What is m gradient in a blood test. The role of electrophoresis in the diagnosis of multiple myeloma

Dalrymple (Dalrymple, 1846), Bens-Jones (N. Vepse-Jones, 1848), Mackintyer (W. Macintyre, 1850) for the first time reported a disease characterized by pain in bones, softening and increased fragility of bones, as well as the presence in urine of a special thermolabile protein substance. OA Rustitsky in 1873 described the pathological picture in detail, and O. Kahler in 1889 presented the clinical, morphological and pathogenetic analysis of the disease, in connection with which it was named Rustitsky's disease - Kahler. In 1949, GA Alekseev introduced the term "myeloma", which combines a variety of pathological changes in the bone marrow, bones, kidneys and other organs, as well as the syndrome of protein pathology.

Multiple myeloma usually occurs over the age of 40 and affects men and women equally. The prevalence of the disease in Western European countries, the USSR and the USA is 1.1-3.1, and the mortality rate is 0.8-1.0 per 100,000 inhabitants.

Etiology. The hypothesis of somatic mutation in immunocompetent B-lymphocytes seems likely. No specific chromosomal aberrations have been identified in multiple myeloma.

Immunochemical classification Multiple myeloma is based on the difference in classes of immunoglobulins (paraproteins) synthesized and secreted by mutant plasma cells. Allocate G-, A-, D and E-myeloma. The number of patients with G-myeloma is about 60%; A myeloma - about 25%; D-myeloma - about 3% of all patients with multiple myeloma; E-myeloma is one of the rarest forms. Paraprotein is also typed by the light chains (k or A,) that are part of its molecule. In addition, Bene-Jones myeloma (the so-called light chain disease) is isolated, in which the paraprotein is represented by light chain dimers of types or X. This form of multiple myeloma

makes up about 10% of all forms Multiple myeloma Bens-Jones myeloma should not be equated with Bence-Jones proteinuria, which can be detected in any form of Multiple myeloma The so-called non-secreting myeloma is also described, in which paraprotein is not detected either in blood serum or in urine , which is associated with a violation of the mechanism of synthesis and secretion of paraprotein by plasma cells.

The pathogenesis of myeloma is associated with the proliferation in the bone marrow and less often in other organs of plasma cells (see the complete body of knowledge), which have the property of infiltrating destructive growth with the secretion of monoclonal high molecular weight (200,000-300,000) immunoglobulin (paraprotein) and suppression of normal clones of immunocompetent cells (see complete body of knowledge).

The consequence of tumor growth of plasma cell infiltrates in the bone marrow is the destruction of the bones of the skeleton. Extra bone marrow myelomas can have the property of malignant tumors developing in various organs and tissues (stomach, intestines, lungs, lymph nodes, and so on), while the process of metastasis, apparently, also takes place.

The secretion of paraprotein into the bloodstream and into the surrounding tissues causes the development of the so-called hyperviscosity syndrome (syndrome of high blood viscosity) and tissue dys- (para-) proteinosis. Suppression of normal clones of immunocompetent cells leads to the development of immunodeficiency syndrome (see the complete body of knowledge Immunological insufficiency)), in which there is a tendency to repeated (especially respiratory) infections. An important link in the pathogenesis of multiple myeloma is the development of amyloidosis (paraamyloidosis), which is observed in 10-20% of patients (more often with D-myeloma and light chain disease) and serves as one of the manifestations of tissue dysproteinosis (see the complete body of knowledge Amyloidosis). In this case, the main constituent part of the protein of amyloid fibrils is the light chains of the paraprotein molecule or their fragments.

Renal paraproteinosis in combination with tubular blockade by protein agglomerates and frequently developing ascending urological infection - pyelonephritis (see the complete body of knowledge) - form the pathogenetic basis of myeloma nephropathy ("myeloma kidney") with renal failure and the development of uremia (see the complete body of knowledge Renal failure) ...

Pathological anatomy. Morphologically, the substrate for multiple myeloma is tumor proliferation of plasma cells, which primarily arise in the bone marrow. The process is localized mainly in the bones and in most cases is accompanied by a sharp resorption of bone tissue (see the complete body of knowledge Osteoporosis). At the same time, as a rule, there are signs of a violation of protein metabolism in the form of tissue dis (para-) proteinosis. The combination of these changes determines the pathological picture of the disease characteristic of Multiple myeloma.

At autopsy, the most typical changes are found in flat and sometimes tubular bones. They are fragile, soft, often cut with a knife. Fractures, deformation of bones, in particular compression of the vertebral bodies, sometimes with compression of the spinal cord, can be observed. In the diffuse-nodular form, Multiple myeloma, which occurs most often with a detailed picture of the disease, the bone marrow has a variegated appearance in the section, contains multiple grayish-pink nodular growths of various sizes (color figure 8). In the nodes and around them, due to hemorrhages and necrosis, dark red and yellowish areas are often detected. Tumor masses sometimes invade adjacent tissues (muscles, skin, pleura, dura mater, and so on). In the diffuse form of multiple myeloma, the bone marrow is juicy, variegated due to the alternation of proliferation of plasma cells, hemorrhages, and necrosis. The number of bone plates is reduced, the cortical layer is thinned. In rare cases, osteoporosis is absent. The size and weight of the spleen, liver, lymph nodes, nodes are usually within normal limits or slightly increased. In some cases, there is a significant increase in their volume due to massive specific lesions. Rare cases of development of extensive nodular growths in the skin, pleura, lungs, kidneys, in the brain and others are described. The kidneys may be enlarged, pale, smooth; with pronounced sclerotic changes, a picture of a secondary wrinkled kidney is revealed. In some cases, there are punctate and spotted hemorrhages in the skin, serous and mucous membranes, and tissue of internal organs. As a rule, there are signs of general anemia, dystrophy of the parenchymal organs, often purulent-inflammatory processes.

Histologically, in the bone marrow with multiple myeloma, proliferations of plasma cells of various types are found. Histologically, plasma cells in multiple myeloma are most often characterized by a rough, eccentrically located nucleus and a fairly abundant basophilic cytoplasm; sometimes the nucleus with a fine structure of chromatin contains 1-3 nucleoles, and the basophilia of the cytoplasm is poorly expressed. There are various transitional forms between these options (Figure 1); for multiple myeloma is characterized by the presence of giant bi- and multinucleated plasma cells and so on. flaming cells, abundant cytoplasm of which has uneven contours and a pinkish tint around the edges. Often there are various variants of plasma cells containing Russell's acidophilic bodies, the number and location of which in the cytoplasm determine the type of cells, designated as grape cells, morula cells, thesaurocytes (accumulation cells) or Mott cells. Some authors have observed cytochemically negative crystalline inclusions in the cytoplasm of myeloma cells.

Figure: one. Micropreparation of bone marrow punctate of a patient with myeloma disease (various types of plasma cells): a - a typical plasma cell with rough nuclear chromatin and sharply basophilic cytoplasm; b - plasma cell with a fine structure of nuclear chromatin and weakly basophilic cytoplasm; c - double-nuclear plasma cell; gram - "flaming" plasma cell; e - plasma cell with Russell's little bodies; the fields of the slides are covered with erythrocytes.

Electron microscopy of plasma cells in multiple myeloma reveals hypertrophy of protein-synthesizing structures - a rough endoplasmic reticulum in the form of bags and cisterns pushing the nucleus to the periphery, polyribosomes and a developed Golgi complex. Acidophilic bodies are detected in the form of optically dense granules containing an amorphous protein substance. They are believed to be composed of condensed paraprotein. Due to the high content of protein and ribonucleoproteins, the cytoplasm of these cells is sharply pyroninophilic, has a PER-positive reaction, luminescence when stained with thioflavin T. Along with mature plasmocytes, plasmablasts, atypical giant single and multinucleated cells are detected. The cellular composition of growths varies in different cases and often differs in different parts of the skeleton. The proliferation of plasma cells can be nodular, diffuse or diffusely nodular. The first option, as shown by the results of trepanobiopsy, occurs mainly in the early stages of the disease. At the same time, against the background of normal bone marrow, multiple, rather large sizes (from 200 micrometers and more) focal proliferation of plasma cells (Figure 2), penetrating into the adjacent tissue, are revealed. Progression Myeloma is characterized by the development of diffuse infiltration of the bone marrow by plasma cells (Figure 3). This is often accompanied by the development of extensive knotty growths (color table, art. 33, figure 8 and 9). The number of cells of normal hematopoiesis is markedly reduced. Fields of myelofibrosis, fat cells can be detected. Characterized by a significant thinning of the bone plates up to their complete disappearance in large areas, the expansion of the canals of osteons (Haversian canals), partial destruction of the cortex with the germination of plasma cells into the periosteum. Resorption of bone tissue proceeds according to the type of smooth, axillary and osteoclastic resorption. It is believed that osteoporosis is caused by impaired bone formation due to increased secretion in the bone marrow of a factor that stimulates osteoclasts. Reparative processes are sharply reduced, however, in a number of cases, focal bone formation of a primitive structure is observed, mainly in the area of \u200b\u200bmicro-fractures and in the areas of hemorrhage along the periphery of the nodular growths (Figure 4). Occasionally resorption of bone tissue is absent, there is a thickening of the bone plates.

Microscopically, knotty and diffuse proliferations of plasma cells in the spleen, liver, lymph nodes, and other organs are often detected. Calcareous metastases in the kidneys, lungs and other organs are often found. Differences in the frequency and intensity of specific lesions of internal organs in different immunochemical variants of myeloma were not found.

Tissue paraproteinosis is expressed in the accumulation of protein masses in the lumens of blood vessels, protein impregnation of their walls and organ stroma, deposition of amyloid (paraamyloid) and, occasionally, crystalline substances. Protein, amyloid-like deposits are oxyphilic, stained positively in the SHIK reaction, unlike amyloid, they do not have anisotropy. In the kidneys, especially with prolonged Bens-Jones proteinuria (see the complete body of knowledge of Bens-Jones protein), a picture of paraproteinemic nephrosis develops. Characterized by an abundance of protein casts in the tubules (Figure 5), dystrophy of the epithelium, its death and desquamation, focal nephrohydrosis, edema, and possible plasma cell infiltration of the stroma. The cylinders can be surrounded by giant cells, saturated with calcium salts. Glomerular changes are insignificant. There is a thickening of the basement membrane, deposition of protein substances in the mesangium, sometimes hyperplasia of its cells; dystrophy of podocytes with deposition of protein granules in their cytoplasm. Nephrosclerosis is often observed (see full body of knowledge). For multiple myeloma, protein edema of the lung tissue is typical (Figure 6), myocardial stroma. Amyloid (paraamyloid) in multiple myeloma differs from its other varieties by the high content of low molecular weight fragments in the protein component. Amyloid often does not react positively with Congo red, metachromasia with methyl violet and toluidine blue; luminesces with thioflavin T and S, has anisotropic properties.

Figure: 2. Bone marrow micropreparation for myeloma disease (trepanobiopsy): 1 - plasma cells forming focal growths; 2 - areas of normal hematopoiesis; staining with hematoxylineosin; × 400. Figure: 3. Micropreparation of bone marrow in case of myeloma (trepanobiopsy): 1 - diffuse infiltration of bone marrow by plasma cells; 2 - bone tissue; staining with hematoxylin-eosin; × 80. Figure: 4. Microscopic specimen of the vertebra in myeloma: 1 - infiltration of the periosteum by plasma cells; 2 - area of \u200b\u200bmicro-fracture; 3 - bone marrow fibrosis; 4 - the formation of bone substance; staining with hematoxylin-eosin; × 140.

Characterized by a predominant lesion of the walls of blood vessels, heart, tongue, striated muscles, nerves, skin, tendons and synovial membranes of the joints. Massive deposition of amyloid in the myeloma nodes in the bones is possible with the formation of large tumors of a peculiar type. In rare cases, crystalline substances fall out in plasma cells and extracellularly in tumor growths, as well as in the kidneys, corneal vessels, the origin of which is associated with a violation of the synthesis of light x-chains. When treated with cytostatics in the bone marrow, there is a decrease in the volume of tumor growths in combination with the development of hypoplastic changes, fields of sclerosis, and the formation of imperfect bone substance.

The clinical picture. In a typical course, the main clinical symptom is bone pain (ossalgia), which is most often localized in the spine, ribs, less often in the tubular bones and in the bones of the skull. The growth of a tumor or diffuse plasma cell infiltrates outside the bone tissue is accompanied by radicular pain (see the complete body of knowledge Radiculitis), paraplegia (see the complete body of knowledge), hemiplegias (see the complete body of knowledge), exophthalmos (see the full body of knowledge), and so on. Cases of plasma cell infiltration of the pleura or peritoneum with the development of specific pleurisy (see the complete body of knowledge) or ascites (see the complete body of knowledge) and with a high content of plasma cells and paraprotein in the exudate. With organ localization of plasma cell tumors (lungs, stomach, intestines, lymph nodes, liver, spleen and others) clinical, the picture corresponds to that of a malignant tumor of this organ or is supplemented by symptoms such as an increase in lymph, nodes, liver, spleen, and so on.

Some researchers distinguish plasma cell leukemia as an independent nosological form, which, unlike ordinary multiple myeloma, in addition to an increased content of plasma cells in the blood, is characterized by severe hemorrhagic diathesis associated with thrombocytopenia, rapid course and extensive plasma cell infiltration in various organs.

In the study of blood at the onset of the disease, an accelerated ROE is detected, which is associated with the predominance of coarse proteins (paraproteins) in the plasma, which are detected by electrophoresis (Figure 7). The belonging of a paraprotein to one of the Ig classes is determined by immunoelectrophoresis (see complete body of knowledge) with monospecific antisera (Figure 8) or radial immunodiffusion on agar gel according to Mancini (see complete body of knowledge Immunodiffusion.); the latter method is also used for the quantitative determination of paraproteins. By the same methods and by simple diffusion on agar, using monospecific antisera against K and X light chains, the type of Ig light chains is determined. Multiple myeloma is characterized by a decrease (depression) in the concentration of immunoglobulins that do not belong to paraprotein (the so-called “non-M-components”, or physiological immunoglobulins), which is associated with a violation of humoral immunity.

As the disease progresses, normochromic normocytic non-hemolytic anemia develops, less often thrombocytopenia; Plasma cells often appear in the blood, the number of which can reach 10-50% or more of all blood cells. In the latter case, they usually speak of leukemization Multiple disease

In some patients with multiple myeloma, blood tests reveal such signs of dyshemopoiesis as erythroblastemia, macro and even megalocytosis of erythrocytes, leukemoid (myeloid) shift in the leukocyte formula; sometimes lymphocytosis occurs as a reflection of the immunoproliferative process in the bone marrow.

Of the complications, one should bear in mind pathological bone fractures in the places of their tumor destruction (see the complete body of knowledge. Fractures), the development of a themia of paraparesis and plegias when the brain or spinal cord is compressed by a tumor growing from the bones of the skull or vertebrae. Secondary radicular syndrome occurs due to plasma cell infiltration of the meninges and compression of the roots of the spinal nerves.

The development of renal paraamyloidosis in combination with tubular blockade with protein agglomerates usually leads to functional renal failure with the development of irreversible uremic intoxication. Deposition of amyloid in the myocardium reduces its contractility; there are cases when the deposition of amyloid in the myocardium with multiple myeloma was mistakenly diagnosed as a heart attack or aneurysm of the heart. There are also complications (polyneuropathies, arthropathies, and so on) associated with different localization of paraamyloidosis in multiple myeloma

Sometimes with multiple myeloma, as with Waldenstrom's disease (see the complete body of knowledge of Waldenstrom's disease), hyperviscous syndrome develops, which is composed of hemorrhages and symptoms of cerebropathy, retinopathy and is associated with the circulation in the bloodstream of complexes of globulin molecules. At the same time, various disorders in the blood coagulation system are revealed. Approximately 30% of patients with multiple multiple myeloma in severe course reveal an increase in the calcium content in the blood of more than 6 milli-equivalent, which is most often associated with intense bone resorption and impaired urinary calcium excretion. Clinical, the picture of hypercalcemia in multiple myeloma is expressed by hyperreflexia, muscle rigidity, drowsiness, lethargy; some patients develop disorientation and even psychosis, as well as stupor and coma, which can disappear when the level of calcium in the blood is normalized.

Infectious complications associated with an immunodeficiency state pose a great danger in multiple myeloma. Most often, respiratory infections (bronchitis, pneumonia) develop with a prolonged, recurrent course. Ascending urological infections cause pyelonephritis; various pustular lesions of the skin and mucous membranes can lead to the development of purulent meningitis, phlegmon, sepsis and the like. Among the causes of death of patients with multiple myeloma, pneumonia, urosepsis, uremia, pulmonary heart disease prevail. In some cases, death is due to cerebral hemorrhage, paraproteinemic coma.

The diagnosis of myeloma should be established as early as possible in order to apply timely treatment and prevent such unreasonable prescriptions as active physiotherapeutic and balneological procedures.

The diagnosis is established on the basis of clinical, picture (pain in the bones, especially in the spine), blood test (accelerated ROE, hyperproteinemia, hypergammaglobulinemia, presence of an M-gradient) and urine (Bence-Jones proteinuria). The reliability of the diagnosis is confirmed by the study of bone marrow punctate, in which, as a rule, proliferation of plasma cells is detected, the number of which exceeds 10%, sometimes reaching 70-100%.

For the diagnosis of multiple myeloma, along with cytological analysis of sternal punctate, since the beginning of the 60s, an intravital histological examination of the bone marrow "crumb" obtained from a bone puncture is carried out, or more often trepanobiopsy is performed (see the complete body of knowledge). A number of oncologists note the value of this method for the diagnosis of multiple myeloma in cases of a small number or absence of plasma cells in the punctate. The identification of the paraprotein class using immunoelectrophoresis and radial immunodiffusion expands the understanding of the nature of the process, and also helps in differential diagnosis.

X-ray diagnostics. X-ray changes in the skeletal system in multiple myeloma are very diverse. The following clinical and radiological forms of myeloma are distinguished: 1) multiple-focal, or multiple-nodular, 2) diffuse-porotic, 3) osteosclerotic and 4) solitary (isolated).

The multiple focal form occurs in more than 70% of cases, and is radiographically characterized by the formation of multiple rounded defects up to several centimeters in diameter. Changes are detected most often in flat bones (Figure 9), less often in long and short tubular bones. Each defect is clearly contoured, with no reactive changes from the surrounding tissue. In the tubular bones, the cortical substance from the inside becomes thinner, the medullary cavity expands, in the place of the largest nodes the bone slightly swells and thickens (Figure 10, a). In some cases, complete destruction of the cortical substance of the bone can be observed (Figure 10, b) with the spread of the tumor into soft tissues. A characteristic picture is revealed when the bones of the skull are affected, in which multiple, as if knocked out by a punch, bone defects are visible (Figure 11). In the spine, a diffuse rarefaction of the bone structure, flattening of the vertebral bodies (brevispondilia, “fish vertebrae”), and curvature of the spinal column are found. Against the background of diffuse rarefaction of the bone substance of the vertebral bodies, the emphasis of the arches and processes of the vertebrae is noticeable, which, as a rule, is absent in metastatic lesions of the spine.

The diffuse-porotic form occurs in 9-15% of cases and is characterized by a general widespread osteoporosis of the bone system (see the complete body of knowledge Osteoporosis) without limited foci of bone resorption. Often it is not a separate form, but a phase of the disease, which then turns into a multiple-focal form of the lesion, which dictates the need for repeated x-ray examinations of the skeleton. With this form, the x-ray picture can remain normal for a long time. The gradually arising general demineralization of the skeleton is devoid of specificity and does not differ from systemic osteoporosis of other origins. However, this osteoporosis can have characteristic features, be fine-grained, in some cases coarse-grained or spotted, and localized most often in the flat bones of the skull, pelvis, and ribs.

The osteosclerotic form is rare (in about 3% of cases) and is manifested by pronounced osteosclerosis of a focal-nested or diffuse nature (see the complete body of knowledge Osteosclerosis) and sometimes gives an X-ray picture of the marble vertebra (see the complete body of knowledge).

The solitary form (solitary myeloma) is even less common; some researchers, for example A.S. Reinberg, consider this form as an early phase of multiple myeloma, others - as an independent disease (a primary tumor of the bone marrow, which has all the signs of tumor growth). Solitary myeloma most often occurs in the pelvic bones (usually in the wing of the ilium), spine, bones of the cranial vault, ribs, and less often in the proximal humerus or femur. Radiographically, two varieties of this form can be distinguished: a classic purely destructive large solitary bone defect clearly demarcated from the surrounding tissue (Figure 12), and cystotrabecular myeloma - a large cystic or cellular formation (Figure 13). There is usually no reactive sclerosis in the circumference of the tumor node. In rare cases, solitary myeloma can occur in other organs and tissues. Solitary gastric myeloma radiographically gives a picture similar to infiltrative cancer or lymphogranulomatosis of the stomach.

Differential diagnosis should be carried out with various bone diseases, in particular the spine (spondyloarthrosis, tuberculous spondylitis, ankylosing spondylitis, and others), as well as with metastases of malignant neoplasms in the bone (cancer of various localization, sarcoma). In this case, the main diagnostic value is the morphological examination of bone marrow punctates (trepanates), proteinogram and immunochemical data.

Bene-Jones myeloma, in which persistent proteinuria is sometimes the only symptom for a long time, is distinguished from chronic kidney disease on the basis of a heat test for Bence-Jones protein in urine or urine electrophoresis.

The main criteria for the differential diagnosis of multiple myeloma and Waldenstrom's macroglobulinemia are the identification of paraprotein and the presence of plasma cell proliferation in the bone marrow. In Waldenstrom's disease, the paraprotein belongs to the IgM class, and the bone marrow is infiltrated with lymphatic cells. X-ray examination of the bones of the skeleton, as a rule, in Waldenstrom's disease does not reveal the foci of osteolysis characteristic of Multiple myeloma; during an external examination of a patient with Waldenstrom's disease, signs of systemic lymphoid hyperplasia (enlargement of lymph, nodes, liver, spleen) are often found, rare in multiple myeloma

Differential diagnosis between multiple myeloma and symptomatic paraproteinemias with reactive plasmacytosis in collagenoses, chronic liver diseases, tuberculosis, malignant neoplasms, leukemias, lymphomas, and so on is based on the difference in clinical, pictures, data of morphological studies (as opposed to myeloma cells, plasma disease lie in the form of small clusters or single elements scattered in the tissue) and X-ray signs. The importance is attached to the dynamics of the M-gradient, the magnitude of which in symptomatic paraproteinemia correlates with the degree of activity of the underlying disease. Concentrations of physiological Ig when examined by radial immunodiffusion are usually normal or slightly increased in symptomatic paraproteinemia and clearly reduced in multiple myeloma

Variety of X-ray manifestations Multiple myeloma requires differential diagnosis with other diseases. The greatest difficulties arise in the differential diagnosis of multiple focal myeloma with cancer metastases in the bone. Differentiation is based on a complex of clinical, laboratory and X-ray data. Myeloma nodes are most often located in the ribs and sternum, do not cause periosteal reaction and osteosclerosis, unlike cancer metastases.

Differential diagnosis with osteomalacia (see full body of knowledge), hyperparathyroidism (see full body of knowledge) and generalized fibrous osteodystrophy of Recklinghausen (see full body of knowledge Parashyroid osteodystrophy) is of certain importance. With osteomalacia, osteoporosis is more diffuse; there are no round defects in the bones characteristic of myeloma. Hyperparathyroidism and Recklinghausen's disease are distinguished by larger sizes of individual defects, a predominant lesion of the tubular bones.

From diseases of the blood system Multiple myeloma should be differentiated from those forms of leukemia (see the complete body of knowledge), which can occur with pronounced destructive changes in the skeleton. In such cases, bone marrow and serum protein data are primarily taken into account.

Certain difficulties may arise in the differential diagnosis of multiple eosinophilic granuloma of bones (see the complete body of knowledge). The discrepancy between the extensive destructive process and the general good condition of the patient, the absence of changes in the hemogram and paraproteinemia suggest multiple eosinophilic granuloma. The final diagnosis is based on puncture or biopsy data from the lesion.

Of practical importance is the differential diagnosis of osteoporotic changes in multiple myeloma with common osteoporosis of various etiology, in particular dyshormonal. In multiple myeloma, osteoporosis is widespread throughout the skeleton, in contrast to dyshormonal, which is limited mainly to the spine and ribs.

Multiple myeloma must be differentiated from the so-called essential benign gammopathy, in which an acceleration of ROE, moderate hyperproteinemia and an M-gradient in the zone of γ or β-globulins are detected, but there are no morphological and radiological signs of myeloma and there are no grounds for the diagnosis of any disease that may be the cause of symptomatic paraproteinemia. The criterion for essential benign gammopathy is the stability of the concentration of paraprotein and physiological Ig.

Treatment. The first course of therapy is usually carried out in a hospital; further treatment can be carried out on an outpatient basis under the supervision of a doctor and with regular (at least 1 time per week) blood tests.

The agents used are aimed at suppressing the proliferation of a pathological clone of paraprotein-producing plasma cells. Alkylating cytostatic drugs are mainly used: sarcolysin and cyclophosphamide. Along with these drugs, cytostatic phase-specific chemotherapy drugs are used, such as Natulan, Vincristine. The use of corticosteroid hormones (in a daily dose of 30-40 milligrams of prednisolone) increases the effectiveness of any chemotherapy in multiple myeloma In treatment regimens that prescribe loading doses of chemotherapy, doses of prednisolone are increased to 100-150 milligrams per day or more. The doses of chemotherapy drugs used and the intervals between their administration are strictly individual. The choice of dose depends on the initial state of the patient, on the sensitivity to the drug. So, sarcolysin is preferable with intact hematopoiesis (the number of leukocytes is not less than 4000 in 1 microliter and platelets - 100,000 in 1 microliter) and with normal renal function. The appointment of cyclophosphamide is permissible for leukopenia, thrombocytopenia, as well as with moderate azotemia. With a pronounced immunodeficiency state of the body, large doses of cytostatic drugs should be avoided. Replacement of the drug, as well as the use of combined treatment regimens with these drugs are recommended when resistance to one of them develops.

Sarcolysin is usually prescribed in a dose of 5-10 milligrams orally or intravenously daily or every other day (some recommend using sarcolysin 10-20 milligrams per week); 200-300 milligrams per course of treatment (with intravenous administration, the course dose rarely exceeds 150-200 milligrams). The treatment is repeated up to 5-6 courses or more with a break of 1 g / 2-2 months

Cyclophosphamide is used intravenously in a single dose of 200-600 milligrams with an interval of 1-2 days; the dose per course is 8-10 g, the intervals between courses are 1-1½ months. Large doses of cyclophosphamide up to 1000 milligrams can be administered once a week. With a pronounced radicular syndrome caused by specific infiltration of the spinal cord membranes, cyclophosphamide is injected into the spinal canal. In polychemotherapy, the listed drugs are used in various combinations.

The generally accepted tactics of radiation therapy for multiple myeloma In generalized forms, remote gamma therapy is prescribed as an adjunct to large foci of destruction in the supporting bones with severe pain (especially radicular) syndrome and with rapid tumor growth with the threat of pathological bone fracture or compression of the spinal cord or brain. In this case, radiation therapy with a total dose of 4500-5000 glad to the focus is prescribed simultaneously with chemotherapy or preceding it. Radiation therapy acquires an independent significance with solitary scrap; in these cases, it is prescribed after the removal of the tumor.

In cases of clinically expressed hyperviscous syndrome, 7-10 sessions of plasmapheresis are shown (see the complete body of knowledge) with the extraction of 500-700 milliliters of plasma per session; if necessary (anemia), donor blood is transfused at the same time. In case of multiple myeloma with leukopenia and thrombocytopenia, it is advisable to use component transfusion therapy; with developing renal failure - all the means used for renal failure of any origin, up to hemodialysis (see the complete body of knowledge), the use of which is limited, since the development of uremic intoxication in multiple myeloma usually coincides with the terminal stage of the disease.

Infectious complications require the use of the maximum tolerated doses of antibiotics, preferably a wide spectrum of action in various combinations of 2-3 drugs.

With hypercalcemia, active cytostatic therapy is carried out in combination with increased doses of corticosteroid hormones (prednisone up to 100 milligrams per day intravenously), hydration and plasmapheresis. Of the symptomatic remedies, analgesics, vitamins (D), anabolic hormones are often used.

Surgical treatment is indicated for solitary myeloma and can be used as an adjunct to chemotherapy and radiation therapy for generalized forms, if the location of one of the tumor foci threatens important functions of organs or body parts closely located or directly involved in the process (laminectomy and removal of the tumor for the purpose of decompression spinal cord, orthopedic and reconstructive operations for the destruction of large tubular bones, etc.). With pronounced destructive changes in the spine, corrective measures include light traction on an inclined plane, a lightweight corset, and it is also recommended to sleep on a shield.

Forecast. With proper treatment, restoration of the patient's activity and objective signs of a decrease in the mass of tumor cells (a decrease in the concentration of paraprotein, the size of tumors) are observed in 70% of patients. Life expectancy depends on the nature of complications, as well as on the individual characteristics of the course of the disease, probably associated with the proliferative activity of plasma cells, and with a favorable response to treatment is 2-4 years, in some cases it exceeds 10 years.

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Paraproteins in blood serum are normally absent.

Immunoglobulinopathies, or gammopathies, unite a large group of pathological conditions characterized by polyclonal or monoclonal hypergammaglobulinemia. Immunoglobulins are composed of two heavy (H) chains (molecular weight 50,000) and two light (L) chains (molecular weight 25,000). The chains are connected by disulfide bridges and consist of structures called domains (H - of 4, L - of 2 domains). Under the action of proteolytic enzymes, Ig is divided into fragments: Fc-fragment and Fаb-fragment. Human Ig heavy chains are represented by five structural variants, which are denoted by the letters of the Greek alphabet: γ, α, μ, δ, ε. They correspond to 5 classes of Ig - G, A, M, D, E. Light chains are represented by two structurally different variants: κ (kappa) and λ (lambda), which correspond to two types of Ig of each class. In each Ig molecule, both heavy and both light chains are identical. All people normally have Ig of all classes and both types, but their relative content is not the same. The ratio of κ and λ molecules within different Ig classes is also not the same. Revealing the violation of Ig ratios or their fragments plays an important role in the diagnosis of monoclonal immunoglobulinopathies.

Monoclonal immunoglobulinopathy (paraproteinemia) is a syndrome manifested in the accumulation of Ig or their fragments in the blood serum and / or urine of patients homogeneous in all physicochemical and biological parameters. Monoclonal Ig (paraproteins, M-proteins) are the secretion product of one clone of B-lymphocytes (plasma cells), therefore they represent a pool of structurally homogeneous molecules with heavy chains of the same class (subclass), light chains of the same type and variable regions of the same structure. Monoclonal immunoglobulinopathies are usually divided into benign and malignant. In benign forms of monoclonal gammopathies, the proliferation of plasma cells is controlled (possibly by the immune system) in such a way that there are no clinical symptoms. In malignant forms, an uncontrolled proliferation of lymphoid or plasma cells occurs, which determines the clinical picture of the disease.

Classification of monoclonal immunoglobulinopathies

Immunoelectrophoresis of blood serum proteins allows the detection of monoclonal (pathological) IgA, IgM, IgG, H and L chains, paraproteins. In ordinary electrophoresis, normal Ig, dissimilar in properties, are located in the γ zone, forming a plateau or a wide band. Due to their homogeneity, monoclonal Ig migrates mainly to the γ zone, occasionally to the β zone and even to the α region, where they form a high peak or a clearly demarcated band (M-gradient).

Multiple myeloma (Rustitsky-Kalera disease) is the most common paraproteinemic hemoblastosis; it is detected no less often than chronic myelo- and lymphocytic leukemia, lymphogranulomatosis and acute leukemia. The class and type of pathological Ig secreted by myeloma determines the immunochemical variant of the disease. The frequency of classes and types of pathological Ig in myeloma generally correlates with the ratio of classes and types of normal Ig in healthy people.

Along with an increase in the content of pathological Ig in the serum of patients with multiple myeloma, normal Ig in a reduced concentration is determined. The total protein content is sharply increased - up to 100 g / l. The activity of the process in G-myeloma is assessed by the number of plasma cells in the sternal punctate, the concentration of creatinine and calcium in the blood serum (their increase in calcium indicates the progression of the disease). The concentration of M-protein (in urine it is called Bens-Jones protein) serves as a criterion for assessing the progression of the disease in A-myeloma. The concentration of paraproteins in serum and urine varies during the course of the disease under the influence of therapy.

To make a diagnosis of multiple myeloma, the following criteria must be met.

Large criteria

1. Plasmacytoma by biopsy.
2. Plasmacytosis in the red bone marrow (more than 30% of cells).
3. Monoclonal (pathological) Ig peaks during serum protein electrophoresis: more than 35 g / L for the IgG peak or more than 20 g / L for the IgA peak. Excretion of κ and λ-chains in an amount of 1 g / day or more, detected by urine electrophoresis in a patient without amyloidosis.

Small criteria

1. Plasmacytosis in the red bone marrow of 10-30% of cells.
2. The peak of PIg in serum is less than indicated above.
3. Lytic lesions of the bones.
4. The concentration of normal IgM is below 0.5 g / L, IgA is below 1 g / L or IgG is below 0.6 g / L.

To make a diagnosis of multiple myeloma, at least 1 major and 1 minor criteria or 3 minor criteria are required with the mandatory presence of the criteria given in points 1 and 2.

To determine the stage of myeloma, the standardizing Dury-Salmon system is used, which reflects the volume of the tumor lesion.

All groups of myelomas are divided into subclasses depending on the state of renal function: A - serum creatinine concentration below 2 mg% (176.8 μmol / L), B - more than 2 mg%. In case of multiple myeloma, a high concentration of β 2 -microglobulin in the blood serum (more than 6000 ng / ml) suggests an unfavorable prognosis, as well as a high LDH activity (above 300 IU / L, setting the reaction at 30 ° C), anemia, renal failure, hypercalcemia, hypoalbuminemia, and large tumor volume.

Light chain diseases (Bence Jones myeloma) account for approximately 20% of myeloma cases. In Bens-Jones myeloma, exclusively free light chains are formed, which are detected in urine (Bens-Jones protein), in the absence of serum pathological Ig (M-gradient).

Stages of multiple myeloma

Rare immunochemical variants of myeloma include non-secreting myeloma, in which paraproteins can be found only in the cytoplasm of myeloma cells, as well as diclonic myelomas and M-myeloma.

Waldenström's macroglobulinemia is a chronic subleukemic leukemia of a B-cell nature, morphologically represented by lymphocytes, plasmocytes and all transitional forms of cells synthesizing PIgM (macroglobulin). The tumor has a low grade of malignancy. In the red bone marrow, proliferation of small basophilic lymphocytes (plasmacytoid lymphocytes) is detected, the number of mast cells is increased. On the electrophoretogram of blood serum proteins, an M-gradient is detected in the zone of β- or γ-globulins, less often the paraprotein does not migrate in the electric field, remaining in place. Immunochemically, it represents PIgM with one type of light chains. The concentration of PIgM in blood serum in Waldenström macroglobulinemia ranges from 30 to 79 g / l. In 55-80% of patients, Bens-Jones protein is found in the urine. The concentration of normal Ig in the blood decreases. Renal failure is uncommon.

Lymphomas. IgM-secreting lymphomas are most often recorded, the second place is taken by paraproteinemic lymphomas, secreting IgG, lymphomas with IgA-paraproteinemia are detected extremely rarely. A decrease in the concentration of normal Ig (usually to a small extent) with lymphomas is recorded in most patients.

Heavy chain diseases - B-cell lymphatic tumors, accompanied by the production of monoclonal fragments of Ig heavy chains. Heavy chain diseases are very rare. There are 4 types of heavy chain disease: α, γ, μ, δ. Γ heavy chain disease usually occurs in men younger than 40 and is characterized by enlargement of the liver, spleen, lymph nodes, edema of the soft palate and tongue, erythema, and fever. Bone destruction, as a rule, does not develop. The concentration of pathological globulin in the blood serum is low, the ESR is normal. In the bone marrow, lymphoid cells and plasma cells of varying degrees of maturity are found. The disease progresses quickly and ends in death within a few months. Heavy chain disease is diagnosed mainly in the elderly, and is more often manifested by hepatosplenomegaly. The tumor substrate is lymphoid elements of varying degrees of maturity. Single cases of heavy chain δ disease are described; it proceeds as myeloma. Heavy chain disease α is the most common form, developing mainly in children and persons under 30 years of age, 85% of cases are reported in the Mediterranean. Immunoelectrophoresis of blood serum and urine is the only method for diagnosing the disease, since the classical M-gradient on the electrophoregram of blood serum proteins is often absent.

Associated paraproteinemia accompanies a number of diseases, in the pathogenesis of which immune mechanisms play a role: autoimmune diseases, tumors, chronic infections. These diseases include AL amyloidosis and cryoglobulinemia.

The basic principle of the electrophoretic research method is that the molecules in the solution, having an electric charge, under the action of the forces of the electric field are displaced towards the oppositely charged electrode. The migration rate of a substance in a medium with the same electric field strength depends on the size of the particles and their electric charge. In the case of protein molecules, due to their amphoteric properties, the direction and rate of displacement largely depend on the pH of the medium in which migration occurs. The charge of various proteins in solutions with the same pH depends on the amino acid composition, since the dissociation of protein chains leads to the formation of groups with a positive or negative charge. Under the influence of the forces of the electric field, the components of the accelerated system are distributed according to their charge, acquiring the corresponding speed of movement, i.e. electrophoretic separation occurs.
The introduction of electrophoretic "carriers" has led to improved technologies and at the same time to simplify fractionation. Filter paper, cellulose acetate, various gels (polyacrylamide), agarose, etc. are used as "carriers". In this case, during electrophoresis, along with the separation of particles according to their charges, the so-called "molecular sieve effect" comes into force, when the gel structure behaves like a filter in relation to ions. Ions exceeding its porosity do not pass or pass very slowly, while smaller ions penetrate faster through the pores of the carrier. Thus, the speed of movement depends not only on the charge of the ion, but also on the size of the pores of the gel, the shape of the pores, the size of the moving ions, the interaction between the gel matrix and the moving ions (adsorption, etc.).
The history of the creation of electrophoresis began in 1807, when F. Reis, a professor at Moscow State University, discovered such phenomena as electroosmosis and electrophoresis. However, the practical use of this process in biology and medicine began much later and is associated with the name of the Nobel Prize winner in chemistry Arne Tiselius, who in the 30s of the last century developed the method of electrophoresis in free liquid and designed a device for electrophoretic separation and analysis of a mixture of proteins by the method of free or movable boundaries. The main disadvantage of this method was the release of heat when an electric current passed through the liquid, this prevented a clear separation of fractions and led to the blurring of boundaries between individual zones. In 1940, D. Philpot proposed using columns with a density gradient of buffer solutions, and in the 50s the method was improved and a device for density gradient electrophoresis was created.
However, the method was imperfect because after switching off the electric current, the zones formed during electrophoresis “spread out”. Subsequent advances in electrophoresis are associated with the stabilization of zones in a solid support environment. So, in 1950, filter paper began to be used as a solid carrier, in 1955 it was proposed to use starch, and already in 1957 Cohn proposed using cellulose acetate films as a solid carrier, which until now remain one of the most frequently used carriers in clinical research.
Around the same time, a method was developed in which agarose was used as a basis. In 1960, the method of capillary electrophoresis was developed, and only in 1989, the first analyzer was created and introduced into practice, which was based on the method of capillary electrophoresis.
The main importance of electrophoresis is the detection of abnormalities in the protein profile and, since the 1960s, serum protein electrophoresis has become a popular screening method for laboratory research. To date, more than 150 individual serum proteins are already known, and a significant part of them can be quantified using various modern enzyme immunoassays, immunochemiluminescent, nephelometric and immunoturbidimetric methods. But with all the information content and evidence of these analyzes, they are still largely inaccessible due to the comparative high cost, and also require expensive equipment in the laboratory (nephelometer).
At the same time, typical shifts in the protein composition of blood serum can be determined by a much more accessible electrophoretic method, which also allows one to evaluate the general picture of the protein spectrum and obtain significant diagnostic information with one glance. That is why the electrophoretic analysis of serum proteins remains, along with the biochemical blood test, a popular screening research method. For example, in the United States, Japan and some Western European countries, the traditions of determining the protein fractions of blood serum before performing a biochemical blood test have been preserved. However, most often, protein electrophoresis is prescribed after biochemical and general clinical blood tests.
Protein electrophoresis helps to identify diseases of the liver and kidneys, the immune system, some malignant neoplasms (multiple myeloma), acute and chronic infections, genetic breakdowns, etc. A number of peculiar electrophoretic "syndromes" are known - typical pictures of electrophoregrams characteristic of some pathological conditions. Among them are:
1. Monoclonal gammopathies are the collective name for a whole class of diseases in which pathological secretion of abnormal immunoglobulins, altered in chemical structure, molecular weight or immunological properties, occurs by one clone of plasma cells or B-lymphocytes. These immunoglobulins then disrupt the functions of certain organs and systems, for example, the kidneys, which leads to the development of symptoms of the disease.
2. Acute inflammation with activation of the complement system and an increase in the synthesis of acute phase proteins
(a1-antitrypsin, haptoglobin, fibrinogen, etc.). It is manifested by an increase in the proportion of a1- and a2-globulins and can be confirmed by measuring ESR, studying the concentration of C-reactive protein, fibrinogen (in dynamics) and other acute phase proteins.
3. Chronic inflammation with increased synthesis of a number of acute phase proteins, as well as immunoglobulins; is manifested by a moderate increase in a2- and b-globulins, an increase in g-globulins and a slight decrease in albumin. Similar deviations can be observed in chronic infections, collagen diseases, allergies, autoimmune processes and malignancy.
4. Severe liver diseases are accompanied by a decrease in the synthesis of albumin and a-globulins, which is reflected in the electropherograms. In chronic hepatitis and liver cirrhosis, both the relative and the absolute amount of g-globulins increase (b- and g-fractions can merge due to the accumulation of IgA), and the excess of g-globulins over albumin is a very unfavorable prognostic sign.
5. Nephrotic syndrome is accompanied by an increase in protein filtration in the kidneys and selective proteinuria -
loss with urine of a large amount of albumin and part of low molecular weight globulins (a1-antitrypsin, transferrin). At the same time, the liver increases the synthesis of larger proteins of the a2-globulin family (macroglobulin, apo-B), which accumulate in the blood and form a picture with a significant decrease in albumin and an increase in
a2-globulins.
6. Impaired absorption or significant loss of proteins is possible both with nephrotic syndrome and with massive burns, Laelle syndrome, pathology of the gastrointestinal tract, etc. In the latter case, the absolute content of total protein and especially albumin decreases, and on the proteinogram, the proportion of albumin is reduced with a relatively uniform increase in all globulins. The introduction of protein preparations (immunoglobulins, albumin or blood plasma) during the treatment of patients is immediately reflected in the electrophoretic picture, which makes it possible to monitor the dynamics of losses or excretion of the incoming proteins.
7. Severe immunodeficiency of congenital or acquired genesis is usually accompanied by a pronounced decrease in the g-globulin fraction. In this case, it is desirable to carry out an additional quantitative determination of IgG, IgA and IgM.
Due to the fact that clinical electrophoresis is the "gold standard" for detecting monoclonal gammopathies, I would like to dwell in more detail on the diagnosis of this disease.
Monoclonal gammopathies are a group of malignant neoplasms of B-lymphocytic cells, the morphological substrate of which are cells that produce monoclonal immunoglobulin (paraprotein). The number of newly diagnosed cases of multiple myeloma in the United States in 2010, according to the American Cancer Society, was 20 180. The number of deaths from this disease was 10 650. The average age of men at the time of diagnosis was 62 years (75% were over 70 years old). women - 61 years old (79% were over 70 years old). The incidence is 7.8 per 100 thousand population.
In the UK in 2007, 4040 cases of newly diagnosed multiple myeloma were reported. The incidence is 6.5 per 100 thousand population. In the Republic of Belarus (according to the Belarusian Cancer Registry (BKR), in 2007, 39,003 cases of diseases with a newly diagnosed diagnosis were registered, which corresponds to an average of 106.9 cases of diseases per day.
At the same time in Russia in 2007, according to the Bulletin of the Russian Cancer Research Center of the Russian Academy of Medical Sciences, only 2372 primary cases of multiple myeloma were registered, the incidence was 1.7 per 100 thousand population.
Such a significant difference in the incidence of multiple myeloma in the United States, European countries and Russia is due to the lack of a single algorithm in the diagnosis of this disease, screening programs in our country. The National Comprehensive Cancer, the most influential cancer organization in America, is recommended by the National Comprehensive Cancer for a suspected multiple myeloma -
includes the following diagnostic measures:
General blood test (with the obligatory calculation of the blood count).
A detailed biochemical blood test (separation of serum proteins into fractions, creatinine, urea, electrolytes, liver enzymes, beta-2-microglobulin level).
Immunofixation electrophoresis (to establish the type of paraproteinemia).
Electrophoresis of urine proteins and immunofixation of urine proteins (daily urine) for the diagnosis of light chain disease.

It should be noted that the main importance in these recommendations is given to the method of electrophoresis and immunofixation of serum and urine proteins to identify the monoclonal component (paraprotein). The presence of paraprotein in serum or urine is the most frequent and earliest laboratory manifestation of multiple myeloma. To detect it, protein electrophoresis is performed, and then -
immunofixation electrophoresis of serum and urine. With monoclonal gammopathies, the content of gamma globulins in the serum usually increases, and on the electropherogram in this zone, an acute
peak called M-gradient
(from the word "monoclonal"). The magnitude of the M-gradient reflects the mass of the tumor. The M-gradient is a reliable and sufficiently specific tumor marker for mass examinations. Immunofixation electrophoresis is also indicated for patients with a high likelihood of multiple myeloma, but conventional electrophoresis did not reveal any additional bands. Light chains (kappa or lambda) in blood serum are detected only by the method of immunofixation and provided that their concentration exceeds 10 norms. Therefore, it is always necessary to carry out electrophoresis of urine proteins simultaneously with serum electrophoresis.
Considering that multiple myeloma is a disease that in most cases is diagnosed in people over 50 years old, as well as the importance of diagnosing this disease at an early subclinical stage (the average duration of the disease at
Stage I - 62 months, with III - 29 months), in the USA and a number of European countries there are screening programs for people over 50 years old. The essence of such programs lies in the annual fulfillment of the obligatory list of screening laboratory tests, in which the electrophoresis of serum and urine proteins is included on a par with the general analysis of blood, urine and biochemical studies.
In some cases, the M-gradient can be observed in practically healthy people. In these cases, we are talking about monoclonal gammopathy of unknown origin. This condition occurs much more often - in 1% of people over 50 and almost 10% over 75. This condition does not require treatment, but requires constant monitoring, since such patients are likely to develop multiple myeloma. Monitoring should include regular examinations with the measurement of the level of M-gradient (paraprotein) in serum by electrophoresis; for low risk of progression, check-up intervals should be 6 to 12 months.
In recent years, significant progress has been made in the treatment of this disease. The five-year disease-free survival rate increased from 24% in 1975 to 35% in 2003. These successes can be explained, on the one hand, by the development of new, modern chemotherapy regimens, in a number of cases with high-dose polychemotherapy with bone marrow allotransplantation, and, on the other hand, by adequate diagnosis and development of uniform criteria for assessing the response to the therapy, as well as monitoring the concentration level. paraprotein in serum and / or urine by electrophoresis to determine residual disease.
Thus, at present, none of the research groups involved in the diagnosis and treatment of multiple myeloma has no doubts about the extreme importance of analyzing the separation of protein fractions of blood serum and conducting immunofixation electrophoresis as the only, most accurate and accessible method for diagnosing and monitoring multiple myeloma. myeloma.

LITERATURE:

1. Gilmanov A.Zh., Salyakhova R.M. Whey Protein Electrophoresis: Modern Analysis Possibilities, http://med.com.ua
2. Sergeeva NA / Electrophoresis in the modern diagnostic process // Clin. lab. diagn. - 1999. - No. 2. - P. 25 - 32.
3. Shevchenko OP, Dolgov VV, Olefirenko GA / Electrophoresis in a clinical laboratory. Serum proteins / From: "Triada", Tver, 2006, 160 p.
4. Jemal, A., Siegel, R., Xu, J. et al. (2010) Cancer statistics, 2010. CA: A Cancer Journal for Clinicians, 60, 277-300.
5. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma, Blood. 2008 Mar 1; 111 (5): 2521-6.
6. Davydov MI, Axel EM / Statistics of malignant neoplasms in Russia and the CIS countries in 2007 // Bulletin of the Russian Oncology Center. Volume 20, No.3 (77), appendix 1,
july - September 2009, 158 p.
7. National Comprehensive Cancer Network / Clinical Practice Guidelines in Oncology // Multiple Myeloma, version 1.2011, 52 pg.

Monoclonal gammopathies (immunoglobulinopathies, paraproteinemias) are a heterogeneous group of diseases characterized by monoclonal proliferation of B-lymphoid cells secreting immunoglobulins.

The main distinguishing feature of these diseases is the production of monoclonal immunoglobulin (M-component, M-gradient, M-protein, paraprotein), which is determined in blood serum and / or urine.

The bulk (almost 80%) of all immunoglobulins make up IgG, which provide the whole variety of antibodies to bacteria, their toxins, viruses and other antigens. Normal IgGs are a mixture of 4 subclasses: IgG1, IgG2, IgG3, and IgG4. All types of IgG cross the placenta and provide passive immunization of the fetus. The ratio of IgG of different subclasses in the paraprotein in multiple myeloma and monoclonal gammopathies of unknown origin does not differ from the ratio in normal serum.

Class A immunoglobulins (about 20% of all immunoglobulins) are contained in blood serum, there are many of them in secretions (intestinal and respiratory tracts, saliva, lacrimal fluid, milk). They have antiviral and antimicrobial activity, prevent the penetration of microorganisms through the mucous membranes. Immunoglobulins of class M are determined mainly on the surface of B-lymphocytes and play a major role in the first stage of the immune response in bacteremia and viremia in the early stages of infection. Immunoglobulins of class D are found in serum in very small amounts (less than 1%), their function is still unclear.

In small amounts in whey blood contains IgE, their content increases with allergic diseases and helminthic invasions.

With electrophoresis, normal immunoglobulins, dissimilar in their properties, are located in the zone y, forming a gently rising plateau on the electrophoretogram or a wide band during immunofixation. Monoclonal immunoglobulins, homogeneous in all physicochemical and biological parameters, migrate mainly to zone y, rarely to zone b and even a, where they form a high peak or a clearly delimited band. Until now, in many countries, the method of electrophoresis on cellulose acetate is used, which allows detecting the presence of paraprotein if its content in serum exceeds 7 g / l.

Monoclinal gammopathies

First 70s of XX century... The most common method is agarose electrophoresis, which allows the determination of monoclonal immunoglobulin at a concentration of at least 0.5 g / l in blood plasma, and in urine - 0.002 g / l. To determine the class and type of immunoglobulin, the method of immunofixation using monospecific antisera to heavy and light chains of immunoglobulins is used. The amount of paraprotein is determined by electrophoregram densitometry.

Tumor cells paraproteinemic hemoblastosis preserve the differentiation of normal lymphoid and plasma cells and the ability to a high level of synthesis and secretion of immunoglobulin. In both normal and pathological immune responses, each plasma cell can synthesize and secrete up to 100,000 antigen-specific immunoglobulin molecules every minute. Based on the synthesis and secretion of electrophoretically and immunochemically homogeneous immunoglobulin and the correspondence of its amount to the tumor mass, it was shown that malignant plasma cells are monoclonal, i.e., they originate from one transformed lymphocyte or plasma cell.

Fine intracellular synthesis of H- and L-chains in cellsproducing antibodies are well balanced. In some cases, in malignant clones, the balance between the synthesis of H- and L-chains is disrupted towards increased production of the latter. Monoclonal dimers and monomers of L-chains, having a small molecular weight, are filtered by the renal glomeruli, then partially undergo reabsorption and catabolism in the renal tubules, and partially excreted in the urine (Bence Jones protein).

The structure of H-chains, apparently, remains normal in multiple myeloma and Waldenstrom's macroglobulinemia.

Malignant plasma cell proliferation, such as multiple myeloma, Waldenstrom's macroglobulinemia, are characterized by the production of monoclonal immunoglobulin and certain clinical symptoms. M-protein is found in some cases in practically healthy people. In such cases, they talk about monoclonal gammapaties of undetermined significance (MGNG, MGUS - monoclonal gammapaties of undetermined significance).

In the 60-70s of the XX century, when it was used electrophoresis technique on cellulose acetate, monoclonal gammopathy was diagnosed in 0.7-1.2% of the healthy population. Since the beginning of the 1980s, after the introduction into practice of a more sensitive technique - agar electrophoresis, M-paraprotein began to be detected in 5% of the healthy population aged 22 to 55 years (when using cellulose acetate electrophoresis in the same group, monoclonal gammopathy was recorded only in 0.33%). The frequency of monoclonal gammopathy increases to 7-8% in the group over 55 years old and reaches 10% in the group over 80 years old, while in 80% of persons with an identified M-gradient its concentration in serum is very low - less than 5 g / l.

According to the Mayo Clinic, of all monoclonal gammopathies in half of the cases, monoclonal gammopathies of unknown origin (MGNG) are detected (52%), in 12% of patients - amyloidosis and in 33% - malignant paraproteinemia: multiple myeloma (19%), indolent myeloma (5%), solitary plasmacytoma (3%) , Waldenstrom's macroglobulinemia (3%), other types of lymphomas with paraprotein secretion (3%). In 3% of cases, monoclonal gammopathy accompanies other malignant tumors.

A key indicator for the diagnosis of a malignant protein-producing tumor is a high concentration of M-paraprotein in the blood serum.

Research has shown J. Moller-Petersen and E. Schmidt, the assumption of multiple myeloma turned out to be correct in 90% of cases when the concentration of M-paraprotein in serum is more than 30 g / l, and the assumption of MGNH - in 90% of cases with lower values \u200b\u200bof the concentration of M-paraprotein.

Main differential diagnostic criteria for distinguishing myoclonal gammopathy of unknown origin from smoldering myeloma and multiple myeloma

Thus, the higher serum M-protein level, the more likely it is that the patient has developed a malignant tumor with the secretion of paraprotein.

Probability development of a malignant tumor associated with the duration of the monoclonal. R. Kyle et al. (Mayo Clinic) observed a large group of patients with monoclonal gammopathies. With a follow-up period of 10 years, malignant transformation occurred in 16% of patients with MGNH, at 20 years - in 33%, and with a follow-up period of 25 years - in 40% of patients. The risk of transformation is 1-2% per year. Monoclonal gammopathies of unknown origin are most often transformed into myeloma (68%), much less often in patients with monoclonal gammopathies of unknown origin (MGNG) transformation into Waldenstrom's macroglobulinemia (11%) and lymphoma (8%), even less often into heavy chain disease.

In most cases monoclonal gammopathies of unknown origin will not have time to undergo malignant transformation, since in 80% of patients with monoclonal gammopathies, the concentration of M-paraprotein in the blood serum is significantly lower than 30 g / l, and the age of the absolute majority of people with identified paraproteinemia is over 40 years.

Immoglobulin class detected when monoclonal gammopathies of unknown origin (MGNG), largely determines the type of possible transformation. The risk of transformation into Waldenstrom's lymphoma or macroglobulinemia is higher in patients with monoclonal gammopathies of unknown origin (MGNG) and IgM production, while monoclonal gammopathy of unknown origin (MGNG) with production of IgA or IgG is more often transformed into multiple myeloma, AL-amyloidosis or other diseases accompanied by plasma cell proliferation.

The main medical tactic is to observe the patient - "watch and wait". Most often, monoclonal gammopathy of unknown origin is transformed into myeloma, therefore, it became necessary to systematize the criteria that determine the risk of such transformation and the observation algorithm. The table presents the criteria for differentiating monoclonal gammopathy of unknown origin from smoldering myeloma, which also uses the “watch and wait” tactic, and from multiple myeloma, which requires chemotherapy.

Besides the task primary differential diagnosis, there is a problem of determining the tactics of patient management and predicting the possible transformation of monoclonal gammopathy of unknown origin.

In recent years, a number of authors have proposed various prognostic criteria to help determine the follow-up algorithm and the need for treatment initiation.
Researchers from MD Anderson Cancer Center (USA) in multivariate statistical analysis showed that the most significant prognostic factors are the level of paraprotein in the blood serum and the presence of spinal lesions according to magnetic resonance imaging (MRI). The low risk of transformation was in patients with no changes in the spine according to MRI and a paraprotein level of 30 g / L or less; the median follow-up before progression was 79 months. Patients with either MRI changes or paraprotein levels above 30 g / l were included in the intermediate risk group. The median time to progression was 30 months. A high risk of transformation was in the group of patients who had MRI changes and a paraprotein level\u003e 30 g / l; median to progression 17 months

For patients with an intermediate prognostic group, an additional prognostic factor was the type paraprotein - IgA. When normal MRI was combined with the absence of other risk factors or the presence of only one of them, the median before progression was 57 months, and the presence of changes on MRI in combination with one or two prognostic factors reduced the median to progression to 20 months. Not all investigators support an unfavorable predictive value for IgA paraprotein.

In recent years, research, aimed at identifying cytogenetic changes that could predict a close transformation of monoclonal gammopathy of unknown origin. The method of fluorescence in situ hybridization (FISH) revealed 14q32 rearrangement in almost half of patients with monoclonal gammopathy of unknown origin, deletion of chromosome 13 was detected 2 times less frequently than in multiple myeloma, at (4; 14) almost never occurred in monoclonal gammopathy of unknown origin ( 2%). Correlation of these cytogenetic changes with the clinical course in monoclonal gammopathy of unknown origin could not be identified.

Upon detection monoclonal gammopathy of unknown origin and after confirming this diagnosis, in accordance with modern requirements, it is recommended to adhere to the following observation algorithm. In the absence of complaints in the patient during the first year, a study of the level of paraprotein is carried out every 3 months and an MRI scan - after six months. If within 1 year the increase in the level of paraprotein and changes in MRI are not detected, then the study of paraprotein is performed 1 time in 6-12 months, and MRI - 1 time per year.

Paraproteins in blood serum are normally absent.

Immunoglobulinopathies, or gammopathies, unite a large group of pathological conditions characterized by polyclonal or monoclonal hypergammaglobulinemia. Ig is composed of two heavy (H) chains (molecular weight 50,000) and two light (L) chains (molecular weight 25,000). The chains are connected by disulfide bridges and consist of structures called domains (H - of 4, L - of 2 domains). Under the action of proteolytic enzymes, Ig are divided into fragments

you: Fc-fragment and Fab-fragment. Human Ig heavy chains are represented by five structural variants, which are denoted by the letters of the Greek alphabet. They correspond to 5 classes of Ig - G, A, M, D, E. Light chains are represented by two structurally different variants: k (kappa) and X (lambda), which correspond to two types of Ig of each class. In each Ig molecule, both heavy and both light chains are identical. All people normally have Ig of all classes and both types, but their relative content is not the same. The ratio of k and X molecules within different Ig classes is also not the same. Detection of violations of Ig ratios or their fragments plays an important role in the diagnosis of monoclonal immunoglobulinopathies.

Monoclonal immunoglobulinopathy (paraproteinemia) is a syndrome manifested in the accumulation of Ig or their fragments in the blood serum and / or urine of patients homogeneous in all physicochemical and biological parameters. Monoclonal Ig (paraproteins, M-proteins) are the secretion product of one clone of B-lymphocytes (plasma cells), therefore they represent a pool of structurally homogeneous molecules with heavy chains of the same class (subclass), light chains of the same type and variable regions of the same structure. Monoclonal immune globulinopathies are usually divided into benign and malignant. In benign forms of monoclonal gammopathies, the proliferation of plasma cells is controlled (possibly by the immune system) in such a way that there are no clinical symptoms. In malignant forms, an uncontrolled proliferation of lymphoid or plasma cells occurs, which determines the clinical picture of the disease. The classification of monoclonal immunoglobulinopathies is given in Table ..

Table Classification of monoclonal immunoglobulinopathies

Immunoelectrophoresis of blood serum proteins allows detecting monoclonal (pathological) IgA, IgM, IgG, H and L chains, paraproteins. In ordinary electrophoresis, normal Ig, dissimilar in properties, are located in the y zone, forming a plateau or a wide band. Due to their homogeneity, monoclonal Ig migrates mainly to the Y zone, occasionally to the p zone and even to the a region, where they form a high peak or a clearly demarcated band (M-gradient).

Multiple myeloma (Rustitsky-Kalera disease) is the most common paraproteinemic hemoblastosis; it is detected no less often than chronic myelo- and lymphocytic leukemia, lymphogranulomatosis and acute leukemia. The class and type of pathological Ig secreted by myeloma determines the immunochemical variant of the disease. The frequency of classes and types of pathological Ig in myeloma generally correlates with the ratio of classes and types of normal Ig in healthy people (table).

Along with an increase in the content of pathological Ig in the serum of patients with multiple myeloma, normal Ig in a reduced concentration is determined. The total protein content is sharply increased - up to 100 g / l. The activity of the process in G-myeloma is assessed by the number of plasma cells in the sternal punctate, the concentration of creatinine and calcium in the blood serum (their increase in calcium indicates the progression of the disease). The concentration of M-protein (in urine it is called Bens-Jones protein) serves as a criterion for assessing the progression of the disease in A-myeloma. The concentration of paraproteins in serum and urine varies during the course of the disease under the influence of therapy.

To make a diagnosis of multiple myeloma, the following criteria must be met.

Big criteria

1. Plasmacytoma based on biopsy results.

2. Plasmacytosis in the red bone marrow (more than 30% of cells).

3. Peaks of monoclonal (pathological) Ig in serum protein electrophoresis: more than 35 g / l for the peak of IgG or more than 20 g / l for the peak of IgA. Excretion of k- and lambda-chains in an amount of 1 g / day or more, detected by urine electrophoresis in a patient without amyloidosis.

Small criteria

1. Plasmacytosis in the red bone marrow of 10-30% of cells.

2. The peak of PIg in serum is less than indicated above.

3. Lytic lesions of bones.

4. The concentration of normal IgM is below 0.5 g / L, IgA is below 1 g / L, or IgG is below 0.6 g / L.

Table Main immunochemical variants of multiple myeloma and their characteristics

To make a diagnosis of multiple myeloma, at least 1 major and 1 minor criteria or 3 minor criteria are required with the mandatory presence of the criteria given in points 1 and 2.

To determine the stage of myeloma, the standardizing Dury-Salmon system is used, which reflects the volume of the tumor lesion (table).

All groups of myelomas are divided into subclasses depending on the state of renal function: A - serum creatinine concentration below 2 mg% (176.8 μmol / L), B - more than 2 mg%. In case of multiple myeloma, a high concentration of b 2 -microglobulin in the blood serum (more than 6000 ng / ml) suggests an unfavorable prognosis, as well as a high LDH activity (above 300 IU / L, setting the reaction at 30 ° C), anemia, renal failure, hypercalcemia, hypoalbuminemia, and large tumor volume.

Light chain diseases (Bence Jones myeloma) account for approximately 20% of myeloma cases. In Bens-Jones myeloma, exclusively free light chains are formed, which are detected in the urine (Bens-Jones protein), in the absence of serum pathological Ig (M-gradient).

Multiple Myeloma Stages Table

Rare immunochemical variants of myeloma include non-secreting myeloma, in which paraproteins can be found only in the cytoplasm of myeloma cells, as well as diclonic myelomas and M-myeloma.

Waldenström's macroglobulinemia is a chronic subleukemic leukemia of a B-cell nature, morphologically represented by lymphocytes, plasmocytes and all transitional forms of cells synthesizing PIgM (macroglobulin). The tumor has a low grade of malignancy. In the red bone marrow, proliferation of small basophilic lymphocytes (plasmacytoid lymphocytes) is detected, the number of mast cells is increased. On the electrophoretogram of blood serum proteins, an M-gradient is detected in the zone of b- or y-globulins, less often the paraprotein does not migrate in the electric field, remaining in place. Immunochemically, it represents PIgM with one type of light chains. The concentration of PIgM in blood serum in Waldenström macroglobulinemia ranges from 30 to 79 g / l. In 55-80% of patients, Bens-Jones protein is found in the urine. The concentration of normal Ig in the blood decreases. Renal failure is uncommon.

Lymphomas. IgM-secreting lymphomas are most often recorded, the second place is taken by paraproteinemic lymphomas, secreting IgG, lymphomas with IgA-paraproteinemia are detected extremely rarely. A decrease in the concentration of normal Ig (usually to a small extent) with lymphomas is recorded in most patients.

Heavy chain diseases - B-cell lymphatic tumors, accompanied by the production of monoclonal fragments of Ig heavy chains. Heavy chain diseases are very rare. There are 4 types of heavy chain disease. Heavy chain disease usually occurs in men under 40 and is characterized by enlarged liver, spleen, lymph nodes, edema of the soft palate and tongue, erythema, and fever. Bone destruction, as a rule, does not develop. The concentration of pathological globulin in the blood serum is low, the ESR is normal. In the bone marrow, lymphoid cells and plasma cells of varying degrees of maturity are found. The disease progresses quickly and ends in death within a few months. Heavy chain disease is diagnosed mainly in the elderly, and is more often manifested by hepatosplenomegaly. The tumor substrate is lymphoid elements of varying degrees of maturity. Single cases of heavy chain disease 8 have been described; it proceeds as multiple myeloma. Heavy chain disease a is the most common form, developing mainly in children and persons under 30 years of age, 85% of cases are reported in the Mediterranean. Immunoelectrophoresis of blood serum and urine is the only method for diagnosing the disease, since the classical M-gradient on the electrophoretogram of blood serum proteins is often absent.

Associated paraproteinemia accompanies a number of diseases, in the pathogenesis of which immune mechanisms play a role: autoimmune diseases, tumors, chronic infections. These diseases include AL amyloidosis and cryoglobulinemia.

Idiopathic paraproteinemias occur in the elderly and may present as premyeloma conditions. In such cases, a thorough examination is necessary to identify the initial stage of the disease and long-term follow-up.