (Argyriou
`et al. 2014). Recently, it was reported that the oral admin-
`istration of lafutidine, a H2-blocker with gastroprotective
`activity, at a dose of 10 mg twice daily, might be able to
`prevent or improve neurotoxicity. In this small series of just
`eight patients, it was shown that there was no BIPN a