HAEM4Backup:Primary Amyloidosis

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Primary Author(s)*

Heather E. Williams, PhD, MS, PgD, ErCLG

Cancer Category/Type

Mature B-cell neoplasms

Cancer Sub-Classification / Subtype

Monoclonal immunoglobulin deposition disease

Definition / Description of Disease

  • A member of the group of “monoclonal immunoglobulin deposition diseases” that are characterized by visceral and soft tissue deposition of aberrant immunoglobulin (Ig), which subsequently results in organ dysfunction[1][2][3][4][5][6][7][8][9]
  • These monoclonal Ig deposition diseases overlap as clinically similar conditions—but likely represent chemically distinctive manifestations of similar pathological processes, which can be placed into two major categories: 1) primary amyloidosis (detailed herein); 2) light chain and heavy chain deposition diseases[9][10]
  • An acquired systemic amyloidosis, primary amyloidosis or the preferred term “AL amyloidosis,” results from a plasma cell (pc) or in rare instances, a lymphoplasmacytic neoplasm
  • AL amyloidosis is a rare clonal plasma cell dyscrasia, with a particularly devastating clinical phenotype that results from the extracellular amyloid fibril deposition in vital organs[11][12][13]
  • The AL amyloid fibrils derive from N-terminal region of monoclonal immunoglobulin light chains that consist of the whole or part of the variable (VI) domain[14]
    • The structure and unique nature of all monoclonal light chains influences their inherent propensity (for some) to form amyloid fibrils[14]
    • The amyloid formed from monoclonal light chains can exist in a partly unfolded state, which involves loss of tertiary or higher order structures[14]. Amyloids will readily aggregate in the ß-sheet structure to create protofilaments and fibril; this process is progressive as a ‘seeding” event serves as a template that facilities further amyloid deposition, which allows expansion of deposition by capturing further precursor molecules[14]

Synonyms / Terminology

  • Immunoglobulin light chain amyloidosis (AL)
  • AL amyloidosis (preferred in recent literature over Primary Amyloidosis, the WHO term)
  • AL amyloidosis (ALA)

Epidemiology / Prevalence

  • AL amyloidosis is an uncommon disorder and its exact incidence is unknown[15]
  • Within the US, the incidence is estimated at 9-14 cases per million person years, but the true prevalence may be higher due to under diagnosis[10][16][17]
  • Considered a disease of the elderly, the incidence of AL amyloidosis increases with age[10][16]
    • A small proportion of patients (~1.3%) are diagnosed under the age of 34, with the median age at diagnosis of 63 years of age[18]
  • There is a male predominance, with men reported in recent studies to account for 55-70% of patients[5][18][19]
  • There is limited data regarding AL amyloidosis incidence across ethnic populations, however, the disease is known to occur in all races and geographical regions[9]

Clinical Features

  • The signs and symptoms that raise the clinical suspicion for a possible diagnosis of amyloidosis are generally nonspecific; therefore, the establishment of an AL amyloidosis is difficult and is highly reliant upon a clinical suspicion[17]
  • Clinical presentations vary, ranging from more rapidly progressive symptoms to slowly evolving or a paucity of symptoms among others[16]
  • Nearly 25% of patients are diagnosed late, and many present with advanced, irreversible cardiac damage, and often succumb to within 12 months of the diagnosis[12]
  • Clinical presentations generally relate and are of a consequence of amyloid in organs and tissues, and it is often the presentation of symptoms within a particular organ that predominate, which initiates the diagnosis[12][17]
  • Signs of the disease in the early stages include peripheral neuropathy (~15-20%), carpal tunnel syndrome (~21%), and bone pain (~5%)[9]. Other major symptoms, in addition to the extremely common presenting symptoms of fatigue and weight loss, relate to congestive heart failure (~15-20%), nephrotic syndrome (~28%), or malabsorption (~5%) are common[5][9]
  • Physical observations include hepatomegaly (~25-30%), macroglossia (~10%), and purpura, commonly of periorbital or facial presentation (~15%)[5]
  • Individuals with congestive heart failure or nephrotic syndrome often present with edema[5]
  • Few patients present with splenomegaly, lymphadenopathy, skin and soft tissue thickening, a hoarse voice (due to vocal cord infiltration), hypoadrenalism or hypothyroidism (due to deposits within the adrenal or thyroid glands, respectively)[20]
  • Overlooking the diagnosis of AL amyloidosis leads to therapy delay, and is a relatively common event, and it represents an error of diagnostic consideration which has resulted in an unsatisfactory survival for patients[15]

Sites of Involvement

  • The accumulation of amyloid light chain progressively disrupts numerous tissues and organs, e.g. subcutaneous fat, kidneys, heart, liver, gastrointestinal tracts, peripheral nervous system, and bone marrow, ultimately leading to organ failure[9]
  • The deposition of amyloid does not evoke (or of little) reaction locally within the tissues, and there is poor correlation between the level of amyloid depositions and the degree of impairment to organ function[14]
  • The morbidity and mortality in AL amyloidosis results from the effects of the toxic monoclonal protein, and impact to cardiac function is a critical determinate of survival[21][22]
  • AL amyloidosis is a progressive and fatal disease, with significant mortality within one year of diagnosis[12][23]

Morphologic Features

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Immunophenotype

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Finding Marker
Positive (universal) EXAMPLE CD1
Positive (subset) EXAMPLE CD2
Negative (universal) EXAMPLE CD3
Negative (subset) EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and Multiple Myeloma (MM). However, notably, the frequency of the [t(11;14)(q13;q32), IGH-CCND1] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and MM. The [t(11;14)(q13;q32), IGH-CCND1] occurs at higher frequency in AL amyloidosis (~40% of patients) than in MGUS and MM (15-20%)[9][24]. The [t(11;14)(q13;q32), IGH-CCND1] fusion results from the juxtaposition of the CCND1 proto-oncogene at 11q13 with the immunoglobulin heavy chain (IGH) locus at 14q32[25][26][27].

Characteristic Chromosomal Aberrations / Patterns

Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations[24]. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence in situ Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases[28][29]. Following enrichment of plasma cells using magnetic activated cell sorting with CD138 immunobeads, interphase FISH analysis can be performed with MM specific probe sets or panels. These panels vary, but may include enumeration of CKS1B (1q21), CDKN2C (1p32), D9Z1/D15Z4 (CEN9, CEN15), RB1 (13q14), TP53 (17p13), and break-apart probes for MYC (8q24.1) or IGH (14q32.3) translocations, often with sequential reflex testing with dual-fusion FISH probes for the five common IGH partners: [t(4;14)(p16.3;q32); IGH-FGFR3], [t(6;14)(p21;q32); IGH-CCND3], [t(11;14)(q13;q32); IGH-CCND1], [t(14;16)(q32;q23); IGH-MAF], [t(14;20)(q32;q12); IGH-MAFB]. Common cytogenetic aberrations overlap with those found in MM and MUGS, although frequencies differ; the aberrations include the t(11;14)(q13;q32), CCND1-IGH aberration that predominates (and as such a FISH panel may be tailored specifically for AL amyloidosis), with fewer cases of hyperdiploid and high-risk karyotypes[30][31][32][33]. Hyperdiploidy and t(11;14) are mutually exclusive in AL amyloidosis[30][31][34]. Recent studies have further characterized the clonal distribution of these aberrations: main clones are likely to contain the t(11;14) or t(v;14) IGH-v translocations, and hyperdiploidy, whereas subclones similar to those in Monoclonal gammopathy of undetermined significance (MGUS) and MM often carry gain of CKS1B (1q21), and deletions of 8p21 (PNOC), RB1 (13q14), and TP53 (17p13)[24]. Of note, the frequency of the t(11;14) aberration has been shown to decrease with the progression of the plasma cell dyscrasia[24]. However, the impact of plasma cell FISH on the outcomes of AL amyloidosis remains uncertain, with some well characterized genotype-outcome associations recently reported[12][35].

Genomic Gain/Loss/LOH

Copy number aberrations (CNAs) in AL amyloidosis are recurrent, although a subset (~10%) do not have aberrant chromosomal changes resolvable by CC or FISH (see Characteristic chromosomal aberrations /Patterns)[34]. Overall, genetic profile studies by Paiva et al. (2016) indicate CNA in AL amyloidosis range in frequency, but are similar to those observed in MM; the most frequent include 1) gains of (from highest frequency) chromosomes 9, 19, 5, and losses of X and 16; 2) whole arm alterations include gains of (from highest frequency) 15q and 1q, and losses of Yp, 13q, and 22q[36]. Nearly 90% of patients with t(11;14) have concomitant gains of 11q22.3/11q23, a result of an unbalanced translocation der(14)t(11;14)(q13;32)[34]. Copy neutral loss of heterozygosity (CN-LOH) was also observed in 50% of the cohort[34]. Stratifications analogous to those used in MM have been proposed and include: 1) hyperdiploid (HD): a subgroup with concomitant gains of 1q21; 2) t(11;14) 3) non-hyperdiploid (NHD) with deletion of 13q14/t(4;14); 4) t(v;14) IGH-unknown partner[34][37]. Furthermore, WES analyses have identified an average of 15 non-recurrent mutations per patient, but have failed to identify a unifying gene mutation specific for AL amyloidosis[36]. Recent genomic profiling using a combined WES and targeted gene sequencing panel approach have identified recurrent mutations in AL amyloidosis (see Gene mutations (SNV/INVDEL)[38].

Gene Mutations (SNV/INDEL)

Few studies have evaluated the genetic profile of bone marrow plasma cells from AL amyloidosis patients[34][39][36][40]. A comprehensive evaluation by Paiva et al. (2016) identified 38 significantly deregulated (3 upregulated/35 downregulated) genes in AL amyloidosis plasma cells. Specifically, the tumor suppressor genes cadherin 1 (CDH1) and RCAN family member 3 (RCAN), and the pro-apoptotic genes GLI pathogenesis related 1 (GLIPR1) and Fas cell surface death receptor (FAS) were downregulated, whereas significant overexpression of the interferon induced transmembrane protein 1 (IFITM1) gene known to be associated with the development of aggressive solid tumors was observed[36][41]

Huang et al. (2019) identified four recurrent mutations in an AL amyloidosis cohort using a combination of WES and targeted gene sequencing panels[38]. The recurrent mutations include: ankyrin repeat and SOCS box containing 15 [ASB15 (c.844C>T)], activating signal cointegrator 1 complex subunit 3 [ASCC3 (c.1595A>G)], H1.4 linker histone, cluster member [HIST1H1E (c.311C>T)] and KRAS proto-oncogene, GTPase [KRAS (c.35G >A)][38]. In addition, the presence of these mutations in the ASB15, ASCC3 and HIST1H1E genes were found to be associated with inferior overall survival[38].

Overall, although AL amyloidosis and MM share similarity in recurrent genetic aberrations, the genetic profile of plasma cells in AL amyloidosis  involves substantially fewer genetic alterations (that are largely unique from genes altered in MM) when compared to MM—where the deregulation of ~400 genes has been documented[36][42][43]. Of note, individuals with t(11;14) had a lower total overall aberration burden when compared with other AL amyloidosis groups[34].

Other Mutations

Genetic analysis may be used to distinguish AL amyloidosis from hereditary amyloidosis. Testing for mutations in the transthyretin, fibrinogen Aα‐chain, lysozyme or apolipoprotein A-I genes are associated with hereditary disease. Genetic testing is often necessary as clinical features between diseases may be indistinguishable and family history evaluations may not be reflective given reduced penetrance[44][45].

Epigenomics (Methylation)

Not applicable

Genes and Main Pathways Involved

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Diagnostic Testing Methods

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Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

An early stage diagnosis provides patients with the broadest options for treatment, including eligibility for dose intensive chemotherapy regiments. However, the diagnosis requires a high clinical suspicion in individuals with nephrotic range proteinuria with or without renal insufficiency, non-dilated cardiomyopathy, peripheral neuropathy, hepatomegaly or automatic neuropathy in the presence (or absence) of paraprotein detectable in the serum or urine[14]. Prognosis is highly variable, however, it is extremely poor in the absence of treatment. Nearly twenty years ago, the median survival was dismal at 1-2 years, with less than 5% of all AL amyloidosis patients alive ten or more years following diagnosis, however within the last decade this median survival has changed dramatically, and ~30-40% patients survive more than ten years[5][12][23]. The most frequent cause of death (reported in ~40% of cases) is the presence of amyloid-related cardiac disease[19][46][47].

To preserve and improve the function of organs infiltrated by amyloid deposits, treatments focus on substantially reducing the supply of monoclonal immunoglobulin light chains to stabilize or regress existing amyloid deposits[20][48]. Chemotherapies used are based on regimens proven effective in patients with multiple myeloma, however clinical benefits are often delayed for many months to allow for adequate suppression of an underlying plasma cell dyscrasia[14]. These range from low, intermediate, or high dose approaches alone or in combination with other newly emerging novel therapies[14][49]. More intensive chemotherapies are associated with intense treatment related toxicity. Recent studies have linked the presence of specific genetic profiles (i.e. t(11;14)) to poor outcomes and suggested that the use of specific therapies (i.e. bortezomib) are associated with the poorest of outcomes, however, this link has not been firmly established—inversely patients with 1q deletion have superior outcomes when treated on bortezomib-based regimens[11][12][50].

Familial Forms

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Other Information

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Links

Monoclonal Immunoglobulin Deposition Diseases

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References

  1. ↑ Aucouturier, Pierre; et al. (1993). "Heavy-Chain Deposition Disease". New England Journal of Medicine. 329 (19): 1389–1393. doi:10.1056/NEJM199311043291905. ISSN 0028-4793.
  2. ↑ J, Buxbaum (1992). "Mechanisms of disease: monoclonal immunoglobulin deposition. Amyloidosis, light chain deposition disease, and light and heavy chain deposition disease". PMID 1582976.
  3. ↑ Herzenberg, Andrew M.; et al. (1996). "Monoclonal heavy chain (immunoglobulin G3) deposition disease: report of a case". American Journal of Kidney Diseases. 28 (1): 128–131. doi:10.1016/S0272-6386(96)90141-9.
  4. ↑ Kambham, Neeraja; et al. (1999). "Heavy chain deposition disease: The disease spectrum". American Journal of Kidney Diseases. 33 (5): 954–962. doi:10.1016/S0272-6386(99)70432-4.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Ra, Kyle; et al. (1995). "Primary systemic amyloidosis: clinical and laboratory features in 474 cases". PMID 7878478.
  6. ↑ Preud'homme, Jean-Louis; et al. (1994). "Monoclonal immunoglobulin deposition disease (Randall type). Relationship with structural abnormalities of immunoglobulin chains". Kidney International. 46 (4): 965–972. doi:10.1038/ki.1994.355.
  7. ↑ Preud'Homme, Jean-Louis; et al. (1994). "Monoclonal immunoglobulin deposition disease: A review of immunoglobulin chain alterations". International Journal of Immunopharmacology. 16 (5–6): 425–431. doi:10.1016/0192-0561(94)90032-9.
  8. ↑ Serpell, L. C.; et al. (1997). "The molecular basis of amyloidosis". Cellular and Molecular Life Sciences. 53 (12): 871. doi:10.1007/s000180050107.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 McKenna RW, et al., (2017). Plasma cell neoplasms: Monoclonal immunoglobulin deposition diseases, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow, SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p254-255.
  10. ↑ 10.0 10.1 10.2 Ra, Kyle; et al. (1992). "Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989". PMID 1558973.
  11. ↑ 11.0 11.1 Ah, Bryce; et al. (2009). "Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis". doi:10.3324/haematol.13369. PMC 2649355. PMID 19211640.CS1 maint: PMC format (link)
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 G, Merlini (2017). "AL amyloidosis: from molecular mechanisms to targeted therapies". doi:10.1182/asheducation-2017.1.1. PMC 6142527. PMID 29222231.CS1 maint: PMC format (link)
  13. ↑ Ryšavá, Romana (2019). "AL amyloidosis: advances in diagnostics and treatment". Nephrology Dialysis Transplantation. 34 (9): 1460–1466. doi:10.1093/ndt/gfy291. ISSN 0931-0509.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 14.7 "Guidelines on the diagnosis and management of AL amyloidosis". British Journal of Haematology. 125 (6): 681–700. 2004. doi:10.1111/j.1365-2141.2004.04970.x. ISSN 0007-1048.
  15. ↑ 15.0 15.1 Gertz, Morie A. (2018). "Immunoglobulin light chain amyloidosis: 2018 Update on diagnosis, prognosis, and treatment: GERTZ". American Journal of Hematology. 93 (9): 1169–1180. doi:10.1002/ajh.25149.
  16. ↑ 16.0 16.1 16.2 Staron, Andrew; et al. (2019). "A new era of amyloidosis: the trends at a major US referral centre". Amyloid. 26 (4): 192–196. doi:10.1080/13506129.2019.1640672. ISSN 1350-6129.
  17. ↑ 17.0 17.1 17.2 Vaxman, Iuliana; et al. (2020). "When to Suspect a Diagnosis of Amyloidosis". Acta Haematologica: 1–8. doi:10.1159/000506617. ISSN 0001-5792.
  18. ↑ 18.0 18.1 Tp, Quock; et al. (2018). "Epidemiology of AL amyloidosis: a real-world study using US claims data". doi:10.1182/bloodadvances.2018016402. PMC 5965052. PMID 29748430.CS1 maint: PMC format (link)
  19. ↑ 19.0 19.1 Ra, Kyle; et al. (1986). "Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases". PMID 3719098.
  20. ↑ 20.0 20.1 Mahmood, S.; et al. (2014). "Update on treatment of light chain amyloidosis". Haematologica. 99 (2): 209–221. doi:10.3324/haematol.2013.087619. ISSN 0390-6078. PMC 3912950. PMID 24497558.CS1 maint: PMC format (link)
  21. ↑ Comenzo, R L; et al. (2012). "Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis". Leukemia. 26 (11): 2317–2325. doi:10.1038/leu.2012.100. ISSN 0887-6924.
  22. ↑ Kumar, Shaji; et al. (2012). "Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements". Journal of Clinical Oncology. 30 (9): 989–995. doi:10.1200/JCO.2011.38.5724. ISSN 0732-183X. PMC 3675680. PMID 22331953.CS1 maint: PMC format (link)
  23. ↑ 23.0 23.1 Ra, Kyle; et al. (1999). "Long-term survival (10 years or more) in 30 patients with primary amyloidosis". PMID 9920856.
  24. ↑ 24.0 24.1 24.2 24.3 Bochtler, Tilmann; et al. (2018). "Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma". Blood Advances. 2 (20): 2607–2618. doi:10.1182/bloodadvances.2018023200. ISSN 2473-9529. PMC 6199662. PMID 30327369.CS1 maint: PMC format (link)
  25. ↑ Hayman, Suzanne R.; et al. (2001). "Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis". Blood. 98 (7): 2266–2268. doi:10.1182/blood.V98.7.2266. ISSN 1528-0020.
  26. ↑ Fonseca, Rafael; et al. (2000). "FISH Demonstrates Treatment-Related Chromosome Damage in Myeloid but not Plasma Cells in Primary Systemic Amyloidosis". Leukemia & Lymphoma. 39 (3–4): 391–395. doi:10.3109/10428190009065839. ISSN 1042-8194.
  27. ↑ Saleem, Mohamed; et al. (2016). "Fusion genes in malignant neoplastic disorders of haematopoietic system". Hematology. 21 (9): 501–512. doi:10.1080/10245332.2015.1106816. ISSN 1607-8454.
  28. ↑ Bochtler, Tilmann; et al. (2013). "Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia". Journal of Clinical Oncology. 31 (31): 3898–3905. doi:10.1200/JCO.2013.50.7921. ISSN 0732-183X.
  29. ↑ Gw, Dewald; et al. (1985). "The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis". PMID 3926026.
  30. ↑ 30.0 30.1 Bochtler, Tilmann; et al. (2008). "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. 111 (9): 4700–4705. doi:10.1182/blood-2007-11-122101. ISSN 0006-4971.
  31. ↑ 31.0 31.1 Bochtler, Tilmann; et al. (2011). "Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14)". Blood. 117 (14): 3809–3815. doi:10.1182/blood-2010-02-268987. ISSN 0006-4971.
  32. ↑ Cj, Harrison; et al. (2002). "Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis". PMID 11972529.
  33. ↑ Kobayashi, Hiroki; et al. (2019). "Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma". Japanese Journal of Clinical Oncology. 49 (2): 195–198. doi:10.1093/jjco/hyy202. ISSN 1465-3621.
  34. ↑ 34.0 34.1 34.2 34.3 34.4 34.5 34.6 Granzow, Martin; et al. (2017). "Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis". Haematologica. 102 (7): 1281–1290. doi:10.3324/haematol.2016.160721. ISSN 0390-6078. PMC 5566044. PMID 28341732.CS1 maint: PMC format (link)
  35. ↑ Muchtar, E; et al. (2017). "Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category". Leukemia. 31 (7): 1562–1569. doi:10.1038/leu.2016.369. ISSN 0887-6924.
  36. ↑ 36.0 36.1 36.2 36.3 36.4 Paiva, Bruno; et al. (2016). "Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis". Blood. 127 (24): 3035–3039. doi:10.1182/blood-2015-10-673095. ISSN 0006-4971.
  37. ↑ Cremer, Friedrich W.; et al. (2005). "Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics". Genes, Chromosomes and Cancer. 44 (2): 194–203. doi:10.1002/gcc.20231. ISSN 1045-2257.
  38. ↑ 38.0 38.1 38.2 38.3 Huang, Xu-Fei; et al. (2020). "Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival". Amyloid. 27 (1): 36–44. doi:10.1080/13506129.2019.1678464. ISSN 1350-6129.
  39. ↑ López-Corral, L; et al. (2012). "SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status". Leukemia. 26 (12): 2521–2529. doi:10.1038/leu.2012.128. ISSN 0887-6924.
  40. ↑ Weinhold, N; et al. (2014). "Immunoglobulin light-chain amyloidosis shares genetic susceptibility with multiple myeloma". Leukemia. 28 (11): 2254–2256. doi:10.1038/leu.2014.208. ISSN 0887-6924.
  41. ↑ Yu, Fang; et al. (2015). "IFITM1 promotes the metastasis of human colorectal cancer via CAV-1". Cancer Letters. 368 (1): 135–143. doi:10.1016/j.canlet.2015.07.034.
  42. ↑ Abraham, Roshini S.; et al. (2005). "Functional gene expression analysis of clonal plasma cells identifies a unique molecular profile for light chain amyloidosis". Blood. 105 (2): 794–803. doi:10.1182/blood-2004-04-1424. ISSN 0006-4971.
  43. ↑ Davies, Faith E.; et al. (2003). "Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis". Blood. 102 (13): 4504–4511. doi:10.1182/blood-2003-01-0016. ISSN 0006-4971.
  44. ↑ Lachmann, Helen J.; et al. (2002). "Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis". New England Journal of Medicine. 346 (23): 1786–1791. doi:10.1056/NEJMoa013354. ISSN 0028-4793.
  45. ↑ Li, Danyang; et al. (2019). "Typing of hereditary renal amyloidosis presenting with isolated glomerular amyloid deposition". BMC Nephrology. 20 (1). doi:10.1186/s12882-019-1667-5. ISSN 1471-2369. PMC 6929319. PMID 31870425.CS1 maint: PMC format (link)
  46. ↑ Warsame, R; et al. (2015). "Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death". Blood Cancer Journal. 5 (5): e310–e310. doi:10.1038/bcj.2015.34. ISSN 2044-5385. PMC 4423220. PMID 25933374.CS1 maint: PMC format (link)
  47. ↑ Tahir, Usman A.; et al. (2019). "Predictors of Mortality in Light Chain Cardiac Amyloidosis with Heart Failure". Scientific Reports. 9 (1). doi:10.1038/s41598-019-44912-x. ISSN 2045-2322. PMC 6561903. PMID 31189919.CS1 maint: PMC format (link)
  48. ↑ Jd, Gillmore; et al. (1997). "Amyloidosis: a review of recent diagnostic and therapeutic developments". PMID 9375734.
  49. ↑ National Comprehensive Cancer Network. Systemic Light Chain Amyloidosis (Version 1.2020). https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf Accessed July 20th, 2020.
  50. ↑ Bochtler, Tilmann; et al. (2015). "Translocation t(11;14) Is Associated With Adverse Outcome in Patients With Newly Diagnosed AL Amyloidosis When Treated With Bortezomib-Based Regimens". Journal of Clinical Oncology. 33 (12): 1371–1378. doi:10.1200/JCO.2014.57.4947. ISSN 0732-183X.

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