Diagnosis and treatment of AL amyloidosis in 2022


  • Victor H. Jimenez-Zepeda, MD




Light chain (AL) amyloidosis is a rare, progressive and typically fatal disease (when advanced) characterized by organ dysfunction secondary to deposition of misfolded fibrils of immunoglobulin light chains that are produced by clonal plasma cells or B cells. Although less than 10% of AL patients qualify for CRAB criteria of symptomatic myeloma (Calcium elevation, Renal dysfunction, Anemia, and Bone disease), the majority of these patients have significant impairment of vital organs, such as the heart, kidney and liver. This implies that the common risk factors used for the assessment of multiple myeloma (MM) are not applicable to AL. AL amyloidosis affects 8–12 individuals per million person-years, and its clinical presentation is variable depending on the extent and number of vital organs affected. The locations of amyloid deposits can vary among patients, thus contributing to the heterogeneity of the clinical manifestations. The heart and kidney, which are the most affected organs, can lead to renal failure, cardiomyopathy, and pericardial and pleural effusions. Initial symptoms at onset are often non-specific (e.g., weight loss, fatigue). Despite advances in the diagnostic tools and treatment options, early mortality rates remain high; the expected one-year mortality is approximately 30%. Unfortunately, by the time the AL diagnosis is made, and treatment is initiated, the disease has often become advanced.

Author Biography

Victor H. Jimenez-Zepeda, MD

Dr. Victor H. Jimenez-Zepeda is a hematologist practicing in Calgary, AB and a member of the Arnie Charbonneau Cancer Research Institute and Tom Baker Cancer Center. He is co-director of the Amyloidosis Program of Calgary. He serves as a member of the steering committee for the Myeloma Canada Research Network Database and is a member of other prestigious international societies such as the International Myeloma Society, International Society of Amyloidosis, European Hematology Association, and the American Society of Hematology among others.


McCausland KL, White MK, Guthrie SD, et al. Light Chain (AL) Amyloidosis: The Journey to Diagnosis. Patient. 2018 Apr;11(2):207-216. DOI: https://doi.org/10.1007/s40271-017-0273-5

Kourelis TV, Kumar SK, Gertz MA, 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 Dec 1;31(34):4319-24. DOI: https://doi.org/10.1200/JCO.2013.50.8499

Kyle RA, Linos A, Beard CM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood. 1992 Apr 1;79(7):1817-22. DOI: https://doi.org/10.1182/blood.V79.7.1817.bloodjournal7971817

Pinney JH, Smith CJ, Taube JB, et al. Systemic amyloidosis in England: an epidemiological study. Br J Haematol. 2013 May;161(4):525-32. DOI: https://doi.org/10.1111/bjh.12286

Lousada I, Comenzo RL, Landau H, et al. Light Chain Amyloidosis: Patient Experience Survey from the Amyloidosis Research Consortium. Advances in therapy. 2015 Oct;32(10):920-8. DOI: https://doi.org/10.1007/s12325-015-0250-0

Nuvolone M, Merlini G. Systemic amyloidosis: novel therapies and role of biomarkers. Nephrol Dial Transplant. 2017 May 1;32(5):770-780.

Muchtar E, Dispenzieri A, Lacy MQ, et al. Overuse of organ biopsies in immunoglobulin light chain amyloidosis (AL): the consequence of failure of early recognition. Ann Med. 2017 Nov;49(7):545-551. DOI: https://doi.org/10.1080/07853890.2017.1304649

Dasari S, Theis JD, Vrana JA, et al. Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples. Mayo Clin Proc. 2020 Sep;95(9):1852-1864. DOI: https://doi.org/10.1016/j.mayocp.2020.06.029

Fernandez de Larrea C, Verga L, Morbini P, et al. A practical approach to the diagnosis of systemic amyloidoses. Blood. 2015 Apr 2;125(14):2239-44. DOI: https://doi.org/10.1182/blood-2014-11-609883

Sidiqi MH, Dasari S, McPhail ED, et al. Monoclonal gammopathy plus positive amyloid biopsy does not always equal AL amyloidosis. Am J Hematol. 2019 May;94(5):E141-E143. DOI: https://doi.org/10.1002/ajh.25440

Phull P, Sanchorawala V, Connors LH, et al. Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR). Amyloid. 2018 Mar;25(1):62-67. DOI: https://doi.org/10.1080/13506129.2018.1436048

Mahmood S, Bridoux F, Venner CP, et al. Natural history and outcomes in localised immunoglobulin light-chain amyloidosis: a long-term observational study. Lancet Haematol. 2015 Jun;2(6):e241-50. DOI: https://doi.org/10.1016/S2352-3026(15)00068-X

Dispenzieri A, Gertz MA, Kyle RA, et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2004 Sep 15;104(6):1881-7. DOI: https://doi.org/10.1201/9781420037494-30

Fotiou D, Theodorakakou F, Kastritis E. Biomarkers in AL Amyloidosis. Int J Mol Sci. 2021 Oct 9;22(20). DOI: https://doi.org/10.3390/ijms222010916

Palladini G, Foli A, Milani P, et al. Best use of cardiac biomarkers in patients with AL amyloidosis and renal failure. Am J Hematol. 2012 May;87(5):465-71. DOI: https://doi.org/10.1002/ajh.23141

Palladini G, Milani P, Merlini G. Predicting survival in light chain amyloidosis. Haematologica. 2019 Jul;104(7):1294-1296. DOI: https://doi.org/10.3324/haematol.2019.218859

Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004 Sep 15;22(18):3751-7. DOI: https://doi.org/10.1200/JCO.2004.03.029

Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012 Mar 20;30(9):989-95. DOI: https://doi.org/10.1200/JCO.2011.38.5724

Lilleness B, Ruberg FL, Mussinelli R, et al. Development and validation of a survival staging system incorporating BNP in patients with light chain amyloidosis. Blood. 2019 Jan 17;133(3):215-223. DOI: https://doi.org/10.1182/blood-2018-06-858951

Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009 Aug;55(8):1517-22. DOI: https://doi.org/10.1373/clinchem.2009.126664

Dispenzieri A, Larson DR, Rajkumar SV, et al. N-glycosylation of monoclonal light chains on routine MASS-FIX testing is a risk factor for MGUS progression. Leukemia. 2020 Oct;34(10):2749-2753. DOI: https://doi.org/10.1038/s41375-020-0940-8

Kourelis T, Murray DL, Dasari S, et al. MASS-FIX may allow identification of patients at risk for light chain amyloidosis before the onset of symptoms. Am J Hematol. 2018 Nov;93(11):E368-E370. DOI: https://doi.org/10.1002/ajh.25244

Muchtar E, Jevremovic D, Dispenzieri A, et al. The prognostic value of multiparametric flow cytometry in AL amyloidosis at diagnosis and at the end of first-line treatment. Blood. 2017 Jan 5;129(1):82-87. DOI: https://doi.org/10.1182/blood-2016-06-721878

Puig N, Paiva B, Lasa M, et al. Flow cytometry for fast screening and automated risk assessment in systemic light-chain amyloidosis. Leukemia. 2019 May;33(5):1256-1267. DOI: https://doi.org/10.1038/s41375-018-0308-5

Bryce AH, Ketterling RP, Gertz MA, et al. Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis. Haematologica. 2009 Mar;94(3):380-6. DOI: https://doi.org/10.3324/haematol.13369

Warsame R, Kumar SK, Gertz MA, et al. Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death. Blood Cancer J. 2015 May 1;5:e310. DOI: https://doi.org/10.1038/bcj.2015.34

Muchtar E, Dispenzieri A, Kumar SK, et al. Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category. Leukemia. 2017 Jul;31(7):1562-1569. DOI: https://doi.org/10.1038/leu.2016.369

Bochtler T, Hegenbart U, Kunz C, et al. Gain of chromosome 1q21 is an independent adverse prognostic factor in light chain amyloidosis patients treated with melphalan/dexamethasone. Amyloid. 2014 Mar;21(1):9-17. DOI: https://doi.org/10.3109/13506129.2013.854766

Jimenez-Zepeda VH, Lee H, McCulloch S, et al. Treatment response measurements and survival outcomes in a cohort of newly diagnosed AL amyloidosis. Amyloid. 2021 Sep;28(3):182-188. DOI: https://doi.org/10.1080/13506129.2021.1921725

Palladini G, Milani P, Merlini G. Management of AL amyloidosis in 2020. Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):363-371. DOI: https://doi.org/10.1182/hematology.2020006913

Gertz MA, Falk RH, Skinner M, et al. Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents. Am J Cardiol. 1985 Jun 1;55(13 Pt 1):1645-32. DOI: https://doi.org/10.1016/0002-9149(85)90995-6

Dubrey S, Pollak A, Skinner M, et al. Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation. Br Heart J. 1995 Nov;74(5):541-4. DOI: https://doi.org/10.1136/hrt.74.5.541

Feng D, Syed IS, Martinez M, et al. Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis. Circulation. 2009 May 12;119(18):2490-7. DOI: https://doi.org/10.1161/CIRCULATIONAHA.108.785014

Falk RH, Alexander KM, Liao R, et al. AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. J Am Coll Cardiol. 2016 Sep 20;68(12):1323-41. DOI: https://doi.org/10.1016/j.jacc.2016.06.053

Patel KS, Hawkins PN, Whelan CJ, et al. Life-saving implantable cardioverter defibrillator therapy in cardiac AL amyloidosis. BMJ Case Rep. 2014 Dec 22;2014. DOI: https://doi.org/10.1136/bcr-2014-206600

Varr BC, Zarafshar S, Coakley T, et al. Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis. Heart Rhythm. 2014 Jan;11(1):158-62. DOI: https://doi.org/10.1016/j.hrthm.2013.10.026

Jaccard A, Moreau P, Leblond V, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. DOI: https://doi.org/10.1056/NEJMoa070484

Sidiqi MH, Aljama MA, Buadi FK, et al. Stem Cell Transplantation for Light Chain Amyloidosis: Decreased Early Mortality Over Time. J Clin Oncol. 2018 May 1;36(13):1323-1329. DOI: https://doi.org/10.1200/JCO.2017.76.9554

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 Nov 10;33(32):3741-9.

Sharpley FA, Petrie A, Mahmood S, et al. A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom. Br J Haematol. 2019 Dec;187(5):642-652. DOI: https://doi.org/10.1111/bjh.16143

Milani P, Basset M, Nuvolone M, et al. Indicators of profound hematologic response in AL amyloidosis: complete response remains the goal of therapy. Blood Cancer J. 2020 Sep 1;10(8):90. DOI: https://doi.org/10.1038/s41408-020-00355-6

Sidana S, Milani P, Binder M, et al. A validated composite organ and hematologic response model for early assessment of treatment outcomes in light chain amyloidosis. Blood Cancer J. 2020 Apr 14;10(4):41. DOI: https://doi.org/10.1038/s41408-020-0306-5

Palladini G, Dispenzieri A, Gertz MA, 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 Dec 20;30(36):4541-9. DOI: https://doi.org/10.1200/JCO.2011.37.7614

Palladini G, Paiva B, Wechalekar A, et al. Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis. Blood Cancer J. 2021 Feb 16;11(2):34. DOI: https://doi.org/10.1038/s41408-021-00428-0

Manwani R, Cohen O, Sharpley F, et al. A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib. Blood. 2019 Dec 19;134(25):2271-2280. DOI: https://doi.org/10.1182/blood.2019000834

Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. DOI: https://doi.org/10.1182/blood-2003-08-2788

Palladini G, Sachchithanantham S, Milani P, et al. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. DOI: https://doi.org/10.1182/blood-2015-01-620302

Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 07 01;385(1):46-58.

Basset M, Milani P, Nuvolone M, et al. Sequential response-driven bortezomib-based therapy followed by autologous stem cell transplant in AL amyloidosis. Blood Adv. 2020 Sep 8;4(17):4175-4179. DOI: https://doi.org/10.1182/bloodadvances.2020002219

Kastritis E, Leleu X, Arnulf B, et al. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. DOI: https://doi.org/10.1200/JCO.20.01285

Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013 Apr 25;121(17):3420-7. DOI: https://doi.org/10.1182/blood-2012-12-473066

Manwani R, Foard D, Mahmood S, et al. Rapid hematologic responses improve outcomes in patients with very advanced (stage IIIb) cardiac immunoglobulin light chain amyloidosis. Haematologica. 2018 Apr;103(4):e165-e168. DOI: https://doi.org/10.3324/haematol.2017.178095

Mahmood A SS, Harrison S, Manwani R, Sharpley F, Quarta C, Rezk T, Martinez A, Yoong K, Rabin N, Popat R, Kyriacou C, Papanikolau X, D’Sa S, Lachmann H, Whelan C, Gillmore J, Fontana M, Hawkins P and Wechaleckar A. Bortezomib-High dose Methylprednisolone offers improved hematological response and overall survival compared to Bortezomib-Dexamethasone in Systemic Light Chain Amyloidosis. EHA Library. 2019 [cited PB2127 p.]. DOI: https://doi.org/10.1097/01.HS9.0000566992.77698.56

Jimenez-Zepeda VH, Lee H, Fine N, et al. Cyclophosphamide, Bortezomib and Methylprednisolone (CyBorMe) for the Treatment of AL Amyloidosis: Initial Experience From a Single Center. Indian J Hematol Blood Transfus. 2021 Oct;37(4):675-678. DOI: https://doi.org/10.1007/s12288-021-01406-z

Palladini G, Milani P, Merlini G. Management of AL amyloidosis in 2020. Blood. 2020 12 03;136(23):2620-2627. DOI: https://doi.org/10.1182/blood.2020006913

Richards DB, Cookson LM, Berges AC, et al. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015 Sep 17;373(12):1106-14. DOI: https://doi.org/10.1056/NEJMoa1504942

Gertz MA, Landau H, Comenzo RL, 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 Apr 1;34(10):1097-103. DOI: https://doi.org/10.1200/JCO.2015.63.6530

Edwards CV, Rao N, Bhutani D, et al. Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood. 2021 Dec 23;138(25):2632-2641. DOI: https://doi.org/10.1182/blood.2020009039



How to Cite

Jimenez-Zepeda VH. Diagnosis and treatment of AL amyloidosis in 2022. Can Hematol Today [Internet]. 2022 Mar. 1 [cited 2024 Apr. 15];1(1):29–35. Available from: https://canadianhematologytoday.com/article/view/1-1-4-jimenez-zepeda