The identification of a monoclonal protein in serum protein electrophoresis (SPEP) is a common event requiring medical consultation. A monoclonal protein may be the hallmark of a malignant disease, such as multiple myeloma or Waldenstrom's Macroglobulinemia (and less often of other lymphoproliferative disorders), of diseases associated with a malignant plasma cell clone, such as AL amyloidosis or other plasma cell related disorders, or, quite commonly may have no direct impact and belong to monoclonal gammopathies of undetermined significance (MGUS). Jan Waldenstrom introduced the term “essential hyperglobulinemia” in order to describe patients who had a small serum protein electrophoretic spike but no evidence of overt multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM), primary amyloidosis (AL), or related disorders. The seminal work by Kyle indicated that some patients with this monoclonal gammopathy develop MM, or WM or AL or other lymphoproliferative malignancies, and introduced the term “monoclonal gammopathy of undetermined significance” (MGUS)[1]. Kyle also described patients with histologic and biochemical features of myeloma (bone marrow clonal plasma cells (BMPC) involvement of 10% or higher, presence of a serum M-protein value higher than 3 g/dl) that did not have lytic bone lesions, anemia, renal impairment or other clinical manifestations of myeloma who remained stable, with no need for chemotherapy, for several years[2]. Alexanian also presented data on “indolent myeloma”[3], that included patients who had no clinical features of overt myeloma such as anemia and renal dysfunction and had fewer than three lytic bone lesions. Among these patients, median time to initiation of chemotherapy was two years, but some patients remained stable for several years. Thus, the term “smoldering” MM or “asymptomatic” or “indolent” MM, entered the clinical practice. The definitions, however, were not strict among different groups. In 2003 a consensus paper defined MGUS and asymptomatic or smoldering myeloma (Table 10.1). MGUS requires that M-protein in serum is <30 g/l and that bone marrow clonal plasma cells are <10% with no evidence of other B cell proliferative disorders and no end organ damage (anemia, renal impairment, hypercalcemia, lytic bone lesions).