Supportive Care in AL Amyloidosis

Immunoglobulin light-chain (AL) amyloidosis is a systemic disease characterized by the production and deposition of light chain-derived amyloid fibrils in different organs. Prompt treatment directed to the underlying plasma cell clone is crucial in order to achieve a rapid, deep and durable hematologic response. The decrease in the production of the amyloidogenic light chains is a required condition to obtain the organ response, which is commonly delayed. Meanwhile, supportive treatment is aimed to maintain quality of life of these patients and preserve their involved organs’ function. From simple measures, such as salt restriction or compressive stockings, to very complex interventions, such as heart transplantation in very selected patients with isolated severe cardiac involvement, this supportive care is essential and has to be necessarily included in the multidisciplinary management of this disease.

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Bilateral periorbital ecchymoses

Hämostaseologie ◽

10.5482/hamo-14-03-0018 ◽

2014 ◽

Vol 34 (03) ◽

pp. 249-252 ◽

Cited By ~ 9

Author(s):

L. Alberio ◽

F. Biasiutti ◽

B. Lämmle ◽

G. Colucci

Keyword(s):

Light Chain ◽

Amyloid Fibrils ◽

Cell Clone ◽

Systemic Disease ◽

Coagulation Factor ◽

Al Amyloidosis ◽

Factor X ◽

The Face ◽

One Year ◽

Diagnostic Work

SummaryImmunoglobulin light chain (AL) amyloidosis is a systemic disease caused by a plasma cell clone synthesizing an unstable light chain, which forms amyloid fibrils. Deposition of amyloid fibrils affects primarily kidney, heart, nervous system, spleen, liver, gastrointestinal tract and the skin. Skin bleeding in these patients is called amyloid purpura. Classically, it occurs spontaneously and bilaterally in the periorbital region. Vessel wall fragility and damage by amyloid are the principal causes of periorbital and gastrointestinal bleeding. Additionally, coagulation factor inhibitory circulating paraprotein, hyperfibrinolysis, platelet dysfunction or isolated acquired factor X deficiency may contribute to even more severe, diffuse bleedings.Early diagnosis remains essential for improvsis. Although pictures of amyloid purpura have been often reported in the literature, the clinical diagnosis may be delayed. We report a case of cutaneous manifestation of AL amyloi-dosis diagnosed not until one year after the appearance of the first symptoms. Diagnostic work-up revealed that the patient suffered from multiple myeloma with secondary AL amyloidosis. Atraumatic ecchymoses at the face, particularly the eyelids as well as in the neck should raise the suspicion of AL amyloi-dosis.

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Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

Blood Cancer Journal ◽

10.1038/s41408-021-00428-0 ◽

2021 ◽

Vol 11 (2) ◽

Cited By ~ 2

Author(s):

Giovanni Palladini ◽

Bruno Paiva ◽

Ashutosh Wechalekar ◽

Margherita Massa ◽

Paolo Milani ◽

...

Keyword(s):

Minimal Residual Disease ◽

Organ Dysfunction ◽

Light Chain ◽

Residual Disease ◽

Cell Clone ◽

Cardiac Response ◽

Al Amyloidosis ◽

Next Generation ◽

Organ Response ◽

Minimal Residual

AbstractLight chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.

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Dissecting the Molecular Features of Systemic Light Chain (AL) Amyloidosis: Contributions from Proteomics

Medicina ◽

10.3390/medicina57090916 ◽

2021 ◽

Vol 57 (9) ◽

pp. 916

Author(s):

Paola Rognoni ◽

Giulia Mazzini ◽

Serena Caminito ◽

Giovanni Palladini ◽

Francesca Lavatelli

Keyword(s):

Light Chain ◽

Amyloid Fibrils ◽

Cell Clone ◽

Experimental Models ◽

Critical Discussion ◽

Al Amyloidosis ◽

Primary Role ◽

Molecular Features ◽

Amyloid Light Chain ◽

Models Of Disease

Amyloidoses are characterized by aggregation of proteins into highly ordered amyloid fibrils, which deposit in the extracellular space of tissues, leading to organ dysfunction. In AL (amyloid light chain) amyloidosis, the most common form in Western countries, the amyloidogenic precursor is a misfolding-prone immunoglobulin light chain (LC), which, in the systemic form, is produced in excess by a plasma cell clone and transported to target organs though blood. Due to the primary role that proteins play in the pathogenesis of amyloidoses, mass spectrometry (MS)-based proteomic studies have gained an established position in the clinical management and research of these diseases. In AL amyloidosis, in particular, proteomics has provided important contributions for characterizing the precursor light chain, the composition of the amyloid deposits and the mechanisms of proteotoxicity in target organ cells and experimental models of disease. This review will provide an overview of the major achievements of proteomic studies in AL amyloidosis, with a presentation of the most recent acquisitions and a critical discussion of open issues and ongoing trends.

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Daratumumab plus CyBorD for patients with newly diagnosed light chain (AL) amyloidosis

Therapeutic Advances in Hematology ◽

10.1177/20406207211058334 ◽

2021 ◽

Vol 12 ◽

pp. 204062072110583

Author(s):

Foteini Theodorakakou ◽

Meletios A. Dimopoulos ◽

Efstathios Kastritis

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Standard Of Care ◽

Response Rates ◽

Complete Response ◽

Phase Iii ◽

Al Amyloidosis ◽

Large Phase ◽

Organ Response

Primary systemic immunoglobulin light chain (AL) amyloidosis is caused by a plasma cell clone of, usually low, malignant potential that expresses CD38 molecules on their surface. Treatment of AL amyloidosis is based on the elimination of the plasma cell clone. The combination of cyclophosphamide–bortezomib–dexamethasone (CyBorD) is the most widely used and is considered a standard of care; however, complete hematologic response rates and organ response rates remain unsatisfactory. Daratumumab, an anti-CD38 monoclonal antibody, has demonstrated encouraging results, with rapid and deep responses, in patients with relapsed or refractory AL amyloidosis as monotherapy with a favorable toxicity profile. The large phase-III, randomized, ANDROMEDA study evaluated the addition of daratumumab to CyBorD in previously untreated patients with AL amyloidosis and demonstrated that addition of daratumumab can substantially improve hematologic complete response rates, survival free from major organ deterioration or hematologic progression, and organ responses. In this review, we discuss the role of daratumumab in the treatment of AL amyloidosis, its mechanism of action, and the results of ANDROMEDA study that led to the first approved therapy for AL amyloidosis.

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Cardiac AL Amyloidosis – the role of serum Immunoglobulin Free Llight Chain assay (sFLC) in diagnosis and prognostic classification

Diagnostyka Laboratoryjna ◽

10.5604/01.3001.0013.7979 ◽

2017 ◽

Vol 53 (3) ◽

pp. 175-184

Author(s):

Emilia Czyżewska ◽

Anna Rodziewicz-Lurzyńska ◽

Dagna Bobilewicz

Keyword(s):

Light Chain ◽

Amyloid Fibrils ◽

Cell Clone ◽

Myocardial Dysfunction ◽

Myocardial Damage ◽

Amyloid Deposit ◽

Al Amyloidosis ◽

Neoplastic Process ◽

The Difference ◽

Immunoglobulin Light Chain Amyloidosis

Systemic immunoglobulin light chain amyloidosis (AL amyloidosis) is a cancer in which the amyloid fibrils are formed from amyloid immunoglobulin free light chain (FLC) κ or λ, produced by a plasma cell clone. The created protein adopts the structure of β-sheets, and depositing in tissues and organs leads to their function impairment. Cardiomyopathies are the main cause of death in patients with amyloidosis. Diagnosis of cardiac involvement is too late owing to nonspecific symptoms and no early characteristic changes observed in imaging studies. The currently valid prognostic classification of AL amyloidosis created by Kumar et al. is based on biochemical parameters evaluating function and the degree of myocardial damage: concentration of troponin (Tn) and N-terminal fragment of B-type natriuretic peptide (NT-proBNP) and the value of dFLC, representing the difference between the concentration of serum FLC (sFLC) involved and not involved in the neoplastic process. There are reports indicating that myocardial dysfunction in AL amyloidosis stems not only from the amyloid deposit in the organ, but it is also the result of the cardiotoxicity amyloid precursor – FLC, circulating in the blood.

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Conventional Therapy for Amyloid Light-Chain Amyloidosis

Acta Haematologica ◽

10.1159/000507072 ◽

2020 ◽

Vol 143 (4) ◽

pp. 365-372

Author(s):

Paolo Milani ◽

Giovanni Palladini

Keyword(s):

Stem Cell ◽

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Alkylating Agents ◽

Proteasome Inhibitors ◽

Response Rates ◽

Al Amyloidosis ◽

Cell Transplant ◽

Conventional Chemotherapy

The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.

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Recent Advances in the Diagnosis, Risk Stratification, and Management of Systemic Light-Chain Amyloidosis

Acta Haematologica ◽

10.1159/000495455 ◽

2019 ◽

Vol 141 (2) ◽

pp. 93-106 ◽

Cited By ~ 28

Author(s):

Iuliana Vaxman ◽

Morie Gertz

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Proteasome Inhibitors ◽

Clinical Manifestations ◽

Al Amyloidosis ◽

Amyloid Deposits ◽

Protein Fibrils ◽

Risk Patients ◽

Intensive Search

The term amyloidosis refers to a group of disorders in which protein fibrils accumulate in certain organs, disrupt their tissue architecture, and impair the function of the effected organ. The clinical manifestations and prognosis vary widely depending on the specific type of the affected protein. Immunoglobulin light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, characterized by deposition of a misfolded monoclonal light-chain that is secreted from a plasma cell clone. Demonstrating amyloid deposits in a tissue biopsy stained with Congo red is mandatory for the diagnosis. Novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, venetoclax) and autologous stem cell transplantation, used for eliminating the underlying plasma cell clone, have improved the outcome for low- and intermediate-risk patients, but the prognosis for high-risk patients is still grave. Randomized studies evaluating antibodies that target the amyloid deposits (PRONTO, VITAL) were recently stopped due to futility and currently there is an intensive search for novel treatment approaches to AL amyloidosis. Early diagnosis is of paramount importance for effective treatment and prognosis, due to the progressive nature of this disease.

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Baseline Serum Albumin and Proteinuria Predict Renal Response after Autologous Stem Cell Transplantation in AL Amyloidosis.

Blood ◽

10.1182/blood.v106.11.1166.1166 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1166-1166

Author(s):

Nelson Leung ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

Mark R. Litzow ◽

Shaji K. Kumar ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Light Chain ◽

Al Amyloidosis ◽

Baseline Serum ◽

Monoclonal Protein ◽

Renal Response ◽

Hematologic Response ◽

Organ Response

Abstract Introduction: High dose melphalan followed by autologous stem cell transplantation (ASCT) is an effective treatment for patients with light chain associated (AL) amyloidosis. Longer patient survival and higher rates of organ response have now been documented by multiple studies. However, predictors of organ response remain unknown. Previously, we have reported the benefits of renal response after ASCT in this population. This study was conducted to investigate the characteristics that would predict renal response after ASCT. Methods: The study was performed retrospectively on consecutive patients that underwent ASCT at our institution from March of 1996 to December of 2004. Exclusion criteria include baseline proteinuria < 1 g/d, dialysis prior to ASCT and lack of laboratory data at follow up to determine renal response. Renal response was defined by > 50% reduction in baseline proteinuria with < 25% decline in renal function as measured by serum creatinine. Treatment related mortality and dialysis dependence prior to meeting criteria of response were viewed as treatment failures. Hematologic response was determined by 50% reduction of monoclonal protein (free light chain) or complete eradication if the monoclonal protein was too small to be quantified. Results: A total of 135 patients met criteria for study. Median age was 56.2 years at the time of transplant, 53.7% were male. Median baseline proteinuria and GFR were 6.4 g/d and 70 ml/min/1.73m2 respectively. Renal response was achieved in 35.6% of the patients while hematologic response was 71.1% in the 128 patients evaluated. Patient’s age, sex, albumin, GFR, proteinuria, conditioning regimen, and hematologic response were evaluated and the following were found to be associated with renal response: albumin (p = 0.001), proteinuria (p = 0.008), and hematologic response (p = 0.0002). The cutoff for albumin was found to be 1.6 mg/dl and proteinuria was 3.5 g/d. Multivariate analysis using a logistic regression model showed hematologic response and proteinuria to be independent predictors of renal response. The impact of proteinuria and hypoalbuminemia was then investigated together (Table 1). When combined, they were a better predictor then either one alone (Hazard ratio = 6.34 for combined, 3.43 for proteinuria, 3.32 for hypoalbuminemia). The combination was also a better independent predictor of renal response in the multivariate analysis. In this group of patients, renal response was associated with longer survival but hematologic response was not (p = 0.02). Discussion: Our study showed that besides hematologic response, baseline serum albumin and proteinuria are independent predictors of renal response in AL patients after ASCT. Hypoalbuminemia and nephrotic range proteinuria, both markers of the severity of renal disease, have strong negative impact on response. This implies that there may be a limit to the reversibility of organ damage even when hematologic response is achieved. This study also points out the importance of organ (renal) response in this disease as hematologic response alone did not predict long term outcome. Our results suggest ASCT should be done early for AL to insure optimal organ response and patient outcome. Table 1 The Effects of Hypoalbuminemia and Proteinuria on Renal Response after ASCT Hypoalbuminemia & Proteinuria No Renal Response Renal Response None 39.3% 60.7% One 66.2% 33.8% Both 81.8% 18.2%

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Response to Bortezomib Based Induction Therapy in Newly Diagnosed Light Chain (AL) Amyloidosis.

Blood ◽

10.1182/blood.v114.22.1867.1867 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1867-1867 ◽

Cited By ~ 1

Author(s):

Veerpal Singh ◽

Ayman Saad ◽

Jeanne Palmer ◽

Jasleen K Randhawa ◽

Parameswaran N. Hari

Keyword(s):

Light Chain ◽

Liver Dysfunction ◽

Cardiac Involvement ◽

Response Rate ◽

Initial Therapy ◽

Al Amyloidosis ◽

Karnofsky Performance Score ◽

Significant Activity ◽

Newly Diagnosed ◽

Organ Response

Abstract Abstract 1867 Poster Board I-892 Bortezomib has been shown to have significant activity in the suppression of light chain production and induction of responses in patients with relapsed refractory AL Amyloidosis. We analyzed the outcomes of 16 (9 male) newly diagnosed biopsy proven AL Amyloidosis patients treated with Bortezomib based regimens at our institution. All patients received initial therapy with Bortezomib and dexamethasone (dex). Patients with a Karnofsky performance score ( KPS) >70 received Bortezomib at starting doses of 1.3 mg/m2 along with dexamethasone 40 mg on days 1,4,8, 11 ( with a 10 day rest period). Patients with a lower KPS received Bortezomib/Dex on a weekly schedule as tolerated. Dose adjustments were made based on side effects such as neuropathy, hypotension, GI disturbances or electrolyte imbalances. Patients tolerating Bortezomib/dex with improvement in KPS had cyclophosphamide (4) or lenalidomide (1) added to their initial therapy. Patients: Median age was 64 years (39–88). Nine had kappa light chain involvement. Organ involvement was renal (73%), cardiac (63%), hepatic (25%), tongue or soft tissue (20%), GI (30%). Median KPS was 70 (50 –100). Ten of the 16 patients were treated as in-patients due to multi-organ dysfunction. Five patients required hemodialysis within a month of diagnosis. Cardiac involvement was stage 3 (Mayo risk group) in 25%. Three patients were unevaluable: 2 dying before 2 cycles and 1 discontinued therapy (Grade 3 liver dysfunction). Median follow up was 5 months (range 2–33 mo). Results: Evaluable (receiving at least 2 cycles) patients have all had a free light chain response. The overall hematological response rate was 100% with 55% partial remission (PR) and 45% complete remission (CR). Median cycles to achievement of a light chain response was 2 (range 1–4). Four patients underwent autologous stem cell transplantation with no mortality. Five (40%) of the responders have had an organ response (3 renal, 1 macroglossia, 1 cardiac) with only patients alive for >5 months having any evidence of organ response. Five (40%) of the evaluable patients have died with progressive cardiac involvement (2), relapsed disease (2) or renal failure (1) with refusal of dialysis. In patients receiving at least one dose of bortezomib, non-hematologic toxicity (>grade 2) included -neuropathy (20%), hypotension (20%), severe diarrhea (12%), sepsis (12%), paralytic ileus (6%), liver dysfunction (6%), sudden death (6%). Conclusions: Bortezomib in combination with dexamethasone has a high response rate in newly diagnosed AL amyloidosis. This regimen was well tolerated in a cohort of severe, multisystem amyloidosis patients with low treatment related mortality. Light chain responses were fast whereas organ responses were not seen prior to 5 months of therapy. The regimen also served as a platform for further intensification with the addition of lenalidomide, cyclophosphamide or autologous transplant in responders. Disclosures: Off Label Use: Bortezomib for the therapy of amyloidosis. Hari:Millenium: Honoraria, Research Funding.

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Bortezomib with Dexamethasone in Newly Diagnosed Patients with Primary Systemic Light Chain Amyloidosis or Multiple Myeloma-Associated AL Amyloidosis

Blood ◽

10.1182/blood.v120.21.5036.5036 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5036-5036 ◽

Cited By ~ 1

Author(s):

Beihui Huang ◽

Juan Li ◽

Junru Liu ◽

Dong Zheng ◽

Mei Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Light Chain ◽

Conflicts Of Interest ◽

Complete Response ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

Hematologic Response ◽

Best Response ◽

Organ Response

Abstract Abstract 5036 Objective: To assess the efficacy and tolerability of bortezomib with dexamethasone for patients with primary systemic light chain (AL) amyloidosis or multiple myeloma-associated AL amyloidosis. Methods: Twelve newly diagnosed patients with primary systemic AL amyloidosis and six patient with multiple myeloma-associated AL amyloidosis were treated with a combination of bortezomib (1. 3 mg/m2 d1, 4, 8, 11) and dexamethasone (20 mg d1–4). Results: Sixteen patients was evaluable. 12/16 had a hematologic response and 6/16 (37. 5%) a hematologic complete response. Median cycles to response was 1 cycle and median cycles to best response was 2 cycles. In patients with primary AL amyloidosis, 8/10 (80. 0%) had a hematologic response and 5/10 (50. 0%) a hematologic complete response. In patients with myeloma-associated AL amyloidosis, 7/10 (70. 0%) had a hematologic response and 1/6 (16. 7%) a hematologic complete response. Twelve patients (75. 0%) had a response in at least one affected organ, in which 7 in patients with primary AL amyloidosis and 5 in myeloma-associated AL amyloidosis. Person correlation between hematologic response and organ response was 0. 667 (p=0. 005). Fatigue, diarrhea and infection were the most frequent side effects. Three patients developed herpes zoster and had to stop chemotherapy. Conclusions: VD produces rapid and high hematological responses in the majority of patients with newly diagnosed AL regardless of primary or associated with myeloma. It is well tolerated with few side effects. This treatment may be a valid option as first-line treatment for newly diagnosed patients with primary systemic AL amyloidosis and multiple myeloma-associated AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

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