Multiple myeloma — the malignant tumor of system of V-lymphocytes arising at the level pre - In - cellular stages of monoclonal development and keeping differentiation potency to a final stage — a plasmocyte. Definition of a multiple myeloma as plazmokletochny tumor with a paraproteinemia not absolutely precisely as the option of a disease at which pathological cells synthesize immunoglobulins is allocated, but do not cosecrete them in blood (the so-called not cosecreting myeloma).
Epidemiology There are data on considerable fluctuations of the standardized indicators of incidence of a multiple myeloma in various countries. In our country according to selective researches of a multiple myeloma meets in 5,3% of cases of all diseases of hemoblastoses. The annual average standardized incidence indicators in various territories fluctuated from 0,3 to 1,1 (see Hemoblastoses).
The multiple myeloma is observed equally often at men and women. More often aged people get sick 50 years are more senior.
Etiology and pathogeny The origin of paraproteinemic hemoblastoses from one cell is confirmed by uniformity of paraproteins on a class, type of L-chains, hallo - and to an idiotype, compliance of amount of the cosecreted immunoglobulins to the mass of a tumor.
Results of immunomorphological researches convince that tumoral process at a multiple myeloma and Valdenstrem's macroglobulinemia arises at the level of V-kletok-predshestvennits and does not depend on antigenic incentive.
At a terminal stage of a course of these diseases along with the general manifestations characteristic of hemoblastoses, find changes of products of monoclonal Ig.
Classification According to immunochemical classification allocate 5 main forms MM: G, A, D, E and Bens-Jones; treat rare forms not cosecreting and the M-myeloma. Frequency of distribution of immunological types of a myeloma approximately corresponds to concentration of various classes of normal immunoglobulins in blood serum: The G-myeloma is found in 50% of cases, the A-myeloma — in 25%, a D-myeloma — in 1%, the M-myeloma and not cosecreting form meet very seldom.
Light chains of N and lambda in a molecule of paraproteins are distributed approximately evenly, as well as at Bens-Jones's paraproteinemia, at a D-myeloma usually find a lambda chain. The Plazmokletochny leukosis is allocated as the independent nosological form different from a multiple myeloma with fast progressing of process, existence of a significant amount of plasmocytes in blood, thrombocytopenia with the expressed hemorrhagic syndrome, an extensive plasmatic infiltration in various bodies.
Depending on the size of tumoral weight distinguish three stages of a multiple myeloma. At the 1st stage it low (to 0,6 mg/sq.m), at the 2nd — average (0,6 — 1,2 mg/sq.m), at the 3rd — high (more than 1,2 mg/sq.m); 1012 cells approximately make 1 kg. Reliable distinctions between survival of patients and initial size of tumoral weight which in a course of disease allows to estimate effect of therapy also are noted.
Approximate formulation of the diagnosis: 1. A multiple myeloma of IgG, the 1st stage with a little increased spleen and an insignificant infiltration of marrow plasmocytes. 2. A multiple myeloma of IgA, the 3rd stage with damage of bones (edges, a breast, a calvaria, a basin, a backbone, the lower extremities); the expressed plazmokletochny infiltration of marrow, increase in a spleen and liver; a hyper viscous syndrome, hemorrhages (nasal, gingival, intestinal), with an iron deficiency anemia; acute renal failure.
Clinic. The developed clinical picture of a disease is usually preceded by the asymptomatic period of various duration.
The main syndromes of the developed clinical picture of a multiple myeloma
Damages of a skeleton
Radiological the miyelomatozny tumors of various sizes in edges, a breast, a backbone, a clavicle, a skull, extremities which are shown the pains in the beginning having flying character are found, then they become more intensive and long. Quite often there are pathological changes with deformation of a thorax, a compression of bodies of lumbar and chest vertebrae
Defeats of a nervous system
They are connected in most cases with tumoral damage of bones of a calvaria and a backbone therefore can develop a paraplegia, a syndrome of a prelum of roots of spinal nerves, a hemiplegia or a hemiparesis. In some cases diencephalic and pituitary and mental disorders, giperkaltsiyemichesky encephalopathy are observed
The myelome nephropathy arising at 60 — 90% of patients is characterized by a proteinuria, a renal failure, an angioretinopatiya, hypostases and a hamaturia. Owing to destruction of bones the hypercalcemia and a giperkaltsiurikemiya is observed. At 1/3 patients the azotemia is a cause of death
Hyper viscous syndrome
It is caused by high content in serum of proteins, meets at a myeloma of IgG and IgA. Changes of an eyeground and possible development of heavy disturbances of the central nervous system are connected with the increased viscosity of blood
Disturbances of platelet, plasma and vascular factors of a hemostasis. Paraproteins settle on membranes of thrombocytes. They form complexes with V, VII, VIII factors of coagulation, a prothrombin, fibrinogen
Disturbances of a hemogenesis
More often normokhromny anemia develops. At bleedings it has iron deficiency character, in cases of deficit of B12 vitamin and folic acid in marrow lines of a megaloblastichesky hemopoiesis come to light. The miyelomonokletochny infiltration is found in 86 — 90% of patients at researches of a marrowy hemopoiesis
Decrease in content in blood serum of level of normal immunoglobulins (frequent less than 20%), disturbance the antiteloobrazovaiiya, reduction of quantity of granulocytes and their functional deficiency cause predisposition of patients to infections
At this disease tumoral defeats have multiple character. Only in 2 — 10% of cases allocate solitary plazmokletochny tumors which look as cysts in soft tissues, in a respiratory path, an oral cavity, kidneys, ovaries, intestines. However after certain time at most of patients, even after radical excision or radiation of the center, the diffusion form of an illness develops.
At the long course of process increase a spleen (in 15 — 31,2% of cases), a liver (in 17 — 46% of cases), lymph nodes, are surprised kidneys, is more rare — a thyroid gland, adrenal glands, ovaries, lungs, a pericardium and a digestive tract.
At histologic research of a liver along with a specific plazmokletochny infiltration find also nonspecific changes as a "muscat" liver, her fatty dystrophy. Increase in a spleen is caused by a plazmotsitarny infiltration on the course of sine or growths of plazmotsitomny nodes.
The ascending nephrosclerosis caused by big reabsorbtsionny load of proximal departments of tubules owing to filtering of a glomerulama of large numbers of a protein of Bens-Jones is the cornerstone of a renal failure.
The hyperuricemia caused by the increased cellular disintegration which often amplifies against chemotherapy leads to adjournment of klistall of uric acid in distal departments of tubules, ureters, an urethra. Preliminary preparation by dehydration before an intravenous piyelografiya, use of some contrast agents can cause an acute renal failure. In 2 — 5% of cases the cryoglobulinemia is found. Its clinical manifestation are the symptom of a cold allergy, a Crocq's disease, "tinglings", numbness of extremities and a true phenomenon of Reynaud. Trophic changes of extremities, gangrene of fingers, hemorrhages, fibrinferments of large blood vessels are sometimes observed.
At 10 — 20% of patients with a multiple myeloma the paraamiloidosis develops. Its confirmation requires research of bioptat of skin, mucous membranes, lymph nodes, muscles and other fabrics. In 10 — 12% of cases it can be a cause of death.
Typical myeloma cells are characterized by a rounded or oval shape, kernels round, are located excentricly and support one or several nukleol. Sometimes it is cells of bigger diameter and 2 — 3 kernels, cytoplasm of their bazofiln or bright blue with various shades contain. In marrow also histiocytes, lymphocytes and lymphoid cells with a cytoplasm basophilia are found.
In most cases of a multiple myeloma the typical M-component and (or) Bens-Jones's protein define. There are rare forms of an illness at which myeloma cells do not cosecrete monoclonal abnormal immunoglobulin ("not cosecreting myelomas"). Structural identification M-kompoiyenta is established by methods of an immunoelectrophoresis and immunodiffusion.
The simple form of a cryoglobulinemia which symptomatology corresponds to a syndrome of the increased viscosity of blood is characteristic of paraproteinemic hemoblastoses. The mixed form of a cryoglobulinemia meets at limfoproliferativny V-cellular tumors, autoimmunno aggressive, infectious and parasitic diseases.
Verification of the diagnosis Immunological researches with a set of antiserums against heavy and light chains of immunoglobulins allow to differentiate a multiple myeloma and Valdenstrem's macroglobulinemia (existence of IgM), diseases of heavy chains, a mu, at, and (lack of light chains in an immunoglobulin molecule). The diagnosis of not cosecreting myeloma is verified by means of reaction of Coons (an immunofluorescence method).
Detection only of a monoclonal gammapathy without morphological substrate of an illness does not serve as the proof of existence of a paraproteinemic hemoblastosis. In similar cases repeated researches of marrow, histologic researches of other centers of defeat are necessary. It is necessary to remember that monoclonal gammapathies can have reactive character at many diseases, occur as a constitutional and age high-quality form at elderly people. Differential dianosticheskimi criteria in similar cases are the low level of paraproteins in blood, absence of dynamics of its increase, sufficient content of normal immunoglobulins, normal indicators of a gemogramma and a miyelogramma at dynamic research. Finally it is possible to be convinced of high quality of a monoclonal gammapathy only at long-term supervision over the patient.
Treatment At patients with a multiple myeloma somatic and hematologic compensated (stages of IA and NA) abstain from cytostatic therapy under control of monthly research of a gemogramma and level of pathological immunoglobulin (Pig). At part of patients within several years the slow form of an illness can come to light. At emergence of signs of progressing of process (increase of tumoral weight, existence of a pain syndrome, anemia, increase of quantity of Pig) resort to cytostatic therapy. The alkylating drugs were widely used: sarcolysine, melfalan (left-handed isomer of sarcolysine), Cyclophosphanum (endoksan), derivative nitrozomochevina.
Sarcolysine is applied orally on 10 — 20 mg every other day, the course dose makes 100 — 300 mg. It appoint at initial quantity of leukocytes 5*109/l and thrombocytes 150*109/l. At decrease in quantity of leukocytes to 1 — 1,5*109/l, thrombocytes below 50*109/lsarkolizin cancel. In polyclinic conditions it is not recommended to continue administration of drug at quantity of leukocytes less than 3*109/l and thrombocytes less than 100*109/l. In the beginning intervals between therapy courses (usually apply 3 — 4 courses) make 1,5 — 2 months, then at stabilization of medical effect they increase to 3 — 4 and even 6 months. At bad portability of oral administration of sarcolysine, in case of sharply expressed the ossalgy drug is administered intravenously (10 — 20 mg with an interval of 1 — 2 day, on a course of treatment of 100 — 200 mg). After 1,5 — a 2-month break at normal quantity of leukocytes and thrombocytes treatment is repeated, but use a smaller dose of sarcolysine (80 — 100 mg on a course of treatment). At such tactics of treatment development of a deep irreversible cytopenia usually is not observed.
Cyclophosphanum differing in reversible tsitopenichesky action is applied even at an initial leykotsitopeniya (1,5 — 2*109/l) and thrombocytopenia (50 — 100*109/l) intravenously in 1 — 3 day in a single dose from 100 to 200 mg. When progressing a cytopenia intervals between administrations of drug increase. The course dose usually makes 8 — 10 g. Repeated courses (2 — 3 times) are conducted in 1,5 — 2 months. In breaks between courses appoint the supporting treatment the same single doses of drug (once a week). In cases of the persistent radicular pains caused by infiltrative and destructive process in vertebrae iitratekalny introduction of Cyclophosphanum in a single dose of 400 mg with an interval of 7 — 14 days is justified.
Positive takes at treatment by sarcolysine (melfalany) and Cyclophosphanum are observed at 50% of patients, at a combination of these drugs to corticosteroid hormones efficiency considerably increases.
At development of resistance to monochemotherapy in the conditions of a hospital use polychemotherapy, in particular schemes TsSVP (Cyclophosphanum, sarcolysine, Vincristinum and Prednisolonum) and TsNP (Cyclophosphanum, Natulanum, Prednisolonum).
The polychemotherapy as the first method can be applied at the III stage of the multiple myeloma proceeding with sharply expressed osteodestructive syndrome. At a cytopenia, an azotemia, infectious and inflammatory processes it is not recommended to appoint it.
The course of treatment according to the scheme TsSVP (table) lasts 19 days, intervals between courses 5 — 12 weeks. Depending on the reached effect and signs of a miyelodepressiya the optimum duration of an intercourse break can make 4 — 6 weeks. Recommend to carry out 6 — 10 courses of treatment. If after carrying out 2 — 3 courses of effect it is not observed, use other schemes of therapy.
Approximately treatment can be begun at number of leukocytes in blood not less than 4*109/l, and to stop — at 2 * 109/l. In need of treatment continuation, despite the expressed leykotsitopeniya, it is necessary to extend intervals between administrations of drugs, to reduce a sarcolysine dose to 10 mg by introduction and to increase Prednisolonum dose to 60 and even to 100 mg a day.
The course of treatment according to the scheme TsNP proceeds 10 days (table). Breaks between courses make 6 — 12 weeks. Depending on efficiency of treatment carry out from 3 to 7 and more courses. The scheme TsNP is less effective. At both schemes of polychemotherapy of a leykotsitopeniye develops approximately to the same extent, however the dispepsichesky phenomena are rather more often observed when using the scheme TsNP
Schemes of polychemotherapy of a multiple myeloma
Schemes of polychemotherapy
Dose and way of introduction
Days of treatment
400 mg intravenously
1, 3, 5, 8, 10, 12, 15. 17, 19
20 mg intravenously
10 mg intravenously
1,4 mg/m intravenously
30 mg/m inside
with 1 on 19
400 mg intravenously
with 1 on 10
100 mg/m inside
with 1 on 10
40 mg/m inside
with 1 on 10
Inclusion of Prednisolonum in these and other schemes is justified not only because it increases sensitivity of patients to cytostatic therapy, but also because Prednisolonum blocks ossifluence. prevents development of a hypercalcemia.
Considering possible mutagen effect of the alkylating drugs (increase of cases of developing of acute miyeloblastny and miyelomonoblastny leukoses at their long use), successful treatment should be limited for 2 years, including the period of induction of remission. Radiation therapy of a multiple myeloma is appointed in the presence of the large centers of bone destruction, sharply expressed local pains caused by changes and which are not stopped chemotherapy and also a radicular syndrome at a compression of bodies of vertebrae, the considerable sizes of myagkotkanny tumors. Total doses on the center of defeat make 2500 — 4000 Gr, one-time — 75 — 200 Gr (depending on localization). The moderate leykotsitopeniya (2 — 4*109/l) and thrombocytopenia (50 — 75*109/l) are not contraindication to local radiation, even in combination with chemotherapy.
Focal radiation therapy (4000 — 5000 Gr) at a solitary plasmacytoma is carried out after an oncotomy of any localization, and at impossibility of an operative measure is the first and main remedy.
The patient make reconstructive and orthopedic operations in cases of heavy disturbances of functions of extremities with the subsequent himio-and (or) radiation therapy.
At an acute renal failure there are indications to a hemodialysis, a plasma exchange. Repeated plasma exchanges (1000 — 1800 and more than a ml) are carried out also at a cryoglobulinemia.
The system of treatment of a multiple myeloma which is applied now is effective more than at 60% of the patients keeping working capacity and social activity. When using sarcolysine of remission are more long, than at use of Cyclophosphanum (33 and 26 months according to). In the developed disease stage monochemotherapy in combination with glucocorticoid hormones and polychemotherapy are effective equally. The survival median at patients with a multiple myeloma, resistant to cytostatic treatment, makes 11 months, in cases of an irreversible renal failure — 8 months. Among adequately treated patients approximately 3,5% of patients have a life expectancy 10 and more than flying.