Pathophysiology and Management of Peripheral …Peripheral neuropathy (PN) is one of the most...

Chiaki Nakaseko, MD, PhD

Department of Hematology Chiba University Hospital

Pathophysiology and Management of

Peripheral Neuropathy in Multiple Myeloma

and Other Plasma Cell Dyscasias

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

日本骨髄腫学会ＣＯＩ開示

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 Neurological Problems in Plasma Cell Dyscrasias

Peripheral neuropathy (PN) is one of the most

important complications of multiple myeloma and other

plasma cell dyscrasias.

PN can be caused by the disease 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 and thalidomide.

PN significantly affects patients’ QoL and treatment.

Potential Targets for Disease-related and

Drug-induced Peripheral Neuropathy

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

1. Small fibers 2. Afferent sensory fibers 3. Dorsal root ganglion 4. Efferent motor fibers

Sensory axon

Motor axon

Pain receptors

Interneuron

Demyelination and Axonal Degeneration in Peripheral Neuropathy

MGUS-related Neuropathy

Approximately 10% of patients with cryptogenic

polyneuropathy are secondary to a monoclonal

gammopathy.

Although IgG are the most common M-proteins found in

general population, peripheral neuropathies are more

commonly 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

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

1. The demyelinating, predominantly

sensory neuropathies associated

with anti-MAG Ab

2. The axonal, sensory neuropathies

associated with anti-sulfatide and

anti-chondroitin sulfate Ab

3. The motor neuropathies associated with anti-GM1 Ab

Schwann cell

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

Demyelination due to anti-MAG Antibody

Left Median Nerve Electrophysiological Study

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

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

A. Anti-MAG Neuropathy B. CIDP associated with IgG MGUS

Conduction block

Wrist

Elbow

Axilla

ERB’s

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

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

A. IgM B. Anti-MAG Ab Placebo (n=13)

Rituximab (n=13)

Placebo (n=13)

Rituximab (n=13)

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

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

A. Neuropathy Leg Score B. 10m walk time

Placebo

Rituximab

Paraproteinemia and Neurological Disorder (1)

Clinical Electrodiagnostic Nerve biopsy

IgM MGUS Slowly progressive, distally predominant, and sensory more than motor

Demyelinating. Markedly prolonged distal motor latencies. Reduced TLI.

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

IgG and IgA MGUS

Distally predominant sensorimotor or proximal 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. Rarely axonal or mixed.

See IgM MGUS

★CIDP: chronic inflammatory demyelinating polyneuropathy


Systemic Amyloidosis

Merlini et al. J Clin Oncol 2011; 29:1924-33

Type Abbre-

viation

Precursor Site of

Synthesis

Syndrome and Organ Involved

Immunoglobulin

light chain

amyloidosis

AL Monoclonal

light chain

BM

plasma

cells

・Primary amyloidosis

・10-15% of MM

・Involvement of heart, kidneys, liver,

GI tract, peripheral nerves, autonomic

nerves, soft tissues

Reactive

amyloidosis

AA Serum

amyloid A

Liver ・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 Variant

transthyretin

Liver ・Hereditary

・Involvement of peripheral nerves,

autonomic nerves, heart, eye,

leptomeninges, rarely kidneys

Most Common Types of Systemic Amyloidoses

★To date, at least 28 different proteins have been identified as

causative agents of amyloid diseases

Clinical manifestations at diagnosis in 202

Japanese Patients with systemic AL amyloidosis

Matsuda M et al. Intern Med 2014; 53: 403-12

(n)

Amyloid Neuropathy


Congo red stain Viewed with polarized light

POEMS syndrome

16

P:polyneuropathy

O:organomegaly

E:endocrinopathy

M:M proteinemia

S:skin changes

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

POEMS syndrome （Crow-Fukase syndrome, Takatsuki dis）

19

Clinical Features in POEMS syndrome

Watanabe et al. Lancet 1996; 347:702

Serum

VEGF

21

Specific features of POEMS syndrome

Heavy chain

light chain

M protein

BM plasma cells

Serum VEGF

IgA > IgG

l*1,2

<2000

<5%

Extremely elevated*3

IgG > IgA

k > l

>3000

>10%

Not elevated

> 95% of cases

POEMS syndrome

Multiple myeloma

(mg/dl)

IgG >IgA

k > l

<3000

<10%

Not elevated

MGUS

*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

Revised Diagnostic Criteria of POEMS syndrome

Mandatory major criteria

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

Other major criteria (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

Other symptoms and signs

Clubbing、weight loss, hyperhidrosis, pulmonary hypertension, restrictive lung disease, thrombotic diathesis, diarrhea, low vitamin 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 both proximal and distal muscles in a pattern similar to CIDP, leads to greater disability.

Cranial neuropathies are usually absent except for papilledema, and autonomic symptoms are rare.

22

Severe Peripheral Neuropathy in POEMS Syndrome

Electrodiagnostic studies commonly demonstrate both axonal and demyelinating features.

Conduction block, which is common in CIDP, is rare in POEMS.

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 by upregulated VEGF, and upregulated inflammatory cytokines could modulate profiles of POEMS neuropathy.

*

** **

Overall Neuropathy Limitations Score (ONLS)

Before and After ASCT

Requires support to walk

Requires wheelchair

Able to walk independently

Months after ASCT

0 12 24 36 48 6

(N=15)

25

PN of POEMS is reversible!

Multiple Myeloma

26

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

27


Patient Demographic and Clinical Characteristics (n = 27)


Reduced Innervation Density and Sensory Function in Patients With MM

Touch Detection Thresholds Bumps Detection


Reduced Innervation Density and Sensory Function in Patients With MM

Manual dexterity Sharpness Detection Threshold


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

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

Paraproteinemia and Neurological Disorder (2)

Clinical Electrodiagnostic Nerve biopsy

Primary Amyloidosis

Neuropathy painful and Sensorimotor Dysautonomia

Axonal sensorimotor neuropathy. Carpal tunnel syndrome.

Amyloid on Congo-red staining. Light chains on immuno-histochemistry.

POEMS Syndrome

Ascending sensorimotor symptoms. Weakness eventually predominating

Mixed axonal, demyelinating. No conduction block or dispersion. Normal TLI.

Axonal degeneration. Loss of myelinated fibers. Inflammation and uncompacted myelin lamellae

Multiple Myeloma

Neuropathies are heterogeneous

Almost always axonal, but very rarely demyelinating.

Axonal degeneration. May show amyloid deposits.


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 pain

Motor

• Weakness • Tremor

Autonomic

• Constipation • Impotence • Orthostatsis • Bradycardia

Grade 1 Grade 2 Grade 3 Grade 4

Sensory neuropathy

Asymptomatic; loss of deep tendon reflexes or paresthesia

Moderate symptoms: limiting instrumental ADL

Severe symptoms: limiting self-care ADL

Life-threatening consequences: urgent intervention indicated

Motor neuropathy

Asymptomatic; clinical or diagnostic observation only

Moderate symptoms: limiting instrumental ADL

Severe symptoms: limiting self-care ADL; assistive device indicated

Life-threatening, disabling (eg, paralysis)

Neuralgia Mild pain Moderate pain; limiting instrumental ADL

Severe pain; limiting self-care ADL

-

Definition of Peripheral Neuropathy According to CTCAE ver 4

‘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.

Treatment of Neuropathic Pain

Groups Specific drug

Gabapentinoids Gabapentin, Pregabalin

Tricyclic antidepressants Amitriptyline, Nortriptyline, Imipramine

SNRI Paroxetine, Duloxetine, Venlafaxine

Anti-epileptics Carbamazepine, Oxcarbazepine

Narcotis Morphine, Oxicodon, Fentanyl

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

Thalidomide-induced versus bortezomib-induced neurological damage, according to

neural structure involved

Dose-modification guidelines for thalidomide-induced 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 weekly Once weekly schedule: - Reduce current bortezomib dose by one level

Grade 2 Discontinue thalidomide. If the neuropathy resolves to grade 1 or better, treatment may be restarted at 50% dose reduction, if the benefit-to-risk ratio is favorable

Biweekly schedule: - Reduce current bortezomib dose by one

level or prolong dosing interval to once weekly

Once 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 a peripheral neuropathy event ～VISTA trial

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

Bortezomib-induced neuropathy: Axonal membrane depolarization precedes development of neuropathy


Study design Clinical and neurophysiological assessment was performed at

baseline, prior to every cycle, and at treatment completion

Flow chart of patient involvement

Patient characteristics


Sequential changes in parameters of threshold electrotonus and recovery cycle


TEd = deporalizing threshold electrotonus

Sensory nerve

Supersxcitability: 過剰興奮性


Sequential changes in parameters of threshold electrotonus and recovery cycle

Motor nerve


Our results show that bortezomib induces sensory-dominant

axonal depolarization prior to the development of axonal

degeneration.

Membrane depolarization can lead to nerve hyperexcitability, consistent with positive symptoms such as 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 bortezomib-induced neuropathy, when obvious axonal loss has not yet developed.

Results

Conclusions

We should aware that the incidence of paraprotein-

associated peripheral neuropathy is significantly high.

Most of PN are reversible by plasma cell-targeting

therapies.

Collaborative approach with neurologists and

physiatrists from the diagnosis is necessary.

An appropriate evaluation and effective management of

treatment-emergent PN is critical to minimize the

incidence and severity of this complication in patients

with plasma cell dyscrasias.

Pathophysiology and Management of Peripheral …Peripheral neuropathy (PN) is one of the most...

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