Detection, Monitoring, and Discrimination of Amyloidogenic vs Innocent Light Chains in Systemic Amyloidoses

Immunoglobulin light chains (LCs) span the spectrum of B-cell clonal disorders from monoclonal gammopathy of undetermined significance to multiple myeloma and Waldenström macroglobulinemia. Beyond serving as disease markers, monoclonal immunoglobulins can cause organ damage in monoclonal gammopathies of clinical significance (MGCS). In AL amyloidosis the pathogenic agent is a monoclonal light chain (LC). AL amyloidosis is a treatable yet rapidly progressive condition in which early diagnosis is critical for organ preservation and survival. High-sensitivity laboratory tools for detection of amyloidogenic LCs are essential in diagnosis, while precise quantitative methods are required for monitoring treatment response and for identifying relapse, where standardized relapse definitions remain an unmet need. With increasingly effective therapies, deep hematologic response assessment and measurable residual disease detection-through mass spectrometry-based methods, flow cytometry, and next-generation sequencing-are central to decision-making. Emerging strategies to discriminate "innocent" from amyloidogenic LCs will enable pre-symptomatic intervention in patients with apparently benign monoclonal gammopathies. These approaches include biomarkers of early organ damage and LC-intrinsic features that enhance amyloid propensity (N-glycosylation, preferential germline gene usage, and reduced stability). Such tools also hold promise for the differential diagnosis of non-AL amyloidoses, particularly transthyretin (ATTR) cardiac amyloidosis-the most common form in elderly males and African-American populations-who are at elevated risk of coexisting LC-producing clones. Rapid and accurate exclusion of AL amyloidosis in this setting is now a clinical imperative. This review synthesizes current laboratory approaches and future directions for LC detection and monitoring in systemic amyloidoses, highlighting their impact on hematologic practice.