The plasma cell dyscrasias (or monoclonal gammopathies, MG) are proliferative plasma cell disorders characterized by the production and secretion of a monoclonal component (MC) constituted by the whole immunoglobulin (Ig) or of a part of it. Indeed, when an expanding plasma cell clone is present, the single Ig produced may be in such a quantity that it reaches a sufficiently high concentration in serum or urine to be detectable with appropriate techniques, usually electro phoretic (Fig. 1).

Fig1. Under normal conditions, only polyclonal plasma cells are present in the bone marrow, each of which secretes its particular immu noglobulin. The consequent great variety of molecular forms of immu noglobulins will lead to a Gaussian distribution of the γ zone of the electrophoretic trace shown in the lower left. On the other hand, when a single clone reproduces at a much higher rate than the rest of the plasma cell population, the concentration of the immunoglobulin secreted by it may be such as to be clearly visible as a narrow migration band such as that highlighted on the electrophoretic trace at the bottom right

Therefore, MC can be used as a serological marker of the clinical condition, for diagnostic purposes to detect the plasma cell clone, as well as during patient monitoring to assess the evolution of the disease. Unlike other tumor bio markers, MCs present an extreme biochemical variability, because each single monoclonal Ig has a unique sequence in the variable region and can be constituted by the whole Ig or by a part of it. This means that the molecular weight range of an MC can vary from 24 kDa in the case of monomeric free light chains up to 900 kDa for pentameric IgM. Furthermore, although some plasma cell dyscrasias occur with serum concentrations of MC in the order of g/L, under other clinical conditions MC is present at very low concentrations or is even virtually absent. Thus, while the presence of an MC in serum or urine defines the clinical condition of MG, its absence on electrophoretic tracing cannot exclude it, because there are oligosecretory/nonsecretory plasma cell clones that do not produce sufficient MC to be visualized; or visualization is not possible due to technical problems, such as when MC is masked by other proteins comigrating in the same electrophoretic position. The clinical conditions that can be associated with the presence of MC are numerous and range from frankly neoplastic forms (such as multiple myeloma – MM) to clinically silent forms, up to clinical manifestations of organ damage due to the toxicity of the specific protein secreted by the plasma cell clone. For the latter group, the term Monoclonal Gammopathies of Clinical Significance (MGCS) has been coined.

Based on the type of clinical manifestations, MGs can be classified as shown in Table 1.

Table1. Classification of the monoclonal gammopathy according to clinical manifestations

Among the clinically occult forms, i.e., those conditions in which MG is not associated with clinical manifestations, the most frequently encountered is Monoclonal Gammopathy of Undetermined Significance (MGUS), a term coined by Robert Kyle in 1978. MGUS is defined as the presence of a MC in serum or urine without clinical evidence of multiple myeloma, AL amyloidosis, Waldenström’s disease, or other related disorders. Epidemiologically, MGUS is far from to be a rare condition, its prevalence increases with age, is higher in males and in Africans and African-Americans than in Caucasians. In an important population-based study in the United States, the prevalence of this condition in the general population over 50 years of age was 3.2%, a figure quite similar to that found in studies conducted in Italy. Smoldering or asymptomatic myeloma (SMM) is considered an intermediate condition between MGUS and MM, as it has biochemical and cellular characteristics intermediate between MGUS and MM but without presenting the clinical symptoms of the latter. Although asymptomatic, MGUS and SMM are considered “premalignant” conditions, as it has been shown that almost all cases of MM are preceded by either condition. While MGUS is associated with a risk of progression of approximately 1% per year, the risk of progression of SMM is 10% in the first 5 years after diagnosis and then gradually decreases to 1%, like MGUS, within 15 years. Many of those with MGUS and all those with SMM require continuous monitoring, to prevent organ damage, such as bone injury or renal insufficiency. The most common proliferating plasma cell neoplasm is MM, second among hematologic neoplasms only to non-Hodgkin’s lymphoma. In 2015, 18,545 cases were observed in Italy, 5643 of which were newly diagnosed; the number is substantially stable, with 5759 new cases in 2020. MM predominantly affects the elderly population with a mean age at diagnosis of 69 years, while it occurs very rarely under 40 years. Myelomatous cells reside in the bone marrow, where they often prevail over other cell types causing typical lytic lesions in bone tissue. In these neoplastic forms with large expanding clones of secreting plasma cells, the clinic is dominated by systemic effects caused by the expansion of the malignant clone, such as anemia, bone lesions, hypercalcemia, renal damage, and infections. Despite the significant increase in 5-year survival from 25% between 1975 and 1977, to 43% between 2002 and 2008, MM is still considered a poor prognosis disease. In the nonneoplastic forms with small or very small clones, the clinical manifestations may be due to biological effects caused by the biochemical characteristics of the MC. These can range from vasculitis and neuropathy, due to the specific antibody activity of MC, to cardiac or renal functional deficit due to the deposition of MC in organs or tissues. Among these, the most frequently encountered pathology is immunoglobulin light-chain amyloidosis (AL amyloidosis), characterized by a plasma cell clone producing light chains with conformational abnormalities that cause systemic proteotoxicity with rapid deterioration of the function of vital organs where amyloid fibrils are deposited. In this group of diseases, cryoglobulinemias can also be encountered. Cryoglobulins are Ig that in vitro precipitate if they are subjected to temperatures below 37 °C, but they redissolve when brought to 37 °C again. In Brouet’s 1974 classification, which remains the most widely used, three types of cryoglobulinemia are distinguished based on clonality and immunoglobulin class. Type I consists of monoclonal Ig only, usually IgG or IgM. Type II is a mixture of polyclonal IgG and a monoclonal IgM, with rheumatoid activity. Finally, in Type III, both polyclonal IgG and IgM are present. Type II and Type III are called mixed cryoglobulinemias. Cryoglobulins are associated with a clonal expansion of B cells, either in the context of lymphoproliferative disorders or in the presence of a persistent stimulation of the immune system triggered by a chronic infection or an autoimmune disease. The term cryoglobulinemia refers to the presence of cryoglobulins in the serum, whereas the term cryoglobulinemic disease or vasculitis is used to describe conditions in which there are symptoms related to the presence of cryoglobulins, since many subjects with cryoglobulinemia remain asymptomatic. The two main pathogenetic mechanisms are the precipitation of cryoglobulins in the micro vessels and the inflammatory process mediated by the presence of immune complexes.

The prevalence of the main plasma cell dyscrasias, obtained from an impressive case series from the Mayo Clinic, is reported in Table 2.

Table2. Prevalence of different monoclonal gammopathies^a