Typically, patients developing this type of amyloidosis have had excess κ or λ free light chains in their urine for years before diagnosis. At diagnosis, however, they typically have a relatively small plasma cell burden (bone marrow plasma cells <5% to 7% of total nucleated cells) and in only <5% to 10% of cases do other findings indicate the presence of a malignant condition (i.e. definitive signs of multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia associated with over-production of a clonal light chain). Nonetheless, these individuals often evidence serious involvement of the kidney (proteinuria, nephrotic syndrome) or heart (restrictive cardiomyopathy, arrhythmias) in 70% or 60% of cases, respectively, and of dysfunction in the peripheral nervous system (numbness, paresthesias) or autonomic nervous system (orthostatic hypotension) in 20% or 15% of cases, respectively. They may also exhibit evidence of liver involvement (liver failure, increases in circulating liver enzymes, bleeding due to factor X deficiency), gastrointestinal track deficiencies (malabsorption), and amyloid deposition in surface tissues (macroglossia, shoulder pad masses, cutaneous nodules). Arthritis in multiple joints, often manifested before diagnosis, is also a common feature of AL amyloidosis and has led to initial misdiagnoses of rheumatoid arthritis. Diagnosis of the disease requires evidence of increased levels of a κ or λ myeloma protein in blood and/or blood, presence of an amyloid-related organ-involvement syndrome, detection in tissues of amyloid deposition based on birefringence-staining with Congo red, and detection in tissues of κ or λ deposition based on electron microscopy or mass spectrometry.
Genetic mutations thought to be involved in the development and/or progression of the latter disease include the L265P mutation in the MYD88 gene found in >90% of Waldenström macroglobulinaemia patients as well as various mutations in the CXCR gene found in 27% to 40% of Waldenström macroglobulinaemia patients.The clonal plasma cells involved in plasma cell dyscrasias exhibit a high degree of genetic instability. For example, the clonal plasma cell population formed by initial genetic alterations that lead to multiple myeloma contains cells that develop further genetic changes that enhance their survival, proliferation, tissue-injuring, and metastatic capacities. This allows the new cell clones to crowd out older cell clones and thereby  establish a more malignant disease. Repetition of such genetic changes underlie the evolution of a clinically silent plasma cell dyscrasia to an overt malignancy. The progressive genetic changes in clonal plasma cells include accumulating numerous single nucleotide polymorphisms, increases and decreases in gene and chromosome copy numbers, and chromosomal translocations. Genes affected include those regulating genome stability itself (e.g. KIF2B) as well as cellular activation, proliferation, and apoptosis (e.g. CIDEC, TP52, ATM, KRAS, NRAS, Wnt, and NF-κB).