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Multiple myeloma gammopathies

IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features

Leukemia volume 34, pages 1373–1382 (2020)Cite this article

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Abstract

This study evaluates newly diagnosed IgM (6%, n = 75/1174) vs. non-IgM light chain amyloidosis patients. IgM amyloid patients had lower light chains (12.5 vs. 22.5 mg/dL; p < 0.001). Heart (56% vs. 73%, p = 0.002) and >1 organ involvement (31% vs. 44%, p = 0.02) was less common in IgM amyloidosis, while soft tissue and peripheral nerve involvement was more common. t(11;14) was less common (27% vs. 50%, p = 0.008) in IgM amyloidosis. Rates of MYD88L265P and CXCR4WHIM mutation in IgM amyloidosis were 58% (29/50) and 17% (8/46). Diagnosis after hematopathology review in IgM amyloidosis was pure plasma cell neoplasm (PPCN) in 23% (16/70), lymphoplasmacytic neoplasm (LPL) in 63% (44/70) patients, and other (14%). LPL vs. PPCN groups had distinct genetic abnormalities: t(11;14): 0% (0/18) vs. 60% (9/15), p < 0.001; MYD88L265P mutation: 84% (27/32) vs. 0% (0/14), p < 0.001; CXCR4 mutation: 29% (8/28) vs. 0% (0/14), p = 0.04. Overall survival was shorter in IgM AL when stratified by Mayo 2012 stage; stage 1/2 (59 vs. 125.9 months, p = 0.003) and stage 3/4 (6.5 vs. 12.9 months, p = 0.075), likely due to lower hematologic response rates (6 months: 39% vs. 59%, p = 0.008). We characterized two subtypes of IgM amyloidosis (LPL/PPCN). This can aid in therapeutic decision-making, with treatment directed at the clonal disease.

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References

  1. Gertz MA, Kyle RA, Noel P. Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenstrom’s macroglobulinemia. J Clin Oncol. 1993;11:914–20.

    Article  CAS  Google Scholar 

  2. Gertz MA, Buadi FK, Hayman SR. IgM amyloidosis: clinical features in therapeutic outcomes. Clin Lymphoma Myeloma Leuk. 2011;11:146–8.

    Article  CAS  Google Scholar 

  3. Palladini G, Russo P, Bosoni T, Sarais G, Lavatelli F, Foli A, et al. AL amyloidosis associated with IgM monoclonal protein: a distinct clinical entity. Clin Lymphoma Myeloma. 2009;9:80–3.

    Article  CAS  Google Scholar 

  4. Wechalekar AD, Lachmann HJ, Goodman HJ, Bradwell A, Hawkins PN, Gillmore JD. AL amyloidosis associated with IgM paraproteinemia: clinical profile and treatment outcome. Blood. 2008;112:4009–16.

    Article  CAS  Google Scholar 

  5. Zanwar S, Abeykoon JP, Ansell SM, Gertz MA, Dispenzieri A, Muchtar E, et al. Primary systemic amyloidosis in patients with Waldenstrom macroglobulinemia. Leukemia. 2019;33:790–4.

    Article  Google Scholar 

  6. Milani P, Merlini G. Monoclonal IgM-related AL amyloidosis. Best Pract Res Clin Haematol. 2016;29:241–8.

    Article  Google Scholar 

  7. Terrier B, Jaccard A, Harousseau JL, Delarue R, Tournilhac O, Hunault-Berger M, et al. The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients. Medicine. 2008;87:99–109.

    Article  CAS  Google Scholar 

  8. Sissoko M, Sanchorawala V, Seldin D, Sworder B, Angelino K, Broce M, et al. Clinical presentation and treatment responses in IgM-related AL amyloidosis. Amyloid. 2015;22:229–35.

    Article  CAS  Google Scholar 

  9. Sachchithanantham S, Roussel M, Palladini G, Klersy C, Mahmood S, Venner CP, et al. European Collaborative Study defining clinical profile outcomes and novel prognostic criteria in monoclonal immunoglobulin M-related light chain amyloidosis. J Clin Oncol. 2016;34:2037–45.

    Article  CAS  Google Scholar 

  10. Muchtar E, Dispenzieri A, Kumar SK, Ketterling RP, Dingli D, Lacy MQ, et al. Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category. Leukemia. 2017;31:1562–9.

    Article  CAS  Google Scholar 

  11. 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  CAS  Google Scholar 

  12. Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood. 2014;123:2791–6.

    Article  CAS  Google Scholar 

  13. 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  CAS  Google Scholar 

  14. Chakraborty R, Novak AJ, Ansell SM, Muchtar E, Kapoor P, Hayman SR, et al. First report of MYD88 L265P somatic mutation in IgM-associated light-chain amyloidosis. Blood. 2016;127:2936–8.

    Article  CAS  Google Scholar 

  15. Thakral B, Kanagal-Shamanna R, Systemic AL. amyloidosis associated with Waldenstrom macroglobulinemia: an unusual presenting complication. Blood. 2016;127:168.

    Article  CAS  Google Scholar 

  16. Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol. 2005;79:319–28.

    Article  Google Scholar 

  17. Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012;30:4541–9.

    Article  CAS  Google Scholar 

  18. Palladini G, Hegenbart U, Milani P, Kimmich C, Foli A, Ho AD, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124:2325–32.

    Article  CAS  Google Scholar 

  19. Milani P, Basset M, Russo F, Foli A, Merlini G, Palladini G. Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome. Blood. 2017;130:625–31.

    Article  CAS  Google Scholar 

  20. Dittrich T, Bochtler T, Kimmich C, Becker N, Jauch A, Goldschmidt H, et al. AL amyloidosis patients with low amyloidogenic free light chain levels at first diagnosis have an excellent prognosis. Blood. 2017;130:632–42.

    Article  CAS  Google Scholar 

  21. Sidana S, Tandon N, Dispenzieri A, Gertz MA, Buadi FK, Lacy MQ, et al. Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains. Leukemia. 2018;32:729–35.

    Article  CAS  Google Scholar 

  22. Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al. Response assessment in Waldenstrom macroglobulinaemia: update from the VIth International Workshop. Br J Haematol. 2013;160:171–6.

    Article  Google Scholar 

  23. Rosado FG, Morice WG, He R, Howard MT, Timm M, McPhail ED. Immunophenotypic features by multiparameter flow cytometry can help distinguish low grade B-cell lymphomas with plasmacytic differentiation from plasma cell proliferative disorders with an unrelated clonal B-cell process. Br J Haematol. 2015;169:368–76.

    Article  Google Scholar 

  24. Morice WG, Chen D, Kurtin PJ, Hanson CA, McPhail ED. Novel immunophenotypic features of marrow lymphoplasmacytic lymphoma and correlation with Waldenstrom’s macroglobulinemia. Mod Pathol. 2009;22:807–16.

    Article  CAS  Google Scholar 

  25. Shi M, Ternus JA, Ketterling RP, Jevremovic D, McPhail ED. Immunophenotypic and laboratory features of t(11;14)(q13;q32)-positive plasma cell neoplasms. Leuk Lymphoma. 2018;59:1913–9.

    Article  CAS  Google Scholar 

  26. Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101:4569–75.

    Article  CAS  Google Scholar 

  27. Binder M, Rajkumar SV, Ketterling RP, Dispenzieri A, Lacy MQ, Gertz MA, et al. Occurrence and prognostic significance of cytogenetic evolution in patients with multiple myeloma. Blood Cancer J. 2016;6:e401.

    Article  CAS  Google Scholar 

  28. Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR 3rd, Dogan A. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114:4957–9.

    Article  CAS  Google Scholar 

  29. Pika T, Hegenbart U, Flodrova P, Maier B, Kimmich C, Schonland SO. First report of ibrutinib in IgM-related amyloidosis: few responses, poor tolerability, and short survival. Blood. 2018;131:368–71.

    Article  CAS  Google Scholar 

  30. Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N. Engl J Med. 2012;367:826–33.

    Article  CAS  Google Scholar 

  31. Sidana S, Tandon N, Dispenzieri A, Gertz MA, Buadi F, Lacy M, et al. Factors predicting organ response in light chain amyloidosis (AL). J Clin Oncol. 2017;35 15_suppl:8048.

    Article  Google Scholar 

  32. Muchtar E, Dispenzieri A, Leung N, Lacy MQ, Buadi FK, Dingli D, et al. Optimizing deep response assessment for AL amyloidosis using involved free light chain level at end of therapy: failure of the serum free light chain ratio. Leukemia. 2019;33:527–31.

    Article  CAS  Google Scholar 

  33. Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011;29:3389–95.

    Article  CAS  Google Scholar 

  34. Flinn IW, Thompson DS, Boccia RV, Miletello G, Lipman A, Flora D, et al. Bendamustine, bortezomib and rituximab produces durable complete remissions in patients with previously untreated, low grade lymphoma. Br J Haematol. 2018;180:365–73.

    Article  CAS  Google Scholar 

  35. Sidiqi MH, Buadi FK, Dispenzieri A, Warsame R, Lacy MQ, Dingli D, et al. Autologous stem cell transplant for IgM-associated amyloid light-chain amyloidosis. Biol Blood Marrow Transplant. 2019;25:e108–11.

    Article  CAS  Google Scholar 

  36. Gertz MA, Hayman SR, Buadi FK. Transplantation for IgM amyloidosis and IgM myeloma. Clin Lymphoma Myeloma. 2009;9:77–9.

    Article  Google Scholar 

  37. Marzolini MA, Thomson KJ, Dorman J, D’Sa S. BEAM-conditioned autologous SCT improves the quality of response in Waldenstrom’s macroglobulinaemia and lymphoplasmacytic lymphoma: a single centre’s 10-year experience. Bone Marrow Transplant. 2014;49:1231–2.

    Article  CAS  Google Scholar 

  38. Kyriakou C, Canals C, Sibon D, Cahn JY, Kazmi M, Arcese W, et al. High-dose therapy and autologous stem-cell transplantation in Waldenstrom macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2010;28:2227–32.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge Ms Kim Henderson and Ms Katie Halverson for their assistance in testing stored biospecimens.

Funding

Funding

Katherine McCleary Research Fund and K. Edward Jacobi Research Partners Fund of the International Waldenström’s Macroglobulinemia Foundation; Amyloidosis Foundation.

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Author notes

  1. These authors contributed equally: Rebecca L. King, Morie A. Gertz

Authors and Affiliations

  1. Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA, USA

    Surbhi Sidana

  2. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Surbhi Sidana, Angela Dispenzieri, Stephen M. Ansell, Eli Muchtar, Wilson I. Gonsalves, Taxiarchis V. Kourelis, Prashant Kapoor, S. Vincent Rajkumar, Martha Q. Lacy, Francis K. Buadi, Nelson Leung, Robert A. Kyle, Shaji K. Kumar & Morie A. Gertz

  3. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Daniel P. Larson, Patricia T. Greipp, Rong He, Ellen D. McPhail, David L. Murray, Surendra Dasari & Rebecca L. King

  4. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA

    Marina Ramirez-Alvarado

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Contributions

SS and MAG designed the study, collected the data, performed the analysis, and wrote the first draft of the manuscript. RLK and DL reviewed and analyzed the hematopathology data. PTG supervised FISH testing on cryopreserved bone marrow aspirates. RH supervised MYD88 and CXCR4 mutation testing on cryopreserved bone marrow aspirates. EDM supervised mass spectrometry testing on archival samples. EDM and SD reviewed mass spectrometry testing. All authors critically reviewed the manuscript.

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Correspondence to Rebecca L. King or Morie A. Gertz.

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Conflict of interest

SS: Consultancy: Janssen. AD: research funding from Celgene, Takeda, Prothena, Janssen, Pfizer, Alnylam, and GSK. PK: research funding from Celgene and Takeda. MQL: research funding from Celgene. SKK: research funding and membership on an entity’s Board of Directors or advisory committees: AbbVie, Celgene, Janssen, KITE, and Merck. Membership on an entity’s Board of Directors or advisory committees: Oncopeptides and Takeda. Research funding from Novartis and Roche. MAG: honoraria/consultancy from Ionis, Alnylam, Prothena, Celgene, Janssen, Spectrum, Annexon, Apellis, Amgen, Medscape, Abbvie, Research to Practice, Physicians Education Resource, and Teva. The other authors declare that they have no conflict of interest.

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Sidana, S., Larson, D.P., Greipp, P.T. et al. IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features. Leukemia 34, 1373–1382 (2020). https://doi.org/10.1038/s41375-019-0667-6

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