AL (Light Chain) Amyloidosis

Details

AL amyloidosis is a systemic disease caused by clonal plasma cell dyscrasia producing misfolded immunoglobulin light chains that aggregate into amyloid fibrils, depositing extracellularly in organs. It is distinct from ATTR amyloidosis (caused by transthyretin misfolding) and is fundamentally a hematologic disease requiring plasma-cell-directed therapy. Lambda chains are responsible in 75–80% of cases; kappa in 20–25%. The heart (70–80%) and kidneys (60–70%) are most commonly involved; cardiac involvement is the leading cause of death. Five-year survival improved from 15% (mid-1980s) to 48% (mid-2010s) with modern therapies.

Pathophysiology

• Abnormal immunoglobulin light chain folding (proteolytic event or amyloidogenic amino acid sequence) → thermodynamic instability → self-aggregation → fibril formation stabilised by glycosaminoglycan and serum amyloid P protein → organ dysfunction. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Organ dysfunction arises from both architectural disruption and direct oligomeric cytotoxicity — demonstrated in C. elegans and zebrafish models. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• t(11;14) translocation (IgH + cyclin D1) in ~50%; hyperdiploidy in only ~10% (unlike myeloma). Somatic IGLV gene mutations decrease protein stability. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Organ tropism governed by light chain variable-region germline genes: IGLV6-57 → kidney; IGLV1-44 → cardiac; IGKV1-33 → liver. (sources/lc-amyloidosis-nejm-2024, rating: very high)

Epidemiology

• Incidence: ~10–12 cases/million person-years (Olmsted County 1950–2015); global crude rate 10.4/million person-years across 38 countries. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• ~74,000 cases globally in the 20 years preceding 2018; 20-year prevalence 51 cases/million. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• US: prevalence rose 15.5 → 40.5 cases/million (2007–2015) reflecting improved recognition; incidence stable. (sources/lc-amyloidosis-nejm-2024, rating: very high)

Clinical Presentation

• Cardiac (70–80%; leading cause of death): Low ECG voltage; concentric ventricular thickening; diastolic dysfunction; poor atrial contractility (thromboembolic risk in sinus rhythm); elevated troponin/NT-proBNP; bradyarrhythmias preceding terminal decompensation. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Renal (60–70%): Nephrotic-range proteinuria, hypoalbuminaemia, secondary hyperlipidaemia, oedema. Kidney failure without proteinuria in interstitial/vascular deposits. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Nervous system: Small-fibre neuropathy; autonomic dysfunction (GI dysmotility, orthostatic hypotension, neurogenic bladder). (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Other: Macroglossia (10–20%; pathognomonic when present); cholestasis/hepatomegaly; functional hyposplenism; factor X deficiency ("easy bruising"); cutaneous ecchymoses; nail dystrophy; alopecia; amyloid arthropathy. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Diagnostic clues: bilateral carpal tunnel, unexplained restrictive cardiomyopathy, nephrotic proteinuria, peripheral neuropathy with autonomic features, macroglossia, raccoon eyes, hepatomegaly without imaging abnormalities, monoclonal gammopathy/myeloma with atypical features. (sources/lc-amyloidosis-nejm-2024, rating: very high)

Diagnosis

• Requires: (1) tissue amyloid evidence (Congo red → apple-green birefringence under polarised light) AND (2) plasma cell dyscrasia evidence. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Tissue sampling: Abdominal fat-pad aspiration positive in 70–75%. Fat + bone marrow biopsy identifies 85%. Organ biopsy if both negative with high clinical suspicion.
• Plasma cell dyscrasia: Serum AND urine immunofixation electrophoresis + serum free light chain assay (monoclonal component often below protein electrophoresis threshold). Bone marrow biopsy mandatory in all: assess plasma cell burden, exclude myeloma/lymphoproliferative disorders.
• Fibril typing: Mass spectrometry is gold standard (sensitivity 88%, specificity 96%). Critical to distinguish AL from ATTR — especially V122I ATTR variant in Black patients, where both conditions can co-present with monoclonal gammopathy. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Immunohistochemistry and immunogold electron microscopy are acceptable alternatives at experienced centres.

Staging

See concepts/AL-Amyloidosis-Staging for full staging detail.

• Mayo 2004: NT-proBNP + troponin; best for early death prediction.
• Mayo 2012: Adds dFLC >180 mg/L; better for late survival prediction. dFLC increasingly less prognostic in modern treatment era.
• European modification (Mayo 2004 + NT-proBNP >8500 pg/mL = stage IIIb): Best for early death.
• Renal staging: 24-hour urinary protein + eGFR — predicts dialysis progression.
• Very low dFLC (<50 mg/L) at diagnosis = substantially better outcomes irrespective of cardiac stage. (sources/lc-amyloidosis-nejm-2024, rating: very high)

Management

Treatment Response Assessment

• Monthly hematologic response monitoring. iFLC <20 mg/L + dFLC <10 mg/L predict longer survival.
• Graded organ response predicts survival. Time to best response: cardiac 24 months, renal 29 months, hepatic 35 months.
• MRD negativity (next-generation flow cytometry, mass spectrometry) increasingly important. (sources/lc-amyloidosis-nejm-2024, rating: very high)

First-Line Therapy

• Stem-cell transplantation (SCT): Only 10–20% eligible. CR in 40%; median OS 7.6 years; CR patients: median OS 15 years, 30% survive >20 years. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Daratumumab + CyBorD (preferred first-line): ANDROMEDA trial — 78% VGPR or better; 50–55% organ response at 18 months. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• CyBorD alone or bortezomib-melphalan-dexamethasone if daratumumab unavailable. BMDex can overcome t(11;14) and 1q21 gain negative effects.

Relapsed/Refractory

• Options: proteasome inhibitors (bortezomib, ixazomib), anti-CD38 (daratumumab), IMiDs, venetoclax (especially t(11;14): 80% VGPR+), bendamustine, second SCT, bispecific antibodies (teclistamab: 88% VGPR+), CAR-T (BCMA: 100% VGPR+ small series).
• No consensus on sequencing; guiding principles: depth/duration of initial response, switch drug class. (sources/lc-amyloidosis-nejm-2024, rating: very high)

Antifibril Antibodies (Investigational)

• Birtamimab: Anti-SAA antibody cross-reacting with AL fibrils; AFFIRM-AL phase 3 trial ongoing (Mayo stage IV patients).
• Anselamimab (CAEL-101): Anti-misfolded light chain antibody; phase 3 trials (stages IIIa/IIIb) completed enrollment.
• Neither approach has demonstrated confirmed clinical benefit at time of publication. (sources/lc-amyloidosis-nejm-2024, rating: very high)

Supportive Care

• Cardiac: sodium restriction, diuretics, ACEi for afterload; avoid calcium-channel blockers and digoxin (except selected AF). Amiodarone/ICD for VT; pacemaker for syncope. Anticoagulation with caution (bleeding risk + atrial thrombus risk even in sinus rhythm).
• Renal: diuretics, ACEi/ARB for proteinuria; SGLT2 inhibitors under investigation; dialysis for ESRD.
• Neuropathy: gabapentin, duloxetine, pregabalin.
• Bleeding: factor replacement, splenectomy for factor X deficiency; iron for deficiency. (sources/lc-amyloidosis-nejm-2024, rating: very high)

Contradictions / Open Questions

• dFLC utility diminishing in modern era: dFLC was incorporated into Mayo 2012 staging as a survival predictor, but in the era of highly effective anti-plasma-cell therapies (daratumumab-CyBorD), dFLC appears less prognostic — the staging system may need updating. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Antifibril therapies — clinical benefit unproven: Birtamimab and anselamimab target amyloid deposits directly and could theoretically provide organ recovery beyond what clone-directed therapy achieves. However, birtamimab's VITAL trial was terminated early for futility and survival benefit relies on post-hoc analysis of a subgroup. Confirmation in AFFIRM-AL is awaited. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• AL vs ATTR differential — mass spectrometry not widely available: Mass spectrometry is the gold standard for fibril typing (sensitivity 88%, specificity 96%) and is critical in Black patients where V122I ATTR variant mimics AL clinically. Most centres rely on less accurate immunohistochemistry, risking misclassification and wrong treatment. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• No defined criteria for starting second-line therapy: When to transition from first-line to second-line therapy in progressive disease has no consensus definition, creating practice variation. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• High-risk cardiac disease (stage IIIb/NYHA III–IV): Approximately 20% of patients present with advanced cardiac disease; there is no established treatment standard and outcomes remain poor. (sources/lc-amyloidosis-nejm-2024, rating: very high)
• Scintigraphy Grade ≥2 in >20% of AL patients: Bone scintigraphy cannot reliably exclude AL — monoclonal protein testing is mandatory before making a non-biopsy ATTR diagnosis. See concepts/Cardiac-Amyloidosis-Imaging and entities/ATTR-Amyloidosis.

Connections

• Related to entities/ATTR-Amyloidosis — key differential; distinct pathophysiology and treatment
• Related to concepts/AL-Amyloidosis-Staging — Mayo 2004/2012/European/renal staging systems
• Related to concepts/Cardiac-Amyloidosis-Imaging — multimodality imaging for cardiac AL; AL vs ATTR differentiation
• Related to entities/Atrial-Fibrillation — atrial thrombus risk in sinus rhythm; anticoagulation dilemma
• Related to entities/Heart-Failure — restrictive cardiac phenotype; multidisciplinary management

Sources

• sources/lc-amyloidosis-nejm-2024