Leukemia (2011) 1 - 13
& 2011 Macmillan Publishers Limited
All rights reserved 0887-6924/11
www.nature.com/leu
REVIEW
Management of treatment-emergent peripheral neuropathy
in multiple myeloma
PG Richardson1, M Delforge2, M Beksac3,PWen1, JL Jongen4, O Sezer5, E Terpos6, N Munshi1, A Palumbo7, SV Rajkumar8,
JL Harousseau9, P Moreau9, H Avet-Loiseau9, JH Lee10, M Cavo11, G Merlini12, P Voorhees13, WJ Chng14, A Mazumder15, S Usmani16,
H Einsele17, R Comenzo18, R Orlowski19, D Vesole20, JJ Lahuerta21, R Niesvizky22, D Siegel20, M-V Mateos23, M Dimopoulos6, S Lonial24,
S Jagannath25, J Blade
´ 26, J San Miguel23, G Morgan27, KC Anderson1, BGM Durie28 and P Sonneveld4 on behalf of the International
Myeloma Working Group29
Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused
by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and
particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown
that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during
therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM
therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective
management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while
maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current
management practices are outlined, and recommendations regarding optimal strategies for PN management during MM
treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose
modification and treatment discontinuation as indicated. Areas requiring further research include the development of
MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy
of pharmacological interventions.
Leukemia advance online publication, 23 December 2011; doi:10.1038/leu.2011.346
Keywords: bortezomib; immunomodulatory drug; multiple myeloma; peripheral neuropathy; proteasome inhibitor; thalidomide
INTRODUCTION
as thalidomide-induced PN (TiPN), is less well understood. Because
Peripheral neuropathy (PN) is an important complication of
of the difficulty and complexity of diagnosing and differentiating
multiple myeloma (MM) and associated conditions1-- 3 that can
autonomic PN in this setting, this discussion is focused on sensory,
be caused both by the disease and by the therapies used to treat
motor and sensorimotor neuropathy. Autonomic dysfunction may
MM. 1,2,4 Over the past decade, new treatment options, specifically
occur with both bortezomib and thalidomide treatment and can
the proteasome inhibitor bortezomib, and the immunomodula-
be managed with supportive measures.
tory drugs thalidomide and lenalidomide, have revolutionized MM
therapy, improving response and long-term outcomes. This review
focuses on treatment-emergent PN with these novel MM agents
ETIOLOGY OF PN IN MM PATIENTS
and other agents in their classes (including carfilzomib, marizomib
MM-associated PN
and pomalidomide), plus other US Food and Drug Administration/
Rates of PN caused by MM have been reported from 1 - 2%(ref. 1) to
European Medicines Agency-approved agents and other recom-
20%.5
Although
the
exact
etiology
of
MM-associated
mended MM therapies associated with PN (Supplementary
PN is unknown, amyloid deposition, immunoglobulin M anti-
Table 1). A large body of data exists characterizing bortezomib-
bodies directed at myelin-associated glycoprotein, a glycoconju-
induced PN (BiPN), whereas PN associated with other agents, such
gate component of nerves involved in interactions between
1Dana-Farber Cancer Institute, Boston, MA, USA; 2University Hospital Leuven, Leuven, Belgium; 3Ankara University, Ibn-i Sina Hospital, Ankara, Turkey; 4Erasmus Medical Center
and Erasmus University, Rotterdam, The Netherlands; 5University Medical Center, Hamburg, Germany; 6School of Medicine, University of Athens, Athens, Greece; 7University of
Torino, Torino, Italy; 8Mayo Clinic, Rochester, MN, USA; 9Intergroupe Francophone du Mye´lome, Nantes, France; 10Gachon University GIL Hospital, Incheon, Korea; 11Sera`gnoli
Institute of Hematology, Bologna University School of Medicine, Bologna, Italy; 12Amyloidosis Research and Treatment Center, University of Pavia, Pavia, Italy; 13The University of
North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; 14Department of Haematology and Oncology, National University Health System,
Singapore, Singapore; 15New York University School of Medicine, New York, NY, USA; 16Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences,
Little Rock, AR, USA; 17University of Wurzburg, Wurzburg, Germany; 18Tufts Medical Center, Boston, MA, USA; 19Department of Lymphoma and Myeloma, The University of Texas
M.D. Anderson Cancer Center, Houston, TX, USA; 20Hackensack University Medical Center, Hackensack, NJ, USA; 21PETHEMA, Hospital Universitario 12 de Octubre, Madrid, Spain;
22Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY, USA; 23Hospital Universitario
Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain; 24Winship Cancer Institute of Emory University, Atlanta, GA, USA; 25Mount Sinai Hospital, New York, NY, USA; 26Institute of
Hematology and Oncology, Institut d'Investigacions Biome`diques August Pi I Sunyer, Hospital Cli´nic, University of Barcelona, Barcelona, Spain; 27Royal Marsden Hospital, London,
UK and 28Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA, USA. Correspondence: Dr PG Richardson, Dana-Farber Cancer Institute, 44 Binney Street, Dana 1B02,
Boston, MA 02115, USA
E-mail: paul_richardson@dfci.harvard.edu
29All members of the International Myeloma Working Group are listed in the online-only Supplementary Information.
Received 24 June 2011; revised 27 July 2011; accepted 1 November 2011

Management of peripheral neuropathy in myeloma
PG Richardson et al
2
Schwann cells and axons, and cytokine-mediated injury have been
that vincristine causes distal axonal degeneration through
suggested as possible mechanisms, in addition to neurological
localized axonal toxicity21 that is likely caused by vincristine
complications in the form of radiculopathy from direct compres-
binding to tubulin and disrupting microtubule polymerization.6
sion.1,2,4 The etiological mechanisms involved are likely to be
Preclinical data suggest that cisplatin-induced PN results from
complex in terms of causative pathways, as small fiber injury,
direct toxic damage to the DRG,6 but may also involve
segmental demyelination and axonal degeneration can occur.1,2,4
degeneration of both the peripheral and central processes of
PN is also associated with the related disorders of monoclonal
large-diameter sensory neurons.22
gammopathy of undetermined significance,1 primary and familiar
amyloidosis
and
POEMS
(polyneuropathy,
organomegaly,
endocrinopathy, M protein and skin changes) syndrome.1,6 The
SYMPTOMS, INCIDENCE AND CLINICAL CHARACTERISTICS
pathology of PN in MM patients is distinct from that seen
Symptoms
with other paraproteinemias,2 highlighting the importance of
MM-associated PN is predominantly sensory or sensorimotor, and
MM-specific management strategies.
typically involves segmental demyelination and distal axonal
degeneration without involvement of the dorsal roots.2 Symptoms
Proteasome-inhibitor-induced PN
are usually symmetric and include paresthesias, numbness,
Proteasome inhibitors inhibit the 26S proteasome, either rever-
burning sensation and weakness; these are generally mild, but
sibly (bortezomib, MLN9708,7 CEP-18770(ref. 8)) or irreversibly
in rare cases can be disabling or even life-threatening.
(carflizomib, marizomib), disrupting protein regulation and
Treatment-emergent PN symptoms are usually symmetric, distal
preventing proteasomal degradation of ubiquitinated proteins.
and progressive, although there are some differences among
In mice, ubiquitinated aggregates accumulated in the cytoplasm
therapies.2,4 BiPN is predominantly sensory and mild (although
of the dorsal root ganglia (DRG), suggesting that this is the
severe sensory and motor PN have been reported in up to 15% of
primary target in proteasome-inhibitor-induced PN.9--11 The BiPN
patients).23 Symptoms include a burning sensation, hyperesthesia,
seen in a SwissOF1 mouse model showed pathological character-
hypoesthesia, paresthesia, discomfort and neuropathic pain or
istics similar to those seen in the clinic.12,13 Accumulation of
weakness,23 which may start distally and progress proximally.
neuronal cytoplasmic aggregates has been demonstrated with
Thalidomide is known to cause nerve damage that may be
proteasome inhibitors of different chemical scaffolds, suggesting
permanent, and the symptoms of TiPN can occur after treatment
that this is both a mechanism-based and class effect.9,10
has stopped.24 Thalidomide is reported to cause a primarily
However, in a rat model of PN, carfilzomib did not damage
sensory/sensorimotor,
length-dependent
axonal
neuropathy,
the DRG.14 One hypothesis is that the boron-based moiety
typically with tingling or painful distal paresthesia affecting the
of bortezomib, but not the epoxyketone-based component of
feet and sometimes the hands, as well as sensory loss in the lower
carfilzomib, inhibits non-proteasomal targets, which may be
limbs.19,25,26 Motor changes may affect patients with TiPN25 and
involved in BiPN.14,15 In preclinical studies using an in vitro neuron
can present as muscle weakness or, more frequently, tremor.
model, the mitochondrial serine protease HtrA2/Omi was directly
Neurotoxicity with vincristine develops as a distal symmetric
or indirectly impacted by bortezomib, but not carfilzomib.15
sensorimotor neuropathy.27 Frequently, sensory impairment and
Additionally, Cathepsin G activity was reduced and neurite growth
paresthesia occur; with prolonged exposure this can be followed
was impeded significantly in the presence of bortezomib, but not
by neuritic pain and motor difficulties.28 Although there are no
carfilzomib.15 Another hypothesis is that, unlike the reversible
specific data on MM patients, cisplatin can lead to long-term
inhibitor bortezomib, a substantial proportion of carfilzomib
peripheral sensory nerve damage in patients with successfully
molecules may irreversibly bind to proteasomes in red blood
treated epithelial ovarian cancer.29
cells and hepatocytes, thereby restricting their tissue distribution
so that fewer molecules reach the DRG.16
Incidence
Proteasome-inhibitor-induced PN may also affect microtubule-
In a multicenter phase 2 study of single-agent bortezomib
associated proteins and cause microtubule stabilization, with
designed to carefully assess the impact of BiPN in frontline MM
similar preclinical results seen with proteasome inhibitors of
patients, 64% showed treatment-emergent sensory BiPN, includ-
different chemical structure.17
ing 3% grade 3 (no grade 4).5 In phase 3 trials of bortezomib-
based combinations in frontline MM, BiPN has been reported in up
Immunomodulatory-drug-induced PN
to 70% of patients, including grade X3 sensory BiPN in up to 16%
Thalidomide has multiple mechanisms of action in MM, including
(Table 1).30 - 40 The incidence of BiPN in the relapsed setting is
inhibition of angiogenesis, induction of apoptosis, increasing
similar to that seen in the frontline setting (Table 2).41 - 44
natural killer cell and T-cell numbers, antiproliferative effects and
Importantly, development of BiPN does not appear to adversely
inhibition of cytokine secretion. Some preclinical and clinical data
impact response rates or outcomes.32,43
suggest that thalidomide may affect the DRG, leading to DRG
The incidence of treatment-emergent PN with newer protea-
degeneration.18 Other studies have suggested that TiPN is due to
some inhibitors has been relatively low. In phase 1/2 studies of
downregulation of tumor necrosis factor-a (TNF-a), leading to
carfilzomib45 - 50 in hematological malignancies, PN rates of p10%
Wallerian degeneration and loss of myelinated fibers.19 The
overall and 0 - 3% grade 3 were reported; similarly, significant
systemic inflammatory disorder leukocytostatic vasculitis has been
treatment-emergent PN has not been reported in three phase 1
reported, albeit rarely, in patients treated with thalidomide,20
trials of marizomib to date.51 - 53 Results from larger studies will be
which may have a role in neuropathy. There are no available data
important to confirm these preliminary results. Many patients in
regarding the etiology of PN associated with lenalidomide and
these trials had received prior bortezomib; some had experienced
pomalidomide, likely, at least in part, because lenalidomide is
BiPN but did not develop PN in the carfilzomib or marizomib trials.
associated with substantially lower rates of PN and much less
The lack of dose-limiting PN and the lower rate of neurotoxicity
severe PN compared with thalidomide.
reported in these preliminary studies is promising; however,
further studies, additional data, and longer follow-up are required
to confirm the incidence of PN with these newer agents.
PN induced by other MM agents
The incidence of TiPN is generally similar to that reported for
Limited information is available about the mechanisms by which
BiPN, with incidences of up to 75% reported in patients who
other neurotoxic agents cause PN in MM. Preclinical data suggest
received 412 months of treatment.54 In frontline MM patients,
Leukemia (2011), 1 - 13
& 2011 Macmillan Publishers Limited

Management of peripheral neuropathy in myeloma
PG Richardson et al
3
NP
%
1%
2
PN
1
(11%
VMP
y,
o
to
R
%
R
R
R
R
R
,
R
R
R
R
R
R
NR
N
3
N
N
N
N
N
NR
NR
NR
NR
V
patients
1
4
0
8
7
3%
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18%
f
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11%
3%
:
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NR
NR
NR
NR
NR
Discon.
o
grade
T
due
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sensor
motor
PN);
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4)
y
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motor
b
grade
0
d
d
e
3/4
7
2
N
0
7
1
2
2
26
12
sensor
0
0
0
0
0
0
3
2
7
5
PN)
1
2/0
2/0
6/0
10
2
11
6/1
4/5
8
PN
Grade
P
1
2%
(3
(neurology)
(neurology)
(o
5
7
12
(13%
PN,
13
b
7
c
c
X
R
R
1/2
65
32
NR
NR
50
54
NR
NR
5
NR
50
NR
NR
NR
NR
N
N
NR
NR
Grade
18/8
30/4
16/3
21/16
32/19
14/19
NR/6
NR/4
NR/8
NR/
19/18
NR/23
NR/11
NR/14
treatment-emergent
of
6%
PN)
c
c
y,
3%
R
R
Incidence
All
46
28
54
34
72
35
NR
NR
76
66
NR
NR
(44%
,
5
NR
NR
39
21
55
NR
NR
NR
NR
34
14
70
53
NR
NR
N
N
NR
NR
grades
47
sensor
motor
e
e
N
7
1
240
242
235
235
145
143
223
222
371
373
201
201
344
338
129
126
113
116
125
196
153
152
154
241
239
99
100
130
130
8
9
254
257
NR
(13.5
placebo
until
additional
cycles
cycles
months
therapy
9
8
induction+2/2
(3.6
:
:
cycles
cycles
of
NR
)T
4
NR
NR
years/NR
years/NR
les
consolidation
months
months
les
les
les
les
les
les
les/T
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les/T
les
3
3
les
cyc
onths
onths
cyc
cyc
cyc
cyc
cyc
cyc
cyc
cyc
cyc
months)
weeks/NR
weeks+maintenance/
weeks/NR
cyc
to
to
cyc
cycles/
m
m
cycles/
cycles/
cycles/
Planned/Median
duration
4/4
cycles
NR/6.9
NR/6.4
9
3/3
9/9
9/8
months
6/6
12
months)
12
12
(11
NR
36
36
3/3
6
6
Up
9+maintenance
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9/9
MM
4
6
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36
4
Up
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1
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days
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2
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les
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cyc
cycles
mg/day
cycles
3-week;
diag
cyc
aintenance
one
mg/m
cycles
cycles
y
onths;
mg/day
mg/day
50
les
m
months
m
:
10
T
3
T
3
50
4-week
cyc
4-week
mg/day
100
:
cycles
;
y
T
15;
newly
;
4-week
cycles
les
10
cycles
mg/da
- er
-4
4-week
-4
then
3-week
0
1,
in
cycles
1
les
ev
22;
-4);
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1
cycles
100
5
every
11,
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les
:
:
(cisplatin
1
T
ys
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les
T
11,
11,
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day
;
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8
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cycles
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;
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3
1
1
y
-9
6-week
y
1
1
mg/m
mg/da
;
day
1,4,8,11;
cyc
ys
5
4-week
6-week
y
4-week
mg/day
VMP
sy s days
e
then
mg/m
4-week
days
cycles
mg/day
days
;
;
4-week
y
y,
ys
days
a
ya
1.3
schedule
mg/m
;
days
da
,
,
les
y
y
;
,
as
2
:
0.4
200
,
d
d
2
mg/da
2
y
mg/da
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da 2
V
2
,
arm
phase
10
-
y,
0.4
200
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2
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2
2
2
y
and
mg/da
-
5-week
cycles;
cycles
cycles
4-week
cycles
cycles
cycles
mg/da
cycles
200
e
mg/m
ke
100
-400
mg/m
mg/da
mg/da
cycles
MPT
mg/day
g/day
mg/m
mg/da
mg/m
mg/m
V
m
mg/da
400
10
100
- mg/m mg/m
fiv
1.3
in
dose
:
cycles
-
s
0
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1.3
NR;
200
1.3
100
100
p
10
T
1.3
:
a
2
:
:
:
:
:
:
R:
;
1.3
1
:
1.3
V
vincristine:
(cisplatin
5
200
:
25
combinations
:
100
:
V
V
T
vincristine
V
1.3,mg/m
1,8,22,29
T
T
T
R:
V
:
:
v
V
1.3,mg/m
;
V
PN
3-week
:
4-week
:
:
:
T
T
4-week
R
V
:
R:
6-week
;
4-week
;
6-week
;
6-week
4-week
T
V
;
V
V
D;
D;
D;
D;
D;
,
;
;
maintenance;
of
A
sed
A
A
Planned
VD;
4-week
V
DCEP
TD;
Dex;
TD;
MP;
RD;
Rd;
PA
V
TA
V
combinations
VMP;
days
MP;
MPT
MP;
MPT
MP
MPT
MP;
MPR;
MPR-R;
MP;
VTD;
TD;
VD;
vTD;
VMP;
1,8,15,22,
VTP
VP
VT
VMPT
VT
VMP;
vs
s
combinations
combinations
37
56
v
,
35
57,58
61
55
60
120
31
119
P
P
40
VT
70
AD
AD
P
PR+R
VTP
incidence
V
V
M
M
M
M
TD
DCEP
MP
VMP
dex
MP
Rd
s
s
VMP
s
s
s
s
vTD
s
or
v
v
v
v
v
v
vs
vs
v
vs
± 33
vs
vs
vs
A,
s
VP 34
D
D
v
VD
TD
TD
RD
PA
TA
D
VIST
MPT
MPT
MPT
MPR
VTD
V
VMP
by
VMPT+VT
Clinical
DCEP
-prednisone-based
3,
3,
3,
3,
3,
3,
3
3,
3,
3,
3,
3,
3
3,
3,
±
1.
D
32
llowed
Phase
VA
Phase
Phase
Phase
Phase
Phase
Phase
MP
Phase
Phase
Phase
Phase
maintenance
Phase
Phase
Phase
fo
maintenance
Phase
maintenance
Table
Study/Regimen
Dexamethasone-based
Doxorubicin+dexamethasone-ba
Melphalan
Bortezomib+thalidomide
& 2011 Macmillan Publishers Limited
Leukemia (2011), 1 - 13

Management of peripheral neuropathy in myeloma
PG Richardson et al
4
rates of overall and grade X3 PN of up to 55% and 10%,
8,
1,
respectively, have been seen (Table 2).31,34 - 36,55 - 61 Systematic
rade
PN
A,
G
ys
reviews of studies of single-agent thalidomide and of thalido-
to
5
15
IST
during
da
and
mide - dexamethasone in relapsed MM reported an overall
V
Discon.
2
due
incidence of 22% grade 1/2 and 6% grade 3/4 TiPN,62 and an
elphalan,
thalidomide;
rates
m
;
overall incidence of 27%,63 respectively. In contrast, no severe PN
,
examethasone.
20.5%
4
mg/m
PT
d
r
and markedly reduced overall incidences compared with thalido-
1.3
y,
examethasone;
PN
o
:
y,
M
d
2
3
V
mide have been reported in studies of lenalidomide (Tables 2
and 3; rates of grade X3 PN: 0 - 2%).64 - 71 Preliminary data also
(%)
prednisone,
rade
3/4
sensor
sensor
both)
both)
dexamethasone;
Grade
g
suggest low-to-intermediate incidences with pomalidomide.72,73
PN
Grade
,
b
cycles;
(3
neuralgia,
3
(16
neuralgia,
8
.
%
When administered as part of the vincristine, doxorubicin,
8
3
8
5
rednisone;
low-dose
thalidomide,
9
2
p
,
,2
aintenance.
dexamethasone or pegylated/liposomal doxorubicin, vincristine,
m
tezomib
review
5-week
T
dexamethasone regimens, vincristine has been associated with
melphalan,
V
bor
,
the
rade
rates of grade X2 neurotoxicity of 10 - 13% and 15%, respec-
,
tezomib
g
(two
elphalan,
D
in
tively.33,74,75 The relatively low reported incidence and severity
1/2
V
bor
Grade
NR/13
NR/26
m, lenalidomide,
,
14%
during
may be because of the generally short duration of treatment or
,
tezomib
treatment-emergent
MP
d
TD
phase
R
V
the infusional administration route, which results in low peak
of
bor,
were
concentrations. In a phase 3 Eastern Cooperative Oncology Group
addressed
study, with a planned treatment duration of 10 cycles (B1 year),
yeloma;
asone;
VMPT
PAD)
neuropathy
the vincristine, carmustine, melphalan, cyclophosphamide and
Incidence
All
NR
NR
m
examethasone;
3
grades
d
methasone;
prednisone regimen was associated with 24% grade X2 PN,76
consolidation
specifically
llowing
possibly due to the bolus administration of vincristine.
exameth
exa
d
d
the
Grade
rednisone;
(fo
Although administration of neurotoxic agents in combination
multiple
in
p
,
N
orubicin,
4%
might be expected to increase the risk of PN, clinical evidence
372
139
x
agents
MM,
od
or
A;
suggests this is not always the case. Studies of bortezomib plus
rubicin,ox
VIST
thalidomide (VT) alone or with dexamethasone, prednisone,
elphalan,
do
in
or melphalan - prednisone have not reported a notable increase
lenalidomide,
m
agents
maintenance
respectively
orubicin;
,
,
,
in therateorseverityofPN(Table1).31,34,35,77 --80 Furthermore,
xo RD; vincristine,
TD
lower-than-expected rates of severe PN have been reported for
d
,D
nda
bortezomib plus lenalidomide combinations,81,82 with grade 3 PN
AV tezomib
tezomib
eurotoxic
employed
or
carmustine,
n
or
rates of 3% and 2% with bortezomib, lenalidomide and dexametha-
b
r
b
therapy
VTD
,
sone (RVD) in frontline and relapsed/refractory patients, respec-
fo
of
liposomal
neuropathy
l,
tively.81,82 An exception is the phase 1/2 EVOLUTION study, in which
with
tezomib;
VMP
regimen
during
17% of patients experienced grade 3/4 PN;83 unlike the other RVD
cycles
cycles
Doxi
PN
bor
vincristine,
the
,
studies, dexamethasone dosing was not partnered with bortezomib
Planned/Median
duration
9/9
9/9
provided
eripheral
V
ith
Rates
3/4
dosing. The low rates seen in most RVD studies may be associated
p
w
rednisone;
only
using
with the anti-inflammatory effects of lenalidomide or the dosing
;
p
y
32,
PN,
grade
are
schedule of dexamethasone, or both.
29,
and
protocol.
0%
Low rates of BiPN have also been reported when bortezomib is
mg/da
25,
tezomib
cycles
alternating
etails
administered in combination with pegylated liposomal doxo-
dexamethasone;
d
and
50
examethasone;
:
22,
d
bor
rubicin (4% versus 9% for bortezomib alone)39 or, in mostly small
T
ex,
1%
D
d .
studies, with novel, investigational agents such as heat-shock
11,
22;
6-week
melphalan
treatment
4
8,
examethasone;d
r
protein 90, p38 MAPK and histone - deacetylase inhibitors.84 - 89
o
15,
4,
ith
rednisonep indicated;
3
bi-weekly
For some studies this may be partially associated with a limited
ntire
8,
1,
w
g/day;
e
cisplatin;
ise
r
treatment duration, or possibly with a patient selection bias.
1,
ys
m
thalidomide,
w
ed
,
fo
da
0
grade
Negligible PN has been seen when these agents have been
5
orubicin,x D
days
2
:T
o
T
other
receiv
combined with lenalidomide.
2
;
d
15%
-9
,
shown
,
mg/m
Assessment
5
etoposide,
2
,
mg/m
unless
1.3
lophosphamide,
les
ates
atientsp
Effects of dose and schedule
a
:
R
1.3
V
tezomib
cyc
11 c
:
;
cyc
grade
The incidence of BiPN increased with cumulative dose using the
V
nd
;
ly
bor
examethasone;
Myeloma:
a
ly
29,
phamide
,
26%
VMPT
standard dose and schedule, generally occurring after five 3-week
d
8
schedule
3
22,
4,
7
cycles (cumulative bortezomib dose
eek
B26 mg/m2) and reaching a
,
PAD
1,
and
w
bi-week
8
ultiple
were
plateau after approximately eight cycles (cumulative dose
,1
M
melphalan,
ys
and
,
cyclophos
ted;
da
AD)
B42 mg/m2) in the APEX trial in relapsed MM,43 and reaching a
orubicin,
dose
VMP
VMP
In
cycles
-4
x
transplantation.
V
o
plateau after approximately four 6-week cycles (cumulative dose
or
or
1
repor
d
on2
B45 mg/m2) in the VISTA trial in frontline MM.32 The subsequent
patients
not
risk of late-developing BiPN is low.32,42,43 Similarly, there is a
Planned
VMPT
5-week
VMPT
cycles
Therapy
carmustine,
R,
mg/m
ollowing(f VMP
relatively limited risk of developing BiPN among patients who
N
1.3
66
have received prior bortezomib; prospective and retrospective
)
MP 30
dexamethasone,
at
e
V
ly
VD+DCEP+first
,
thalidomide,
studies have shown that retreatment with bortezomib is
r
,
Standard
o
vincristine,
associated with rates of neuropathy of 16 - 39%, including 5 - 9%
,
DCEP
TAD
after
ntinued
dosed
grade 3 neuropathy (which included multiple MedDRA terms not
MPT
bi-week
thalidomide;
Initial
is
maintenance
mg/day).
V
vs
typically included in BiPN),90,91 and extended bortezomib therapy
(Co
3
as
9.2%
10:
does not increase the rate or severity of PN,92 suggesting that
1.
PN
T
4
prolonged exposure or retreatment does not result in cumulative
tezomib
Phase
weekly
CADE
22;
thalidomide;
ro
neurotoxicity; however, this may be because of a patient selection
Table
Study/Regimen
Abbreviations:
prednisone,
T,
VEL
VnBMCP/VnBAD
Bora 3 thalidomide 15,
bias.30,34,35,92,93
Leukemia (2011), 1 - 13
& 2011 Macmillan Publishers Limited

Management of peripheral neuropathy in myeloma
PG Richardson et al
5
Table 2.
Clinical incidence of PN in key phase 3 studies in patients with relapsed MM
Incidence of treatment-
Median duration of
Prior neurotoxic
emergent PN (%)
Discontinued.
Study/regimen
Planned dose and schedulea
therapy received
N
agents
due to PN
All
Grade
Grade
grades
1/2
3/4
Single-agent bortezomib
Phase 3 APEX,
V; 3-week cycles; then days 1, 8, 15, 22,
24+15/18 weeks
333
Vinca alkaloid
37
10/18
8/o19%
V vs dex43b
5-week cycles
75%; T 48%
Dex; 5-week cycles, then 4-week cycles
20+20/15 weeks
336
Vinca alkaloid
9NR
o1/o1NR
72%; T 50%
Phase 3 V+liposomal
V+Doxil; V: 1.3 mg/m2 days 1, 4, 8, 11,
8/5 cycles (24/15 weeks)
324
T/R 40%
35
NR
4
NR
doxorubicin (V+Doxil)
3-week cycles
vs V alone39
V: as for V+Doxil
8/5 cycles (24/15 weeks)
322
T/R 43%
39
NR
9
NR
Phase 3 MMY-3021
Subcutaneous V; 3-week cycles; ±dex
8 cycles/24 weeks
148
T/R 42%
38
32
6
NR
subcutaneous vs
intravenous V±dex44
Intravenous V, 3-week cycles; ±dex
8 cycles/24 weeks
74
T/R 53%
53
37
16
NR
Dexamethasone-based combinations
Phase 3 MM010, R+dex
R: 25 mg d 1 - 21; dex; 4-week cycles
Until disease progression/
176
T 30%, V 5%
NR
NR
0
NR
vs dex64
p11.3 monthsc
Dex; 4-week cycles
Until disease progression/
175
T 38%, V 4%
NR
NR
0
NR
p4.7 monthsc
Phase 3 MM009, R+dex
R: 25 mg days 1 - 21; dex; 4-week
Until disease progression/
177
T 42%, V 11%
NR
NR
2/0
NR
vs dex68
cycles
p11.1 monthsc
Dex; 4-week cycles
Until disease progression/
176
T 46%, V 11%
NR
NR/NR
1/0
NR
p4.7 monthsc
Abbreviations: APEX, Assessment of Proteasome Inhibition for Extending Remissions; Dex, dexamethasone; Dox, liposomal doxorubicin; NR, not reported;
PN, peripheral neuropathy; R, lenalidomide; T, thalidomide; V, bortezomib. aBortezomib is dosed at 1.3 mg/m2 on days 1, 4, 8, and 11 unless otherwise
indicated; details are only provided for neurotoxic agents or agents specifically addressed in the review. bBortezomib data from updated APEX analysis.43
cBased on median time to progression.
Table 3.
NCI CTCAE assessment of peripheral neuropathy; these definitions are not specific to MM and the classification of a PN event as grade 1 - 4
may be subject to investigator bias
Grade
01
2
3
4
5
Version 3.0
Neuropathy--
Normal
Asymptomatic; loss of deep
Sensory alteration or paresthesia
Sensory alteration or
Disabling
sensory
tendon reflexes or paresthesia
(including tingling), interfering
paresthesia interfering
(including tingling) but not
with function, but not interfering
with ADL
interfering with function
with ADL
Neuropathic pain
None
Mild pain not interfering with
Moderate pain; pain or analgesics
Severe pain; pain or
Disabling
function
interfering with function, but not
analgesics severely
interfering with ADL
interfering with ADL
Version 4.0
Peripheral sensory
Asymptomatic; loss of deep
Moderate symptoms; limiting
Severe symptoms;
Life-threatening
Death
neuropathy
tendon reflexes or paresthesia
instrumental ADL
limiting self-care ADL
consequences; urgent
intervention indicated
Peripheral motor
Asymptomatic; clinical or
Moderate symptoms; limiting
Severe symptoms;
Life-threatening
Death
neuropathy
diagnostic observations only;
instrumental ADL
limiting self-care ADL;
consequences; urgent
intervention not indicated
assistive device indicated
intervention indicated
Neuralgia
Mild pain
Moderate pain; limiting
Severe pain; limiting
---
---
instrumental ADL
self-care ADL
Abbreviations: ADL, activities of daily living; MM, multiple myeloma; PN, peripheral neuropathy. In NCI CTCAE version 4.0, `instrumental' ADL refers to
preparing meals, shopping for groceries or clothes, using the telephone, managing money and so on, whereas `self-care' ADL refers to bathing, dressing
and undressing, feeding self, using the toilet, taking medications and not being bedridden.
Studies that used lower doses or a weekly dosing schedule, in
(cumulative 18-month incidence of sensory PN: 27%, including
which patients received a lower dose intensity of bortezomib,
4% grade X3, versus 46%, including 21% grade X3).30 Compared
have reported a lower incidence of BiPN (Table 1).30,34,35,40,42,94
with VISTA,32 the incidence of grade 3/4 BiPN with bortezomib,
A subanalysis of the Gruppo Italiano Malattie EMatologiche
melphalan, prednisone was lower in the Programa para el
dell'Adulto study of bortezomib, melphalan, prednisone, thalido-
Tratamiento de Hemopati´as Malignas study of bortezomib,
mide versus bortezomib, melphalan, prednisone in elderly,
melphalan, prednisone versus bortezomib, thalidomide, predni-
previously untreated patients showed a significantly lower
sone 34 (Table 1), possibly associated with the use of only one
incidence of PN with weekly versus bi-weekly bortezomib
versus four 6-week cycles of bi-weekly bortezomib dosing. Smaller
& 2011 Macmillan Publishers Limited
Leukemia (2011), 1 - 13

Management of peripheral neuropathy in myeloma
PG Richardson et al
6
studies of weekly regimens using higher doses of bortezomib
variations contribute to the risk of BiPN.100 Additionally, an
(1.5 - 1.6 mg/m2) have also reported a low incidence of BiPN.95,96
independent pharmacogenomic analysis of whole blood samples
Additionally, data from a randomized phase 3 trial44 showed a
from patients enrolled in the VISTA trial identified an association
significant reduction in overall, grade X2, and grade X3 BiPN
between time to onset of BiPN and the immune gene CTLA4.101
with the use of subcutaneous versus intravenous administration of
An analysis of the genetic factors that affect TiPN identified
bortezomib in patients with relapsed MM. No loss of efficacy was
significant associations with SNPs in the ABC genes (ABCC1) and in
seen and pharmacokinetic studies showed a reduction in Cmax but
neurological genes such as SERPINB2, indicating that TiPN may
not systemic exposure, as well as equivalent proteasome
also be associated with neuro-inflammation and/or accumulation
inhibition.44
of damage or the inability to repair neuronal damage,102 although
The incidence and severity of TiPN is both dose- and duration-
the identified genes were distinct to those associated with BiPN.
related, with actuarial incidence increasing over the course of
The same authors also analyzed the genetic factors that affect
treatment.25 Although TiPN can occur after relatively short-term
vincristine-induced PN and detected little overlap in the genes
use (less than 20 g cumulative dose,25 B14 weeks at 200 mg/day),
associated with TiPN and vincristine-induced PN.102
it
generally
occurs
following
chronic
use
over
several
It is important to also highlight the possibility that different
months,6,24,25,54,97 and has even been reported some time after
patient populations in different regions of the world may be
treatment has been stopped.24 Nonetheless, relatively low-dose,
affected differently in terms of treatment-emergent PN by the
short-term thalidomide use has been shown to improve outcomes
agents under discussion.
in the context of a double transplant protocol, and to be feasible,
with limited rate of grade 3/4 TiPN (4%) and thalidomide
Reversibility
discontinuation due to TiPN (2%).98 Vincristine-induced PN is also
Although prolonged painful PN could adversely impact patient
associated with duration of exposure.28
quality of life, BiPN is at least partially reversible in the majority of
patients; for example, 60% of BiPN events completely resolved
Predisposing factors
within a median of 5.7 months in VISTA,32 and 64% of patients
with grade X2 BiPN experienced improvement/resolution within
In the phase 3 VISTA trial of bortezomib, melphalan, prednisone
a median of 3.6 months in APEX.43 Similarly, in transplant-eligible
versus melphalan, prednisone in frontline MM, by multivariate
patients who received induction with bortezomib, thalidomide,
analysis, a history of PN was the only consistent risk factor for any-
dexamethasone in a Gruppo Italiano Malattie EMatologiche
grade, grade X2 and grade X3 BiPN; age, baseline diabetes,
dell'Adulto phase 3 trial, 78% of patients with grade 3/4 PN
disease stage and creatinine clearance did not affect the
experienced improvement/resolution within a median of 26
incidence.32 Consistent with these findings, in the APEX trial of
days.31 The reversibility of BiPN has also been demonstrated in
bortezomib versus dexamethasone in relapsed/refractory MM,
preclinical neurophysiological and histological studies in a mouse
patients with baseline PN symptoms by FACT/GOG-Ntx assess-
model.12,13 Such reversibility may contribute to the feasibility of
ment appeared to have a higher risk of grade X3 BiPN, but age,
bortezomib retreatment; 90,91 however, patients who experienced
baseline glycosylated hemoglobin level and history of diabetes
prior BiPN should be treated with caution.
did not appear to affect the overall or grade 3/4 rates of BiPN.43
There is mixed evidence for the reversibility of TiPN. In the Total
Importantly, in the relapsed setting, prior therapy with known
Therapy 2 trial grade X2 PN improved to less than grade 2 within
neurotoxic agents did not appear to affect the incidence of
3 - 4 months of stopping thalidomide in 90% of affected
BiPN.42,43,90,91
patients.99 However, thalidomide is known to cause nerve damage
Evaluations of possible predisposing factors of TiPN have
that may be permanent,24 and some studies have reported that
reported conflicting results. In a study in relapsed/refractory MM
TiPN may resolve slowly or not at all.6,24
patients, age, sex and prior therapy were not predictive of TiPN.25
Complete recovery of cisplatin-induced PN is only likely to occur
However, in the Total Therapy 2 study (in which patients received
several years after cisplatin discontinuation.29
the neurotoxic agents thalidomide, vincristine and cisplatin),
frontline patients aged X65 years had a higher incidence of TiPN
than those aged o65 years.99
CLINICAL RECOMMENDATIONS
It has been postulated that parameters intrinsic to MM (for
Clinical examples of PN cases commonly seen in MM patients are
example, proinflammatory proteins and vascular mediators) may
shown in Box 1. As discussed recently,3 in the absence of curative
contribute to the emergence of PN and be reflected in primary
therapy for treatment-emergent PN in MM, prevention is a key
tumor cell gene expression profiles. Recent results from the
strategy for preserving quality of life and future treatment options.
phase 3 Dutch-Belgian Cooperative Trial Group for Hematology
All MM patients who are to receive neurotoxic drugs should be
Oncology and Intergroupe Francophone du Myelome trials have
clinically assessed for PN signs and symptoms before treatment
identified changes in gene expression profiles in MM plasma cells
initiation, particularly those with baseline PN, and throughout
that were significantly associated with BiPN and vincristine-
therapy. The use of dose modification for management of BiPN
induced PN, as well as significantly associated single-nucleotide
and TiPN remains the `gold standard' of care.
polymorphisms (SNPs).100 By gene expression profiling, genes
involved in drug-induced apoptosis, mitochondrial dysfunction
and peripheral nervous system development were significantly
Importance of early detection and monitoring
associated with early-onset (within one cycle) BiPN, whereas
Regular monitoring for treatment-emergent PN and early detec-
peripheral blood analyses identified significant SNPs located in
tion and intervention are important to manage symptoms and
genes involved in cell death, DNA repair and the development
prevent the development of more severe neuropathy,4 ideally
and function of the nervous system.100 Genes significantly
including assessment by the patient and/or oncology nurse with
associated with late-onset (cycles 2 and 3) BiPN again included
each dose of drug. This is particularly true for the small subgroup
those involved in nervous system development and function, and
of patients who develop severe, early-onset BiPN (in APEX, 14 [4%]
significant SNPs were identified in inflammatory genes and DNA
patients discontinued bortezomib because of grade X2 BiPN
repair genes. Vincristine-induced PN was associated with a
within the first three cycles);43 this may respond to high-dose
different set of genes, suggesting that different molecular
corticosteroids and may be associated with viral infections. Clinical
mechanisms are involved compared with BiPN. These findings
experience suggests that regular monitoring is also important
suggest that both MM-related and inherent patient genetic
post-transplantation in patients with prior PN as, in a small
Leukemia (2011), 1 - 13
& 2011 Macmillan Publishers Limited

Management of peripheral neuropathy in myeloma
PG Richardson et al
7
Box 1.
How do we manage our patients with PN?
Patient A
Patient A, a 70-year-old gentleman, was diagnosed with International Staging System stage I MM in 2008. The patient received melphalan -
prednisone - lenalidomide. During treatment, his fasting glucose levels increased transiently, but the patient had no prior history of diabetes mellitus.
Following melphalan - prednisone - lenalidomide withdrawal due to inadequate response, the patient received salvage therapy with eight cycles of
bortezomib-dexamethasone. He achieved a very good partial response after seven cycles but started to complain of loss of feeling and numbness at
the tips of both upper and lower extremities from the fifth cycle. He subsequently reported pain, primarily in the lower extremities, and sleeping
became problematic; however, the symptoms did not interfere with his daily activities.
The patient was referred to a neurologist at the first appearance of symptoms and was monitored monthly thereafter. At the same time, he started
to feel dizzy when suddenly standing. He had a history of constipation. The neurologist diagnosed grade 1 progressing to grade 2 peripheral and
autonomic neuropathy. The patient was prescribed gabapentin 800 mg tid. Per dose-modification guidelines, the bortezomib dose was reduced to
1.0 mg/m2. After symptomatic relief, the gabapentin dose was reduced to 400 mg bid after completion of bortezomib-dexamethasone. At the end of
cycle eight, BiPN was re-evaluated as grade 1 and continues to improve. In all, 7 months after the start of neurological symptoms, the patient's main
concern is residual but mild numbness on the underside of his feet. He has noticed a gradual, sustained improvement in his other neurological
symptoms, confirmed by neurological examination. He is still receiving gabapentin 400 mg bid and remains in complete response (CR).
Patient B
Patient B, a 53-year-old gentleman, was diagnosed with International Staging System stage III MM in 2004. He achieved a CR with vincristine,
doxorubicin, dexamethasone induction followed by high-dose melphalan and autologous stem cell transplantation (HDT-ASCT), without symptoms
or signs suggestive of neuropathy. After symptomatic relapse in 2007, he received re-induction with bortezomib - dexamethasone. After four
bortezomib infusions, the patient started to experience numbness in his feet, which rapidly progressed to a severe ataxia in both hands and feet,
left him unable to walk, and severely affected dexterity. Within a few days he was unable to sit without support. The patient experienced dysesthesias
in all four limbs, but did not consider these painful. On neurological examination a minimal quadriparesis of both proximal and distal muscles
(Medical Research Council grade 4+) was present. Pinprick sensation was absent below the elbow and knee, vibration perception was absent below
the elbows and pelvis. Tendon reflexes were absent in the arms and legs. By EMG examination, sural, median and ulnar sensory nerve potentials
could not be evoked, whereas motor NCS were normal. Following immediate discontinuation of bortezomib, the patient gradually recovered and
was able to walk without support within 6 months, and has since returned to good functional status. Following the abbreviated bortezomib-based
treatment the patient was treated with dexamethasone alone for 6 months. At restaging he had achieved a stringent CR, which was ongoing in April
2010.
Patient C
Patient C, a 54-year-old gentleman, was diagnosed with International Staging System stage I MM in 2001. He received pamidronate, thalidomide and
dexamethasone and achieved CR within 6 months. He then underwent HDT-ASCT, received thalidomide maintenance (100 mg daily) together with
continued bisphosphonates, and remained in CR for the next 7 years. After B1 year on thalidomide, he developed paresthesias in both feet. EMG
examination and NCS suggested a small-fiber neuropathy. Over subsequent years, the paresthesias became more prominent, despite receiving
nutritional supplements including alpha-lipoic acid, vitamin B complex and L-carnitine. Electrophysiological studies were consistent with a moderate,
generalized, axonal and sensory polyneuropathy. Pregabalin was eventually added, and thalidomide dosing was reduced to 50 mg daily, leading to
improvements in TiPN symptoms.
In early 2008, relapsed MM in his left proximal femur was proven on biopsy as well as recurrent disease in his thoracic spine and several other bony
sites documented on PET/CT. He received radiation therapy to areas of symptomatic bone disease, followed by salvage induction with six 21-day
cycles of lenalidomide, bortezomib, low-dose dexamethasone (RVd). His pain completely resolved and a follow-up PET/CT scan confirmed CR. The
patient successfully underwent a second HDT-ASCT, after which his neuropathy worsened significantly, with symptoms beginning after high-dose
cyclophosphamide was administered for stem cell mobilization. He developed a burning sensation, numbness and a sensation of coldness in his legs
and feet, which worsened after re-engraftment and recovery. Neurological examination was notable for slight weakness of toe extensors, mild loss of
sensation to cold and vibration distally in the lower extremities, and loss of ankle jerks. EMG and NCS analyses showed a generalized axonal sensory
polyneuropathy. His symptoms were controlled with pregabalin 300 mg twice-daily and doxepin 25 mg at night. The use of emollients (cocoa butter,
menthol-based cream) also proved helpful, together with regular therapeutic massage of his extremities. Nutritional supplements appeared to have
some additional benefit and his BiPN improved to grade 1 (mild lower extremity hypoesthesia and paresthesia only).
Following sustained improvement in BiPN, he received two cycles of RVd. Full restaging confirmed sustained CR and his BiPN remained stable. The
patient then received maintenance therapy with lenalidomide and weekly bortezomib 1.0 mg/m2. He also continued on bisphosphonate infusion
without complication. His BiPN remains mild (grade 1) and is not painful, with no limitations to his activities of daily living, and his symptoms are well
controlled on low doses of pregabalin and doxepin. A total of 2 years after the second ASCT he remains in CR.
Commentary
The patients presented are from the United States, Europe and the Near East, showing the commonalities and differences in PN management
according to international practice.
In the first case, following initial melphalan - prednisone - lenalidomide therapy, salvage therapy with bortezomib-based treatment resulted in a
high quality response. Unfortunately, by the fifth cycle, PN began to emerge with symptoms typical of BiPN. Bortezomib dose reduction and the use
of gabapentin provided symptomatic relief and allowed completion of the planned eight cycles of therapy. Importantly, the patient entered CR and,
while requiring ongoing treatment for mild residual BiPN, he had a sustained neurological improvement, with no significant residual impact on his
activities of daily living.
The second patient reflects an especially challenging presentation of BiPN in which after just one cycle of treatment a rapidly progressive and
severe PN emerged, prompting discontinuation. Interestingly, although the sensory aspects were profound and ataxia was noted, EMG examination
showed normal motor nerve conduction and confirmed marked sensory nerve dysfunction. In keeping with the reversibility of BiPN, the patient
recovered after cessation of bortezomib. His disease responded with dexamethasone, which may also have helped reverse at least the inflammatory
component of BiPN.
The third patient represents initially an example of TiPN, demonstrating the cumulative nature of thalidomide-associated neurotoxicity. This
proved manageable with pregabalin and dose reduction. Unfortunately, the patient's disease recurred, prompting salvage with RVd. Interestingly,
BiPN with RVd was not a clinical feature until after cyclophosphamide administration. This relationship to alkylator exposure has been reported, and
in this patient's case was also more apparent after HDT-ASCT. Comprehensive evaluation confirmed a generalized axonal sensory polyneuropathy.
Use of both pregabalin and doxepin proved successful, as did the use of emollients and supplements. His BiPN improved over time and he was able
to proceed to consolidation therapy with RVd. Maintenance followed, incorporating bortezomib on a weekly schedule and at reduced dose;
conversely, he is tolerating lenalidomide at full dose without significant complication.
In summary, these three cases illustrate in detail the importance of a proactive, integrated approach to the management of treatment-emergent
PN in MM. In all three patients, the successful outcomes reflect how through dose-reduction, schedule change and the rational use of combination
therapies for MM as well as appropriate pharmacotherapy for PN, nutritional supplements and supportive care, this otherwise daunting and
dose-limited complication can be successfully managed.
& 2011 Macmillan Publishers Limited
Leukemia (2011), 1 - 13

Management of peripheral neuropathy in myeloma
PG Richardson et al
8
number of patients, PN symptoms may become relatively more
The value of NCS has been highlighted in cases of TiPN. Some
problematic even several months post-transplant.
electrophysiological studies have shown that patients with TiPN
The NCI CTC definitions of PN are commonly used in the clinic
have decreased sensory nerve action potential amplitudes,19,25,97
(Table 3). These definitions may be more useful when used
which has been suggested as the most sensitive parameter for
in
conjunction
with
neuropathy-specific
patient-completed
detecting TiPN.109 Consequently, assessment of peripheral nerve
questionnaires such as the FACT/GOG-Ntx,103 the (reduced) Total
function has been proposed to manage TiPN. However, the
neuropathy score,42,104 the European Organisation for Research
procedures are more invasive than questionnaires and may not
and Treatment of Cancer CIPN20 questionnaire,105 and the
always reliably assess the severity of treatment-emergent PN; it
CI-PERINOMS tool,106 which may identify PN symptoms before
has therefore been suggested that these procedures alone should
adverse event reporting by physicians. However, none were
not be used for diagnosis and treatment decisions, but may help
developed specifically for MM, and each has limitations. Impor-
to distinguish confounding cases in conjunction with other
tantly, attempts to correlate patient-reported neuropathy using
assessments.6
these tools with that reported by neurologist examination or
clinical assessment have shown varying results. The reduced Total
Treatment of treatment-emergent PN
neuropathy score has been correlated with NCI CTC grading in
Care should be taken when prescribing agents for the treatment of
some analyses,104 but data from bortezomib studies in re-
treatment-emergent PN as their use could result in continued
lapsed42,43 and frontline5 MM have not shown a correlation
dosing of neurotoxic MM therapy at the same intensity, which in
between neuropathy reported by neurologist examination, clinical
turn could possibly cause permanent nerve damage because of
assessment and patients using the FACT/GOG-Ntx questionnaire.
prolonged treatment. Several interventions have been investigated
There remains a need for more sensitive, patient-focused
for chemotherapy-induced PN, but none has yet been prospectively
PN
assessment
tools
that
specifically
focus
on
the
PN
assessed in MM-specific PN or in combination with the agents
symptoms of MM patients. One suggestion is the develop-
discussed here. Commonly used approaches include anti-epileptic
ment of a simple visual analog scale, similar to that used to assess
agents and antidepressants. Acetyl-L-carnitine has shown activity in
pain in solid tumors,107 with which patients could easily assess
the treatment of chemotherapy-induced PN.110 Alpha-lipoic acid,
their current symptoms relative to a previous visit and any
which is approved in the European Union for treatment of diabetic
improvement or worsening of symptoms would be quickly
neuropathy, has been shown to be effective against oxaliplatin-
detected.
induced polyneuropathy in patients with advanced colorectal
Knowledge of predisposing factors may allow identification of
cancer.111 Recently, double-blind, placebo-controlled studies have
patients at risk of PN; however, at present, there is little consistent
shown promising results with topical baclofen, amitriptyline and
evidence for predisposing factors, particularly in frontline MM.
ketamine112 in chemotherapy-induced PN, and with the antide-
In addition, pharmacogenomic analysis may allow the develop-
pressant venlafaxine in colorectal cancer patients with oxaliplatin-
ment of a SNP classifier for predicting PN; further work is needed
induced PN.113 Positive results have also been reported with topical
to determine the feasibility of this approach.
menthol cream in a patient with bortezomib-induced neuropathic
pain,114 as well as with electro-acupuncture in lung and breast
cancer patients.115 No controlled comparative data are available in
Neurological assessment in the management of
treatment-emergent PN
MM patients; treatment remains empiric.
Early neurological assessment, after each cycle of therapy, may be
useful in the effective management of treatment-emergent PN in
Prophylaxis
conjunction with more regular assessment by the treating
On the basis of trials and anecdotal evidence in MM, potential PN
physician, patient and oncology nurse. The incidence of PN has
prophylaxis in MM patients could include: vitamin supplements,
been shown to differ by clinical and neurologist assessment, with
including multi-B complex with B1, B6 and B12, folic acid and
one study reporting a baseline clinical incidence of 20%, whereas
vitamin E; magnesium supplement; increased dietary potassium
54% of patients who had a neurological assessment showed
intake; amino acid supplements, fish oils, omega-3 fatty acids,
abnormal findings at diagnosis.5 Early neurological assessment
evening primrose oil, and flax seed oil; medications as indicated,
may therefore allow early identification of cases of treatment-
including gabapentin, pregabalin, amitriptyline and duloxetine;
emergent PN and neurological monitoring (using nerve conduc-
and topical creams such as cocoa butter.5 Daily vitamins,
tion studies (NCS) and the reduced Total neuropathy score) has
gabapentin and nortryptiline have been combined in a step-wise
been shown to reduce the incidence of BiPN.108 However, in
cocktail for frontline MM patients experiencing grade X1PNor
contrast, another study in patients with relapsed/refractory MM who
neuropathic pain treated at the Dana - Farber Cancer Institute
were treated with thalidomide indicated that careful clinical
(Supplementary Table 2).5 There remains a need for prospective
examination was better for monitoring PN than nerve electro-
evaluation of the effects of these interventions in the prevention
physiological studies.25 Further studies are needed to determine
of PN specifically associated with different MM therapies.
whether action should be taken based on abnormal neurological
Additionally, neuro-rehabilitation through physical and occupa-
findings alone.
tional therapy might be considered for prospective evaluation in
Clinical assessment by a neurologist can be useful firstly in
patients developing TiPN or BiPN.
determining whether PN is treatment-emergent or MM-asso-
ciated. Electromyograms (EMGs) may be useful in this respect
Agent-specific recommendations for PN management
because many MM-associated polyneuropathies are primarily
Although the choice of MM agent for each individual patient is
demyelinating, whereas treatment-emergent PN is largely axonal.
based on many factors, it is important that the burden of MM-
Second, a neurologist may reliably discern motor neuropathy from
associated PN be considered together with that of treatment-
myopathy, which is mostly steroid-induced in MM patients. Third,
emergent PN; MM agents that induce rapid and durable responses
clinical neurological assessment may accurately determine the
may also reduce the burden of MM-associated PN.
severity of motor neuropathy, sensory neuropathy and neuralgia
according to the NCI CTC criteria. Finally, a neurologist may start
Bortezomib. On the basis of experience in phase 2 studies,
and monitor symptomatic treatment of PN using anti-epileptic or
evidence-based dose-modification guidelines were developed
antidepressant medications. Such patients should be monitored
for the management of BiPN and are included in the prescribing
until their pain is adequately controlled.
information for bortezomib (Table 4).43 Table 4A reflects existing
Leukemia (2011), 1 - 13
& 2011 Macmillan Publishers Limited

Management of peripheral neuropathy in myeloma
PG Richardson et al
9
Table 4.
Currently recommended (A) and new proposed (B) dose-modification guidelines for bortezomib-related neuropathic pain and/or peripheral
sensory or motor neuropathy
(A) Currently recommended dose-modification guideline for bortezomib-related neuropathic pain and/or peripheral sensory or motor neuropathy23
Severity of peripheral neuropathy signs and symptoms
Modification of bortezomib dose and regimen
Grade 1 (paresthesias, weakness and/or loss of reflexes) without pain or loss
No action
of function
Grade 1 with pain or Grade 2 (interfering with function, but not with activities
Reduce bortezomib dose to 1.0 mg/m2
of daily living)
Grade 2 with pain or Grade 3 (interfering with activities of daily living)
Withhold treatment until toxicity resolves. When toxicity resolves, reinitiate with
a reduced dose of bortezomib at 0.7 mg/m2 and change treatment schedule to
once per week
Grade 4 (sensory neuropathy that is disabling or motor neuropathy that is
Discontinue bortezomib
life-threatening or leads to paralysis)
(B) New proposed dose-modification guideline (see text for discussion)3
Severity of peripheral neuropathy
signs and symptoms
Modification of bortezomib dose and regimen
Supportive data
Grade 1 (paresthesias, weakness
Reduce current bortezomib dose by one level
Prior peripheral neuropathy was the only risk factor associated with
and/or loss of reflexes) without
(1.3 - 1.0 - 0.7 mg/m2) Or, for patients receiving a
bortezomib-related peripheral neuropathy in newly diagnosed patients
pain or loss of function
twice-weekly schedule, change to a once-per-week
treated with VMP32
schedule using the same dose
Baseline peripheral neuropathy was a risk factor for development
Consider starting with 1.3 mg/m2 once per week in
bortezomib-related peripheral neuropathy of grade X3 in relapsed/
patients with history of prior peripheral neuropathy
refractory MM patients treated with single-agent bortezomib42
A VMP regimen using bortezomib 1.3 mg/m2 once weekly from the start of
therapy showed reduced neurotoxicity and delivered a similar cumulative
dose of bortezomib to that in VISTA, and resulted in similar efficacy30
Grade 1 with pain or Grade 2
For patients receiving twice-weekly bortezomib,
Early reduction of bortezomib from 1.3 mg/m2 twice weekly to once weekly
(with no pain, but limiting
reduce current dose by one level, or change to a
in patients receiving VMP showed reduced neurotoxicity, delivered similar
instrumental activities of daily
once-per-week schedule using the same dose.
cumulative dose of bortezomib to that in VISTA, and resulted in similar
living)
For patients receiving bortezomib on a once-per-week
efficacy34
schedule:
Dose-reduction strategies including dose reduction from 1.3 to 1.0 mg/m2,
reduce current dose by one level, OR
changing from twice-weekly to once-weekly dosing, and withholding of
consider temporary discontinuation; upon
bortezomib resulted in improvement or resolution of peripheral neuropathy
resolution (grade p1), restart once-per-week dosing
in most patients with bortezomib-related peripheral neuropathy32,43
at lower dose level in cases of favorable benefit-to-
risk ratio
Grade 2 with pain, Grade 3
Discontinue bortezomib
Discontinuation as part of a peripheral neuropathy management strategy
(limiting self care and activities
resulted in improvement or resolution of clinically significant neuropathy in
of daily living), or Grade 4
71% of patients in an analysis of two phase 2 studies of bortezomib42
Abbreviations: MM, multiple myeloma; VMP, bortezomib, melphalan - prednisone. In part A, grading for this currently recommended dose-modification
guideline is based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. In APEX, the dose-modification
guideline used was the same, but based on NCI CTC version 2.0 grading; in addition, patients experiencing grade 3 peripheral neuropathy with pain were to
discontinue bortezomib. In part B, a for part A, grading is based on NCI CTCAE v3.0.
guidelines. Table 4B is a recommended approach generated by
Thalidomide. Dose modification and discontinuation should also
consensus for combination regimens. Early monitoring and
be used for TiPN. As suggested recently,117 in clinical practice,
prompt use of these evidence-based dose-modification guidelines
thalidomide is often dose-reduced in cases of grade 2 TiPN and
have been shown to lead to improvement or resolution of BiPN,
discontinued for grade X3 TiPN, with resumption of dosing if TiPN
while maintaining therapeutic efficacy,43 and these guidelines
improves to grade 1. However, there remains a need for a
should be used routinely. Use of weekly bortezomib dosing in
validated dose-modification guideline for TiPN. On the basis of
combination regimens might be an effective dose-modification
available data, it has been suggested that thalidomide be limited
strategy for grade 1 BiPN, but further research is needed to
to o200 mg/day to minimize TiPN and should be dose-reduced or
determine how this might be integrated into the current
discontinued in patients with grade 2 or 3 TiPN, respectively.118
guidelines.
We recommend that thalidomide be discontinued once grade 2
The reversibility of BiPN in a substantial proportion of patients has
TiPN occurs, and restarted with a 50% dose reduction upon
been repeatedly demonstrated.5,32,42,43,94,116 Patients with prior BiPN
resolution to grade p1 if the risk-benefit ratio is favorable.3
are not necessarily precluded from receiving subsequent bortezo-
Additionally, patients with grade 1 TiPN should have their
mib-based therapy, although such patients should be treated with
thalidomide dose reduced by 50%.3 Dose modification and dis-
appropriate caution. One possible approach would be to commence
continuation can also be used to reduce the risk of TiPN evolving.
retreatment with bortezomib using a lower dose or a once-weekly
For example, during maintenance treatment, the thalidomide
schedule, with subsequent escalation if tolerated.
dose could be reduced to 50 mg/day as soon as a patient has
Additionally, recent data44 showing a substantial reduction in BiPN
achieved a plateau response. Some studies have suggested that
with subcutaneous versus intravenous administration of bortezomib
thalidomide use should be limited to 6 months,25 although
highlights the potential importance of regimens utilizing subcuta-
prolonged use, limited to 6 - 12 months, may be feasible if low
neous bortezomib for minimizing the incidence of BiPN.
doses are administered.
& 2011 Macmillan Publishers Limited
Leukemia (2011), 1 - 13

Management of peripheral neuropathy in myeloma
PG Richardson et al
10
CONCLUSIONS AND FUTURE DIRECTIONS
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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
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Leukemia (2011), 1 - 13

Document Outline

Management of treatment-emergent peripheral neuropathy in multiple myeloma