Advances in diagnosis and management of systemic light chain amyloidosis

Systemic light chain (AL) amyloidosis is a rare and life-threatening disorder characterized by the deposition of misfolded immunoglobulin light chains as insoluble amyloid fibrils in various tissues and organs, leading to progressive structural and functional impairment. Commonly affected sites include the heart, kidneys, liver, gastrointestinal tract, and nervous system, with cardiac involvement being the primary determinant of prognosis. Due to its nonspecific clinical presentation and multisystem nature, AL amyloidosis is often diagnosed at an advanced stage, contributing to high early mortality. This review synthesizes recent advances in the diagnosis, risk stratification, and treatment of AL amyloidosis, highlighting the integration of novel biomarkers, imaging modalities, and targeted therapies that are reshaping clinical management.

Pathogenesis and risk factors

AL amyloidosis arises from clonal plasma cell disorders, most commonly monoclonal gammopathy of undetermined significance or multiple myeloma. These cells produce unstable light chains that misfold, aggregate into β-sheet-rich fibrils, and deposit in tissues, causing direct cellular toxicity, oxidative stress, and chronic inflammation. Key risk factors include advanced age (median 56 years) and pre-existing plasma cell dyscrasias. Early recognition in high-risk populations is essential for improving outcomes.

Clinical presentation and diagnostic approaches

Clinical manifestations are highly variable and depend on the organs involved. Cardiac amyloidosis presents as heart failure or arrhythmias, whereas renal involvement leads to proteinuria and renal insufficiency. Peripheral neuropathy, hepatomegaly, gastrointestinal dysmotility, and characteristic signs such as macroglossia and periorbital purpura may also occur, though the latter are present in only about 15% of patients.

Diagnosis relies on a combination of histological, laboratory, and imaging studies:

• Histopathology: Tissue biopsy (e.g., abdominal fat, bone marrow, or affected organs) with Congo red staining showing apple-green birefringence under polarized light remains the diagnostic gold standard.

• Serum and urine studies: Serum free light chain (sFLC) assay, combined with immunofixation electrophoresis, achieves a sensitivity of 97–100%. Elevated cardiac biomarkers (troponin, NT-proBNP) aid in diagnosis and prognosis.

• Imaging: Echocardiography and cardiac magnetic resonance imaging are critical for assessing cardiac involvement. Advanced techniques such as ¹⁸F-florbetapir PET/CT help differentiate AL from other amyloid types.

Staging and risk stratification

The Mayo 2012 staging system, based on cardiac troponin T (≥0.025 µg/L), NT-proBNP (≥1800 ng/L), and the difference between involved and uninvolved free light chains (dFLC ≥180 mg/L), stratifies patients into four prognostic groups. This system guides treatment intensity and predicts survival, emphasizing the central role of cardiac involvement in outcomes.

Evolving treatment strategies

The treatment goal is rapid and deep reduction of amyloidogenic light chains to halt or reverse organ damage.

• First-line therapy: For transplant-eligible patients, bortezomib-based induction followed by autologous stem cell transplantation (ASCT) yields high rates of hematologic response, with complete response (CR) rates reaching 60% post-consolidation. For ineligible patients, daratumumab combined with bortezomib, cyclophosphamide, and dexamethasone (Dara-CyBorD) has become the standard, significantly improving hematologic and organ responses.

• Relapsed/refractory disease: Options include pomalidomide, ixazomib, and bendamustine, though response rates remain modest. Retreatment with daratumumab-based regimens shows promise. Emerging therapies such as the BCMA-targeting bispecific antibody teclistamab and BCMA-directed CAR-T cell therapy have demonstrated encouraging efficacy in early studies, including deep responses in refractory cases.

• Organ-directed support: In cases of irreversible organ damage, kidney or heart transplantation may be considered, often combined with subsequent ASCT to prevent disease recurrence.

Prognosis and the role of minimal residual disease (MRD)

Achieving hematologic CR and organ response correlates with improved survival. The depth of response is increasingly assessed using MRD detection by next-generation flow cytometry. MRD negativity is associated with higher rates of cardiac and renal response, though its impact on overall survival requires further validation.

Future perspectives

The treatment landscape for AL amyloidosis is rapidly evolving, driven by immunotherapy and precision medicine. Daratumumab-based regimens represent a significant advance, while bispecific antibodies and CAR-T therapies offer new avenues for refractory disease. Future efforts should focus on:

• Early diagnosis through increased clinical awareness and sensitive biomarkers.

• Personalized treatment based on genetic and molecular profiling.

• Large multicenter studies to validate novel therapies and MRD-driven strategies.

Conclusion

AL amyloidosis remains a challenging disease, but significant progress in diagnostic accuracy and therapeutic efficacy has improved patient outcomes. The integration of advanced imaging, biomarker-driven staging, and immunotherapy has transformed management, enabling deeper and more rapid responses. Continued research into the mechanisms of amyloid formation and resistance, along with the development of targeted and cellular therapies, holds promise for further advancing the care of patients with this complex condition.