Further genetic or epigenic changes produce a new clone of bone marrow plasma cells, usually descendant from the original clone, that causes the more serious, but still asymptomatic premalignant disorder smoldering multiple myeloma. This myeloma is characterized by a rise in the number of bone marrow plasma cells or levels of the circulating myeloma protein above that seen in MGUS. Subsequent genetic and epigenetic changes lead to a new, more aggressive clone of plasma cells, which cause further rises in the level of the circulating myeloma protein, further rises in the number of bone marrow plasma cells, or the development of one or more of a specific set of "CRAB" symptoms, which are the basis for diagnosing malignant multiple myeloma and treating the disease. In a small percentage of multiple myeloma cases, further genetic and epigenetic changes lead to the development of a plasma cell clone that moves from the bone marrow into the circulatory system, invades distant tissues, and thereby causes the most malignant of all plasma cell dyscrasias, plasma cell leukemia. Thus, a fundamental genetic instability in plasma cells or their precursors leads to the progression:

Monoclonal gammopathy of undetermined significance → smoldering multiple myeloma → multiple myeloma → plasma cell leukemia

Being asymptomatic, monoclonal gammopathy of undetermined significance and smoldering multiple myeloma are typically diagnosed fortuitously by detecting a myeloma protein on serum protein electrophoresis tests done for other purposes.
Epigenetics
In a study that investigated the DNA methylation profile of multiple myeloma cells and normal plasma cells, a gradual demethylation from stem cells to plasma cells was observed. The observed methylation pattern of CpG within intronic regions with enhancer-related chromatin marks in multiple myeloma is similar to undifferentiated precursor and stem cells. These results may represent a de novo epigenetic reprogramming in multiple myeloma, leading to the acquisition of a methylation pattern related to stemness. Other studies have identified a multiple myeloma specific gene silencing pattern associated with the polycomb repressive complex 2 (PRC2). Increased expression of the PRC2 subunit, EZH2 have been described to be a common feature in multiple myeloma, resulting in an accumulation and redistribution of histone H3 lysine 27 trimethylation which advances with disease severity. Genetics
Chromosomal abnormalities commonly found in this disease, like trisomy of multiple odd-numbered chromosomes, t(11;14), and del(13q), are not associated with a worse prognosis. However, about 25% of patients with newly diagnosed disease have abnormalities associated with a worse prognosis, like t(4;14), t(14;16), and del(17p). Other less common abnormalities associated with a worse prognosis include t(14;20) and ≥4 copies of 1q. : 1730–1 Associated genetic mutations include ATM, BRAF, CCND1, DIS3, FAM46C, KRAS, NRAS and TP53. Development
The genetic and epigenetic changes occur progressively. The initial change, often involving one chromosome 14 translocation, establishes a clone of bone marrow plasma cells that causes the asymptomatic disorder MGUS, which is a premalignant disorder characterized by increased numbers of plasma cells in the bone marrow or the circulation of a myeloma protein immunoglobulin.