Systemic Light Chain Amyloidosis

Authors, Journal, Affiliations, Type, DOI

• Author: Vaishali Sanchorawala, M.D.
• Journal: New England Journal of Medicine, 2024;390:2295–307
• Affiliation: Amyloidosis Center, Boston University Chobanian and Avedisian School of Medicine, Boston Medical Center
• Type: Review article
• DOI: https://doi.org/10.1056/NEJMra2304088

Overview

AL amyloidosis is caused by clonal plasma cell dyscrasia producing misfolded immunoglobulin light chains that aggregate into amyloid fibrils, depositing in organs and causing progressive dysfunction. The heart (70–80%) and kidneys (60–70%) are most commonly involved; cardiac involvement is the leading cause of death. Care has been transformed over four decades — 5-year survival improved from 15% (mid-1980s) to 48% (mid-2010s) — driven by stem-cell transplantation, proteasome inhibitors, and most recently daratumumab-based combinations. This review synthesises current understanding of pathogenesis, staging, treatment, and unmet needs including antifibril antibody strategies in phase 3 trials.

Keywords

AL amyloidosis, immunoglobulin light chain, plasma cell dyscrasia, amyloid fibrils, Congo red, Mayo staging, daratumumab, stem-cell transplantation, birtamimab, anselamimab, organ response

Key Takeaways

Pathogenesis

• Abnormal folding of immunoglobulin light chains — due to proteolytic events or amyloidogenic amino acid sequences — causes thermodynamic and kinetic instability, self-aggregation, and fibril formation stabilised by glycosaminoglycan and serum amyloid P protein.
• Organ dysfunction arises from both architectural disruption by amyloid deposits and direct cytotoxic effects from oligomers (demonstrated in C. elegans and zebrafish models).
• Lambda light chains cause 75–80% of cases; kappa 20–25%. t(11;14) translocation in ~50%; hyperdiploidy (unlike myeloma) in only ~10%. Somatic IGLV gene mutations decrease protein stability and drive fibril formation.
• Organ tropism is determined by light chain variable-region germline genes: IGLV6-57 → kidney; IGLV1-44 → cardiac involvement; IGKV1-33 → liver.

Risk Factors

• MGUS: relative risk 8.8; 1% incidence of AL amyloidosis. AL amyloidosis in 10–15% of myeloma; 38% of myeloma patients have Congo-red positive fat/marrow deposits.
• Monoclonal serum free light chain elevation precedes AL amyloidosis diagnosis by >4 years in all patients.
• Agent Orange exposure may be associated (limited evidence). N-glycosylation of kappa light chains is a predictive factor for earlier diagnosis in MGUS.

Epidemiology

• Incidence: 8.9–12.0 cases/million person-years (Olmsted County 1950–2015); crude global rate 10.4 cases/million person-years across 38 countries.
• ~74,000 cases diagnosed globally in the 20 years preceding 2018. Estimated 20-year prevalence 51 cases/million.
• US claims data: prevalence rose from 15.5 to 40.5 cases/million (2007–2015), while incidence was stable (9.7–14.0 cases/million person-years) — reflecting improved diagnosis and survival.

Clinical Presentations

• Kidney (60–70%): Nephrotic-range proteinuria, hypoalbuminaemia, secondary hyperlipidaemia, oedema. Kidney failure without proteinuria in interstitial/vascular deposits.
• Heart (70–80%; leading cause of death): Low ECG voltage; concentric ventricular thickening; diastolic dysfunction; poor atrial contractility (thromboembolic risk even in sinus rhythm); elevated troponin and NT-proBNP; bradyarrhythmias precede terminal decompensation.
• Nervous system: Small-fibre neuropathy; autonomic dysfunction (GI dysmotility, orthostatic hypotension, neurogenic bladder; dry eyes/mouth).
• Other: Macroglossia (10–20%); cholestasis/hepatomegaly; functional hyposplenism; factor X deficiency ("easy bruising"); cutaneous ecchymoses; nail dystrophy; alopecia; amyloid arthropathy.

Diagnosis

• Requires tissue amyloid (Congo red → green birefringence under polarised light) + evidence of plasma cell dyscrasia.
• Abdominal fat-pad aspiration: positive in 70–75%. Fat + bone marrow: 85%.
• Bone marrow biopsy mandatory in all patients to assess plasma cell burden and exclude myeloma/lymphoproliferative disorders.
• Immunofixation electrophoresis (serum AND urine) + serum free light chain assay — monoclonal component often below protein electrophoresis detection threshold.
• Mass spectrometry of amyloid-containing tissue is now gold standard for fibril typing: sensitivity 88%, specificity 96%. Critical to distinguish AL from ATTR (especially V122I variant in Black patients — both can co-present with monoclonal gammopathy).
• Cardiac imaging: echo (strain, Doppler, restrictive filling); CMR (myocardial thickness, LGE, T1, ECV); PET (18F-florbetapir); bone scintigraphy for ATTR-CA.

Staging System and Risk Stratification

• Mayo Clinic 2004: NT-proBNP + cardiac troponin; most widely used to predict early death.
• European modification of Mayo 2004: Adds NT-proBNP >8500 pg/mL = very high risk (stage IIIb). Best for predicting early death.
• Mayo Clinic 2012: Adds dFLC (difference between involved and uninvolved free light chain, cutoff 180 mg/L) — better for predicting late survival. dFLC increasingly less prognostic in era of effective treatments.
• Renal staging: 24-hour urinary protein excretion + eGFR — predicts progression to dialysis at 2 years.
• Other biomarkers predicting outcomes but not yet in staging: von Willebrand factor, d-dimer, growth differentiation factor-15.
• Patients with very low dFLC (<50 mg/L) at first diagnosis have substantially better outcomes irrespective of cardiac stage.

Management

Supportive Therapy

• Amyloid cardiomyopathy: sodium restriction, careful diuretic use, ACE inhibitors for afterload; digoxin generally not beneficial (except selected AF cases); calcium-channel blockers typically avoided; amiodarone/ICD for ventricular arrhythmias; pacemaker for recurrent syncope. Anticoagulation for thromboembolic risk but caution given bleeding risk.
• Renal: salt restriction, diuretics, ACE inhibitors/ARBs for proteinuria (if not contraindicated); SGLT2 inhibitors under investigation; dialysis for ESRD.
• Neuropathy: gabapentin, duloxetine, pregabalin for neuropathic pain.
• Bleeding: FFP/clotting-factor replacement; splenectomy for acquired factor X deficiency; iron infusions for deficiency.

Assessment of Treatment Response

• Hematologic response graded monthly: CR = negative immunofixation + FLC ratio normal; VGPR = dFLC <40 mg/L; PR = dFLC reduction >50%. iFLC <20 mg/L + dFLC <10 mg/L predict longer survival.
• Organ response is graded (not binary) and predicts survival. Time to best organ response: cardiac 24 months, renal 29 months, hepatic 35 months.
• Emerging importance of measurable residual disease (MRD) — bone marrow MFC and mass spectrometry — may explain residual organ dysfunction despite deep hematologic response.

Treatment of Newly Diagnosed AL Amyloidosis

• Stem-cell transplantation (SCT): Only 10–20% eligible (poor PS, advanced organ dysfunction, multi-organ disease). SCT achieves CR in 40%; median OS 7.6 years; patients with CR: median OS 15 years, 30% survive >20 years.
• First-line (non-SCT eligible, ~80%): Daratumumab + CyBorD (cyclophosphamide, bortezomib, dexamethasone) — preferred based on ANDROMEDA trial: 78% VGPR or better; 50–55% organ response at 18 months.
• CyBorD alone or bortezomib-melphalan-dexamethasone if daratumumab unavailable. BMDex can overcome both 1q21 gain and t(11;14) effects.
• High-risk disease (~20%): stage IIIb or NYHA III–IV — major management challenge.

Treatment of Relapsed/Refractory Disease

• Repeat first-line if initial response lasted >1 year; otherwise switch class.
• Options: proteasome inhibitors, anti-CD38 antibodies (daratumumab), IMiDs, venetoclax (t(11;14) patients; 63% VGPR+, 80% if t(11;14)), bendamustine, second SCT, bispecific antibodies (teclistamab; 88% VGPR+), CAR-T (BCMA-directed; 100% VGPR+ in small series).
• No consensus on when to start second-line or preferred sequencing.

Antifibril Monoclonal Antibodies

• Chemotherapy reduces amyloidogenic precursor but does not clear existing amyloid deposits.
• Birtamimab: Fully humanised anti-SAA antibody cross-reacting with light-chain fibrils; activates macrophage-mediated clearance. VITAL phase 3 (terminated early, interim futility) post-hoc showed survival benefit in Mayo stage IV. AFFIRM-AL phase 3 trial ongoing.
• Anselamimab (CAEL-101): Chimeric anti-misfolded light chain antibody; opsonises fibrils to attract macrophages. Two phase 3 trials (stages IIIa and IIIb) completed enrollment.

Limitations of the Document

• Review article without novel primary data; clinical trial evidence cited is from selected patient populations.
• Epidemiological data limited by absence of comprehensive population databases.
• dFLC as a prognostic tool is increasingly questioned in the modern treatment era.
• AFFIRM-AL and CAEL-101 antifibril trials had not yet reported when published; clinical benefit of direct amyloid-clearing strategies unconfirmed.
• No consensus on relapse criteria or therapy sequencing for second-line.
• Distinction between AL and ATTR can be clinically difficult, especially in Black patients with V122I variant — mass spectrometry not widely available.

Key Concepts Mentioned

• concepts/AL-Amyloidosis-Staging — Mayo 2004, 2012, European modification, renal staging
• concepts/Cardiac-Amyloidosis-Imaging — multimodality imaging framework
• entities/ATTR-Amyloidosis — differential diagnosis; mass spectrometry distinction; V122I variant

Key Entities Mentioned

• entities/AL-Amyloidosis — central subject of this review
• entities/ATTR-Amyloidosis — most important differential; both can co-present with monoclonal gammopathy

Wiki Pages Updated

• Created wiki/sources/lc-amyloidosis-nejm-2024.md
• Created wiki/entities/AL-Amyloidosis.md
• Created wiki/concepts/AL-Amyloidosis-Staging.md
• Updated wiki/entities/ATTR-Amyloidosis.md
• Updated wiki/concepts/Cardiac-Amyloidosis-Imaging.md
• Updated wiki/wikiindex.md
• Updated wiki/sourceindex.md
• Appended log.md