Neuropathies associated with plasma cell disorders

MRC Centre for
Neuromuscular Disease
Neuropathies associated with
myeloma and other plasma cell
UK Myeloma Forum Meeting
London November 2011
Dr Michael Lunn
Consultant Neurologist and Clinical Lead in Neuroimmunology
National Hospital for Neurology and Neurosurgery
Queen Square
London WC1N 3BG
[email protected]
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
• Typical and atypical presentations
• Toxicities of treatment
De humani corporis
fabrica, Basel: Oporinus,
lib. IV, pp.353-4
Wellcome Library,
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
Vasculitic Neuropathy
Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)
Acute motor axonal neuropathy (AMAN)
Acute motor-sensory axonal neuropathy (AMSAN)
Fisher Syndrome and other regional variants
Facial palsies
Pure oculomotor
Functional variants of GBS
Pure dysautonomia
Pure sensory GBS
Ataxic GBS
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 lupuserythematosus
Sjörgren’s syndrome
Mixed connective tissue disease
Serum sickness
Infectious, malignant, related to chemotherapy
Subacute inflammatory demyelinati
ng polyradiculoneuropathy (SIDP)
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
Multifocal motor neuropathy with conduction block (MMNCB)
Chronic relapsing axonal neuropathy
Chronic ataxic sensory neuronopathy
Inflammatory neuropathy associated with infection
HIV neuropathies, including CMV neuropathy
Lyme disease
Chaga’s disease
Paraproteinaemic neuropathy
Monoclonal gammopathy of undetermined significance (MGUS)
Multiple myeloma
Solitary plasmacytoma
Lymphoma or chronic lymphocytic leukaemia
Waldenström’s macroglobulinaemia
Cold agglutinin disease
Primary amyloidosis
POEMS syndrome
Sub-acute sensory neuropathy/neuronopathy
- small cell lung
carcinoma and anti-Hu Abs
Other paraneoplastic tumour
-antibody syndromes
Diabetic lumbo-sacral plexopathy
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
• 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
– Elderly, male, ataxia and tremor
Anti-MAG paraproteinaemic demyelinating
peripheral neuropathy (DADS)
• Chronic progressive sensorimotor demyelinating
– 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 neuropathy
Diagnosis and treatment
EFNS/PNS Recommendations
All patients with paraprotein and neuropathy should be
assessed for a malignant plasma cell dyscrasia
Paraprotein more likely relevant if IgM, DADS or anti-MAG+
Typical phenotype of IgM PDN recognised
IgM PDN sometimes responds to Rx but some are toxic and
their use must be balanced against clinical need
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
– 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
• 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
• 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 syndrome
Polyneuropathy Organomegaly Endocrine changes M-protein Skin changes
35yrs old political analyst
Flu-like illness
Pain in legs
Progressive areflexic flaccid quadraparesis over 7
• Mild ankle swelling. Nil else on G/E
• SNAPs preserved. Mixed DM and axonal motor
• 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 syndrome
Polyneuropathy 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
• Oedema, pleural effusion or ascites
• Endocrinopathy (adrenal, thyroid,
pituitary, gonadal, parathyroid,
• Skin changes (pigmentation, nails,
hair, plethora, cyanosis)
• Papilloedema
• Thrombocytosis or polycythaemia**
• Other symptoms or signs
Weight loss
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
frequency and variability of clinical features
Association with Castleman Disease
Follicles contain
dysplastic CD21+
dendritic cells
Mantle zone of
‘onion skin’ CD20
VEGF induced signal transduction in MM cells
VEGF in diagnosis
• 1996 – Watanabe – greatly increased VEGF
• 1998 …may cause increased vascular
• 2006 - “overproduction of VEGF . . . Is
causative in almost all of the symptoms [of
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 context
D’Souza, Dispenzieri et al. Blood.
Longitudinal VEGF correlates with clinical
condition not haematological CR
D’Souza, Dispenzieri et al. Blood.
“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
• Median survival 33 months
– 102 pts with 58 FU
Nakanishi 1984
• Basic haematological regimens
• Low CR, moderate PR rates
• No RCTs
• Local irradiation +/- surgery
» 54%-74% response (Class IV only)
• Low dose melphalan and dexamethasone
» 56% - 81% response – 38% CR/43% PR
» 100% neurological response – all 31 pts alive at 21/12
Li et al. Blood. 2011;117(24):6445-6449
• Steroids alone
» 22% response
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
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
Mononeuropathies and plasma cell
Multiple myeloma
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
Treatment related toxicity
• 20 years ago prognosis was poor – treatment
– Vincristine
– Melphalan and PBSC support
– Thalidomide, lenalinomide and bortezomib
Distal length dependent
Small fibre (burning) >
• Dose related
– >50g cumulative for TiPN
– 30mg/m2 for BiPN
• Worse in males and w/o
• Coasting in ViPN
• TiPN and ViPN irreversible
• Neuropathies are more interesting than CTCAE
• Anti-MAG neuropathy is typical
• Anti-MAG positivity does not mean anti-MAG
• 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
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