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Multiple myeloma gammopathies

European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias

Leukemia volume 32, pages 1883–1898 (2018)Cite this article

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Abstract

The introduction of novel agents in the management of multiple myeloma and related plasma cell dyscrasias has changed our treatment approaches and subsequently the outcome of patients. Due to current advances, the European Myeloma Network updated the diagnostic and therapeutic recommendations for patients with Waldenström’s macroglobulinemia (WM), AL-amyloidosis, monoclonal immunoglobulin deposition disease (MIDD), POEMS syndrome, and primary plasma cell leukemia. For patients with WM, the combination of rituximab with chemotherapy remains the treatment cornerstone, while the Bruton-tyrosine kinase inhibitor ibrutinib has been introduced and approved for relapsed/refractory disease. The management of light chain amyloidosis depends on the presence and severity of heart disfunction. If present, intensification with an autologous stem cell transplantation (ASCT) is not recommended. Further aggregation of misfolded light chains could be prevented by doxycycline or monoclonal antibodies targeting amyloid deposits. Initial treatment generally consists of melphalan/dexamethasone or bortezomib-based regimens. For relapsing patients, one can consider proteasome inhibitors, immunomodulatory agents, melphalan or daratumumab. Because intact or light-chain immunoglobulins are also the culprits for MIDD, the small monoclonal plasma cells' clones should be treated and generally respond well to bortezomib-based treatment. POEMS syndrome is a well-defined clinical entity that can present as solitary bone lesions or disseminated disease. Radiation therapy is used for patients with localized disease and result in long-lasting response. Systemic treatment should be proposed to patients with disseminated disease, but regimens that can worsen a pre-existing polyneuropathy should be avoided. PPCL is located at the other end of the spectrum of plasma cell disorders and is associated with an aggressive disease course and poor prognosis. It requires an imminent, multi-phase and novel agents-based therapy, including induction, ASCT, consolidation and maintenance, with short treatment-free intervals. Patients not eligible for transplant procedures require personalized, intensive therapeutic approach. Allogeneic stem cell transplantation can be used in selected patients.

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References

  1. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. World health organization classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2008.

  2. Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, et al. Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol. 2003;30:110–5.

    Article  PubMed  Google Scholar 

  3. San Miguel JF, Vidriales MB, Ocio E, Mateo G, Sanchez-Guijo F, Sanchez ML, et al. Immunophenotypic analysis of Waldenstrom’s macroglobulinemia. Semin Oncol. 2003;30:187–95.

    Article  PubMed  CAS  Google Scholar 

  4. Kyle RA, Treon SP, Alexanian R, Barlogie B, Bjorkholm M, Dhopakar M, et al. Prognostic markers and criteria to initiate therapy in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s macroglobulinemia. Semin Oncol. 2003;30:116–20.

    Article  PubMed  Google Scholar 

  5. Dimopoulos MA, Kastritis E, Owen RG, Kyle RA, Landgren O, Morra E, et al. Treatment recommendations for patients with Waldenstrom macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood. 2014;124:1404–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Treon SP, Agus DB, Link B, Rodriguez G, Molina A, Lacy MQ, et al. CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom’s macroglobulinemia. J Immunother. 1991;2001:272–9.

    Google Scholar 

  7. Treon SP, Branagan AR, Hunter Z, Santos D, Tournhilac O, Anderson KC. Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenstrom’s macroglobulinemia. Ann Oncol. 2004;15:1481–3.

    Article  PubMed  CAS  Google Scholar 

  8. Castillo JJ, Kanan S, Meid K, Manning R, Hunter ZR, Treon SP. Rituximab intolerance in patients with Waldenstrom macroglobulinaemia. Br J Haematol. 2016;174:645–8.

    Article  PubMed  Google Scholar 

  9. Kastritis E, Gavriatopoulou M, Kyrtsonis MC, Roussou M, Hadjiharissi E, Symeonidis A, et al. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenstrom macroglobulinemia: final analysis of a phase 2 study. Blood. 2015;126:1392–4.

    Article  PubMed  Google Scholar 

  10. Treon SP, Branagan AR, Ioakimidis L, Soumerai JD, Patterson CJ, Turnbull B, et al. Long-term outcomes to fludarabine and rituximab in Waldenstrom macroglobulinemia. Blood. 2009;113:3673–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Tedeschi A, Ricci F, Goldaniga MC, Benevolo G, Varettoni M, Motta M, Pioltelli P, et al. Fludarabine, cyclophosphamide, and rituximab in salvage therapy of Waldenstrom’s macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2013;13:231–4.

    Article  PubMed  CAS  Google Scholar 

  12. Souchet L, Levy V, Ouzegdouh M, Tamburini J, Delmer A, Dupuis J, et al. Efficacy and long-term toxicity of the rituximab-fludarabine-cyclophosphamide combination therapy in Waldenstrom’s macroglobulinemia. Am J Hematol. 2016;91:782–6.

    Article  PubMed  CAS  Google Scholar 

  13. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203–10.

    Article  PubMed  CAS  Google Scholar 

  14. Treon SP, Hanzis C, Tripsas C, Iaokimidis L, Patterson CJ, Manning RJ, et al. Bendamustine therapy in patients with relapsed or refractory Waldenstrom’s macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011;11:133–5.

    Article  PubMed  CAS  Google Scholar 

  15. Dimopoulos MA, Garcia-Sanz R, Gavriatopoulou M, Morel P, Kyrtsonis MC, Michalis E, et al. Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood. 2013;122:3276–82.

    Article  PubMed  CAS  Google Scholar 

  16. Treon SP, Tripsas CK, Meid K, Kanan S, Sheehy P, Chuma S, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenstrom’s macroglobulinemia. Blood. 2014;124:503–10.

    Article  PubMed  CAS  Google Scholar 

  17. Treon SP, Hanzis C, Manning RJ, Ioakimidis L, Patterson CJ, Hunter ZR, et al. Maintenance Rituximab is associated with improved clinical outcome in rituximab naive patients with Waldenstrom Macroglobulinaemia who respond to a rituximab-containing regimen. Br J Haematol. 2011;154:357–62.

    Article  PubMed  CAS  Google Scholar 

  18. Kyriakou C, Boumendil A, Finel H, Vdernant JP, Cornelissen JJ, Thieblemont C, et al. Autologous stem cell transplantation (ASCT) for the treatment of patients with Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL). a risk factor analysis by the European Society for Blood and Marrow Transplantation (EBMT) Lymphoma Working Party [abstract]. Blood . 2014;124:678. Abstract

    Article  Google Scholar 

  19. Fouquet G, Guidez S, Petillon MO, Louni C, Ohyba B, Dib M, et al. Lenalidomide is safe and active in Waldenstrom macroglobulinemia. Am J Hematol. 2015;90:1055–9.

    Article  PubMed  CAS  Google Scholar 

  20. Treon SP, Tripsas C, Warren D, Patterson C, Sheehy P, Yang G, et al. Phase I study of pomalidomide, dexamethasone, rituximab (PDR) in patients with Waldenstrom’s macroglobulinemia [abstract]. Proceedings of the 12th International Conference on Malignant Lymphoma. 19–22 June 2013. Lugano, Switzerland. Abstract 536.

  21. Ghobrial IM, Witzig TE, Gertz M, Laplant B, Hayman S, Camoriano J, et al. Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom macroglobulinemia. Am J Hematol. 2014;89:237–42.

    Article  PubMed  CAS  Google Scholar 

  22. Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med. 2015;372:1430–40.

    Article  PubMed  CAS  Google Scholar 

  23. Dimoupoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, et al. Ibrutinib therapy in rituximab-refractory patients with Waldenström’s macroglobulinemia: initial results from an international, multicenter, open-label phase 3 substudy (INNOVATETM) [abstract]. Blood. 2015;126:2745. Abstract

    Google Scholar 

  24. Gustine JN, Meid K, Dubeau TE, Treon SP, Castillo JJ. Atrial fibrillation associated with ibrutinib in Waldenstrom macroglobulinemia. Am J Hematol. 2016;91:E312–13.

    Article  PubMed  Google Scholar 

  25. Treon SP, Xu L, Hunter Z. MYD88 mutations and response to ibrutinib in Waldenstrom’s macroglobulinemia. N Engl J Med. 2015;373:584–6.

    Article  PubMed  CAS  Google Scholar 

  26. Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, MacDonald D, Tam C, et al. Ibrutinib for patients with rituximab-refractory Waldenström’s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017;18:241–50. https://doi.org/10.1016/S1470-2045(16)30632-5

    Article  PubMed  CAS  Google Scholar 

  27. Merlini G, Stone MJ. Dangerous small B-cell clones. Blood . 2006;108:2520–30.

    Article  PubMed  CAS  Google Scholar 

  28. Muchtar E, Gertz MA, Kumar SK, Lacy MQ, Dingli D, Buadi FK, et al. Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death. Blood . 2017;129:2111–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Fernandez de Larrea C, Verga L, Morbini P, Klersy C, Levatelli F, Foli A, et al. A practical approach to the diagnosis of systemic amyloidoses. Blood . 2015;125:2239–44.

    Article  PubMed  CAS  Google Scholar 

  30. Foli A, Palladini G, Caporali R, Verga L, Morbini P, Obici L, et al. The role of minor salivary gland biopsy in the diagnosis of systemic amyloidosis: results of a prospective study in 62 patients. Amyloid . 2011;18(Suppl 1):80–82.

    Article  PubMed  Google Scholar 

  31. Schonland SO, Hegenbart U, Bochtler T, Mangatter A, Hansberg M, Ho AD, et al. Immunohistochemistry in the classification of systemic forms of amyloidosis: a systematic investigation of 117 patients. Blood . 2012;119:488–93.

    Article  PubMed  CAS  Google Scholar 

  32. Gilbertson JA, Theis JD, Vrana JA, Lachmann H, Wechalekar A, Whelan C, et al. A comparison of immunohistochemistry and mass spectrometry for determining the amyloid fibril protein from formalin-fixed biopsy tissue. J Clin Pathol. 2015;68:314–7.

    Article  PubMed  Google Scholar 

  33. Palladini G, Russo P, Bosoni T, Verga L, Sarais G, Lavatelli F, et al. Identification of amyloidogenic light chains requires the combination of serum-free light chain assay with immunofixation of serum and urine. Clin Chem. 2009;55:499–504.

    Article  PubMed  CAS  Google Scholar 

  34. Comenzo RL, Vosburgh E, Simms RW, Bergethon P, Sarnacki D, Finn K, et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood . 1996;88:2801–6.

    PubMed  CAS  Google Scholar 

  35. D’Souza A, Dispenzieri A, Wirk B, et al. Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a center for international blood and marrow transplant research study. J Clin Oncol. 2015;33:3741–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Sanchorawala V, Sun F, Quillen K, Sloan JM, Berk JL, Seldin DC. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience. Blood . 2015;126:2345–7.

    Article  PubMed  Google Scholar 

  37. Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, et al. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia . 2013;27:823–8.

    Article  PubMed  CAS  Google Scholar 

  38. Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, et al. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica . 2014;99:743–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007;357:1083–93.

    Article  PubMed  CAS  Google Scholar 

  40. Sitia R, Palladini G, Merlini G. Bortezomib in the treatment of AL amyloidosis: targeted therapy? Haematologica . 2007;92:1302–7.

    Article  PubMed  CAS  Google Scholar 

  41. Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Blade J, et al. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood . 2014;124:2498–506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010;28:1031–7.

    Article  PubMed  CAS  Google Scholar 

  43. Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, et al. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood . 2012;119:4391–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Venner CP, Lane T, Foard D, et al. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood . 2012;119:4387–90.

    Article  PubMed  CAS  Google Scholar 

  45. Venner CP, Gillmore JD, Sachchithanantham S, Mahmood S, Lane T, Foard D, et al. A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis. Leukemia . 2014;28:2304–10.

    Article  PubMed  CAS  Google Scholar 

  46. Palladini G, Milani P, Foli A, Vidus Rosin M, Basset M, Lavatelli F, et al. Melphalan and dexamethasone with or without bortezomib in newly diagnosed AL amyloidosis: a matched case-control study on 174 patients. Leukemia . 2014;28:2311–6.

    Article  PubMed  CAS  Google Scholar 

  47. Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, et al. A randomized phase III trial of melphalan and dexamethasone (MDex) versus bortezomib, melphalan and dexamethasone (BMDex) for untreated patients with AL amyloidosis. Clin Lymphoma Myeloma Leuk. 2015;15(Suppl 3):e59–60.

    Article  Google Scholar 

  48. Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, et al. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012;91:89–92.

    Article  PubMed  CAS  Google Scholar 

  49. Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, et al. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood . 2012;119:5397–404.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, et al. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood . 2012;119:5384–90.

    Article  PubMed  CAS  Google Scholar 

  51. Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, et al. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood . 2010;116:4777–82.

    Article  PubMed  CAS  Google Scholar 

  52. Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, et al. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica . 2017;102:1424–31.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Specter R, Sanchorawala V, Seldin DC, Shelton A, Fennessey S, Finn KT, et al. Kidney dysfunction during lenalidomide treatment for AL amyloidosis. Nephrol Dial Transplant. 2011;26:881–6.

    Article  PubMed  CAS  Google Scholar 

  54. Merlini G, Sanchorawala V, Zonder JA, Kukreti V, Schoenland SO, Jaccard A, et al. Blood. 2014;124:3450. Long-term outcome of a phase 1 study of the investigational oral proteasome inhibitor (PI) ixazomib at the recommended phase 3 dose (RP3D) in patients (Pts) with relapsed or refractory systemic light-chain (AL) amyloidosis (RRAL) [abstract]Abstract

    Article  CAS  Google Scholar 

  55. Lentzsch S, Comenzo RL, Zonder JA, Osman K, Susanna M, Backenroth D, et al. Updated results of a phase 2 study of bendamustine in combination with dexamethasone (Ben/Dex) in patients with previously-treated systemic light-chain (AL) amyloidosis [abstract]. Blood. 2015;126:3041. Abstract

    Google Scholar 

  56. Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood . 2017;130:900–2.

    Article  PubMed  CAS  Google Scholar 

  57. Cohen AD, Landau H, Scott EC, Liedtke M, Kaufman JL, Rosenzweig M, et al. Safety and Efficacy of Carfilzomib (CFZ) in Previously-Treated Systemic Light-Chain (AL) Amyloidosis. Blood . 2016;128:645–45.

    Google Scholar 

  58. Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. Faseb J. 2006;20:234–9.

    Article  PubMed  CAS  Google Scholar 

  59. Wechalekar AD, Whelan C. Encouraging impact of doxycycline on early mortality in cardiac light chain (AL) amyloidosis. Blood Cancer J. 2017;7:e546.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature . 2002;417:254–9.

    Article  PubMed  CAS  Google Scholar 

  61. Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, et al. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015;373:1106–14.

    Article  PubMed  CAS  Google Scholar 

  62. Gertz MA, Landau H, Comenzo RL, Seldin D, Weiss B, Zonder J, et al. First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 2016;34:1097–103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Edwards CV, Gould J, Langer AL, Mapara M, Radhakrishnan J, Maurere MS, et al. Final analysis of the phase 1a/b Study of chimeric fibril-reactive monoclonal antibody 11-1F4 in patients with relapsed or refractory AL amyloidosis. Blood . 2017;130:509–09.

    Google Scholar 

  64. Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22:3751–7.

    Article  PubMed  CAS  Google Scholar 

  65. Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Colby C, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30:989–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Kourelis TV, Kumar SK, Gertz MA, Lacy MQ, Buadi FK, Hayman SR, et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol. 2013;31:4319–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Hwa YL, Kumar SK, Lacy MQ, Gertz MA, Buadi F, Rajkumar SV, et al. Impact of bone marrow plasmacytosis on outcome in patients with AL amyloidosis following autologous stem cell transplant [abstract]. Blood. 2015;126:3177. Abstract

    Google Scholar 

  68. Bochtler T, Hegenbart U, Kunz C, Benner A, Seckinger A, Dietrich S, et al. Gain of chromosome 1q21 is an independent adverse prognostic factor in light chain amyloidosis patients treated with melphalan/dexamethasone. Amyloid . 2014;21:9–17.

    Article  PubMed  CAS  Google Scholar 

  69. Bochtler T, Hegenbart U, Kunz C, Granzow M, Benner A, Seckinger A, et al. Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens. J Clin Oncol. 2015;33:1371–8.

    Article  PubMed  CAS  Google Scholar 

  70. Lin J, Markowitz GS, Valeri AM, Kampham N, Sherman WH, et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol. 2001;12:1482–92.

    PubMed  CAS  Google Scholar 

  71. Sayed RH, Wechalekar AD, Gilbertson J, Bass P, Mahmood S, Sachchithanantham S, et al. Natural history and outcome of light chain deposition disease. Blood. 2015;126:2805–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Batuman V, Guan S. Receptor-mediated endocytosis of immunoglobulin light chains by renal proximal tubule cells. Am J Physiol. 1997;272:F521–30.

    PubMed  CAS  Google Scholar 

  73. Pozzi C, Locatelli F. Kidney and liver involvement in monoclonal light chain disorders. Semin Nephrol. 2002;22:319–30.

    PubMed  CAS  Google Scholar 

  74. Nasr SH, Satoskar A, Markowitz GS, Valeri AM, Appel GB, Stokes MD, et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol. 2009;20:2055–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Nasr SH, Valeri AM, Cornell LD, Fidler ME, Sethi S, D’Agati VD, et al. Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution. Clin J Am Soc Nephrol. 2012;7:231–9.

    Article  PubMed  Google Scholar 

  76. Kastritis E, Migkou M, Gavriatopoulou M, Zirogiannis P, Hadjikonstantinou V, Dimopoulos MA, et al. Treatment of light chain deposition disease with bortezomib and dexamethasone. Haematologica. 2009;94:300–2.

    Article  PubMed  CAS  Google Scholar 

  77. Jimenez-Zepeda VH, Trudel S, Winter A, Reece DE, Chen C, Kukreti V. Autologous stem cell transplant for light chain deposition disease: incorporating bortezomib to the induction therapy. Am J Hematol. 2012;87:822–3.

    Article  PubMed  Google Scholar 

  78. Cohen C, Royer B, Javaugue V, Szalat R, El Karoui K, Caulier A, et al. Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease. Kidney Int. 2015;88:1135–43.

    Article  PubMed  CAS  Google Scholar 

  79. Kourelis TV, Nasr SH, Dispenzieri A, Kumar SK, Gertz MA, Fervenza FC, et al. Outcomes of patients with renal monoclonal immunoglobulin deposition disease. Am J Hematol. 2016;91:1123–8.

    Article  PubMed  CAS  Google Scholar 

  80. Pozzi C, Fogazzi GB, Banfi G, Strom EH, Ponticelli C, Locatelli F. Renal disease and patient survival in light chain deposition disease. Clin Nephrol. 1995;43:281–7.

    PubMed  CAS  Google Scholar 

  81. Leung N, Bridoux F, Hutchison CA, Nasr SH, Cockwell P, Fermand JP, et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood. 2012;120:4292–5.

    Article  PubMed  CAS  Google Scholar 

  82. Gkotzamanidou M, Terpos E, Kastritis E, Dimopoulos MA. Hematologic response and stabilization of renal function in a patient with light chain deposition disease after lenalidomide treatment: a novel therapeutic approach? Clin Lymphoma Myeloma Leuk. 2014;14:e179–181.

    Article  PubMed  Google Scholar 

  83. Bardwick PA, Zvaifler NJ, Gill GN, Newmann D, Greebway GD, Resnick DL. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Med (Baltim). 1980;59:311–22.

    Article  CAS  Google Scholar 

  84. 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;122:68–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Suh YG, Kim YS, Suh CO, Kim YR, Cheong JW, Kim JS, et al. The role of radiotherapy in the management of POEMS syndrome. Radiat Oncol. 2014;9:265.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Kim SY, Lee SA, Ryoo HM, Lee KH, Hyun MS, Bae SH. Thalidomide for POEMS syndrome. Ann Hematol. 2006;85:545–6.

    Article  PubMed  Google Scholar 

  88. Katayama K, Misawa S, Sato Y, Sobue G, Yabe I, Watanabe O, et al. Japanese POEMS syndrome with Thalidomide (J-POST) Trial: study protocol for a phase II/III multicentre, randomised, double-blind, placebo-controlled trial. BMJ Open. 2015;5:e007330.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Dispenzieri A, Moreno-Aspitia A, Suarez GA, Lacy MQ, Colon-Otero G, Tefferi A, et al. Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood. 2004;104:3400–7.

    Article  PubMed  CAS  Google Scholar 

  90. D’Souza A, Lacy M, Gertz M, Kumar S, Buadi F, Hayman S, et al. Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood. 2012;120:56–62.

    Article  PubMed  CAS  Google Scholar 

  91. Karam C, Klein CJ, Dispenzieri A, Dyck PJ, Mandrekar J, D’Souza A, et al. Polyneuropathy improvement following autologous stem cell transplantation for POEMS syndrome. Neurology. 2015;84:1981–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Straume O, Bergheim J, Ernst P. Bevacizumab therapy for POEMS syndrome. Blood. 2006;107:4972–3. author reply 4973-4974

    Article  PubMed  CAS  Google Scholar 

  93. Samaras P, Bauer S, Stenner-Liewen F, Steiner R, Zweifel M, Renner C, et al. Treatment of POEMS syndrome with bevacizumab. Haematologica. 2007;92:1438–9.

    Article  PubMed  Google Scholar 

  94. Dispenzieri A. POEMS syndrome. Blood Rev. 2007;21:285–99.

    Article  PubMed  Google Scholar 

  95. van de Donk NW, Lokhorst HM, Anderson KC, Richardson PG. How I treat plasma cell leukemia. Blood. 2012;120:2376–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Fernandez de Larrea C, Kyle RA, Durie BG, Ludwig H, Usmani H, Vesole DH, et al. Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia. 2013;27:780–91.

    Article  PubMed  CAS  Google Scholar 

  97. Touzeau C, Moreau P. How I treat extramedullary myeloma. Blood. 2016;127:971–6.

    Article  PubMed  CAS  Google Scholar 

  98. Gonsalves WI, Rajkumar SV, Go RS, Dispenzieri A, Gupta V, Singh PP, et al. Trends in survival of patients with primary plasma cell leukemia: A population-based analysis. Blood. 2014;124:907–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Musto P, Simeon V, Todoerti K, Neri A. Primary plasma cell leukemia: identity card 2016. Curr Treat Options Oncol. 2016;17:19.

    Article  PubMed  Google Scholar 

  100. Tiedemann RE, Gonzalez-Paz N, Kyle RA, Santana-Davila R, Price-Troska T, Van Wier SA, et al. Genetic aberrations and survival in plasma cell leukemia. Leukemia. 2008;22:1044–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Neri A, Todoerti K, Lionetti M, Simeon V, Barbieri M, Nozza F, et al. Primary plasma cell leukemia 2.0: advances in biology and clinical management. Expert Rev Hematol. 2016;9:1063–73.

    Article  PubMed  CAS  Google Scholar 

  102. Simeon V, Todoerti K, La Rocca F, Caivano A, Trino S, Lionetti M, et al. Molecular classification and pharmacogenetics of primary plasma cell leukemia: an initial approach toward precision medicine. Int J Mol Sci. 2015;16:17514–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Musto P. Progress in the treatment of primary plasma cell leukemia. J Clin Oncol. 2016;34:2082–4.

    Article  PubMed  Google Scholar 

  104. Musto P, Simeon V, Martorelli MC, Petrucci MT, Cascavilla N, Di Raimondo F, et al. Lenalidomide and low-dose dexamethasone for newly diagnosed primary plasma cell leukemia. Leukemia. 2014;28:222–5.

    Article  PubMed  CAS  Google Scholar 

  105. Royer B, Minvielle S, Diouf M, Roussel, Karlin L, Hulin C, et al. Bortezomib, doxorubicin, cyclophosphamide, dexamethasone induction followed by stem cell transplantation for primary plasma cell leukemia: a prospective phase II study of the Intergroupe Francophone du Myelome. J Clin Oncol. 2016;34:2125–32.

    Article  PubMed  CAS  Google Scholar 

  106. Jung SH, Lee JJ, Kim K, Suh C, Yoon DH, Min CK, et al. Korean multiple myeloma working party. The role of frontline autologous stem cell transplantation for primary plasma cell leukemia: a retrospective multicenter study (KMM160). Oncotarget. 2017;8:79517–26.

    PubMed  PubMed Central  Google Scholar 

  107. Granell M, Calvo X, Garcia-Guiñón A, Escoda L, Abella E, Martínez CM, et al. Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition. Haematologica. 2017 Jun;102:1099–104. Epub 2017 Mar 2

    Article  PubMed  PubMed Central  Google Scholar 

  108. Usmani SZ, Nair B, Qu P, Hansen E, Zhang Q, Petty N, et al. Primary plasma cell leukemia: clinical and laboratory presentation, gene-expression profiling and clinical outcome with Total Therapy protocols. Leukemia. 2012;26:2398–405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Avet-Loiseau H, Roussel M, Campion L, Leleu X, Marit G, Jardel H, et al. Cytogenetic and therapeutic characterization of primary plasma cell leukemia: the IFM experience. Leukemia. 2012;26:158–9.

    Article  PubMed  CAS  Google Scholar 

  110. D’Arena G, Valentini CG, Pietrantuono G, Guariglia R, Martorelli MC, Mansueto G, et al. Frontline chemotherapy with bortezomib-containing combinations improves response rate and survival in primary plasma cell leukemia: a retrospective study from GIMEMA Multiple Myeloma Working Party. Ann Oncol. 2012;23:1499–502.

    Article  PubMed  Google Scholar 

  111. Katodritou E, Terpos E, Kelaidi C, Kotsopoulou M, Delimpasi S, Kyrtsonis MC, et al. Treatment with bortezomib-based regimens improves overall response and predicts for survival in patients with primary or secondary plasma cell leukemia: analysis of the Greek myeloma study group. Am J Hematol. 2014;89:145–50.

    Article  PubMed  CAS  Google Scholar 

  112. Lebovic D, Zhang L, Alsina M, Nishiroti T, Shain KH, Sullivan D, et al. Clinical outcomes of patients with plasma cell leukemia in the era of novel therapies and hematopoietic stem cell transplantation strategies: a single-institution experience. Clin Lymphoma Myeloma Leuk. 2011;11:507–11.

    Article  PubMed  Google Scholar 

  113. Jurczyszyn A, Radocha J, Davila J, Fiala MA, Gozzetti A, Grasko N, et al. Prognostic indicators in primary plasma cell leukaemia: a multicentre retrospective study of 117 patients. Br J Haematol. 2018. https://doi.org/10.1111/bjh.15092. [Epub ahead of print] PubMed PMID: 29315478.

  114. Mina R, D’Agostino M, Cerrato C, Gay F, Palumbo A. Plasma cell leukemia: update on biology and therapy. Leuk Lymphoma. 2017;58:1538–47.

    Article  PubMed  CAS  Google Scholar 

  115. Drake MB, Iacobelli S, van Biezen A, Morris C, Apperley JF, Niederwieser D, et al. Primary plasma cell leukemia and autologous stem cell transplantation. Haematologica. 2010;95:804–9.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Mahindra A, Kalaycio ME, Vela-Ojeda J, Vesole DH, Zhang MJ, Li P, et al. Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research. Leukemia. 2012;26:1091–7.

    Article  PubMed  CAS  Google Scholar 

  117. Nishihori T, Abu Kar SM, Baz R, Alsina M, Harousseau JL, Kharfan-Dabaja MA. Therapeutic advances in the treatment of primary plasma cell leukemia: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013;19:1144–51.

    Article  PubMed  Google Scholar 

  118. Lawless S, Iacobelli S, van Biezen A, Koster L, Chevallier P, Blaise D, et al. Comparison of haematopoietic stem cell transplantation approaches in primary plasma cell leukaemia. Abstr Book 16° Int Myeloma Workshop, 1–4 March, New Delhi. 2017;E32:OP 038.

    Google Scholar 

  119. Morris C, Iacobelli S, Gahrton G, Garderet L, Drake M, van Biezen A, et al. Has allogeneic transplantation a role in the management of plasma cell leukaemia? A study on behalf of the myeloma subcomittee of the chronic leukaemia working party of the EBMT. Abstract 2008. 53th Annual Meeting, 10–13 December 2011.

  120. Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2018;32:252–62.

    Article  PubMed  CAS  Google Scholar 

  121. Gonsalves WI, Buadi FK, Kumar SK. Combination therapy incorporating Bcl-2 inhibition with Venetoclax for the treatment of refractory primary plasma cell leukemia with t (11;14). Eur J Haematol. 2018;100:215–7.

    Article  PubMed  CAS  Google Scholar 

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Author notes

  1. Equal contribution for first authorship: Maria Gavriatopoulou and Pellegrino Musto.

  2. Equal contribution for last authorship: Monika Engelhardt and Evangelos Terpos.

Authors and Affiliations

  1. Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece

    Maria Gavriatopoulou, Efstathios Kastritis, Meletios A. Dimopoulos & Evangelos Terpos

  2. Scientific Direction, IRCCS-CROB, Referral Cancer Center of Basilacata, Rionero in Vulture (Pz), Vulture, Italy

    Pellegrino Musto

  3. Department of Hematology, University Hospital of Liege, Liege, Belgium

    Jo Caers

  4. Department of Molecular Medicine, Amyloidosis Research and Treatment Center, Foundation ‘Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo’, University of Pavia, Pavia, Italy

    Giampaolo Merlini

  5. Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands

    Niels van de Donk & Sonja Zweegman

  6. Division of Hematology, S. Giovanni Battista Hospital, University of Turin, Turin, Italy

    Francesca Gay, Benedetto Bruno & Mario Boccadoro

  7. Department of Internal Medicine V, Amyloidosis Center, University of Heidelberg, Heidelberg, Germany

    Ute Hegenbart

  8. Department of HematoOncology, University Hospital Ostrava and Faculty of Medicine OU, Ostrava, Czech Republic

    Roman Hajek

  9. Department of Hematology & Oncology, Schön Klinik Starnberger See, Berg, Germany

    Christian Straka

  10. Department of Internal Medicine II, University Hospital Würburg, Würzburg, Germany

    Hermann Einsele

  11. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Pieter Sonneveld

  12. Department of Medicine I, Hematology, Oncology & Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany

    Monika Engelhardt

Authors
  1. Maria Gavriatopoulou
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  2. Pellegrino Musto
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  3. Jo Caers
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  4. Giampaolo Merlini
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  5. Efstathios Kastritis
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  11. Benedetto Bruno
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  12. Christian Straka
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  13. Meletios A. Dimopoulos
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  15. Mario Boccadoro
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  17. Monika Engelhardt
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  18. Evangelos Terpos
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Corresponding author

Correspondence to Evangelos Terpos.

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Conflict of interest

Maria Gavriatopoulou has received honoraria for advisory boards and honoraria from Amgen, Takeda, and Janssen. Pellegrino Musto has received honoraria for advisory boards and honoraria from Janssen, Celgene, Takeda, Amgen, and Bristol-Myers Squibb. Efstathios Kastritis has received honoraria for advisory boards and honoraria from Janssen, Celgene, Amgen, Takeda, and Prothena. Niels van de Donk has received research funding and honoraria for participating in advisory boards from Janssen, Celgene, Bristol-Myers Squibb, and Amgen. Francesca Gay has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, and Takeda, and honoraria for participation in advisory boards from Janssen, Amgen, Celgene, Roche, and Takeda. Roman Hájek has received consultancy fees, research funding, and honoraria for participation in advisory boards from Amgen, Takeda, Bristol-Myers Squibb, Celgene, Novartis, and Janssen. Sonja Zweegman has received honoraria for participating in advisory boards and research funding from Janssen, Celgene, Novartis, and Takeda. Meletios A. Dimopoulos has received consultancy fees and honoraria from Celgene, Onyx, Janssen, Novartis, and Amgen, and honoraria for participation in advisory boards from Amgen, Takeda, Celgene, and Janssen. Hermann Einsele has received speakers’ honoraria and honoraria for participation in advisory boards for Celgene, Janssen, Amgen, Bristol-Myers Squibb, and Novartis, and consultancy fees or honoraria from Celgene, Janssen, Bristol-Myers Squibb, and Amgen. Pieter Sonneveld has received honoraria for participating in advisory boards and honoraria from Amgen, Bristol-Myers-Squibb, Celgene, Janssen, and Karyopharm and research support from Amgen, Celgene, Janssen, Karyopharm, and SkylineDx. Monika Engelhardt has received educational grants from Celgene, Janssen, Amgen, Takeda and MSD. Evangelos Terpos has received honoraria from Janssen, Amgen, Takeda, Abbvie, Bristol-Myers Squibb, PharmaMar, and Celgene, research funding from Amgen, Genesis, Janssen, Novartis, and Takeda, honoraria for participation in advisory boards from Takeda, as well as honoraria for participation in the data monitoring committee from Celgene. Jo Caers, Giampaolo Merlini, Ute Hegenbart, Benedetto Bruno, Christian Straka and Mario Boccadoro have no relevant conflicts to disclose.

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Gavriatopoulou, M., Musto, P., Caers, J. et al. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. Leukemia 32, 1883–1898 (2018). https://doi.org/10.1038/s41375-018-0209-7

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  • DOI: https://doi.org/10.1038/s41375-018-0209-7

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