MRC Centre for Neuromuscular Disease

Neuropathies associated with myeloma and other plasma cell

disorders

UK Myeloma Forum MeetingLondon November 2011

Dr Michael LunnConsultant Neurologist and Clinical Lead in Neuroimmunology

National Hospital for Neurology and NeurosurgeryQueen Square

London WC1N 3BG

michael.lunn@uclh.nhs.uk

There is more to neuropathy than…

Common Terminology Criteria for Adverse Events v3.0 (CTCAE) – 2006….is a descriptive terminology which can be utilized for adverse event (AE) reporting.

• Grades 1-5 (minimal involvement – death)• Not really useful for neuropathy, or indeed very

much neurological• There is a lot more to neuropathy than CTCAE

Neuropathies associated with plasma cell disorders

• Anatomy revision

• Neuropathies associated with plasma cell disorders

• Typical and atypical presentations

• Toxicities of treatment

VESALIUS, Andreas (1514-1564)De humani corporis fabrica, Basel: Oporinus, 1543.lib. IV, pp.353-4Wellcome Library, London

skin

Background to ‘inflammatory’ neuropathy

• Paraprotein associated neuropathies part of group of inflammatory neuropathies

• Diverse group of disorders with presumed ‘immune mediated’ pathogenesis

• Inflammatory endoneurial infiltration and destruction of myelin and/or axons

• Wide differential– Primary (eg GBS) and secondary (connective tissue diseases,

paraproteinaemic etc)

Inflammatory Peripheral Neuropathy Idiopathic

Acute Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)

Acute motor axonal neuropathy (AMAN) Acute motor-sensory axonal neuropathy (AMSAN) Fisher Syndrome and other regional variants Pharyngeal-cervical-brachial

Paraparetic Facial palsies Pure oculomotor

Functional variants of GBS Pure dysautonomia Pure sensory GBS Ataxic GBS Subacute Subacute inflammatory demyelinating polyradiculoneuropathy (SIDP) Chronic Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Multifocal motor neuropathy with conduction block (MMNCB) Chronic relapsing axonal neuropathy Chronic ataxic sensory neuronopathy Paraproteinaemic neuropathy Monoclonal gammopathy of undetermined significance (MGUS) Multiple myeloma Solitary plasmacytoma Lymphoma or chronic lymphocytic leukaemia

Waldenström’s macroglobulinaemia Cryoglobulinaemia

Cold agglutinin disease

Primary amyloidosis

Vasculitic Neuropathy

Primary vasculitis Polyarteritis nodosa and Churg-Strauss disease

Wegener’s vasculitis Isolated nerve vasculitis Temporal arteritis Systemic autoimmune diseases with associated vasculitis Rheumatoid arthritis Systemic lupus erythematosus Sjörgren’s syndrome Mixed connective tissue disease Other Serum sickness Infectious, malignant, related to chemotherapy Inflammatory neuropathy associated with infection HIV neuropathies, including CMV neuropathy Leprosy Lyme disease Chaga’s disease Paraneoplastic

Sub-acute sensory neuropathy/neuronopathy - small cell lung carcinoma and anti-Hu Abs

Other paraneoplastic tumour-antibody syndromes Metabolic Diabetic lumbo-sacral plexopathy POEMS syndrome

Neuropathies associated with paraproteins

• Monoclonal gammopathy of undetermined significance– IgM +/- antiMAG paraproteinaemia– IgG and IgA– (others?)

• Waldenström’s macroglobulinaemia• Lymphoma - neurolymphomatosis• POEMS syndrome

– Solitary myeloma (osseous/extraosseous – lytic/sclerotic)• Amyloidosis• Cryoglobulinaemia• Multiple myeloma

Paraproteinaemic neuropathies associated with MGUS

• Neuropathy most commonly associated with MGUS• 3.5% patients with myeloma have neuropathy• Up to 70% with MGUS have neuropathy

• 10% patients with neuropathy have MGUS• IgM>IgG>IgA in association with neuropathy

• Different distribution to MGUS alone

• κ light chain over-represented• -light chain more often associated with malignant dyscrasia

• Neuropathy with IgG/IgA most often like CIDP• Demyelinating neuropathy with IgM separate

Monoclonal gammopathy of undetermined significance (MGUS)

• MGUS neuropathy often low levels of protein (0.5-5g/l) and no immunoparesis

• SPEP 26-66% sensitive. Ifx up to 96% sensitive• SPEP +/- IFx (for ID) if SPEP negative

Keren 1999 Arch Pathol Lab Med

• IFx for Bence-Jones protein useful even if serum negative

• Serum free light chains predict transformation to malignant clone RR 2.5 (CI 1.6-4)

Rajkumar et al Br J Haem 2004; Pratt Br J Haem 2008

• Serum free light chains have increased sensitivity (2mg/l cf 150mg/l) for light chain deposition disease (highly selected) but relevance in neuropathy unclear

Neuropathies and paraproteins

• Distal acquired demyelinating sensory neuropathy (DADS)

• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

• Distal length dependent (axonal/painful) sensory neuropathies

• Multiple mononeuropathies

Brandner S - NHNN

Brandner S - NHNN

Anti-MAG paraproteinaemic demyelinating peripheral neuropathy (DADS)

• Chronic progressive sensorimotor demyelinating neuropathy

– Elderly, male, ataxia and tremor

Anti-MAG paraproteinaemic demyelinating peripheral neuropathy (DADS)

• Chronic progressive sensorimotor demyelinating neuropathy

– Elderly, male, ataxia and tremor

• IgM paraprotein in serum• Paraprotein has ‘anti-MAG’ activity

• sees HNK-1 epitope• also on P0, PMP22, SGPG, SGLPG etc.• not clear which target is pathogenic in vivo ?MAG

• Characteristic neurophysiology and pathology

Myelin separation

Widely spaced myelin

Anti-MAG antibody may be pathogenic

• Witebsky’s postulates not yet fulfilled

– Anti-MAG antibody has defined PN target

– IgM bound to nerve

– Passive transfer to cats and chicks

– Immunisation failed to produce Abs so far – Characteristic myelin pathology

– ?response to treatment – or not

– However disease course prolonged and eventually results in axonal loss ?alternative mechanism

Lunn et al Brain 2002

Paraproteinaemic neuropathyDiagnosis and treatment

EFNS/PNS Recommendations1. All patients with paraprotein and neuropathy should be

assessed for a malignant plasma cell dyscrasia

2. Paraprotein more likely relevant if IgM, DADS or anti-MAG+

3. Typical phenotype of IgM PDN recognised

4. IgM PDN sometimes responds to Rx but some are toxic and their use must be balanced against clinical need

5. IgG and IgA PDN may be indistinguishable from CIDP in presentation and response to Rx

IgM paraproteinaemic (anti-MAG) neuropathy treatment

• Is treatment required at all?

– Elderly male, mild ataxia, tremor and unsteadiness – no falls

– No weakness, distal PP loss and VS to costal margin– IgMκ paraprotein, and demyelinating neuropathy– Anti-MAG antibody positive >70000 Bühlmann Units

Watch and wait….

You may do more good with a stick and some trainers…

IgM paraproteinaemic (anti-MAG) neuropathy treatment

• Are you treating the right thing?– 62 female– Long history severe OA and immobility. Smoker– Numb, painful red feet and ‘venous ulcers’ – Pronounced distal motor loss. PP=VS/JPS loss– Demyelinating neurophysiology– 4 x IgMκ paraproteins and anti-MAG antibodies

• Vasculitis and acquired erythermalgia with vasculitic neuropathy

• CD138 <5% plasma cells but IgM k restricted – ‘appearances are suggestive of myeloma than lymphoplasmacytic lymphoma…IgM very rare’

IgM paraproteinaemic (anti-MAG) neuropathy treatment

• Is treatment required at all?

– Indications:

• Haematological

• Progressive motor or sensory loss with instability• Progressive and disabling tremor• Younger age• Shorter disease duration

IgM paraproteinaemic (anti-MAG) neuropathy treatment

• IVIG confers short term benefit – RCT– Multiple other immunosuppressants used

• Melphalan, chlorambucil, cyclo +/- steroid, fludarabine

• Rituximab (anti-CD20) – promising in some studies• 8 non randomised studies– 6 (79 pts) positive (1 (3 pts) negative)• 1 RCT (Dalakas 2009) with serious flaws – reported ‘positive’ • Further RCT awaits publication (negative primary outcome)

• 375mg/m2 usual dose – recent high dose study added improvement

• Several cases of worsening• Administer in conjunction with PN service and haematology

Practical approach to IgG or IgA associated CIDP treatment

• Clinical and electrophysiological diagnosis– IVIG 2g/kg 5/7 daycase or – prednisolone 1mg/kg po od 4-8/52– PEx – 5 exchanges over 5-10 days

• No response or unusual clinical features– Re-evaluate and consider targeted nerve biopsy

• Treatment alternatives– (methotrexate), azathioprine, cyclophosphamide,

ciclosporin, β-interferon, rituximab, Campath

Alternative pathogenic mechanisms in inflammatory neuropathy

• Cytokine-mediated inflammation and ischaemia in nerves– Peripheral nerve vasculitis and POEMS syndrome

Images courtesy of Said and Zeman

POEMS syndromePolyneuropathy Organomegaly Endocrine changes M-protein Skin changes

• 35yrs old political analyst• Flu-like illness• Pain in legs • Progressive areflexic flaccid quadraparesis over 7

weeks• Mild ankle swelling. Nil else on G/E• SNAPs preserved. Mixed DM and axonal motor

features• Diagnosis SIDP/CIDP – motor predominant

• IVIG x2 – no response

• IgG λ paraprotein – 5g/l• VEGF >4000pg/l

• ?POEMS syndrome

Myelin separation

Widely spaced myelin

Loosened/uncompacted myelin

POEMS syndromePolyneuropathy Organomegaly Endocrine changes M-protein Skin changes

• Scheinker 1938– PN, solitary myeloma and sclerotic pigmented skin

• Crow-Fukase 1956– Increasingly complex relationships of MM and PN

• Bardwick 1980– Coined acronym

• 0.3/100000 Japan (Arimura 2007)

POEMS syndrome diagnostic criteria

Polyneuropathy and monoclonal plasma cell disorder present in all patients; to make diagnosis at least one other major criterion and 1 minor criterion is required.

• Major Criteria• Polyneuropathy• Monoclonal plasma cell disorder

(almost always λ – 95%)• Sclerotic bone lesions• Castleman disease• VEGF elevation

• Minor Criteria• Organomegaly (spleno-, hepato- or

lymphadenopathy)• Oedema, pleural effusion or ascites• Endocrinopathy (adrenal, thyroid,

pituitary, gonadal, parathyroid, pancreatic*

• Skin changes (pigmentation, nails, hair, plethora, cyanosis)

• Papilloedema• Thrombocytosis or polycythaemia**

• Other symptoms or signs• Clubbing• Weight loss• Diarrhoea• Low vitamin B12• Pulmonary hypertension or

restrictive lung disease• Thrombotic episodes• Hyperhydrosis

• Possible associations• Arthralgia• Cardiomyopathy• Fever

*DM and thyroid disease are very common and occurrence of one only not sufficient**Anaemia and thrombocytopaenia distinctly unusual unless Castleman disease present

Dispenzieri 2007

POEMSfrequency and variability of clinical features

Follicles contain dysplastic CD21+ dendritic cells

Mantle zone of ‘onion skin’ CD20 cells

POEMSAssociation with Castleman Disease

VEGF induced signal transduction in MM cells

VEGF in diagnosis

• 1996 – Watanabe – greatly increased VEGF levels

• 1998 …may cause increased vascular permeability

• 2006 - “overproduction of VEGF . . . Is causative in almost all of the symptoms [of POEMS]”

Proposed POEMS pathogenesis

Very high levels of VEGF probably useful in diagnosis

• Not 100% sensitive or specific• Assays vary• Very high levels very suspicious in clinical contextD’Souza, Dispenzieri et al. Blood.

2011;118(17):4663-4665

Longitudinal VEGF correlates with clinical condition not haematological CR

D’Souza, Dispenzieri et al. Blood. 2011;118(17):4663-4665

“The constellation of -restricted monoclonal gammopathy, plasma cell rimming around lymphoid aggregates, and ..[JAK2V617F negative]..

megakaryocytic hyperplasia in a bone marrow is highly suggestive of… [POEMS], especially in the context of a peripheral neuropathy”

Dao LN et al. Blood. 2011;117(24):6438-6444

Treatment paradigms in POEMS

Dispenzieri A et al Blood 2003; 101:2496–2506

POEMS treatment 2• Thalidomide and lenalinamide both notable anti-IL6 and

cytotoxic to plasma cells• Bevacizumab – anti-VEGF human monoclonal

• Bevacizumab or thalidomide but treatment failures, not necessarily with VEGF increase

• Thalidomide (+/- bevacizumab) + low dose systemic chemotherapy

Kuwabara S, Dispenzieri A et al Cochrane 2008 Issue 4

POEMS treatment 2

• Autologous PBSCT• 49 patients – all but one survived 2 years• ?4% mortality in POEMS (vs 2% for other indications)

• Treatment directed at relevant pathogenic aspects of disease with good effect

Kuwabara S, Dispenzieri A et al Cochrane 2008 Issue 4

POEMS or not POEMS?

Mononeuropathies and plasma cell disorders

• Multiple myeloma• Neurolymphomatosis• Cryoglobulinaemia• Amyloidosis• Associated by chance

Acquired amyloid neuropathy

• AL amyloid• MM, MGUS, malignant lymphoma,

Waldenstrom’s macroglobulinaemia• λ >> κ light chains• Deposition of light chain in nerve

Amyloid neuropathy• Length dependent axonal

• sensory loss with prominent small fibre involvement• Pain is often burning, especially nocturnally, or as lancinating stabs• Pain and temperature are selectively involved

• Mononeuropathies (esp Carpal Tunnel v common)

• Autonomic involvement– distal limb anhydrosis, orthostatic hypotension, difficulty voiding

urine, and erectile and ejaculatory difficulty. – Diarrhoea and gastroparesis may be prominent.– Pupils involved (not in hereditary amyloid)

• Nerves may be thickened

Light chain deposition

• 55 years old male• Pain and weakness in L foot, numbness of sole

and inability to curl toes• Diagnosed ‘tarsal tunnel syndrome’• Progressive and severe pain• Weakness in tibial nerve distribution

Numbness in S1 dermatome

MRI Sciatic Nerve

Neurolymphomatosis

Treatment related toxicity

• 20 years ago prognosis was poor – treatment limited…

– Vincristine

– Melphalan and PBSC support

– Thalidomide, lenalinomide and bortezomib

• Distal length dependent• Sensory>>motor• (Autonomic)• Small fibre (burning) >

numbness• Dose related– >50g cumulative for TiPN– 30mg/m2 for BiPN

• Worse in males and w/o steroids

• Coasting in ViPN• TiPN and ViPN irreversible

Summary

• Neuropathies are more interesting than CTCAE• Anti-MAG neuropathy is typical• Anti-MAG positivity does not mean anti-MAG

neuropathy• POEMS has cytokine driven pathogenesis• Myeloma seldom directly affects nerves• Myeloma treatment is potentially neurotoxic

and requires care and assessment

MRC Centre for Neuromuscular Disease