Incidentally Detected Amyloid Light-Chain Amyloidosis Caused by Monoclonal Gammopathy of Undetermined Significance: Possible Time-Dependent Change in Colonic Findings

Amyloid light-chain (AL) amyloidosis is associated with plasma cell disorder and monoclonal light chains. This type of amyloidosis is the prominent type involving the gastrointestinal tract. Monoclonal gammopathy of undetermined significance (MGUS) is the most common plasma cell disorder and a known precursor of more serious diseases. A 72-year-old male was treated for high blood pressure, diabetes, and gout at the clinic of a private physician. Due to a positive fecal occult blood test discovered during colon cancer screening, he underwent colonoscopy and was diagnosed with adenomatous polyps by biopsies. Two months later, he was referred to our hospital for endoscopic resection of the polyps. Although the polyps were successfully removed, a colonoscopy revealed two types of ulcerative lesions. Immunohistopathological evaluations obtained from these lesions and polyps confirmed amyloid deposition. Although esophagogastroduodenoscopy results were normal, a biopsy specimen from the patient’s stomach showed the same type of amyloid deposition. Immunoelectrophoresis showed M-proteins for anti-IgG-λ in the serum and λ type Bence-Jones protein in the urine. His blood, bone marrow, and urine test results led to a diagnosis of MGUS. A coronary angiography revealed multivessel stenosis, and the patient’s cardiac function improved after coronary artery stenting. Hereafter, a combination therapy with bortezomib, lenalidomide, and dexamethasone is planned. This is a case report of systemic AL amyloidosis caused by MGUS, which was incidentally detected by colonoscopy.

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Lenalidomide/Melphalan / Dexamethasone Chemotherapy In 50 Patients With Newly Diagnosed Amyloid Light Chain Amyloidosis: First Results Of a Prospective Single Center Phase 2 Study (Leomex)

Blood ◽

10.1182/blood.v122.21.1993.1993 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1993-1993

Author(s):

Stefan O Schonland ◽

Tilmann Bochtler ◽

Axel Benner ◽

Marianne Gawlik ◽

Christoph Kimmich ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Cardiac Amyloidosis ◽

High Dose ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

Number Of Patients ◽

Plasma Cell Disorder ◽

Amyloid Light Chain ◽

Cell Disorder

Abstract Introduction Amyloid light chain (AL) amyloidosis is a rare and life-threatening protein-misfolding disorder that is causedin most cases by a monoclonal plasma cell disorder. The goal of chemotherapy is to normalize the involved free light chain in serum which leads to an improvement or at least stabilization of organ function in most of these patients. A major challenge is the high treatment-related mortalityand toxicity in patients with advanced cardiac amyloidosis. Study design We performed a prospective single centerphase 2 trial with50 patients not eligible for high-dose treatment.Main inclusion criteria were: newly diagnosed and biopsy proven AL amyloidosis, significant organ involvement, age < 75 yrs and creatinine clearance > 40 ml/min. Treatment schedule was 6 cycles of an oral treatment with lenalidomide 10 mg day 1-21, melphalan 0.15 mg/kg day 1-4 and dexamethasone 20 mg day 1-4 every 4 weeks (L-M-dex). Primary endpoint was the rate of complete remissions (CR) of the underlying plasma cell disorder after 6 treatment cycles. Patients who received at least 3 cycles were eligible for hematologic remission (HR=CR+PR) analysis (At the time of study initiation “very good partial remission”in AL amyloidosis was not yet defined). The study was financially supported by Celgene. Patients and Methods Fiftypatients were included between 2009 and 2012. The median age was 67 years. 74% of patients had cardiac involvement. Outcome was compared with a historical group of 53 AL patients who received M-dex between 2004 and 2009 and fulfilled the same in- and exclusion criteria (patient characteristics see table). Results Forty-five patients (90%) completed 3 cycles and 35 patients (70%) completed 6 treatment cycles; overall 253 cycles could be administered. Reasons of discontinuation were toxicity in 6 patients (including one treatment-related death in the first cycle) or AL progression (9 patients). Ninety adverse events (AE) ≥ CTC grade 3 were recorded including 16 severe AEs. Seventeen hematologic AEs were observed (neutropenia 76%, CTC grade 4 in 2 patients). Most common non-hematologic AE was worsening of cardiac function or symptoms of autonomic neuropathy (14 patients). Furthermore 8 patients suffered from an infection, one patient developed acute renal failure and one patient a deep vein thrombosis. HR was achieved in 78% of patients: CR in 9 (20%)and PR in 26 (58%) of45 evaluable patients, respectively. Organ response was observed in 5 patients at the end of the study (6 months after the end of treatment). In the historical M-dex group HR rate was lower (58%, p=0.06): CR in 6 (15%)andPR in 17(43%) of 40 evaluable patients. OS was significantly improved using L-M-dex (see figure 1, median OS not reached vs. 26 mo., p=0.03). There was also a trend for a better EFS in the L-M-dex group (see figure 2, median EFS 23 vs. 16 mo., p=0.06). Of note, 3 L-M-dex patients (6%) died within 3 months after start of chemotherapy compared to 10 patients (19%) in the M-dex-group. Conclusion This is the largest phase II trial usinglenalidomide, melphalan and dexamethason in newly diagnosed AL amyloidosis patients. Treatment was effective and feasible in this cohort of mostly elderlypatients. 78% of evaluable patients achieved a hematologic remission. The early death rate was low with 6% despite of inclusion of a high number of patients with advanced cardiac amyloidosis. Overall, toxicity was manageable in most patients. Further improvement of these results might be achieved by prolongation of therapy in patients who have responded to and tolerate this combination therapy well. Disclosures: Schonland: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide in amyloidosis. Hegenbart:Janssen: Honoraria.

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Dose-Intensive Melphalan With Blood Stem-Cell Support for the Treatment of AL (Amyloid Light-Chain) Amyloidosis: Survival and Responses in 25 Patients

Blood ◽

10.1182/blood.v91.10.3662 ◽

1998 ◽

Vol 91 (10) ◽

pp. 3662-3670 ◽

Cited By ~ 247

Author(s):

Raymond L. Comenzo ◽

Evan Vosburgh ◽

Rodney H. Falk ◽

Vaishali Sanchorawala ◽

Johann Reisinger ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Performance Status ◽

Al Amyloidosis ◽

Organ Systems ◽

Plasma Cell Disorders ◽

Plasma Cell Disorder ◽

Amyloid Light Chain ◽

Al Amyloid ◽

Cell Disorder

Abstract AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < .01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

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Dose-Intensive Melphalan With Blood Stem-Cell Support for the Treatment of AL (Amyloid Light-Chain) Amyloidosis: Survival and Responses in 25 Patients

Blood ◽

10.1182/blood.v91.10.3662.3662_3662_3670 ◽

1998 ◽

Vol 91 (10) ◽

pp. 3662-3670 ◽

Cited By ~ 3

Author(s):

Raymond L. Comenzo ◽

Evan Vosburgh ◽

Rodney H. Falk ◽

Vaishali Sanchorawala ◽

Johann Reisinger ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Performance Status ◽

Al Amyloidosis ◽

Organ Systems ◽

Plasma Cell Disorders ◽

Plasma Cell Disorder ◽

Amyloid Light Chain ◽

Al Amyloid ◽

Cell Disorder

AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < .01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

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Monoclonal Gammopathy in An African American Cohort From a VA Medical Center.

Blood ◽

10.1182/blood.v114.22.4869.4869 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4869-4869

Author(s):

Avni M Desai ◽

Richard L Amdur ◽

Min-Ling L Liu ◽

Joao Ascensao ◽

Dalia Mobarek ◽

...

Keyword(s):

African American ◽

Plasma Cell ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Medical Center ◽

Kaplan Meier ◽

Plasma Cell Disorder ◽

Actuarial Risk ◽

Cell Disorder ◽

Bence Jones Proteinuria

Abstract Abstract 4869 The information regarding monoclonal gammopathy of unknown significance (MGUS) derives mainly from studies of Caucasian individuals. In contrast, this study describes the characteristics of 492 African American (AA) male patients identified with MGUS from the electronic database at the Washington VAMC. Review of their individual electronic records showed that none of the patients initially had evidence of myeloma or other symptomatic plasma cell or lymphoproliferative disorder. The median age at diagnosis of MGUS was 68 years old (range 28.5 to 95.6 years). The distribution of monoclonal immunoglobulin (M Ig) subtypes were IgG 78.1%, IgA 14.8%, IgM 6.9%; light chain only in the urine 2.9% or in the serum 1.0%, The light chain distribution of the M Igs was 60% kappa, 40% lambda. Fifty-nine patients (12%) had diclonal and 4 (0.8%) had triclonal M Igs. The median amount of M Ig was 0.26 g/dL; 47.8% were too small to quantitate. Ninety-four (25.5%) of 368 tested had Bence-Jones proteinuria, with a similar kappa:lambda distribution and 4 patients showed both light chains. Clinical characteristics were as follows: hepatitis C 15.5%, HIV 5.1%, other significant infections 26.8%, and chronic autoimmune or inflammatory disorders 10.3%. The patients were followed clinically for a median of 4.1 years (range 0.35 to 21.02 years), and the median interval between the first and last electrophoresis was 1.41 years (range 0 to 19.97 years). During this period 21 patients (4.3%) progressed to a malignant plasma cell disorder (myeloma 20, solitary plasmacytoma 1). 133 patients (27.0%) died of other causes, and in 26 (5.3%) the M protein had resolved. The actuarial risk determined by a Kaplan Meier plot of progression to a symptomatic plasma cell disorder was 13.5 % at 11 years. The initial M Ig in the patients who progressed was IgG in 15, IgA in 4, and isolated BJ proteinuria in 2. The only recognized predicting characteristic for progression was the detection of Bence-Jones proteinuria at diagnosis of MGUS: Thirteen of 20 (65%) progressing patients tested were positive as compared to 81 of 348 (23.0%) of the non-progressors (p = .0003) A number of features distinguish this AA MGUS cohort from previous series of Caucasian patients. MGUS was detected at an earlier age: 8.9% (5.2% excluding HCV and HIV patients) were under the age of 50. The percentage of AA patients with very low level M proteins was more than threefold that previously reported. The percentage of patients with IgM M Ig was less than one-half noted in previous studies. The actuarial risk of progression to a symptomatic plasma cell disorder as calculated from a Kaplan Meier plot appears to be comparable to previous reports in predominantly Caucasian series. Dr. Desai worked on this project following completion of her internal medicine residency. She is now a Hematology Oncology fellow at Montefiore Medical Center, New York NY. Disclosures No relevant conflicts of interest to declare.

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Biology of the Transition of Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma

Cancer Control ◽

10.1177/107327489800500301 ◽

1998 ◽

Vol 5 (3) ◽

pp. 209-217 ◽

Cited By ~ 16

Author(s):

John A. Lust ◽

Kathleen A. Donovan

Keyword(s):

Multiple Myeloma ◽

Adhesion Molecules ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Therapeutic Strategies ◽

Plasma Cell Disorder ◽

Novel Therapeutic Strategies ◽

Cell Disorder ◽

Undetermined Significance

Background Approximately 25% of patients with monoclonal gammopathy of undetermined significance (MGUS) eventually develop multiple myeloma (MM) or a related plasma cell disorder that is universally fatal. In this report, we examine the changes that occur in the clonal plasma cell that are likely to be important in the progression of MGUS to active myeloma. Methods Studies that investigate the mechanisms involved in the multistep pathogenesis of monoclonal gammopathies are reviewed. Cytokines such as IL- 6 and IL-1β, adhesion molecules, viruses, and oncogenes including ras, bcl-2, Rb, and p53 are discussed. Results IL-1β is produced by plasma cells from virtually all MM patients but is undetectable in most MGUS patients. IL-1β has potent osteoclast activating factor activity, can increase the expression of adhesion molecules, and can induce paracrine IL-6 production. The increased production of adhesion molecules could explain why myeloma cells are found predominantly in the bone marrow. Subsequently, these “fixed” monoclonal plasma cells could now stimulate osteoclasts through the production of IL-1β and paracrine generation of IL-6 resulting in osteolytic disease. With continued progression of the myeloma, the monoclonal plasma cells may later acquire the ability to produce IL-6 in an autocrine fashion that will be manifested clinically by an elevated labeling index. Conclusions A better understanding of the progression of MGUS to myeloma may lead to novel therapeutic strategies to prevent the development of MM.

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Free Light-Chain Levels in Patients with Transthyretin Amyloid Cardiomyopathy in Attr-ACT

Blood ◽

10.1182/blood-2021-148691 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3787-3787

Author(s):

James E Hoffman ◽

Marla B. Sultan ◽

Balarama Gundapaneni ◽

Ronald Witteles

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Research Funding ◽

Publicly Traded ◽

Monoclonal Gammopathies ◽

Plasma Cell Disorder ◽

The Mean ◽

Amyloid Cardiomyopathy ◽

Cell Disorder

Abstract Introduction: In cardiac amyloidosis (CA), immunoglobulin-derived light chains (AL) and transthyretin (TTR) are the most common amyloidogenic proteins infiltrating the heart. 1 Identification of the specific precursor protein leading to amyloid deposition is needed to establish the correct therapeutic approach. 2 In both AL- and TTR-related CA, an early and accurate diagnosis is critical to achieving the best treatment outcomes. TTR amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed as other causes of heart failure (HF), including AL CA. 3 While almost all patients with AL amyloidosis have elevated serum free light-chain (sFLC) levels and abnormal free kappa:lambda (κ:λ) ratios, 4 patients with ATTR-CM can also have abnormal sFLC levels due to either an unrelated monoclonal gammopathy or relative κ-predominance in renal dysfunction. 2,5 Because ATTR-CM most often occurs in elderly adults and is commonly accompanied by renal comorbidity, we theorized that patients with ATTR-CM may have κ:λ ratios that approach, or exceed, the upper limit of the normal reference range (0.26-1.65 6). High light-chain ratios in these patients have the potential to increase the likelihood of misdiagnosis of a monoclonal plasma cell disorder and may lead to unnecessary referrals to hematologists and/or inappropriate treatments. To explore this theory, we evaluated κ:λ ratios in patients with biopsy-proven ATTR-CM who were enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). 7 Methods: In ATTR-ACT, a double-blind, placebo-controlled, randomized study, patients with biopsy-proven ATTR-CM, and without light-chain amyloidosis, received tafamidis or placebo for 30 months. In the current analysis, sFLC levels and κ:λ ratios were assessed in the intent-to-treat population (N=441), excluding patients with a prior diagnosis of monoclonal gammopathies (n=13; defined by MedDRA preferred terms: 'monoclonal gammopathy', 'plasma cell myeloma', 'plasma cell disorder', and 'hypergammaglobulinemia benign monoclonal'). Subgroup analyses were performed by estimated glomerular filtration rate (eGFR) category (≥60 vs ≥40 to <60 vs <40 mL/min/1.73 m 2). Findings were summarized using descriptive statistics (min/max, mean, median, and interquartile range [IQR]). Results: In 422 patients with ATTR-CM and available sFLC data, and without a prior diagnosis of monoclonal gammopathies, the mean κ:λ ratio was 1.45 (median, 1.20 [IQR, 0.98, 1.47]) (Figure). The ratio increased with declining renal function: eGFR ≥60 mL/min/1.73 m 2, mean, 1.25 (median [IQR], 1.11 [0.94, 1.38]); ≥40 to <60 mL/min/1.73 m 2, 1.52 (1.22 [0.99, 1.49]); and <40 mL/min/1.73 m 2, 1.62 (1.30 [1.05, 1.68)]. Conclusions: In patients with biopsy-proven ATTR-CM without known monoclonal gammopathies who were enrolled in ATTR-ACT, the mean κ:λ ratio showed a κ-predominance, often exceeding the upper range of normal in patients with more advanced kidney dysfunction. The findings suggest that individuals with ATTR-CM can have higher sFLC levels than those normally seen in the general population, and such elevations do not necessarily indicate the presence of monoclonal gammopathy of undetermined significance or AL CA. In an era when most patients with ATTR-CM and without monoclonal gammopathies are diagnosed noninvasively using bone scintigraphy, age- and renal-function-based sFLC norms are critical to ensure appropriate use of diagnostic testing modalities. References: 1. Maleszewski JJ. Cardiovasc Pathol. 2015;24:343-50. 2. Donnelly JP, et al. Cleve Clin J Med. 2017;84:12-26. 3. Witteles RM, et al. JACC Heart Fail. 2019;7:709-716. 4. Falk RH, et al. J Am Coll Cardiol. 2016;68:1323-41. 5. Geller HI, et al. Mayo Clin Proc. 2017;92:1800-5. 6. Katzmann JA, et al. Clin Chem. 2002;48:1437-44. 7. Maurer MS, et al. N Engl J Med. 2018;379:1007-16. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Sultan: Pfizer: Current Employment, Current equity holder in publicly-traded company. Gundapaneni: Pfizer: Current Employment, Current equity holder in publicly-traded company. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding.

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Monoclonal gammopathy of undetermined significance

InnovAiT Education and inspiration for general practice ◽

10.1177/17557380211027921 ◽

2021 ◽

pp. 175573802110279

Author(s):

Vui Yung Chieng ◽

Rod Sampson

Keyword(s):

Primary Care ◽

Multiple Myeloma ◽

Plasma Cell ◽

Potential Risk ◽

Monoclonal Gammopathy ◽

Related Disorder ◽

Risk Of Progression ◽

Plasma Cell Disorder ◽

Cell Disorder ◽

Undetermined Significance

Monoclonal gammopathy of undetermined significance is a premalignant, plasma cell disorder. Due to the potential risk of progression to multiple myeloma or a plasma cell-related disorder, it is important for GPs to recognise and manage patients in this cohort appropriately. This article aims to improve understanding, recognition and management of these patients in primary care.

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Genomic Landscape of Immunoglobulin Light Chain (AL) Amyloidosis and Comparative Analyses with Related Malignant Plasma Cell Disorder- Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.809.809 ◽

2011 ◽

Vol 118 (21) ◽

pp. 809-809

Author(s):

Vishwanathan Hucthagowder ◽

Jahangheer Shaik ◽

Mark Fiala ◽

Jacob Paasch ◽

Rakesh Nagarajan ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Light Chain ◽

Copy Number ◽

Al Amyloidosis ◽

Immunoglobulin Light Chain ◽

Genomic Changes ◽

Genomic Landscape ◽

Plasma Cell Disorder ◽

Cell Disorder

Abstract Abstract 809 Immunoglobulin light chain amlyloidosis (AL) is a rare plasma cell disorder characterized by deposition of misfolded light chains in various organ systems with an average survival of 1–2 years. AL is also the most common form of systemic amyloidosis with 1200–3200 newly diagnosed cases reported annually in the United States. Very little is known regarding specific genomic aberrations associated with AL-amyloidosis. Aside from the light chain selection, no phenotypic or genetic features have been identified that distinguish AL amyloidosis from other plasma cell dyscrasias. Understanding the genetics of AL and the molecular mechanisms involved in amyloid formation may lead to early diagnosis and the identification of novel drug targets and therapies. We therefore have attempted to study the genomic landscape of AL patients and MM for comparison. Genomic copy number and loss of heterozygosity (LOH) analyses were performed on DNA derived from tumor (CD138 sorted cells) and matched germline (skin) from biopsy proven AL patients using Affymetrix single nucleotide polymorphism (SNP) 6.0 arrays. Numerous genomic changes with gains in chromosome 1q, 6, 9, 11q, 15, 19 and 21 and loss on chromosome 1p, 2q, 8, 10, 12, 13, 14, 16, 18, 20 and 22 were observed in more than 10% of the patients. Recurrent genomic changes in about 249 segments involving 457 genes were present in about 1/3 of AL patients. In particular, deletion of IGK, IGH, PIK3CA, FLT3, RB1, PCDH9, GPC6, RASA3, ADAM6 genes and amplification of CFHR1, JAK2, GCNT1, TSC1, PGR genes were observed. Gene network analysis showed five distinct major modules consisting of 51 distinct elements and involving PDGF, TP53, interleukin signaling, TRKA signaling, cell cycle and mitotic pathways were enriched. Allele specific copy number analysis in tumor (ASCAT) profile showed increased ploidy status of the AL genome in 47% of the assessed patients. LOH was observed in chromosomes 4, 5, 6, 8, 9, 12, 13, 18 and 22 in 30% of patients, ranging from 5Mb to entire chromosome. Furthermore, genomic comparisons of AL with multiple myeloma (MM) showed the typical archetype of myeloma's signature with exception of gain of chromosomes 3, 5, 7 and loss of chromosome 6q and 8p. Interestingly deletion of IGH, IGK locus and PIK3CA gene were observed at a higher frequency in AL patients. Categorical analysis using isotype specific classification in AL showed a significantly higher frequency of deletion in chromosome 14, 13, 8 and amplification of chromosome 9q in the kappa type than lambda isotype. To the best of our knowledge, this is the first ultra-high resolution study of the genomic landscape of AL amyloidosis. In this study, we have found several novel genes and pathways associated with this rare disease. The numerous copy number alterations of AL thus reflect the genomic complexity and the heterogeneity of this disease. Additional genome-wide analysis in a larger panel with target organ stratified patients is under way and may further our understanding of genetic changes specifically associated with AL. Disclosures: No relevant conflicts of interest to declare.

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