scholarly journals Clonal plasma cells in AL amyloidosis are dependent on pro survival BCL-2 family proteins and sensitive to BH3 mimetics

2019 ◽  
Author(s):  
Cameron Fraser ◽  
Adam Presser ◽  
Vaishali Sanchorawala ◽  
Shayna Sarosiek ◽  
Kristopher Sarosiek
Keyword(s):  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Single Agent ◽  
Current Treatment ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Current Standard ◽  
Bh3 Mimetics

Immunoglobulin light chain (AL) amyloidosis is a protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains misfold and accumulate as amyloid fibrils in healthy tissues causing devastating multi-organ dysfunction that is rapidly fatal. Current treatment regimens, which include proteasome inhibitors, alkylating agents, and immunomodulatory agents, were developed for the treatment of the more common plasma cell disease, multiple myeloma, and have limited efficacy in AL amyloidosis as demonstrated by the median survival of 2-3 years. The recent development of novel small-molecule inhibitors of the major pro-survival proteins from the apoptosis-regulating BCL-2 family has created an opportunity to therapeutically target abnormal cell populations, yet identifying the extent of these dependencies and how to target them clinically has thus far been challenging. Using bone marrow-derived plasma cells from 45 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins. Specifically, we find that clonal plasma cells in a majority of patients are highly dependent on the pro-survival protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor as a single agent. In addition, BCL-2 inhibition sensitizes clonal plasma cells to several current standard of care therapies. Our results suggest that BH3 mimetics, when deployed rationally, may be highly effective therapies for AL amyloidosis.

scholarly journals Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo

Blood ◽  
1978 ◽  
Vol 52 (4) ◽  
pp. 818-827 ◽  
Author(s):  
RA Kyle ◽  
PR Greipp
Keyword(s):  
Nephrotic Syndrome ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Systemic Amyloidosis ◽  
Light Chains ◽  
Primary Amyloidosis ◽  
Double Blind ◽  
Progression Of Disease ◽  
To Receive

Abstract Satisfactory treatment for primary amyloidosis does not exist. Because the amyloid fibrils consist of a portion of a monoclonal light chain, it appears reasonable to treat amyloidosis with alkylating agents that are effective against the plasma cells that synthesize monoclonal light chains. Fifty-five patients with primary systemic amyloidosis were randomized (double blind) to melphalan-prednisone or placebo. In comparison with the placebo group, patients given melphalan-prednisone were able to continue on treatment for a longer time and to receive larger doses before the code was broken. Among this group, the nephrotic syndrome disappeared in two patients and urinary excretion of protein was reduced by more than 50% in eight others. Of 13 patients who received melphalan-prednisone for more than 12 mo, 6 improved, 3 were stable, and 4 had progression of disease. Survival did not differ significantly between the groups.

scholarly journals Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo

Blood ◽  
1978 ◽  
Vol 52 (4) ◽  
pp. 818-827 ◽  
Author(s):  
RA Kyle ◽  
PR Greipp
Keyword(s):  
Nephrotic Syndrome ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Systemic Amyloidosis ◽  
Light Chains ◽  
Primary Amyloidosis ◽  
Double Blind ◽  
Progression Of Disease ◽  
To Receive

Satisfactory treatment for primary amyloidosis does not exist. Because the amyloid fibrils consist of a portion of a monoclonal light chain, it appears reasonable to treat amyloidosis with alkylating agents that are effective against the plasma cells that synthesize monoclonal light chains. Fifty-five patients with primary systemic amyloidosis were randomized (double blind) to melphalan-prednisone or placebo. In comparison with the placebo group, patients given melphalan-prednisone were able to continue on treatment for a longer time and to receive larger doses before the code was broken. Among this group, the nephrotic syndrome disappeared in two patients and urinary excretion of protein was reduced by more than 50% in eight others. Of 13 patients who received melphalan-prednisone for more than 12 mo, 6 improved, 3 were stable, and 4 had progression of disease. Survival did not differ significantly between the groups.

scholarly journals Clonal Plasma Cells in AL Amyloidosis Are Dependent on Anti-Apoptotic BCL-2 Family Proteins

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2654-2654
Author(s):  
Cameron Fraser ◽  
Vaishali Sanchorawala ◽  
Kristopher Sarosiek ◽  
Shayna Sarosiek
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Al Amyloidosis ◽  
Functional Assay ◽  
Current Standard ◽  
Novel Therapy ◽  
Bh3 Mimetics ◽  
Hematologic Disorders ◽  
Apoptotic Proteins

Abstract Background: Immunoglobulin light chain (AL) amyloidosis is characterized by the production of clonal serum free light chains, which misfold and accumulate in tissues causing life threatening organ dysfunction and ultimately death. The treatment of AL amyloidosis targets the underlying population of clonal plasma cells, but existing therapies are not curative and ineffectively control the disease in many patients. Recent data have shown tremendous success in targeting anti-apoptotic BCL-2 family proteins as a novel therapy in hematologic disorders due to alterations in apoptosis and the function of anti-apoptotic proteins in malignant cells. BH3 profiling, a quantitative and functional assay that measures apoptotic priming and dependence on anti-apoptotic BCL-2 family members, has been used to identify and target apoptotic dependencies in hematologic disorders. Novel inhibitors of anti-apoptotic proteins, referred to as BH3 mimetics, have not yet been explored in AL amyloidosis due to insufficient understanding of apoptotic dependencies in this disease. Methods: To date, bone marrow aspirates have been collected from 44 patients with newly diagnosed or relapsed/refractory AL amyloidosis being evaluated at the Amyloidosis Center at Boston University. BH3 profiling was performed on clonal plasma cells to measure dependencies on anti-apoptotic BCL-2 family proteins. Clonal cells were also treated with BH3 mimetics in vitro, including BCL-2, BCL-xL, and MCL-1 inhibitors as single agents, as well as in combination with current standard therapies (bortezomib, ixazomib, lenalidomide, and pomalidomide). Results: Of the 44 enrolled patients, 16 are female (36%) and 28 are male (64%). The median age is 70 years (range, 47 to 84). Six patients were treatment naïve and the remainder had previous or current treatment for AL amyloidosis. Data obtained with BH3 profiling demonstrated that clonal plasma cells exhibit strong dependencies on anti-apoptotic BCL-2 family proteins, which may be altered by concurrent treatment with standard therapies. In the majority of patients, clonal plasma cells are highly dependent on the anti-apoptotic protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor. Intriguingly, this dependence is altered by treatment with proteasome inhibitors: clonal plasma cells become highly dependent on BCL-2 and undergo apoptosis in response to co-treatment with bortezomib and the FDA-approved BCL-2 inhibitor venetoclax. Conclusions: BH3 profiling can effectively measure apoptotic dependencies in clonal plasma cells derived from bone marrow aspirates in patients with AL amyloidosis. Dependencies on BCL-2 family proteins (particularly MCL-1) are strong, but some variability between patients was observed, especially in combination with standard therapies. Biomarker-driven deployment of BH3 mimetics for treatment of AL amyloidosis would likely be highly effective. Disclosures No relevant conflicts of interest to declare.

scholarly journals Primary Amyloidosis and Acute Leukemia Associated With Melphalan Therapy

Blood ◽  
1974 ◽  
Vol 44 (3) ◽  
pp. 333-337 ◽  
Author(s):  
Robert A. Kyle ◽  
Robert V. Pierre ◽  
Edwin D. Bayrd
Keyword(s):  
Acute Leukemia ◽  
Significant Role ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Light Chains ◽  
Primary Amyloidosis ◽  
Immunoglobulin Light Chains ◽  
Full Consideration

Abstract Amyloid fibrils consist in part of immunoglobulin light chains. Because light chains are synthesized by plasma cells, it seems reasonable to treat patients with amyloidosis with alkylating agents. Two patients who had primary amyloidosis and were treated with melphalan subsequently developed a rapidly fatal acute leukemia. Since melphalan may play a significant role in the development of acute leukemia, we suggest that alkylating agents not be used in the treatment of patients with amyloidosis without full consideration of risks involved, particularly until it has been proved that these drugs are beneficial.

scholarly journals Silver Nanoparticle-Based Assay for the Detection of Immunoglobulin Free Light Chains

Materials ◽  
2019 ◽  
Vol 12 (18) ◽  
pp. 2981 ◽  
Author(s):  
Anna Lizoń ◽  
Magdalena Wytrwal-Sarna ◽  
Marta Gajewska ◽  
Ryszard Drożdż
Keyword(s):  
Light Scattering ◽  
Silver Nanoparticle ◽  
Plasma Cells ◽  
Wide Spectrum ◽  
Metal Nanoparticle ◽  
Light Chains ◽  
Hydrodynamic Diameter ◽  
Al Amyloidosis ◽  
Free Light Chains ◽  
Optimal Test

There is a wide spectrum of malignant diseases that are connected with the clonal proliferation of plasma cells, which cause the production of complete immunoglobulins or their fragments (heavy or light immunoglobulin chains). These proteins may accumulate in tissues, leading to end organ damage. The quantitative determination of immunoglobulin free light chains (FLCs) is considered to be the gold standard in the detection and treatment of multiple myeloma (MM) and amyloid light-chain (AL) amyloidosis. In this study, a silver nanoparticle-based diagnostic tool for the quantitation of FLCs is presented. The optimal test conditions were achieved when a metal nanoparticle (MNP) was covered with 10 particles of an antibody and conjugated by 5–50 protein antigen particles (FLCs). The formation of the second antigen protein corona was accompanied by noticeable changes in the surface plasmon resonance spectra of the silver nanoparticles (AgNPs), which coincided with an increase of the hydrodynamic diameter and increase in the zeta potential, as demonstrated by dynamic light scattering (DLS). A decrease of repulsion forces and the formation of antigen–antibody bridges resulted in the agglutination of AgNPs, as demonstrated by transmission electron microscopy and the direct formation of AgNP aggregates. Antigen-conjugated AgNPs clusters were also found by direct observation using green laser light scattering. The parameters of the specific immunochemical aggregation process consistent with the sizes of AgNPs and the protein particles that coat them were confirmed by four physical methods, yielding complementary data concerning a clinically useful AgNPs aggregation test.

Recurrent diffuse gastric bleeding as a leading symptom of gastrointestinal AL amyloidosis

2017 ◽  
Vol 55 (12) ◽  
pp. 1318-1322 ◽  
Author(s):  
Caspar Franck ◽  
Marino Venerito ◽  
Jochen Weigt ◽  
Albert Roessner ◽  
Peter Malfertheiner
Keyword(s):  
Plasma Cells ◽  
Serum Proteins ◽  
Histopathological Examination ◽  
Disease Incidence ◽  
Clinical Manifestations ◽  
Current Treatment ◽  
Al Amyloidosis ◽  
Gastric Bleeding ◽  
Amyloid Deposits ◽  
Leading Symptom

AbstractAmyloidosis is a rare disease (incidence about 0.8/100 000) characterized by extracellular tissue deposition of fibrils composed of low molecular weight subunits of a variety of serum proteins. Clinical manifestations are largely determined by the type of precursor protein, the tissue distribution and the amount of amyloid deposition. Gastrointestinal (GI) manifestations of amyloidosis are even more uncommon (3 % of all amyloidosis patients). Symptoms of GI amyloidosis are nonspecific, heterogeneous, and include weight loss, GI bleeding, heartburn, early satiety, diarrhea and abdominal pain. The histopathological examination of biopsy specimens from the GI tract leads to the diagnosis.Herein we report the case of a 63-year-old woman with recurrent diffuse gastric bleeding. Endoscopic biopsies revealed distinct amyloid deposits in the mucosa of the stomach. Further histochemical assessment confirmed systemic light chain (AL) amyloidosis with clinically predominant gastrointestinal manifestation. An induction therapy with bortezomib and dexamethasone was initiated.Our report illustrates the importance of the multidisciplinary approach for diagnosis and management of AL amyloidosis. Current treatment of systemic AL amyloidosis is based on cytostatic targeting of immunoglobulin producing plasma cells. Therapeutic options are limited and highly toxic, making the development of novel treatment approaches an urgent need.

P0244OVERTURNING THE CONVENTIONAL PYRAMID OF AL AMYLOIDOSIS MANAGEMENT: DARATUMUMAB ADMINISTERED AS MONOTHERAPY IN SEVERE PATIENTS WITH BIOPSY PROVEN RENAL INVOLVEMENT

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Dario Roccatello ◽  
Roberta Fenoglio ◽  
Elena Rubini ◽  
Carla Naretto ◽  
Simone Baldovino ◽  
...  
Keyword(s):  
Cell Clone ◽  
Therapeutic Option ◽  
Renal Involvement ◽  
Single Agent ◽  
Treatment Protocol ◽  
Infusion Reaction ◽  
Current Treatment ◽  
Al Amyloidosis ◽  
Human Antibody ◽  
Antibody Testing

Abstract Background and Aims Immunoglobulin light chain amyloidosis (AL) with multi-organ involvement is characterized by poor outcome. Current treatment of AL targeting the underlying plasma cell clone has been adapted from the multiple myeloma (MM). Novel powerful drugs are expanding the therapeutic options. Daratumumab is a first-in-class anti-CD38 human antibody (IgG1κ) which proved to be effective in combination with bortezomib in MM refractory to conventional bortezomib-based regimens. Its effectiveness as a single agent and its safety in the treatment of AL amyloidosis is under study. Aim of the study: This study reports the experience with Daratumumab monotherapy in a series of severe patients with AL amyloidosis and multiorgan and biopsy-proven renal involvement. Method Five patients (2 males and 3 females), mean age 64 years (range 52-69) were treated with Daratumumab following antibody testing and extended RBC antigen phenotyping. Treatment protocol was as follows: 16 mg/kg Daratumumab i.v. administered weekly for 8 weeks, then 8 times every two weeks, and then monthly for 1 year. Premedication included oral paracetamol, and i.v. chlorphenamine and methylprednisolone. Results In patient #1, in dialysis, who was refractory to conventional therapies Daratumumab administration resulted in normalization of the FLC ratio with disappearance of serum M-component and Bence-Jones (BJ) proteinuria. In patient #2 who had a relapsing disease, Daratumumab treatment resulted in a rapid decrease of proteinuria (from 6.8 to 2.7gr/24 hours at the 16th dose) and N-terminal propeptide (NT-pro-BNP) levels (from 1844 pg/ml to 330 pg/ml) with disappearance of serum M-component and BJ proteinuria and normalization of the FLC ratio. Patient #3 was treated front-line. He had an impressive decrease of proteinuria from 9.3 to 2.2 gr/24 hrs and NT-proBNP levels (from 850 pg/ml to 225 pg/ml) with normalization of FLC ratio and disappearance of serum M-component. In patient #4, who was intolerant to conventional regimens, Daratumumab therapy resulted in decrease in proteinuria, disappearance of serum M-component and improvement in the FLC ratio, which were paralleled by a reduction of NT-proBNP levels. Patient #5 had a relapsing disease. Daratumumab achieved a decrease of proteinuria (from 2.5 to 1 gr/24 hrs9, a decrease of serum M-component with increase of FLC ratio (0.29, nv: 0.31 – 1.56). This was the only patient who experienced an infusion reaction during the first dose (grade 1). The 4 patients with still preserved renal function also showed renal response with sCr improvement or stabilization and a decrease in proteinuria levels These data were paralleled by the reduction of NT-proBNP values in the 3 patients with cardiac involvement. Conclusion Daratumumab monotherapy resulted in the disappearance of M-proteins in every patient with FLC ratio normalization in 4 out of 5 subjects and impressive decrease of proteinuria and pro-BNP values proving to be an effective therapeutic option for pretreated/naïve patients with severe AL with renal involvement.

scholarly journals Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3571
Author(s):  
Gareth J. Morgan
Keyword(s):  
Small Molecules ◽  
Light Chain ◽  
Amyloid Fibrils ◽  
Systemic Amyloidosis ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Amyloid Formation ◽  
Amyloid Fibril Formation ◽  
Amyloid Light Chain

Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.

scholarly journals Early Serum Free Light Chain Response after High-Dose Melphalan and Stem Cell Transplantation Predicts Hematologic Response in AL Amyloidosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-26
Author(s):  
Vanessa Fiorini Furtado ◽  
Dina Brauneis ◽  
Shayna Sarosiek ◽  
Karen Quillen ◽  
Vaishali Sanchorawala
Keyword(s):  
Light Chain ◽  
Research Funding ◽  
Amyloid Fibrils ◽  
Advisory Board ◽  
Free Light Chain ◽  
Light Chains ◽  
High Dose ◽  
Al Amyloidosis ◽  
Serum Free Light Chain ◽  
High Dose Melphalan

Introduction Immunoglobulin light chain (AL) amyloidosis is a rare disease caused by a clonal plasma cell dyscrasia producing monoclonal light chains that misfold and form amyloid fibrils which can deposit in a variety of tissues and organs. This deposition of amyloid fibrils can lead to progressive organ impairment, multi-organ failure, and death if left untreated. High-dose melphalan and autologous stem cell transplantation (HDM/SCT) is known to improve patient outcomes with hematologic complete responses (CR) rates of 25-67%. Hematologic CR is currently defined as the absence of monoclonal protein in serum and urine by immunofixation electrophoreses and normal serum free light chain ratio (FLCR). Studies have shown that even among patients achieving a normal FLCR after initial therapy with HDM, persistent elevation of the involved FLC (hiFLC) predicts poor prognosis. Serum half-life of FLCs is approximately 2-6 hours, even with diminished glomerular filtration rates, and could be a tool for early treatment response evaluation. We sought to determine the extent to which early FLC responses after HDM/SCT predict hematologic complete response (CR) at 6 months. Methods We analyzed patients with AL amyloidosis who underwent HDM/SCT from 2012-2019 at Boston Medical Center. Exclusion criteria included death within 100 days, lack of FLC data at any time point, pre-SCT normal FLC concentrations and ratio, and chronic renal insufficiency (serum creatinine >1.3 mg/dL) with a normal FLC ratio. All subjects received a total of 140-200 mg/m2 melphalan IV in equally divided doses on days -3 and -2. Stem cells were infused on day 0. FLC measurements were obtained early in the peri-SCT period (< 1 month), at 6 months, and at 12 months after HDM/SCT. The patients were evaluated for response according to the consensus response criteria at 6 months. Statistical analysis to compare CR at 6 months and early post-SCT free light chain levels was performed by Chi-square with significance considered at p<0.05. Results Of the 113 patients with AL amyloidosis treated with HDM/SCT during the specified time period, 32 were excluded (4 died within 100 days of SCT, 15 had normal FLCs pre-SCT, 5 lacked data, and 8 had chronic renal insufficiency (Cr >1.3 mg/dL) with normal FLCR. A total of 81 subjects (females=30) were analyzed. Median follow-up from SCT was 27.6 months (range, 6-145). Median time of early post-SCT FLC measurement was 8 days (range, 7-30). Median age at diagnosis was 58 years (range 30-79) and the iFLC was lambda in 81.5% (n = 66) of patients. Median number of bone marrow plasma cells was 10% (range, 1-50). The mean absolute involved FLC was 196 mg/L ±221 prior to SCT, 60 mg/L ± 77 in the early post-SCT period, 92 mg/L ± 152 at 6 months post-SCT. In early post-SCT period, 39.5% (n=32) had iFLC <20 mg/L, 28% (n=16/57) had dFLC<10 mg/L, and 84% (n=48/57) had normal FLCR. Early post-SCT dFLC <10 mg/dL and early post-SCT iFLC <20 mg/L were statistically associated with prediction of hematologic CR at 6 months (p=0.025 and p=0.001, respectively). However, early post-SCT normal FLCR was not associated with predicting hematologic CR at 6 months. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of early post-SCT iFLC <20 mg/L, dFLC <10 mg/L and normal FLCR to predict hematologic CR at 6 months are presented in table 1. Conclusion This study concludes that achievement of dFLC <10 mg/L and iFLC <20 mg/L in the early post-SCT period is associated with prediction of hematologic CR at 6 months. Early post-SCT dFLC <10 mg/L could be considered a tool for early evaluation of treatment response following HDM/SCT in AL amyloidosis. Key words: immunoglobulin light chains; AL amyloidosis, HDM/SCT Disclosures Sarosiek: Spectrum: Research Funding. Sanchorawala:Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding.

scholarly journals AL Amyloidosis — Pathogenesis and Prognosis Are Determined By the Amyloidogenic Potential of the Light Chain and the Molecular Characteristics of Malignant Plasma Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 187-187
Author(s):  
Anja Seckinger ◽  
Ute Hegenbart ◽  
Susanne Beck ◽  
Martina Emde ◽  
Tilmann Bochtler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasma Cell ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Light Chains ◽  
Molecular Characteristics ◽  
Al Amyloidosis ◽  
Malignant Plasma Cell

Abstract INTRODUCTION. Systemic light chain amyloidosis (AL) is caused by accumulation of plasma cells producing misfolded monoclonal light chains depositing as amyloid fibrils in different organs, most frequently heart and kidney. AIM of our study is first assessing the molecular characteristics of malignant plasma cells from AL-patients in relation to those from MGUS, asymptomatic, and symptomatic myeloma: Are these plasma cells different, does this difference explain amyloidogenicity? Does AL correspond to a certain developmental stage during evolution of symptomatic myeloma? Secondly, to what extent is prognosis determined by amyloid-deposition (organotropism, amount, amyloidogenicity) vs. number and molecular characteristics of malignant plasma cells? PATIENTS & METHODS . Consecutive patients (n=3023) with AL (n=582), MGUS (n=306), asymptomatic (n=444, AMM), or previously untreated, therapy-requiring multiple myeloma (n=1691, MM) were included. CD138-purified plasma cell samples were subjected to iFISH (n=582/306/444/1691), 1297 to gene expression profiling using Affymetrix U133 2.0 plus arrays (n=196/64/272/765), 712 to RNA- (n=124/52/38/489), and 258 to whole exome sequencing (n=115/53/39/51). Samples of normal bone marrow plasma cells, memory B-cells, and polyclonal plasmablasts were used as comparators. The CoMMpass-cohort (n=647) was used as comparator for the mutational spectrum of myeloma. RESULTS . Prognosis. By AL-factors. Expectedly, organ involvement, i.e. heart only vs. kidney only vs. heart+kidney vs. other (overall survival (OS), P=.001), the amount of free light chains (dFLC ≥18 mg/dL, HR=2.56, P=.01), and the cardiac European Mayo IIIB score (I/II/IIIA/IIIB, median OS 110/55/16/3 months, HR=1/1.94/3.73/7.90, P<.001) strongly determine prognosis (Fig. 1A). By malignant plasma cell factors. High proliferation rate (HR=3.58, P=.001) and expression-based risk factors for MM (GEP70 high, HR=2.38, P=.005; Rs-score high HR=4.63, P<.001) identify patients with very adverse prognosis (Fig. 1A). Tumor load, e.g. plasma cell infiltration >10%/>30% (HR=1.31/1.81, P=.01, P=.002) and M-protein ≥ 30g/l (HR=3.01, P=.005), are likewise prognostic (Fig. 1A). In multivariate analysis, all tested AL-specific (European Mayo IIIB score) and malignant plasma cell factors (proliferation or GEP70 and plasma cell infiltration) are independent. Molecular characteristics.iFISH. As MM (96.2%) and AMM (92.8%) AL-patients (93.1%) carry at least one recurrent myeloma typical aberration. The mean number of progression-associated aberrations in AL (n=0.98) fits between MGUS (n=0.85) and AMM (n=1.45) with significant difference compared to AMM (P<.001) unlike to MGUS. Main differences in frequency are found for t(11;14) and hyperdiploidy with a comparable pattern of non-etiologic aberrations. Gene expression (GEP and RNA-seq). Aberrant plasma cells in AL amyloidosis show the least difference with AMM, followed by MGUS and MM. In principal component analysis, AL overlaps with AMM and MGUS, independent of presence or absence of heart involvement (Fig. 1B). Pairwise assessment of similarity using a multivariate generalization of the squared Pearson correlation coefficient shows closest similarity to AMM and MM followed by MGUS, with comparable differences to normal plasma cells, polyclonal plasmablasts, and memory B-cells. Significantly more AL-patients present with higher proliferation rate vs MGUS (P<.001) and AMM (P<.02). AL and MM differ significantly regarding distinct molecular entities as determined by GEP (e.g. TC-classification; Fig. 1C). Mutation spectrum in AL amyloidosis vs. MM. From the 20 most frequently synonymously mutated non-Ig transcripts (CoMMpass-cohort), 16 could likewise be detected in AL amyloidosis, i.e. KRAS, NRAS, IGLL5, DIS3, FAM46C, MUC16, BRAF, TRAF3, PCLO, RYR2, FATA4, CSMD3, TP53, DNAH5, RYR2A, and FLG. CCND1 mutations were significantly more frequent in AL and AMM compared to MM (P=.02). DISCUSSION & CONCLUSION. Pathogenesis and prognosis of AL amyloidosis are explained both by AL-specific and malignant plasma cell characteristics. Aberrant plasma cells in AL amyloidosis show the same aberration- and expression pattern and a "molecular age" between MGUS and AMM, most closely resembling the latter. AL amyloidosis is thus mostly a rather early plasma cell dyscrasia with an unstable and toxic immunoglobulin light chain. Disclosures Seckinger: Celgene: Research Funding; EngMab: Research Funding; Sanofi: Research Funding. Hose:Celgene: Honoraria, Research Funding; Sanofi: Research Funding; EngMab: Research Funding.

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