MRC Centre for Neuromuscular Disease

1. MRC Centre for Neuromuscular Disease Neuropathies associated with myeloma and other plasma cell disordersUK 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 michael.lunn@uclh.nhs.uk

2. 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

3. Neuropathies associated with plasma cell disorders • Anatomy revision • Neuropathies associated with plasma cell disorders • Typical and atypical presentations • Toxicities of treatment

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

5. skin

6. 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)

7. Inflammatory Peripheral Neuropathy Idiopathic Va sculitic Neuropathy Acute Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) Acute motor axonal neuropathy (AMAN) Primary vasculitis Acute motor - sensory axonal neurop athy (AMSAN) Polyarteritis nodosa and Churg - Strauss disease Fisher Syndrome and other regional variants Wegener’s vasculitis Pharyngeal - cervical - brachial Isolated nerve vasculitis Paraparetic Temporal arteritis Facial palsies Systemic autoimmune diseases with associated vasculitis Pure oculomotor Rheumatoid arthritis Functional variants of GBS Systemic lupus erythematosus Pure dysautonomia Sjörgren’s syndrome Pure sensory GBS Mixed connective tissue disease Ataxic GBS Other Subacute Serum sickness Subacute inflammatory demyelinati ng polyradiculoneuropathy (SIDP) Infectious, malignant, related to chemotherapy Chronic Inflammatory neuropathy associated with infection Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Multifocal motor neuropathy with conduction block (MMNCB) HIV neuropathies, including CMV neuropathy Chronic relapsing axonal neuropathy Leprosy Chronic ataxic sensory neuronopathy Lyme disease Chaga’s disease Paraproteinaem ic neuropathy Paraneoplastic Monoclonal gammopathy of undetermined significance (MGUS) Multiple myeloma Sub - acute sensory neuropathy/neuronopathy - small cell lung Solitary plasmacytoma carcinoma and anti - Hu Abs Lymphoma or chronic lymphocytic leukaemia Other paraneoplastic tumour - antibody syndromes Waldenström’s macroglobulinaemia Cryoglobulinaemia Metabolic Cold agglutinin disease Primary amyloidosis Diabetic lumbo - sacral plexopathy POEMS syndrome

8. 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

9. 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

10. 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

11. Neuropathies and paraproteins Distal acquired demyelinating sensory neuropathy (DADS) Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Distal length dependent (axonal/painful) sensory neuropathies Multiple mononeuropathies

12. Brandner S - NHNN

13. Brandner S - NHNN

14. Anti-MAG paraproteinaemic demyelinating peripheral neuropathy (DADS) Chronic progressive sensorimotor demyelinating neuropathy Elderly, male, ataxia and tremor

16. 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

17. Myelin separation

19. Widely spaced myelin

20. 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

22. Lunn et al Brain 2002

23. Paraproteinaemic neuropathyDiagnosis and treatment

24. 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

25. 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…

26. 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’

27. 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

28. 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

29. 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

30. 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

31. 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

32. IVIG x2 – no response IgG λ paraprotein – 5g/l VEGF >4000pg/l ?POEMS syndrome

34. Myelin separation

35. Widely spaced myelin

36. Loosened/uncompacted myelin

37. 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)

38. POEMS syndrome diagnostic criteriaPolyneuropathy 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

39. POEMSfrequency and variability of clinical features

40. POEMSAssociation with Castleman Disease Follicles contain dysplastic CD21+ dendritic cells Mantle zone of ‘onion skin’ CD20 cells

41. VEGF induced signal transduction in MM cells

42. 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]”

43. Proposed POEMS pathogenesis

44. 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. 2011;118(17):4663-4665

45. Longitudinal VEGF correlates with clinical condition not haematological CR D’Souza, Dispenzieri et al. Blood. 2011;118(17):4663-4665

46. “The constellation of -restricted monoclonal gammopathy, plasma cell rimming around lymphoid aggregates, and ..[JAK2V617Fnegative].. 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

47. 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

48. POEMS treatment 2 Kuwabara S, Dispenzieri A et al Cochrane 2008 Issue 4 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

49. POEMS treatment 2 Kuwabara S, Dispenzieri A et al Cochrane 2008 Issue 4 • 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

50. POEMS or not POEMS?