Diagnostic and Treatment Strategies for AL Amyloidosis in an Era of Therapeutic Innovation

Dima, Danai; Mazzoni, Sandra; Anwer, Faiz; Khouri, Jack; Samaras, Christy; Valent, Jason; Williams, Louis

doi:10.1200/op.22.00396

Cited by 22 publications

(17 citation statements)

References 86 publications

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“…Systemic amyloidosis is a rare disease entity, and it is estimated that 10–30% of cases are concomitant with MM 25 , 26 . Notably, it predominantly affects the heart (70%) and can subsequently involve the kidneys (60%) and liver (20%), in that order 27 , 28 . In other words, patients may have been exposed to systemic amyloidosis even before the MM diagnosis 29 , and the undiagnosed systemic amyloidosis could potentially account for various degrees of renal dysfunction and liver dysfunction within the case cohort.…”

Section: Discussionmentioning

confidence: 99%

Quantitative risk factor analysis of prior disease condition and socioeconomic status with the multiple myeloma development: nationwide cohort study

Choi,

Kim,

Jung

et al. 2024

Sci Rep

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Early diagnosis and following management are important determinants of the prognosis of multiple myeloma (MM). However, screening for MM is not routinely performed because it is rare disease. In this study, we evaluated the association of prior disease condition and socioeconomic status (SES) with MM diagnosis and developed a simple predictive model that can identify patients at high risk of developing MM who may need screening using nationwide database from South Korea. According to multivariate logistic regression analysis, eight prior disease conditions and SES before diagnosis were shown to be predictors of MM development and selected for score development. Total prediction scores were categorized into four groups: patients without any risk (≤ 0) intermediate-1 (0.5–9), intermediate-2 (9–14), and high risk (> 14). The odds ratios for developing MM in the intermediate-1, intermediate-2, and high-risk groups were 1.29, 3.07, and 4.62, respectively. The association of prior disease conditions and SES with MM diagnosis were demonstrated and the simple scoring system to predict the MM risk was developed. This scoring system is also provided by web-based application and could be a useful tool to support clinicians in identifying potential candidates for MM screening.

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Section: Discussionmentioning

confidence: 99%

Quantitative risk factor analysis of prior disease condition and socioeconomic status with the multiple myeloma development: nationwide cohort study

Choi,

Kim,

Jung

et al. 2024

Sci Rep

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“…Routine clinical practice involves evaluating hematologic and organ responses every 1–2 cycles during active treatment. These assessments are conducted three months post-autologous stem cell transplantation (ASCT) and every three months after [ 7 ].…”

Section: Assessment Of Therapy Responsementioning

confidence: 99%

“…Currently, the goal of treatment is to reduce amyloid production by targeting the aberrant plasma cell clone in the bone marrow [ 3 , 6 ]. However, the prospect of clearing peripheral amyloid deposits with the novel anti-fibril antibodies looks promising, through approval of these medications is still subject to ongoing clinical trials [ 7 ]. Ongoing Phase III studies testing the efficacy of these anti-fibril medications focus on advanced cardiac amyloidosis.…”

Section: Introductionmentioning

confidence: 99%

Renal AL Amyloidosis: Updates on Diagnosis, Staging, and Management

Shafqat,

Elmaleh,

Mushtaq

et al. 2024

JCM

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AL amyloidosis is caused by the excessive production of nonfunctional immunoglobulins, leading to the formation of amyloid fibrils that damage vital organs, especially the heart and kidneys. AL amyloidosis presents with non-specific symptoms such as fatigue, weight loss, numbness, pain, and nephrotic syndrome. Consequently, diagnosis is often delayed, and patients typically present with advanced disease at diagnosis. The Pavia renal staging model stratifies patients based on their likelihood of progressing to dialysis. Treatment with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (i.e., Dara-CyBorD) was effective in inducing renal response in the landmark phase III ANDROMEDA trial and reducing early mortality. However, determining the most appropriate treatment regimen for relapsed or refractory cases remains a challenge due to various patient- and disease-related factors. Encouragingly, t(11:14) may be a positive indicator of therapy responses to the anti-BCL2 therapy venetoclax. Moreover, it is increasingly possible—for the first time—to clear AL amyloid fibrils from peripheral organs by leveraging novel anti-fibril immunotherapeutic approaches, although these medications are still under investigation in clinical trials. Given these advancements, this review provides a comprehensive overview of the current strategies for diagnosing, staging, treating, and monitoring AL amyloidosis, emphasizing renal involvement.

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“…Current treatment strategies focus principally on reducing synthesis of the amyloidogenic precursor protein, thereby slowing amyloid formation. For patients with AL amyloidosis, this is primarily achieved with plasma cell-directed chemo- and immunotherapeutics, protease inhibitors, and autologous stem cell transplantation ( 14 , 15 ). Similarly, transthyretin production by the liver is reduced using ribonucleic acid interference (RNAi) ( 16 , 17 ) or ligand-conjugated antisense oligonucleotides ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of a prototypic pan-amyloid clearing agent – a novel murine peptide-immunoglobulin fusion

Foster,

Balachandran,

Hancock

et al. 2023

Front. Immunol.

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IntroductionSystemic amyloidosis is a progressive disorder characterized by the extracellular deposition of amyloid fibrils and accessory proteins in visceral organs and tissues. Amyloid accumulation causes organ dysfunction and is not generally cleared by the immune system. Current treatment focuses on reducing amyloid precursor protein synthesis and slowing amyloid deposition. However, curative interventions will likely also require removal of preexisting amyloid deposits to restore organ function. Here we describe a prototypic pan-amyloid binding peptide-antibody fusion molecule (mIgp5) that enhances macrophage uptake of amyloid.MethodsThe murine IgG1-IgG2a hybrid immunoglobulin with a pan amyloid-reactive peptide, p5, fused genetically to the N-terminal of the immunoglobulin light chain was synthesized in HEK293T/17 cells. The binding of the p5 peptide moiety was assayed using synthetic amyloid-like fibrils, human amyloid extracts and amyloid-laden tissues as substrates. Binding of radioiodinated mIgp5 with amyloid deposits in vivo was evaluated in a murine model of AA amyloidosis using small animal imaging and microautoradiography. The bioactivity of mIgp5 was assessed in complement fixation and in vitro phagocytosis assays in the presence of patient-derived amyloid extracts and synthetic amyloid fibrils as substrates and in the presence or absence of human serum.ResultsMurine Igp5 exhibited highly potent binding to AL and ATTR amyloid extracts and diverse types of amyloid in formalin-fixed tissue sections. In the murine model of systemic AA amyloidosis, 125I-mIgp5 bound rapidly and specifically to amyloid deposits in all organs, including the heart, with no evidence of non-specific uptake in healthy tissues. The bioactivity of the immunoglobulin Fc domain was uncompromised in the context of mIgp5 and served as an effective opsonin. Macrophage-mediated uptake of amyloid extract and purified amyloid fibrils was enhanced by the addition of mIgp5. This effect was exaggerated in the presence of human serum coincident with deposition of complement C5b9.ConclusionImmunostimulatory, amyloid-clearing therapeutics can be developed by incorporating pan-amyloid-reactive peptides, such as p5, as a targeting moiety. The immunologic functionality of the IgG remains intact in the context of the fusion protein. These data highlight the potential use of peptide-antibody fusions as therapeutics for all types of systemic amyloidosis.

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Diagnostic and Treatment Strategies for AL Amyloidosis in an Era of Therapeutic Innovation

Cited by 22 publications

References 86 publications

Quantitative risk factor analysis of prior disease condition and socioeconomic status with the multiple myeloma development: nationwide cohort study

Quantitative risk factor analysis of prior disease condition and socioeconomic status with the multiple myeloma development: nationwide cohort study

Renal AL Amyloidosis: Updates on Diagnosis, Staging, and Management

Development and characterization of a prototypic pan-amyloid clearing agent – a novel murine peptide-immunoglobulin fusion

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