197
Views
5
CrossRef citations to date
0
Altmetric
Review

Novel challenges in the management of immunoglobulin light chain amyloidosis: from the bench to the bedside

, , &
Pages 1003-1015 | Received 06 May 2020, Accepted 27 Jul 2020, Published online: 11 Aug 2020

References

  • Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003;349(6):583–596.
  • Benson MD, Buxbaum JN, Eisenberg DS, et al. Amyloid nomenclature 2018: recommendations by the international society of amyloidosis (ISA) nomenclature committee. Amyloid. 2018;25(4):215–219.
  • Kyle RA, Larson DR, Kurtin PJ, et al. Incidence of AL amyloidosis in Olmsted County, Minnesota, 1990 through 2015. Mayo Clin Proc. 2019;94(3):465–471.
  • Merlini G, Stone MJ. Dangerous small B-cell clones. Blood. 2006;108(8):2520–2530.
  • Merlini G, Dispenzieri A, Sanchorawala V, et al. Systemic immunoglobulin light chain amyloidosis. Nat Rev Dis Primers. 2018;4(1):38.
  • Liao R, Jain M, Teller P, et al. Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation. 2001;104(14):1594–1597.
  • Diomede L, Rognoni P, Lavatelli F, et al. A Caenorhabditis elegans-based assay recognizes immunoglobulin light chains causing heart amyloidosis. Blood. 2014;123(23):3543–3552.
  • Mishra S, Guan J, Plovie E, et al. Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish. Am J Physiol Heart Circ Physiol. 2013;305(1):H95–103.
  • Lavatelli F, Imperlini E, Orrù S, et al. Novel mitochondrial protein interactors of immunoglobulin light chains causing heart amyloidosis. Faseb J. 2015;29(11):4614–4628.
  • Nuvolone M, Merlini G. Emerging therapeutic targets currently under investigation for the treatment of systemic amyloidosis. Expert Opin Ther Targets. 2017;21(12):1095–1110.
  • Milani P, Gertz MA, Merlini G, et al. Attitudes about when and how to treat patients with AL amyloidosis: an international survey. Amyloid. 2017;24(4):213–216.
  • Sidana S, Larson DP, Greipp PT, et al. IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features. Leukemia. 2020;34(5):1373-1382
  • Sachchithanantham S, Roussel M, Palladini G, 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(17):2037–2045.
  • Basset M, Defrancesco I, Milani P, et al. Nonlymphoplasmacytic lymphomas associated with light-chain amyloidosis. Blood. 2020;135(4):293–296.
  • Paiva B, Martinez-Lopez J, Corchete LA, et al. Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis. Blood. 2016;127(24):3035–3039.
  • Cuenca I, Alameda D, Sanchez-Vega B, et al. Immunogenetic characterization of clonal plasma cells in systemic light-chain amyloidosis. Leukemia. 2020. DOI:10.1038/s41375-020-0800-6
  • Oliva L, Orfanelli U, Resnati M, et al. The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity. Blood. 2017;129(15):2132–2142.
  • Bochtler T, Hegenbart U, Cremer FW, et al. Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability. Blood. 2008;111(9):4700–4705.
  • 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;31(7):1562–1569.
  • Bochtler T, Hegenbart U, Heiss C, et al. Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14). Blood. 2011;117(14):3809–3815.
  • Bochtler T, Hegenbart U, Kunz C, 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(12):1371–1378.
  • Bochtler T, Hegenbart U, Kunz C, et al. Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study. Blood. 2016;128(4):594–602.
  • 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;21(1):9–17.
  • Wong SW, Hegenbart U, Palladini G, et al. Outcome of patients with newly diagnosed systemic light-chain amyloidosis associated with deletion of 17p. Clin Lymphoma Myeloma Leuk. 2018;18(11):e493–e499.
  • Comenzo RL, Zhang Y, Martinez C, et al. The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden. Blood. 2001;98(3):714–720.
  • Perfetti V, Casarini S, Palladini G, et al. Analysis of V(lambda)-J(lambda) expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r (lambdaIII) as a new amyloid-associated germline gene segment. Blood. 2002;100(3):948–953.
  • Abraham RS, Geyer SM, Price-Troska TL, et al. Immunoglobulin light chain variable (V) region genes influence clinical presentation and outcome in light chain-associated amyloidosis (AL). Blood. 2003;101(10):3801–3808.
  • Prokaeva T, Spencer B, Kaut M, et al. Soft tissue, joint, and bone manifestations of AL amyloidosis: clinical presentation, molecular features, and survival. Arthritis Rheum. 2007;56(11):3858–3868.
  • Kourelis TV, Dasari S, Theis JD, et al. Clarifying immunoglobulin gene usage in systemic and localized immunoglobulin light-chain amyloidosis by mass spectrometry. Blood. 2017;129(3):299–306.
  • Perfetti V, Palladini G, Casarini S, et al. The repertoire of λ light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44. Blood. 2012;119(1):144–150.
  • Radamaker L, Lin YH, Annamalai K, et al. Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis. Nat Commun. 2019;10(1):1103.
  • Swuec P, Lavatelli F, Tasaki M, et al. Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient. Nat Commun. 2019;10(1):1269.
  • Rennella E, Morgan GJ, Yan N, et al. The role of protein thermodynamics and primary structure in fibrillogenesis of variable domains from immunoglobulin light chains. J Am Chem Soc. 2019;141(34):13562–13571.
  • Rennella E, Morgan GJ, Kelly JW, et al. Role of domain interactions in the aggregation of full-length immunoglobulin light chains. Proc Natl Acad Sci U S A. 2019;116(3):854–863.
  • Palladini G, Lavatelli F, Russo P, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood. 2006;107(10):3854–3858.
  • Shi J, Guan J, Jiang B, et al. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway. Proc Natl Acad Sci U S A. 2010;107(9):4188–4193.
  • Teng J, Turbat-Herrera EA, Herrera GA. Extrusion of amyloid fibrils to the extracellular space in experimental mesangial AL-amyloidosis: transmission and scanning electron microscopy studies and correlation with renal biopsy observations. Ultrastruct Pathol. 2014;38(2):104–115.
  • Teng J, Turbat-Herrera EA, Herrera GA. An animal model of glomerular light-chain-associated amyloidogenesis depicts the crucial role of lysosomes. Kidney Int. 2014;86(4):738–746.
  • Teng J, Russell WJ, Gu X, et al. Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns. Lab Invest. 2004;84(4):440–451.
  • Lousada I, Comenzo RL, Landau H, et al. Light chain amyloidosis: patient experience survey from the amyloidosis research consortium. Adv Ther. 2015;32(10):920–928.
  • 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;31(34):4319–4324.
  • Kourelis TV, Kumar SK, Go RS, et al. Immunoglobulin light chain amyloidosis is diagnosed late in patients with preexisting plasma cell dyscrasias. Am J Hematol. 2014;89(11):1051–1054.
  • Palladini G, Campana C, Klersy C, et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation. 2003;107(19):2440–2445.
  • Merlini G, Wechalekar AD, Palladini G. Systemic light chain amyloidosis: an update for treating physicians. Blood. 2013;121(26):5124–5130.
  • Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009;55(8):1517–1522.
  • Palladini G, Russo P, Bosoni T, 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(3):499–504.
  • Fernandez de Larrea C, Verga L, Morbini P, et al. A practical approach to the diagnosis of systemic amyloidoses. Blood. 2015;125(14):2239–2244.
  • Tasaki M, Milani P, Foli A, et al. Simple, reliable detection of amyloid in fat aspirates using the fluorescent dye FSB: prospective study in 206 patients. Blood. 2019;134(3):320–323.
  • Foli A, Palladini G, Caporali R, 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.
  • Li T, Huang X, Cheng S, et al. Utility of abdominal skin plus subcutaneous fat and rectal mucosal biopsy in the diagnosis of AL amyloidosis with renal involvement. PLoS One. 2017;12(9):e0185078.
  • Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002;346(23):1786–1791.
  • Driggin E, Maurer MS. The quintessential form of diastolic heart failure in older adults: wild type transthyretin cardiac amyloidosis. Clin Cardiol. 2020;43(2):171–178.
  • Geller HI, Singh A, Mirto TM, et al. Prevalence of monoclonal gammopathy in wild-type transthyretin amyloidosis. Mayo Clin Proc. 2017;92(12):1800–1805.
  • Schönland SO, Hegenbart U, Bochtler T, et al. Immunohistochemistry in the classification of systemic forms of amyloidosis: a systematic investigation of 117 patients. Blood. 2012;119(2):488–493.
  • Vrana JA, Gamez JD, Madden BJ, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114(24):4957–4959.
  • Brambilla F, Lavatelli F, Di Silvestre D, et al. Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue. Blood. 2012;119(8):1844–1847.
  • Bellavia D, Pellikka PA, Abraham TP, et al. Evidence of impaired left ventricular systolic function by Doppler myocardial imaging in patients with systemic amyloidosis and no evidence of cardiac involvement by standard two-dimensional and Doppler echocardiography. Am J Cardiol. 2008;101(7):1039–1045.
  • Buss SJ, Emami M, Mereles D, et al. Longitudinal left ventricular function for prediction of survival in systemic light-chain amyloidosis: incremental value compared with clinical and biochemical markers. J Am Coll Cardiol. 2012;60(12):1067–1076.
  • Perlini S, Salinaro F, Musca F, et al. Prognostic value of depressed midwall systolic function in cardiac light-chain amyloidosis. J Hypertens. 2014;32(5):1121–1131;discussion 1131.
  • Milani P, Dispenzieri A, Scott CG, et al. Independent prognostic value of stroke volume index in patients with immunoglobulin light chain amyloidosis. Circ Cardiovasc Imaging. 2018;11(5):e006588.
  • Fontana M, Chung R, Hawkins PN, et al. Cardiovascular magnetic resonance for amyloidosis. Heart Fail Rev. 2015;20(2):133–144.
  • Broski SM, Spinner RJ, Howe BM, et al. 18F-florbetapir and 18F-FDG PET/CT in systemic immunoglobulin light chain amyloidosis involving the peripheral nerves. Clin Nucl Med. 2016;41(2):e115–117.
  • Law WP, Wang W, Moore P, et al. Cardiac amyloid imaging with. Amyloid. 2017;24(sup1):162.
  • Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404–2412.
  • 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;22(18):3751–3757.
  • 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;121(17):3420–3427.
  • 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;87(5):465–471.
  • 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;133(3):215–223.
  • 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;30(9):989–995.
  • Milani P, Basset M, Russo F, et al. Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome. Blood. 2017;130(5):625–631.
  • Dittrich T, Bochtler T, Kimmich C, et al. AL amyloidosis patients with low amyloidogenic free light chain levels at first diagnosis have an excellent prognosis. Blood. 2017;130(5):632–642.
  • Sidana S, Tandon N, Dispenzieri A, et al. Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains. Leukemia. 2018;32(3):729-735.
  • Dittrich T, Benner A, Kimmich C, et al. Performance analysis of AL amyloidosis cardiac biomarker staging systems with special focus on renal failure and atrial arrhythmia. Haematologica. 2019;104(7):1451–1459.
  • Palladini G, Milani P, Merlini G. Predicting survival in light chain amyloidosis. Haematologica. 2019;104(7):1294–1296.
  • 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;126(5):612–615.
  • Kimmich CR, Terzer T, Benner A, et al. Daratumumab for systemic AL amyloidosis: prognostic factors and adverse outcome with nephrotic range albuminuria. Blood. 2020;135:1517–1530.
  • Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):2325–2332.
  • Dispenzieri A, Buadi F, Kumar SK, et al. Treatment of immunoglobulin light chain amyloidosis: mayo stratification of myeloma and risk-adapted therapy (mSMART) consensus statement. Mayo Clin Proc. 2015;90(8):1054–1081.
  • Palladini G, Barassi A, Perlini S, et al. Midregional proadrenomedullin (MR-proADM) is a powerful predictor of early death in AL amyloidosis. Amyloid. 2011;18(4):216–221.
  • Kastritis E, Papassotiriou I, Terpos E, et al. Clinical and prognostic significance of serum levels of von Willebrand factor and ADAMTS-13 antigens in AL amyloidosis. Blood. 2016;128(3):405–409.
  • Kastritis E, Papassotiriou I, Merlini G, et al. Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis. Blood. 2018;131(14):1568–1575.
  • Li T, Huang X, Wang Q, et al. A risk stratification for systemic immunoglobulin light-chain amyloidosis with renal involvement. Br J Haematol. 2019;187(4):459–469.
  • 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;30(36):4541–4549.
  • 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;134(25):2271–2280.
  • Muchtar E, Dispenzieri A, Leung N, 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(2):527–531.
  • Milani P, Basset M, Foli A et al. The quest for indicators of profound hematologic response in AL amyloidosis: complete response remains the optimal goal of therapy. Abstract of American Society of Hematology 2019 meeting, 2019
  • Milani P, Murray DL, Barnidge DR, et al. The utility of MASS-FIX to detect and monitor monoclonal proteins in the clinic. Am J Hematol. 2017;92(8):772–779.
  • Kastritis E, Kostopoulos IV, Terpos E, et al. Evaluation of minimal residual disease using next-generation flow cytometry in patients with AL amyloidosis. Blood Cancer J. 2018;8(5):46.
  • Sidana S, Muchtar E, Sidiqi MH, et al. Impact of minimal residual negativity using next generation flow cytometry on outcomes in light chain amyloidosis. Am J Hematol. 2020;95:497–502.
  • Palladini G, Massa M, Basset M et al. Persistence of minimal residual disease by multiparameter flow cytometry can hinder recovery of organ damage in patients with al amyloidosis otherwise in complete response. Abstract for American Society of Hematology 2016 meeting, 2016
  • Popkova T, Hajek R, Jelinek T. Monoclonal antibodies in the treatment of AL amyloidosis: co-targeting the plasma cell clone and amyloid deposits. Br J Haematol. 2020;189(2):228–238.
  • 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(32):3741–3749.
  • Palladini G, Merlini G. What is new in diagnosis and management of light chain amyloidosis? Blood. 2016;128(2):159–168.
  • Gertz MA, Lacy MQ, Dispenzieri A, et al. Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis. Bone Marrow Transplant. 2013;48(4):557–561.
  • Sanchorawala V, Sun F, Quillen K, et al. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience. Blood. 2015;126(20):2345–2347.
  • Browning S, Quillen K, Sloan JM, et al. Hematologic relapse in AL amyloidosis after high-dose melphalan and stem cell transplantation. Blood. 2017;130(11):1383–1386.
  • Cibeira MT, Sanchorawala V, Seldin DC, et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood. 2011;118(16):4346–4352.
  • Tandon N, Muchtar E, Sidana S, et al. Revisiting conditioning dose in newly diagnosed light chain amyloidosis undergoing frontline autologous stem cell transplant: impact on response and survival. Bone Marrow Transplant. 2017;52(8):1126–1132.
  • Landau H, Smith M, Landry C, et al. Long-term event-free and overall survival after risk-adapted melphalan and SCT for systemic light chain amyloidosis. Leukemia. 2017;31(1):136–142.
  • Hwa YL, Kumar SK, Gertz MA, et al. Induction therapy pre-autologous stem cell transplantation in immunoglobulin light chain amyloidosis: a retrospective evaluation. Am J Hematol. 2016;91(10):984–988.
  • 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;103(8):2936–2938.
  • Palladini G, Russo P, Nuvolone M, et al. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007;110(2):787–788.
  • Reece DE, Hegenbart U, Sanchorawala V, et al. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011;118(4):865–873.
  • Reece DE, Hegenbart U, Sanchorawala V, et al. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014;124(16):2498–2506.
  • Palladini G, Milani P, Foli A, 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(12):2311–2316.
  • Venner CP, Gillmore JD, Sachchithanantham S, 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(12):2304–2310.
  • Kastritis E, Leleu X, Arnulf B. A randomized phase III trial of melphalan and dexamethasone (MDex) versus bortezomib, melphalan and dexamethasone (BMDex) for Untreated Patients with AL Amyloidosis. Abstract for the American Society of Hematology. 2016 meeting, 2016.
  • Palladini G, Milani P, Merlini G. Novel strategies for the diagnosis and treatment of cardiac amyloidosis. Expert Rev Cardiovasc Ther. 2015;13(11):1195–1211.
  • 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;103(4):e165–e168.
  • Nuvolone M, Milani P, Palladini G, et al. Management of the elderly patient with AL amyloidosis. Eur J Intern Med. 2018;58:48–56.
  • Grogan M, Gertz M, McCurdy A, et al. Long term outcomes of cardiac transplant for immunoglobulin light chain amyloidosis: the Mayo Clinic experience. World J Transplant. 2016;6(2):380–388.
  • Angel-Korman A, Stern L, Sarosiek S, et al. Long-term outcome of kidney transplantation in AL amyloidosis. Kidney Int. 2019;95(2):405–411.
  • Gertz MA, Comenzo R, Falk RH, 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(4):319–328.
  • Palladini G, Milani P, Foli A, et al. Presentation and outcome with second-line treatment in AL amyloidosis previously sensitive to nontransplant therapies. Blood. 2018;131(5):525–532.
  • Palladini G, Merlini G. When should treatment of AL amyloidosis start at relapse? Early, to prevent organ progression. Blood Adv. 2019;3(2):212–215.
  • Hwa YL, Warsame R, Gertz MA, et al. Delineation of the timing of second-line therapy post-autologous stem cell transplant in patients with AL amyloidosis. Blood. 2017;130(13):1578–1584.
  • Sanchorawala V, McCausland KL, White MK, et al. A longitudinal evaluation of health-related quality of life in patients with AL amyloidosis: associations with health outcomes over time. Br J Haematol. 2017;179(3):461–470.
  • Hari P, Lin HM, Asche CV, et al. Treatment patterns and health care resource utilization among patients with relapsed/refractory systemic light chain amyloidosis. Amyloid. 2018;25(1):1–7.
  • Sanchorawala V. Delay treatment of AL amyloidosis at relapse until symptomatic: devil is in the details. Blood Adv. 2019;3(2):216–218.
  • Tandon N, Sidana S, Gertz MA, et al. Treatment patterns and outcome following initial relapse or refractory disease in patients with systemic light chain amyloidosis. Am J Hematol. 2017;92(6):549–554.
  • Manwani R, Hegenbart U, Mahmood S, et al. Deferred autologous stem cell transplantation in systemic AL amyloidosis. Blood Cancer J. 2018;8(11):101.
  • Dispenzieri A, Lacy MQ, Zeldenrust SR, et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007;109(2):465–470.
  • Palladini G, Russo P, Foli A, et al. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012;91(1):89–92.
  • Sanchorawala V, Shelton AC, Lo S, et al. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016;128(8):1059–1062.
  • Dispenzieri A, Buadi F, Laumann K, et al. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012;119(23):5397–5404.
  • Palladini G, Milani P, Foli A, et al. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017;129(15):2120–2123.
  • Specter R, Sanchorawala V, Seldin DC, et al. Kidney dysfunction during lenalidomide treatment for AL amyloidosis. Nephrol Dial Transplant. 2011;26(3):881–886.
  • Warsame R, LaPlant B, Kumar SK, et al. Long-term outcomes of IMiD-based trials in patients with immunoglobulin light-chain amyloidosis: a pooled analysis. Blood Cancer J. 2020;10(1):4.
  • Lentzsch S, Lagos GG, Comenzo RL, et al. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: results of a Phase II Study. J Clin Oncol. 2020;38:JCO1901721.
  • Milani P, Schonland S, Merlini G, et al. Treatment of AL amyloidosis with bendamustine: a study of 122 patients. Blood. 2018;132(18):1988–1991.
  • Cohen A, Landau H, Scott E, et al. Safety and Efficacy of Carfilzomib (CFZ) in Previously-Treated Systemic Light-Chain (AL) Amyloidosis. (Ed.^(Eds) ( Blood, 2016)
  • Dispenzieri A, Kastritis E, Wechalekar A Primary Results from the Phase 3 Tourmaline-AL1 Trial of Ixazomib-Dexamethasone Versus Physician’s Choice of Therapy in Patients (Pts) with Relapsed/Refractory Primary Systemic AL Amyloidosis (RRAL). (Ed.^(Eds) ( Abstract for the American Society of Hematology 2019 meeting, 2019)
  • Cohen OC, Sharpley F, Gillmore JD, et al. Use of ixazomib, lenalidomide and dexamethasone in patients with relapsed amyloid light-chain amyloidosis. Br J Haematol. 2020;189:643–649.
  • Manwani R, Mahmood S, Sachchithanantham S, et al. Carfilzomib is an effective upfront treatment in AL amyloidosis patients with peripheral and autonomic neuropathy. Br J Haematol. 2019;187(5):638–641.
  • Kaufman GP, Schrier SL, Lafayette RA, et al. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017;130(7):900–902.
  • Roussel M, Merlini G, Chevret S, et al. A prospective phase II of daratumumab in previously treated systemic light chain amyloidosis (AL) patients. Blood. 2020;135:1531–1540.
  • Sanchorawala V, Sarosiek S, Schulman A, et al. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020;135(18):1541–1547.
  • Milani P, Fazio F, Basset M, et al. High rate of profound clonal and renal responses with daratumumab treatment in heavily pre-treated patients with light chain (AL) amyloidosis and high bone marrow plasma cell infiltrate. Am J Hematol. 2020;95:900–905.
  • Palladini G, Kastritis E, Maurer MS, et al. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood. 2020;136(1):71–80.
  • Leung N, Thomé SD, Dispenzieri A. Venetoclax induced a complete response in a patient with immunoglobulin light chain amyloidosis plateaued on cyclophosphamide, bortezomib and dexamethasone. Haematologica. 2018;103(3):e135–e137.
  • Rosenzweig M, Urak R, Walter M, et al. Preclinical data support leveraging CS1 chimeric antigen receptor T-cell therapy for systemic light chain amyloidosis. Cytotherapy. 2017;19(7):861–866.
  • Wall JS, Kennel SJ, Williams A, et al. AL amyloid imaging and therapy with a monoclonal antibody to a cryptic epitope on amyloid fibrils. PLoS One. 2012;7(12):e52686.
  • 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;34(10):1097–1103.
  • Tennent GA, Lovat LB, Pepys MB. Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis. Proc Natl Acad Sci U S A. 1995;92(10):4299–4303.
  • Richards DB, Cookson LM, Berges AC, et al. Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N Engl J Med. 2015;373(12):1106–1114.
  • Richards DB, Cookson LM, Barton SV, et al. Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis. Sci Transl Med. 2018;10:422.
  • Edwards CV, Bhutani D, Mapara M, et al. One year follow up analysis of the phase 1a/b study of chimeric fibril-reactive monoclonal antibody 11-1F4 in patients with AL amyloidosis. Amyloid. 2019;26(sup1):115–116.
  • Merlini G, Ascari E, Amboldi N, et al. Interaction of the anthracycline 4ʹ-iodo-4ʹ-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis. Proc Natl Acad Sci U S A. 1995;92(7):2959–2963.
  • Merlini G, Anesi E, Garini P, et al. Treatment of AL amyloidosis with 4ʹ-lodo-4ʹ-deoxydoxorubicin: an update. Blood. 1999;93(3):1112–1113.
  • Gertz MA, Lacy MQ, Dispenzieri A, et al. A multicenter phase II trial of 4ʹ-iodo-4ʹdeoxydoxorubicin (IDOX) in primary amyloidosis (AL). Amyloid. 2002;9(1):24–30.
  • Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. Faseb J. 2006;20(2):234–239.
  • Wechalekar AD, Whelan C. Encouraging impact of doxycycline on early mortality in cardiac light chain (AL) amyloidosis. Blood Cancer J. 2017;7(3):e546.
  • Andrich K, Hegenbart U, Kimmich C, et al. Aggregation of full-length immunoglobulin light chains from systemic light chain amyloidosis (AL) patients is remodeled by epigallocatechin-3-gallate. J Biol Chem. 2017;292(6):2328–2344.
  • Morgan GJ, Yan NL, Mortenson DE, et al. Stabilization of amyloidogenic immunoglobulin light chains by small molecules. Proc Natl Acad Sci U S A. 2019;116(17):8360–8369.
  • Brumshtein B, Esswein SR, Salwinski L, et al. Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain. Elife. 2015;4:e10935.
  • Bernardi L, Passino C, Porta C, et al. Widespread cardiovascular autonomic dysfunction in primary amyloidosis: does spontaneous hyperventilation have a compensatory role against postural hypotension? Heart. 2002;88(6):615–621.
  • Caccialanza R, Palladini G, Cereda E, et al. Nutritional counseling improves quality of life and preserves body weight in systemic immunoglobulin light-chain (AL) amyloidosis. Nutrition. 2015;31(10):1228–1234.
  • Caccialanza R, Cereda E, Klersy C, et al. Bioelectrical impedance vector analysis-derived phase angle predicts survival in patients with systemic immunoglobulin light-chain amyloidosis. Amyloid. 2020; 27(3):168-173.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.