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).
These cases should have no symptoms or findings of end organ dysfunction attributed to Waldenström macroglobulinemia such as anemia, decreases in any white blood cell count, cold agglutinin disease, hyperviscosity of blood, lymphadenopathy, hepatomegaly, splenomegaly, peripheral neuropathy, cryoglobulinemia, or constitutional symptoms.As determined by a Mayo Clinic study of 48 individuals, smoldering Waldenström macroglobulinemias risk of progression to Waldenström macroglobulinemia is estimated to be ~12% per year and then falling of sharply for at least the next 5 years to 2% per year. In this study the only factor predictive of a more rapid progress was a finding of anemia (hemoglobin level <115 grams/liter). During a 15-year follow-up, the Clinic subsequently reported that patients progressed to Waldenström macroglobulinemia, amyloidosis, or a related IgM-associated neoplasm at a rate of 6%, 39%, 59%, and 68% after the first, third, fifth, and tenth year, respectively. However, the Southwest Oncology Group in a study on 231 individuals reported that the smoldering disease progressed to overt Waldenström macroglobulinemia over 9 years in only 26% of cases. Light chain SMM
Light chain smoldering multiple myeloma (light chain SMM) was previously termed idiopathic Bence Jones proteinuria. The condition is currently diagnosed in asymptomatic individuals who have a 24-hour urinary Bence Jones, i.e. light chain myeloma protein level, that is >0.5 grams and/or bone marrow plasma cells that are 10% to <60% of nucleated cells.