The 40th Annual Meeting of the Japanese Society of Myeloma
Kumamoto, May 16, 2015

Pathophysiology and Management ofPeripheral Neuropathy in Multiple Myeloma
and Other Plasma Cell Dyscasias

Chiaki Nakaseko, MD, PhD
Department of Hematology
Chiba University Hospital日本骨髄腫学会
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筆頭発表者名： 中世古知昭

演題発表に関連し、開示すべきCO I 関係にある企業などはありません。

Paraproteinemic Neuropathies and NeurologicalProblems in Plasma Cell Dyscrasias
 Peripheral neuropathy (PN) is one of the mostimportant complications of multiple myeloma and otherplasma cell dyscrasias.
 PN can be caused by the disease itself, either by theeffects of the monoclonal protein or in the form ofradiculopathy from direct compression, and particularly by certain therapies, including
bortezomib and thalidomide.

 PN significantly affects patients’ QoL and treatment.

Potential Targets for Disease-related andDrug-induced Peripheral Neuropathy
InterneuronPain receptors

Sensory axon

Motor axon
1.
2.
3.
4.

Small fibers
Afferent sensory fibers
Dorsal root ganglion
Efferent motor fibers

Delforge M et al. Lancet Oncol 2010; 11: 1086–95

Demyelination and Axonal Degeneration in
Peripheral Neuropathy

MGUS-related Neuropathy
 Approximately 10% of patients with cryptogenic
polyneuropathy are secondary to a monoclonalgammopathy.
 Although IgG are the most common M-proteins found ingeneral population, peripheral neuropathies are morecommonly associated with IgM monoclonal gammopathy(IgM 60%, IgG 30%, IgA 10%).
 Half the patients with IgM MGUS-related peripheral
neuropathy have anti-myelin-associated glycoprotein(MAG) antibodies and also against other cross-reacting
glycoproteins in myelin.
Ropper AH. N Engl J Med 1998;338:1601-7

Anti-MAG Ab and other Abs against Myelin Protein

1. The demyelinating, predominantly
sensory neuropathies associatedwith anti-MAG Ab
2. The axonal, sensory neuropathies
associated with anti-sulfatide andanti-chondroitin sulfate Ab
3. The motor neuropathies associatedwith anti-GM1 Ab

Schwann cell

Ropper AH. N Engl J Med 1998;338:1601-7

Demyelination due to anti-MAG Antibody

Raheja D, et al. Muscle Nerve 2015; 51: 1–13

Left Median Nerve Electrophysiological Study
A. Anti-MAG Neuropathy

B. CIDP associated with IgG MGUS

Wrist
Elbow

Conduction block
Axilla
ERB’s

MNCV, motor nerve conduction velocity; CB, conduction block; DML, distal motorlatency; TLI, terminal latency index

Rajabally YA. Eur J Neurology 2011, 18: 1291–8

Placebo-Controlled Trial of Rituximab in
IgM anti-MAG Ab Demyelinating Neuropathy
B. Anti-MAG Ab

A. IgM
Placebo (n=13)

Placebo (n=13)

Rituximab (n=13)

Rituximab (n=13)

Dakaras MC et al. Ann Neurol 2009;65:286–93

Placebo-Controlled Trial of Rituximab in
IgM anti-MAG Ab Demyelinating Neuropathy
A. Neuropathy Leg Score

B. 10m walk time

PlaceboRituximab

Dakaras MC et al. Ann Neurol 2009;65:286–93

Paraproteinemia and Neurological Disorder (1)ClinicalElectrodiagnostic

Nerve biopsy

IgM MGUS Slowly progressive,
distally
predominant, andsensory more thanmotor

Demyelinating.
Markedly prolonged
distal motor latencies.
Reduced TLI.

IgM, and complement
deposits on myelin.
Widening of myelin
lamellae

IgG andIgA MGUS

Distally
predominantsensorimotor orproximal weakness
as in CIDP

Axonal or acquired
demyelinating(as in CIDP*).

Endoneurial Ig
deposits.
Widening of myelin
lamellae. Endoneurial
inclusions in IgA.

WM

Neuropathy slowly
progressive, distal,and sensory >motor

Similar to IgM MGUS. See IgM MGUS
Rarely axonal ormixed.

★CIDP: chronic inflammatory demyelinating polyneuropathy

Raheja D, et al. Muscle Nerve 2015; 51: 1–13

Systemic Amyloidosis

Most Common Types of Systemic Amyloidoses
TypeAbbreviation

Precursor

Site ofSynthesis

Syndrome and Organ Involved

Immunoglobulin
light chain
amyloidosis

AL

Monoclonal
light chainBMplasmacells

・Primary amyloidosis
・10-15% of MM・Involvement of heart, kidneys, liver,
GI tract, peripheral nerves, autonomicnerves, soft tissues

Reactiveamyloidosis

AASerumamyloid ALiver・Secondary to chronic inﬂammation,infection, or certain neoplasia
・Involvement of kidneys, GI tract,
spleen, liver, autonomic nerves

Senile systemic
amyloidosis

SSA

Transthyretin
wild type

Liver・Age-related, usually males
・Primarily cardiac involvement

Transthyretin
amyloidosis

ATTR

Varianttransthyretin

Liver・Hereditary・Involvement of peripheral nerves,autonomic nerves, heart, eye,leptomeninges, rarely kidneys★To date, at least 28 different proteins have been identiﬁed as
causative agents of amyloid diseases
Merlini et al. J Clin Oncol 2011; 29:1924-33

Clinical manifestations at diagnosis in 202
Japanese Patients with systemic AL amyloidosis(n)Matsuda M et al. Intern Med 2014; 53: 403-12

Amyloid Neuropathy

Congo red stain

Viewed with polarized light
Raheja D, et al. Muscle Nerve 2015; 51: 1–13

POEMS syndrome

16

POEMS syndrome（Crow-Fukase syndrome, Takatsuki dis）

P:polyneuropathy
O:organomegaly
E:endocrinopathy
M:M proteinemia
S:skin changes

Dispenzieri A, et al. Blood. 2003;101:2496-2506

Clinical Features in POEMS syndrome

19SerumVEGF

Watanabe et al. Lancet 1996; 347:702

Specific features of POEMS syndrome
Multiplemyeloma

POEMSsyndrome

MGUS

Heavy chain

IgG > IgA

IgA > IgG

IgG >IgA

light chaink>ll*1,2k>l> 95% of cases

M protein

>3000

<2000

<3000

BM plasma cells

>10%

<5%

<10%Serum VEGF

Not elevatedExtremelyelevated*3Not elevated(mg/dl)*1 Abe D, et al. Blood 2008; 112:836-9*2 Li J, Ann Hematol 2012; 91, 1251-5.
*3 Watanabe O, et al. Lancet. 1996; 347:702

21

Revised Diagnostic Criteria of POEMS syndrome
Mandatory
major criteria

1. Polyneuropathy (typically demyelinating)
2. Monoclonal plasma cell-proliferative disorder (almost always λ)Other majorcriteria(one required)

3. Castleman disease
4. Sclerotic bone lesions
5. Vascular endothelial growth factor (VEGF) elevation

Minor criteria

6. Organomegaly (splenomegaly, hepatomegaly, lymphadenopathy)
7. Extravascular volume overload (edema, pleural effusion, ascites)
8. Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid,pancreatic)
9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid
hemangiomata, plethora, white nails)
10. Papilledema
11. Thrombocytosis/polycythemia

OtherClubbing、weight loss, hyperhidrosis, pulmonary hypertension,
symptoms and restrictive lung disease, thrombotic diathesis, diarrhea, low vitaminsigns
B12 values
Dispenzieri A. Ann Hematol 2012: 87:805–14

Severe Peripheral Neuropathy in POEMS Syndrome
 Patients initially present with sensory deﬁcits, including
paresthesias and coldness, starting distally.
 Motor symptoms usually follow, beginning in the distal lower
extremities and ascending, and eventually affecting bothproximal and distal muscles in a pattern similar to CIDP, leads
to greater disability.
 Cranial neuropathies are usually absent except forpapilledema, and autonomic symptoms are rare.

22

Severe Peripheral Neuropathy in POEMS Syndrome Electrodiagnostic studies commonly demonstrate bothaxonal and demyelinating features.
 Conduction block, which is common in CIDP, is rare inPOEMS.
 Nerve biopsies usually reveal features of both axonal
degeneration and demyelination. Inﬂammatory inﬁltrates
may be seen in the epineurium and endoneurium.
 In addition to demyelination, nerve edema induced byupregulated VEGF, and upregulated inﬂammatory cytokines
could modulate proﬁles of POEMS neuropathy.

Overall Neuropathy Limitations Score (ONLS)
Before and After ASCT
(N=15)
PN of POEMS is reversible!

Requireswheelchair*
Requiressupport towalk

**

**

36

48

Able to walk
independently

06

1224

Months after ASCT
25

Multiple Myeloma

26

Kosturakis AK, et al. J Clin Oncol 2014; 32:3156-6227

Patient Demographic and Clinical Characteristics (n = 27)

Kosturakis AK, et al. J Clin Oncol 2014; 32:3156-62

Reduced Innervation Density and Sensory
Function in Patients With MM

Touch Detection Thresholds

Bumps Detection

Kosturakis AK, et al. J Clin Oncol 2014; 32:3156-62

Reduced Innervation Density and Sensory
Function in Patients With MM

Manual dexterity

Sharpness Detection Threshold

Kosturakis AK, et al. J Clin Oncol 2014; 32:3156-62

Neuropathy Score and Correlation of Bumps
to Meissner’s Corpuscle (MC) Density

Meissner’s corpuscle (MC) density in theﬁngertips was assessed using in vivo laser
confocal microscopy

Kosturakis AK, et al. J Clin Oncol 2014; 32:3156-62

Paraproteinemia and Neurological Disorder (2)ClinicalElectrodiagnostic

Nerve biopsy

Primary
Neuropathy
Amyloidosis painful andSensorimotor
Dysautonomia

Axonal sensorimotor
Amyloid on Congo-red
neuropathy.
staining. Light chains
Carpal tunnel syndrome. on immunohistochemistry.

POEMS
Syndrome

Ascendingsensorimotor
symptoms.
Weakness
eventually
predominating

Mixed axonal,demyelinating.
No conduction blockor dispersion.
Normal TLI.

Axonal degeneration.
Loss of myelinatedfibers. Inflammation
and uncompacted
myelin lamellae

Multiple
Myeloma

Neuropathies
areheterogeneous

Almost always axonal,
but very rarely
demyelinating.

Axonal degeneration.
May show amyloiddeposits.

Raheja D, et al. Muscle Nerve 2015; 51: 1–13

Therapy-related neuropathy

33

Presenting Symptoms of Drug-induced Peripheral
Neuropathy in Multiple Myeloma
Sensory• Hypoaesthesia• Paraesthesia: numbness, tingling, pin-prick sensation• Hyperaesthesia• Ataxia, gait disturbance• Neuropathic painMotor• Weakness• TremorAutonomic• Constipation• Impotence• Orthostatsis• Bradycardia

Deﬁnition of Peripheral Neuropathy According
to CTCAE ver 4
Grade 1

Grade 2

Grade 3

Grade 4

Sensory
neuropathy

Asymptomatic;loss of deep
tendonreﬂexes orparesthesia

Moderate
symptoms:
limiting
instrumental
ADL

Severesymptoms:
limiting self-care
ADL

Life-threatening
consequences:
urgentintervention
indicated

Motorneuropathy

Asymptomatic;clinical or
diagnostic
observation onlyModerate
symptoms:
limiting
instrumental
ADL

Severesymptoms:
limiting self-care
ADL; assistive
device indicatedLife-threatening,disabling(eg, paralysis)

Neuralgia

Mild pain

Moderate pain;
limiting
instrumental
ADL

Severe pain;
limiting self-care
ADL-‘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 thetoilet, taking medications and not being bedridden.

Treatment of Neuropathic Pain

GroupsSpecific drug

Gabapentinoids
Tricyclic antidepressantsGabapentin, Pregabalin
Amitriptyline, Nortriptyline,
Imipramine
Paroxetine, Duloxetine, Venlafaxine
Carbamazepine, OxcarbazepineMorphine, Oxicodon, Fentanyl

SNRI
Anti-epileptics
Narcotis

Incidence of thalidomide-induced, lenalidomide-induced, andbortezomib-induced peripheral neuropathy in phase 2 and 3 studies

Thalidomide-induced versus bortezomibinduced neurological damage, according toneural structure involved

Dose-modiﬁcation guidelines for thalidomideinduced and bortezomib-induced neurotoxicity
Thalidomide

Bortezomib

Grade 1

Reduce thalidomide dose by
50%

Biweekly schedule:- Reduce current bortezomib dose by one
level or prolong dosing interval to once
weeklyOnce weekly schedule:- Reduce current bortezomib dose by one
level

Grade 2

Discontinue thalidomide.
If the neuropathy resolves tograde 1 or better, treatment may
be restarted at 50% dose
reduction, if the beneﬁt-to-riskratio is favorable

Biweekly schedule:- Reduce current bortezomib dose by one
level or prolong dosing interval to once
weeklyOnce weekly schedule:- Reduce current bortezomib dose by one
level or consider temporary
discontinuation of bortezomib.

>=Grade 3

Discontinue

DiscontinueBortezomib s.c.

Moreau P. et al. Lancet Oncol 2011; 12:431-40

Cumulative bortezomib dose to ﬁrst onset of aperipheral neuropathy event ～VISTA trial

Bortezomib-induced neuropathy: Axonal
membrane depolarization precedes developmentof neuropathy

Nasu S, et al. Clin Neurophysiol. 2014;125:381-7.

Study design
Clinical and neurophysiological assessment was performed atbaseline, prior to every cycle, and at treatment completion

Nasu S, et al. Clin Neurophysiol. 2014;125:381-7.

Flow chart of patient involvement

Patient characteristics

Nasu S, et al. Clin Neurophysiol. 2014;125:381-7.

Sequential changes in parameters of thresholdelectrotonus and recovery cycle

Sensory nerve

Supersxcitability: 過剰興奮性TEd = deporalizing threshold electrotonus
Nasu S, et al. Clin Neurophysiol. 2014;125:381-7.

Sequential changes in parameters of thresholdelectrotonus and recovery cycle

Motor nerve

Nasu S, et al. Clin Neurophysiol. 2014;125:381-7.

Results
 Our results show that bortezomib induces sensory-dominantaxonal depolarization prior to the development of axonal
degeneration.
 Membrane depolarization can lead to nerve
hyperexcitability, consistent with positive symptoms suchas pain and paresthesia.
 Axonal excitability studies have a potential role in the early
diagnosis of neurotoxicity and can provide insights into
targets of therapeutic intervention; changes in excitability
indices can be detected at the earliest phase of bortezomibinduced neuropathy, when obvious axonal loss has not yet
developed.
Nasu S, et al. Clin Neurophysiol. 2014;125:381-7.

Conclusions
 We should aware that the incidence of paraproteinassociated peripheral neuropathy is significantly high.

 Most of PN are reversible by plasma cell-targetingtherapies.
 Collaborative approach with neurologists andphysiatrists from the diagnosis is necessary.
 An appropriate evaluation and effective management oftreatment-emergent PN is critical to minimize theincidence and severity of this complication in patientswith plasma cell dyscrasias.