Skip to main content

Advertisement

SpringerLink
Log in

Advances in the Treatment of Paraproteinemic Neuropathy

  • Neuromuscular Disorders (C Fournier, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Abstract

Purpose of review Several advances have been made on the pathogenesis and therapy of neuropathies associated with paraproteinemia (monoclonal gammopathy). It is important for the neurologist to understand the pathogenetic relevance of this association especially when the hematological disease does not require per se any therapy.

Recent findings Treatment of the neuropathy in patients with malignant paraproteinemia is mainly addressed by the hematologist while the neurologist is mainly involved in the initial diagnosis and in deciding whether the neuropathy is caused by the disease or by the chemotherapy used for the disease. There is little evidence that the neuropathy is caused by the hematological condition in patients with IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) unless there is an evidence of a reactivity of the paraprotein with nerve or evidence of its presence in the nerve. Patients with a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like presentation should be treated as CIDP while there is no evidence that immune or chemotherapy may be effective in the other patients. In most patients with IgM paraproteinemia, that is usually a MGUS or an indolent Waldenström’s macroglobulinemia, the neuropathy is induced by an immune reactivity of the paraprotein with nerve and particularly with the myelin-associated glycoprotein. There are now consistent data also from controlled studies that the anti-CD20 monoclonal antibody rituximab may improve the neuropathy in these patients. POEMS syndrome is a severe condition characterized by a disabling neuropathy whose prognosis has improved in the last few years with therapies against the proliferating plasma cell clone or vascular endothelial growth factor including local radiotherapy and chemotherapy followed by autologous stem cell transplantation. Other therapies are also available for patients not eligible or resistant to transplantation, including lenalidomide and possibly thalidomide or bortezomib.

Summary Several new therapies are now available for patients with paraproteinemic neuropathy consistently improving the prognosis of these neuropathies. In most instances, however, their efficacy needs to be confirmed in controlled trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kelly JJ, Kyle RA, O’Brien PC, Dyck PJ. Prevalence of monoclonal protein in peripheral neuropathy. Neurology. 1981;31:1480–3.

    Article  PubMed  Google Scholar 

  2. Mygland Å, Monstad P. Chronic polyneuropathies in Vest-Agder, Norway. Eur J Neurol. 2001;8:157–65.

    Article  CAS  PubMed  Google Scholar 

  3. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362–9.

    Article  CAS  PubMed  Google Scholar 

  4. •• Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision. J Peripher Nerv Syst. 2010;15:185–95. This not so recent guideline is still one of the most important revision on the diagnosis and treatment of paraproteinemic neuropathies.

    Article  Google Scholar 

  5. Nobile-Orazio E, Barbieri S, Baldini L, Marmiroli P, Carpo M, Premoselli S, et al. Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies. Acta Neurol Scand. 1992;85:383–90.

    Article  CAS  PubMed  Google Scholar 

  6. Vrethem M, Cruz M, Wen-Xin H, Malm C, Holmgren H, Ernerudh J. Clinical, neurophysiological and immunological evidence of polyneuropathy in patients with monoclonal gammopathies. J Neurol Sci. 1993;114:193–9.

    Article  CAS  PubMed  Google Scholar 

  7. Nobile-Orazio E, Manfredini E, Carpo M, Meucci N, Monaco S, Ferrari S, et al. Frequency and clinical correlates of anti-neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy. Ann Neurol. 1994;1994(36):416–24.

    Article  Google Scholar 

  8. •• Dispenzieri A. POEMS syndrome: 2017 update on diagnosis, risk stratification, and management. Am J Hematol. 2017;92(8):814–29. This is an excellent and updated review on the diagnosis, pathogenesis, and therapy of POEMS syndrome.

    Article  PubMed  Google Scholar 

  9. Watanabe O, Maruyama I, Arimura K, Kitajima I, Arimura H, Hanatani M, et al. Overproduction of vascular endothelial growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome. Muscle Nerve. 1998;21:1390–7.

    Article  CAS  PubMed  Google Scholar 

  10. Sung JY, Kuwabara S, Ogawara K, Kanai K, Hattori T. Patterns of nerve conduction abnormalities in POEMS syndrome. Muscle Nerve. 2002;26:189–93.

    Article  PubMed  Google Scholar 

  11. Min JH, Hong YH, Lee KW. Electrophysiological features of patients with POEMS syndrome. Clin Neurophysiol. 2005;116:965–8.

    Article  PubMed  Google Scholar 

  12. Nasu S, Misawa S, Sekiguchi Y, Shibuya K, Kanai K, Fujimaki Y, et al. Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry. 2012;83(5):476–9.

    Article  PubMed  Google Scholar 

  13. Nobile-Orazio E. Neuropathy and monoclonal gammopathy. In: Said G, Krarup C, editors. Handbook of clinical neurology. Vol. 115 (3rd series); Peripheral nerve disorders, vol. 115. Amsterdam: Elsevier BV; 2013. p. 443–59.

    Chapter  Google Scholar 

  14. Viala K, Stojkovic T, Doncker AV, Maisonobe T, Lenglet T, Bruneteau G, et al. Heterogeneous spectrum of neuropathies in Waldenström’s macroglobulinemia: a diagnostic strategy to optimize their management. J Peripher Nerv Syst. 2012;17(1):90–101.

    Article  CAS  PubMed  Google Scholar 

  15. Latov N, Hays AP, Sherman WH. Peripheral neuropathy and anti-MAG antibodies. Crit Rev Neurobiol. 1988;3:301–32.

    CAS  PubMed  Google Scholar 

  16. Baldini L, Nobile-Orazio E, Guffanti A, Barbieri S, Carpo M, Cro L, et al. Peripheral neuropathy in IgM monoclonal gammopathy and Waldenström Macroglobulinemia: a frequent complication in males with low MAG-reactive serum monoclonal component. Am J Hematol. 1994;45:25–31.

    Article  CAS  PubMed  Google Scholar 

  17. Nobile-Orazio E, Francomano E, Daverio R, Barbieri S, Marmiroli P, Manfredini E, et al. Anti-myelin-associated glycoprotein IgM antibody titers in neuropathy associated with macroglobulinemia. Ann Neurol. 1989;26:543–50.

    Article  CAS  PubMed  Google Scholar 

  18. Nobile-Orazio E, Vietorisz T, Messito MJ, Sherman W, Latov N. Anti-MAG IgM antibodies in patients with neuropathy and IgM M-proteins: detection by ELISA. Neurology. 1983;33:939–42.

    Article  CAS  PubMed  Google Scholar 

  19. Kuijf ML, Eurelings M, Tio-Gillen AP, van Doorn PA, van den Berg LH, Hooijkaas H, et al. Detection of anti-MAG antibodies in polyneuropathy associated with IgM monoclonal gammopathy. Neurology. 2009;73:688–95.

    Article  CAS  PubMed  Google Scholar 

  20. • Magy L, Kaboré R, Mathis S, Lebeau P, Ghorab K, Caudie C, et al. Heterogeneity of polyneuropathy associated with anti-MAG antibodies. J Immunol Res. 2015;2015:450391. https://doi.org/10.1155/2015/450391. In this recent study, the authors measured the levels of anti-MAG antibodies using the Buhlman assay and compared the titer of the antibodies with the clinical and pathological features of the neuropathy.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nobile-Orazio E, Meucci N, Baldini L, Di Troia A, Scarlato G. Long-term prognosis of neuropathy associated with anti-MAG IgM M-proteins and its relation with immune therapies. Brain. 2000;123:710–7.

    Article  PubMed  Google Scholar 

  22. Niermeijer JM, Fischer K, Eurelings M, Franssen H, Wokke JH, Notermans NC. Prognosis of polyneuropathy due to IgM monoclonal gammopathy. Neurology. 2010;74:406–12.

    Article  CAS  PubMed  Google Scholar 

  23. •• Lunn MP, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database Syst Rev. 2016;10:CD002827. This very recent review analyzes the effect of immune therapies in anti-MAG neuropathy and shows that, by combining the results of two small negative studies, rituximab proves to be indeed effective in this neuropathy.

    PubMed  Google Scholar 

  24. Dyck PJ, Low PA, Windebank AJ, Jaradeh SS, Gosselin S, Bourque P, et al. Plasmaexhange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med. 1991;325:1482–6.

    Article  CAS  PubMed  Google Scholar 

  25. Oksenhendler E, Chevret S, Léger JM, Louboutin JP, Bussel A, Brouet JC. Plasma exchange and chlorambucil in polyneuropathy associated with monoclonal IgM gammopathy. IgM-associated Polyneuropathy Study Group. J Neurol Neurosurg Psychiatry. 1995;59(3):243–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Codron P, Cousin M, Subra JF, Pautot V, Letournel F, Verny C, et al. Therapeutic plasma exchange in chronic dysimmune peripheral neuropathies: a 10-year retrospective study. J Clin Apher. 2017; https://doi.org/10.1002/jca.21530.

  27. • Baron M, Lozeron P, Harel S, Bengoufa D, Vignon M, Asli B, et al. Plasma exchanges for severe acute neurological deterioration in patients with IgM anti-myelin-associated glycoprotein (anti-MAG) neuropathy. J Neurol. 2017;264(6):1132–5. This interesting study analyzed the effect of plasmaexchange in four patients with anti-MAG neuropathy and an acute neurological deterioration who improved with this therapy.

    Article  CAS  PubMed  Google Scholar 

  28. Comi G, Roveri L, Swan A, Willison H, Bojar M, Illa I, et al. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol. 2002;249(10):1370–7.

    Article  CAS  PubMed  Google Scholar 

  29. Dalakas MC, Quarles RH, Farrer RG, Dambrosia J, Soueidan S, Stein DP, et al. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol. 1996;40(5):792–5.

    Article  CAS  PubMed  Google Scholar 

  30. Mariette X, Chastang C, Clavelou P, Louboutin JP, Leger JM, Brouet JC. A randomised clinical trial comparing interferon-alpha and intravenous immunoglobulin in polyneuropathy associated with monoclonal IgM. The IgM-associated Polyneuropathy Study Group. J Neurol Neurosurg Psychiatry. 1997;63(1):28–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mariette X, Brouet JC, Chevret S, Leger JM, Clavelou P, Pouget J, et al. A randomised double blind trial versus placebo does not confirm the benefit of alpha-interferon in polyneuropathy associated with monoclonal IgM. J Neurol Neurosurg Psychiatry. 2000;69(2):279–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Niermeijer JM, Eurelings M, van der Linden MW, Lokhorst HM, Franssen H, Fischer K, et al. Intermittent cyclophosphamide with prednisone versus placebo for polyneuropathy with IgM monoclonal gammopathy. Neurology. 2007;69(1):50–9.

    Article  CAS  PubMed  Google Scholar 

  33. Gazzola S, Delmont E, Franques J, Boucraut J, Salort-Campana E, Verschueren A, et al. Predictive factors of efficacy of rituximab in patients with anti-MAG neuropathy. J Neurol Sci. 2017;377:144–8.

    Article  CAS  PubMed  Google Scholar 

  34. • Kawagashira Y, Koike H, Ohyama K, Hashimoto R, Iijima M, Adachi H, et al. Axonal loss influences the response to rituximab treatment in neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein antibody. J Neurol Sci. 2015;348(1–2):67–73. In this study, the authors report a correlation between clinical improvement after therapy with rituximab and the short duration of the disease and the preservation of fiber density on nerve biopsy in patients with anti-MAG neuropathy.

    Article  CAS  PubMed  Google Scholar 

  35. Talamo G, Mir MA, Pandey MK, Sivik JK, Raheja D. IgM MGUS associated with anti-MAG neuropathy: a single institution experience. Ann Hematol. 2015;94(6):1011–6.

    Article  CAS  PubMed  Google Scholar 

  36. Campagnolo M, Ferrari S, Dalla Torre C, Cabrini I, Cacciavillani M, Lucchetta M, et al. Polyneuropathy with anti-sulfatide and anti-MAG antibodies: clinical, neurophysiological, pathological features and response to treatment. J Neuroimmunol. 2015;281:1–4.

    Article  CAS  PubMed  Google Scholar 

  37. • Campagnolo M, Zambello R, Nobile-Orazio E, Benedetti L, Marfia GA, Riva N, et al. IgM MGUS and Waldenström-associated anti-MAG neuropathies display similar risposte to rituximab therapy. J Neurol Neurosurg Psychiatry. 2017; https://doi.org/10.1136/jnnp-2017-315736. In this study, the authors reported a comparable response to rituximab in patients with anti-MAG antibodies associated with either MGUS or Waldenström’s macroglobulinemia.

  38. Doneddu PE, Kazmi M, Samuel M, Mahdi-Rogers M, Hadden RD. Deterioration of tremor after treatment with rituximab in anti-MAG neuropathy. J Neurol Sci. 2017;373:344–5.

    Article  PubMed  Google Scholar 

  39. • Dalakas MC, Rakocevic G, Salajegheh M, Dambrosia JM, Hahn AF, Raju R, et al. Placebo controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. Ann Neurol. 2009;65:286–93. This not so recent randomized controlled study first showed that rituximab may have some effects in anti-MAG neuropathy even if the results were only derived by the exclusion of an erroneously included patient.

    Article  CAS  PubMed  Google Scholar 

  40. • Léger JM, Viala K, Nicolas G, Créange A, Vallat JM, Pouget J, et al. Placebo controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy. Neurology. 2013;80(24):2217–25. This negative controlled study on the effect of rituximab in anti-MAG neuropathy shows that the therapy may improve some parameters and, combined with the previous study, permits to show that the therapy is indeed effective in this neuropathy.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Benedetti L, Briani C, Franciotta D, Carpo M, Padua L, Zara G, et al. Long-term effect of rituximab in anti-MAG polyneuropathy. Neurology. 2008;71:1742–4.

    Article  CAS  PubMed  Google Scholar 

  42. Iancu Ferfoglia R, Guimarães-Costa R, Viala K, Musset L, Neil J, Marin B, et al. Long-term efficacy of rituximab in IgM anti-myelin-associated glycoprotein neuropathy: RIMAG follow-up study. J Peripher Nerv Syst. 2016;21(1):10–4.

    Article  CAS  PubMed  Google Scholar 

  43. Gruson B, Ghomari K, Beaumont M, Garidi R, Just A, Merle P, et al. Long-term response to rituximab and fludarabine combination in IgM anti-myelin-associated glycoprotein neuropathy. J Peripher Nerv Syst. 2011;16:180–5.

    Article  CAS  PubMed  Google Scholar 

  44. Gomez A, Hoffman JE. Anti myelin-associated-glycoprotein antibody peripheral neuropathy response to combination chemoimmunotherapy with bendamustine/rituximab in a patient with biclonal IgM k and IgM λ: case report and review of the literature. Clinical Lymphoma, Myeloma & Leukemia. 2016;16(7):e101–8.

    Article  Google Scholar 

  45. • Treon SP. How I treat Waldenström macroglobulinemia. Blood. 2015;126(6):721–32. This is a well done and updated hematological review on the treatment of Waldenström’s macroglobulinemia.

    Article  CAS  PubMed  Google Scholar 

  46. Stino AM, Efebera Y. Lenalidomide-responsive anti-myelin-associated glycoprotein neuropathy. Muscle Nerve. 2017; https://doi.org/10.1002/mus.25709.

  47. Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, et al. Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: a report of 57 cases from the Research on Adverse Drug Event and Reports project. Blood. 2009;113:4834–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. •• Herrendorff R, Hänggi P, Pfister H, Yang F, Demeestere D, Hunziker F, et al. Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy. Proc Natl Acad Sci U S A. 2017;114(18):E3689–98. This excellent study addresses the possibility to perform a selective antigen-specific treatment in patients with anti-MAG neuropathy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stork AC, Jacobs BC, Tao-Gillen AP, Nurslings M, Jansen MD, van den Berg LH, et al. Prevalence, specificity and functionality of anti-ganglioside antibodies in neuropathy associated with IgM monoclonal gammopathy. J Neuroimmunol. 2014;268(1–2):89–94.

    Article  CAS  PubMed  Google Scholar 

  50. Nobile-Orazio E, Gallia F, Terenghi F, Allaria S, Giannotta C, Carpo M. How useful are anti-neural IgM antibodies in the diagnosis of chronic immune-mediated neuropathies? J Neurol Sci. 2008;266:156–63.

    Article  CAS  PubMed  Google Scholar 

  51. Giannotta C, Di Pietro D, Gallia F, Nobile-Orazio E. Anti-sulfatide IgM antibodies in peripheral neuropathy: to test or not to test? Eur J Neurol. 2015;22:879–82.

    Article  CAS  PubMed  Google Scholar 

  52. Willison HJ, O’Leary CP, Veitch J, Blumhardt LD, Busby M, Donaghy M, et al. The clinical and laboratory features of chronic sensory ataxic demyelinating neuropathy with anti-disialosyl IgM antibodies. Brain. 2001;124:1968–77.

    Article  CAS  PubMed  Google Scholar 

  53. Rojas-Garcia R, Gallardo E, Povedano M, de Luna N, Bruna J, Juarez C, et al. Antibodies against disialosyl and terminal NeuNAc (α2-3)Gal ganglioside epitopes in acute relapsing sensory ataxic neuropathy. J Neurol. 2008;255:764–6.

    Article  CAS  PubMed  Google Scholar 

  54. Ahdab R, Lefaucheur JP, Malapert D, Touze E, Caudie C, André C, et al. Neuropathy with anti-disialosyl IgM antibodies and multifocal persistent motor conduction blocks. J Neurol Neurosurg Psychiatry. 2009;80:700–2.

    Article  CAS  PubMed  Google Scholar 

  55. Attarian S, Boucraut J, Hubert AM, Uzenot D, Delmont E, Verschueren A, et al. Chronic ataxic neuropathies associated with anti-GD1b IgM antibodies: response to IVIg therapy. J Neurol Neurosurg Psychiatry. 2010;81:61–4.

    Article  CAS  PubMed  Google Scholar 

  56. •• Stork AC, Lunn MPT, Nobile-Orazio E, Notermans NC. Treatment for IgG and IgA paraproteinemic neuropathy. Cochrane Database Syst Rev. 2015;24(3):CD005376. This is an updated review on the treatment of neuropathies associated with IgG or IgA paraproteinemia.

    Google Scholar 

  57. Rajkumar SV. Multiple myeloma: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89(10):999–1009.

    Article  Google Scholar 

  58. Quasthoff S, Hartung HP. Chemotherapy induced peripheral neuropathy. J Neurol. 2002;249:9–17.

    Article  CAS  PubMed  Google Scholar 

  59. Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Curr Opin Neurol. 2015;28(5):500–7.

    Article  CAS  PubMed  Google Scholar 

  60. Mateos MV, Landgren O. MGUS and smoldering multiple myeloma: diagnosis and epidemiology. Cancer Treat Res. 2016;169:3–12.

    Article  CAS  PubMed  Google Scholar 

  61. Gosselin S, Kyle RA, Dyck PJ. Neuropathy associated with monoclonal gammopathies of undetermined significance. Ann Neurol. 1991;30:54–61.

    Article  CAS  PubMed  Google Scholar 

  62. Yeung KB, Thomas PK, King RHM, Waddy H, Will RG, Hughes RA, et al. The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. Comparative clinical, immunological and nerve biopsy findings. J Neurol. 1991;238:383–91.

    Article  CAS  PubMed  Google Scholar 

  63. Nobile-Orazio E, Casellato C, Di Troia A. Neuropathies associated with IgG and IgA monoclonal gammopathy. Rev Neurol (Paris). 2002;158:979–87.

    CAS  Google Scholar 

  64. Hermosilla E, Lagueny A, Vital C, Vital A, Ferrer X, Steck A, et al. Peripheral neuropathy associated with monoclonal IgG of undetermined significance: clinical, electrophysiologic, pathologic and therapeutic study of 14 cases. J Peripher Nerv Sys. 1996;1:139–48.

    CAS  Google Scholar 

  65. Di Troia A, Carpo M, Meucci N, Pellegrino C, Allaria S, Gemignani F, et al. Clinical features and anti-neural reactivity in neuropathy associated with IgG monoclonal gammopathy of undetermined significance. J Neurol Sci. 1999;164:64–71.

    Article  PubMed  Google Scholar 

  66. Mehndiratta MM, Sen K, Tatke M, Bajaj BK. IgA monoclonal gammopathy of undetermined significance with peripheral neuropathy. J Neurol Sci. 2004;221:99–104.

    Article  CAS  PubMed  Google Scholar 

  67. Vallat JM, Tabaraud F, Sindou P, Preux PM, Vandenberghe A, Steck A. Myelin widenings and MGUS-IgA: an immunoelectron microscopic study. Ann Neurol. 2000;47:808–11.

    Article  CAS  PubMed  Google Scholar 

  68. Vital A, Nedelec-Ciceri C, Vital C. Presence of cristalline inclusions in the peripheral nerve of a patient with IgA lambda monoclonal gammopathy of undetermined significance. Neuropathology. 2008;28:526–31.

    Article  PubMed  Google Scholar 

  69. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346(8):564–9.

    Article  PubMed  Google Scholar 

  70. Ponsford S, Willison H, Veitch J, Morris R, Thomas PK. Long-term clinical and neurophysiological follow-up of patients with peripheral, neuropathy associated with benign monoclonal gammopathy. Muscle Nerve. 2000;23(2):164–74.

    Article  CAS  PubMed  Google Scholar 

  71. Oaklander AL, Lunn MPT, Hughes RAC, van Schaik IN, Frost C, Chalk CH. Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews (review). Cochrane Database Syst Rev. 2017;1:CD010369.

    PubMed  Google Scholar 

  72. Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, et al. POEMS syndrome: definitions and long-term out come. Blood. 2003;101:2496–506.

    Article  CAS  PubMed  Google Scholar 

  73. • Kourelis TV, Buadi FK, Kumar SK, Gertz MA, Lacy MQ, Dingli D, et al. Long-term outcome of patients with POEMS syndrome: an update of the Mayo Clinic experience. Am J Hematol. 2016;91(6):585–9. In this study, the authors reviewed the effect of treatment in a large series of patients with POEMS syndrome followed at their institution.

    Article  CAS  PubMed  Google Scholar 

  74. Kuwabara S, Dispenzieri A, Arimura K, Misawa S, Nakaseko C. Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. Cochrane Database Syst Rev. 2012;6:CD006828.

    Google Scholar 

  75. Humeniuk MS, Gertz MA, Lacy MQ, Kyle RA, Witzig TE, Kumar SK, et al. Outcomes of patients with POEMS syndrome treated initially with radiation. Blood. 2013;122:66–73.

    Article  Google Scholar 

  76. Kourelis TV, Buadi FK, Gertz MA, Lacy MQ, Kumar SK, Kapoor P, et al. Risk factors for and outcomes of patients with POEMS syndrome who experience progression after first-line treatment. Leukemia. 2016;30:1079–85.

    Article  CAS  PubMed  Google Scholar 

  77. Li J, Zhang W, Jiao L, Duan MH, Guan HZ, Zhu WG, et al. Combination of melphalan and dexamethasonefor patients with newly diagnosed POEMS syndrome. Blood. 2011;117:6445–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dispenzieri A, Lacy MQ, Hayman SR, Kumar SK, Buadi F, Dingli D, et al. Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome. Eur J Haematol. 2008;80:397–406.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kuwabara S, Misawa S, Kanai K, Kikkawa Y, Nishimura M, Nakaseko C, et al. Autologous peripheral blood stem cell transplantation for POEMS syndrome. Neurology. 2006;66:105–7.

    Article  CAS  PubMed  Google Scholar 

  80. Kuwabara S, Misawa S, Kanai K, Suzuki Y, Kikkawa Y, Sawai S, et al. Neurologic improvement after peripheral blood stem cell transplantation in POEMS syndrome. Neurology. 2008;71:1691–5.

    Article  CAS  PubMed  Google Scholar 

  81. Giglia F, Chiapparini L, Farisell L, Barbui T, Ciano C, Scarlato M, et al. POEMS syndrome: relapse after successful autologous peripheral blood stem cell transplantation. Neuromuscul Disord. 2007;17:980–2.

    Article  CAS  PubMed  Google Scholar 

  82. Kuwabara S, Kanai K, Misawa S, Nakaseko C. Relapse of POEMS syndrome without increased level of VEGF. Neuromuscul Disord. 2009;19(10):740.

    Article  PubMed  Google Scholar 

  83. Sinisalo M, Hietaharju A, Sauranen J, Wirta O. Thalidomide in POEMS: case report. Am J Hematol. 2004;76:66–8.

    Article  PubMed  Google Scholar 

  84. Kuwabara S, Misawa S, Kanai K, Sawai S, Hattori T, Nishimura M, et al. Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome. J Neurol Neurosurg Psychiatry. 2008;79:1255–7.

    Article  CAS  PubMed  Google Scholar 

  85. Inoue D, Kato A, Tabata S, Kitai T, Takiuchi Y, Kimura T, et al. Successful treatment of POEMS syndrome complicated by severe congestive heart failure with thalidomide. Intern Med. 2010;49:461–6.

    Article  CAS  PubMed  Google Scholar 

  86. •• Misawa S, Sato Y, Katayama K, Nagashima K, Aoyagi R, Sekiguchi Y, et al. Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2016;15:1129–37. This is the first randomized controlled study performed in POEMS syndrome showing that thalidomide is effective in reducing serum VEGF levels even if it does not induce a significant clinical improvement.

    Article  CAS  PubMed  Google Scholar 

  87. Dispenzieri A, Klein CJ, Mauermann ML. Lenalidomide therapy in a patient with POEMS syndrome. Blood. 2007;110:1075–6.

    Article  CAS  PubMed  Google Scholar 

  88. Sethi S, Tageja N, Arabi H, Penumetcha R. Lenalidomide therapy in a rare case of POEMS syndrome with kappa restriction. South Med J. 2009;102:1092–3.

    Article  PubMed  Google Scholar 

  89. Tomás JF, Giraldo P, Lecumberri R, Nistal S. POEMS syndrome with severe neurological damage clinically recovered with Lenalidomide. Haematologica. 2012;97:320–2.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Royer B, Merlusca L, Abraham J, Musset L, Haroche J, Choquet S, et al. Efficacy of Lenalidomide in POEMS syndrome: a retrospective study of 20 patients. Am J Hematol. 2012;88:207–2012.

    Article  Google Scholar 

  91. Vannata B, Laurenti L, Chiusolo P, Sorà F, Balducci M, Sabatelli M, et al. Efficacy of lenalidomide plus dexamethasone for POEMS syndrome relapsed after autologous peripheral stem-cell transplantation. Am J Hematol. 2012;87:641–2.

    Article  CAS  PubMed  Google Scholar 

  92. • Zagouri F, Kastritis E, Gavriatopoulou M, Sergentanis TN, Psaltopoulou T, Terpos E, et al. Lenalidomide in patients with POEMS syndrome: a systematic review and pooled analysis. Leuk Lymphoma. 2014;55:2018–23. This is a well done review on the effect of lenalidomide in previously reported patients with POEMS.

    Article  CAS  PubMed  Google Scholar 

  93. Nozza A, Terenghi F, Gallia F, Adami F, Briani C, Merlini G, et al. Lenalidomide and dexamethasone in patients with poems syndrome: results of a prospective, open-label trial. Br J Haematol. 2017. in press.

  94. Bianco M, Terenghi F, Gallia F, Nozza A, Scarale A, Fayoumi MZ, et al. Comparison of two-year response to lenalidomide or peripheral blood stem-cell transplantation in patients with POEMS. J Peripher Nerv Syst. 2017;22(supplement):244.

    Google Scholar 

  95. Sekiguchi Y, Misawa S, Shibuya K, Nasu S, Mitsuma S, Iwai Y, et al. Ambiguous effects of anti-VEGF monoclonal antibody (bevacizumab) for POEMS syndrome. J Neurol Neurosurg Psychiatry. 2013;84(12):1346–8.

    Article  PubMed  Google Scholar 

  96. He H, Fu W, Du J, Jiang H, Hou J. Successful treatment of newly diagnosed POEMS syndrome with reduced-dose bortezomib based regimen. Br J Haematol. 2017; https://doi.org/10.1111/bjh.14497.

Download references

Author information

Authors and Affiliations

  1. Neuromuscular and Neuroimmunology Service, Department of Medical Biotechnology and Translational Medicine, Humanitas Clinical and Research Institute, Milan University, Via Manzoni 56, 20089, Rozzano, Milan, Italy

    Eduardo Nobile-Orazio MD, PhD & Mariangela Bianco MD

  2. Department of Medical Oncology and Haematology, Humanitas Cancer Center, Humanitas Clinical and Research Institute, IRCCS, Rozzano, Milan, Italy

    Andrea Nozza MD

Authors
  1. Eduardo Nobile-Orazio MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariangela Bianco MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Nozza MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eduardo Nobile-Orazio MD, PhD.

Ethics declarations

Conflict of Interest

Eduardo Nobile-Orazio reports personal compensation for Scientific or Advisory Board participation or for lecturing from Baxter, Italy and USA; CSL Behring, Italy and USA; Kedrion Biopharma, Italy; LFB, France; Novartis, Switzerland; and UCB, UK.

Mariangela Bianco and Andrea Nozza each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Neuromuscular Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nobile-Orazio, E., Bianco, M. & Nozza, A. Advances in the Treatment of Paraproteinemic Neuropathy. Curr Treat Options Neurol 19, 43 (2017). https://doi.org/10.1007/s11940-017-0479-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11940-017-0479-9

Keywords

Search

Navigation