Introduction to multiple myeloma

Introduction Multiple myeloma (MM) is the most common type of malignant plasma cell disease, also known as myeloma, plasma cell myeloma or Kahler disease. It was not until 1889 that Kahler reported cases in detail that multiple myeloma was generally known and recognized. Multiple myeloma is characterized by malignant proliferation of monoclonal plasma cells and secretion of large amounts of monoclonal immunoglobulin. The incidence rate is estimated to be 2~3/100,000, and the ratio of male to female is 1.6:1. Most patients are >40 years old, and black patients are twice as white as whites. Causes (1) Causes of the disease The cause of MM has not yet been fully clarified. Clinical observations, epidemiological investigations and animal experiments suggest that ionizing radiation, chronic antigen stimulation, genetic factors, viral infections, and genetic mutations may be involved in the pathogenesis of MM. The incidence of MM in people affected by atomic bombing and in occupational or therapeutic radiation receiving population is significantly higher than normal, and the higher the dose of radiation, the higher the incidence rate, suggesting that ionizing radiation can induce the disease, and its incubation period Longer, sometimes as long as 15 years or more. Long-term exposure to chemicals such as asbestos, arsenic, pesticides, petrochemicals, plastics and rubber has been reported to induce the disease, but such reports are mostly fragmented and there is insufficient convincing evidence. It is clinically observed that patients with chronic inflammation such as chronic osteomyelitis, cholecystitis, and pyoderma are more likely to develop MM. Animal experiments (injection of mineral oil or embedding of plastic into mice) demonstrated that chronic inflammatory stimuli can induce peritoneal plasmacytoma. The incidence of MM in certain races (such as black race) is higher than that of other races, the incidence of different races in the same region is different, and the incidence of certain families is significantly higher than the normal population, which suggests MM The onset may be related to genetic factors. The relationship between the virus and the pathogenesis of MM has been confirmed in various animal experiments. It has been previously reported that Epstein-Barr virus is associated with the pathogenesis of human multiple myeloma. In recent years, Human Herpes Virus-8 (HHV-8) has been reported to be involved in the pathogenesis of MM. However, whether it is a coupling or a virus is indeed related to the pathogenesis of MM, and further research and clarification are needed. MM may have multiple chromosomal aberrations and oncogene activation, but no specific landmark chromosomal abnormalities were found. Whether chromosomal aberration is the initiating factor of MM is still to be confirmed by research. Malignant tumors are diseases caused by multi-factor, multi-gene, multi-step changes, and MM is no exception. In the dendritic cells cultured in myeloma patients, the herpesvirus associated with Kaposi's sarcoma was found, suggesting a certain relationship between the two. The virus encodes a homologue of interleukin-6 (IL-6). IL-6 can promote the growth of myeloma and stimulate bone resorption. This particular source of cells is still unknown. The analysis of the gene sequence and cell surface markers of immunoglobulins suggests that the posterior germinal cells are malignant. Experimental animals combined with ionizing radiation can sometimes increase the incidence of plasmacytoma. The natural incidence of plasmacytoma in mice living in a sterile environment is reduced. The final injection of mineral oil or solid plastic in the peritoneal cavity of purebred mice results in a granuloma-like appearance. After the inflammatory reaction, most animals develop intraperitoneal plasmacytoma that produces monoclonal immunoglobulin; however, the same method is difficult to cause plasmacytoma in non-pure mice, so genetic factors such as ionizing radiation and chronic antigen stimulation may be Related to the occurrence of this disease (2) Pathogenesis The origin of myeloma cells, originally based on cell morphology and secretory immunoglobulin characteristics, is believed to be derived from plasma cells. Change. Subsequent immunological and molecular biological studies suggest that myeloma cells begin with pre-B cell malignant transformation, which is based on the presence of monoclonal lymphocytes in addition to monoclonal malignant plasma cells in MM patients. The immunoglobulin and immunoglobulin genes on the surface of lymphocytes are rearranged in the same way as tumor cells. The early pre-B cell cytoplasmic IgM can specifically bind to anti-M protein antibodies. However, recent studies have found that myeloma cells not only have plasma cell and B cell characteristics, but also express myeloid cells, erythroid cells, megakaryocytes, and T cell surface antigens. There are also studies suggesting that the common precursor cells of T cells and B cells have the same immunoglobulin gene rearrangement as tumor cells, and the T cell subsets of some MM patients can specifically cross-react with M protein. Based on the above studies, it is currently believed that MM tumor cells mainly express the characteristics of B cells-plasma cells, but their origin is malignant transformation of hematopoiesis precursor cells earlier than the pre-B cells. As for the mechanism of malignant transformation of hematopoietic precursor cells, it has not yet been fully elucidated. There is ample evidence that the occurrence of MM is associated with oncogenes. Studies on induced mouse plasmacytoma found that 90% of the mice had chromosomal translocations, and almost all of the breakpoints appeared in the C-MYC region of the oncogene, forming recombinant C-MYC (rC-MYC) and expressing it. Murine plasmacytoma is associated with C-MYC. C-MYC gene rearrangements, mutations, and elevated mRNA levels have been found in MM patients. Oncogene N-RAS or K-RAS mutations were found in 27% (18% to 47%) of newly diagnosed MM cases and 46% (35% to 71%) of post-treatment MM cases. N-RAS mutations can lead to tumor cell loss of IL-6, which is activated by other hematopoietic factors to proliferate and reduce apoptosis. The high level of P21 is seen in some MM patients, and P2l is a product of the oncogene H-RAS, indicating that some MM patients have high expression of the oncogene H-RAS. In animal experiments, the point mutation-activated H-RAS gene was implanted into Epstein-Barr virus-infected human B cells, resulting in the conversion of B cells into malignant plasma cells, showing growth on semi-solid media, and making nude mice The tumor grows and secretes a large number of malignant plasma cell features such as IgM. For the chromosomal study of MM, although there are no labeled chromosomal abnormalities, some chromosomal abnormalities that have been confirmed in MM are not random, and chromosomes 14 and 14 are most common. Followed by the trisomy of chromosomes 3, 5, 7, 9, and 11, and the monosomy of chromosomes 8, 13 and the long arm of chromosome 6. Also more common in MM. Studies have shown that the long arm deletion of chromosome 6 is associated with increased production of osteoclast activating factor (OAF) and tumor necrosis factor (TNF). The abnormality of chromosome 7 is related to the expression of multidrug resistance gene (MDR1). Chromosomal abnormalities are associated with C-MYC oncogene activation. Therefore, it is generally believed that factors such as radiation, chemical substances, and viral infections may cause gene mutations or chromosomal translocations, and activate oncogenes, such as point mutations to activate H-RAS and gene rearrangement, and activate C-MYC, leading to tumorigenesis. Studies on the relationship between chromosomal abnormalities and oncogene activation, and the relationship between oncogene activation and MM onset are currently under investigation. The relationship between lymphokine cytokines, growth factors, interleukins, colony stimulating factors and myeloma has received attention in recent years. The process of proliferation, differentiation and maturation of B cells to plasma cells is associated with multiple lymphokines: interleukin-1 (IL-1) activates IL-2 gene expression; IL-2 and IL-3 promote early B cell proliferation IL-4 can activate resting B cells to promote B cell proliferation; IL-5 promotes B cell proliferation and differentiation; IL-6 stimulates B cell proliferation and eventually differentiates into plasma cells producing immunoglobulin; IL- 10 can promote the differentiation of B cells into plasma cells and directly stimulate the proliferation of myeloma cells, but IL-10 levels are very low in MM and significantly elevated in plasma cell leukemia, so it is speculated that IL-10 is associated with advanced lesions of MM. Among them, IL-6 has received special attention because IL-6 promotes proliferation of plasma cells and myeloma cells both in vivo and in vitro, while in advanced multiple myeloma patients, especially in the bone marrow, IL-6 levels Significantly higher than normal. It has been shown that IL-6 can promote the expression of BCL-XL and inhibit tumor cell apoptosis. However, there are different opinions on whether IL-6 is a paracrine from normal tissues or an autocrine of myeloma cells. Some researchers have suggested that elevated IL-6 may be derived from the paracrine secretion of monocytes and mesenchymal cells in the bone marrow based on the phenomenon that human myeloma cell lines RPMI 8226 and U266 do not secrete IL-6. secretion. However, most researchers believe that although monocytes, bone marrow stromal cells, T cells, endothelial cells, glomerular cells, keratinocytes can secrete IL-6, myeloma cells (including different strains of RPMI 8226 and U266) ) can also secrete IL-6 by itself. The level of C-reactive protein (CRP) is regulated by IL-6. When IL-6 levels are elevated, CRP levels also increase, so CRP levels can indirectly reflect IL-6 levels. CRP levels in patients with MM are often elevated. According to a variety of lymphokines, especially IL-6, is a B cell-plasma growth factor and differentiation factor, IL-6 levels in the bone marrow of patients with progressive multiple myeloma are abnormally elevated, so it is speculated that IL-6 and other lymphocytes Abnormal regulation of factor secretion may be associated with the onset of MM. Based on this, someone has tried IL-6 antibody to treat MM, and the efficacy has yet to be evaluated. Osteolytic lesions are one of the important features of MM. It is currently believed that osteolytic lesions are not caused mainly by the direct erosion of bone by tumor cells. Instead, the tumor cells secrete factors that activate osteoclasts. These factors include IL-1, lymphotoxin, tumor necrosis factor (TNF), and osteoclast activating factor (OAF). The activity of OAF is via IL-1. Lymphocyte toxin, TNF-mediated. These factors activate osteoclasts, leading to osteoporosis and bone destruction. Another study pointed out that the loss of long arm of chromosome 6 can promote the increase of TNF and OAF, and aggravate osteolytic lesions. Interferon gamma and adrenocortical hormone can inhibit the production of these factors. The diverse clinical manifestations of MM are caused by the uncontrolled hyperplasia, infiltration and secretion of a large number of monoclonal immunoglobulins by malignant clonal plasma cells: excessive proliferation of tumor cells in the primary site of the bone marrow, leading to inhibition of bone marrow hematopoietic function; Extensive infiltration of tumor cells may involve lymph nodes, spleen, liver, respiratory tract and other parts, causing dysfunction of affected tissues and organs: some factors secreted by tumor cells cause osteolytic lesions and related symptoms; a large number of monoclonal immunoglobulins secreted by tumor cells Protein appears in the blood to cause increased blood viscosity and clotting factor dysfunction, while excessive light chain excretion from the kidney causes kidney damage, light chain deposition in tissues and organs causes amyloidosis damage, while normal polyclonal plasma cell proliferation and polyclonal immunity The synthesis of globulin is inhibited, and the immunity of the body is reduced, which is easy to cause secondary infection. MM most commonly invades the bone, and the trabecular bone of the diseased bone is destroyed, and the bone marrow cavity is filled with grayish white tumor tissue. The cortical bone is thinned or damaged by corrosion, and the bone becomes soft and brittle and can be cut with a knife. The cut surface of the tumor tissue is grayish-white gelatinous, and if there is bleeding, it is dark red. Tumor tissue can penetrate the cortical bone and infiltrate the periosteum and surrounding tissues. Under the microscope, the tumor cells are diffusely distributed and have small interstitial mass. They are composed of fine fibrous tissue and thin-walled blood vessels. A small number of tumors can be rich in reticular fibers. Tumor cells are plasma cells of different degrees of differentiation. Those with good differentiation resemble normal mature plasma cells. The poorly differentiated cells are similar to tissue cells. The cell bodies are large, the shape is irregular, the cytoplasm is blue-stained, the paranucleus is not obvious, and the nucleus is large and stained. Fine, with 1 or 2 nucleoli. Binary or multinuclear tumor cells can be seen. There are also tumor cells in a focal distribution. Extramedullary infiltration is more common in the liver, spleen, lymph nodes and other reticuloendothelial tissues, but also in the kidney, lung, heart, thyroid, testis, ovary, digestive tract, uterus, adrenal gland and subcutaneous tissue. In some cases (8% to 15%), the tumor tissue and organs have amyloid deposition, that is, the immunoglobulin light chain is sedimented, stained with Congo red, and presented with special green and two colors under ordinary light microscope and optical microscope. Sex. It can be identified as a light chain by immunofluorescence. There is a foreign body giant cell reaction around this amyloid deposition. Commonly affected organs are tongue, muscle, digestive tract, kidney, heart muscle, blood vessels, joint capsules and skin. Symptoms Clinical manifestations are slow, some patients can be asymptomatic for a long time, but serum protein electrophoresis found a monoclonal immunoglobulin (IG) peak, or urinary light chain positive, called "pre-myeloma", this period can be It lasts for 3 to 5 years. The main clinical manifestations are divided into the following two categories: Myeloma cells infiltrate one tissue and infiltrate bones. The most frequently violated bones are the proximal ends of the skull, ribs, sternum, spine, and long bones of the limbs. Due to the infinite proliferation of tumor cells in the bone marrow cavity, it leads to diffuse osteoporosis or limited bone destruction. Bone pain is the most common early symptom, most commonly seen at the waist, followed by the sternum, ribs and limb bones. The pain at the beginning can be intermittent or migratory, and then gradually increases and persists. Local tenderness, uplift or fluctuations; may be associated with pathological fractures, often not in the weight-bearing part, often several fractures occur simultaneously. X-ray examination can be found to be typical of multiple osteolytic lesions, diffuse osteoporosis, pathological fractures, etc., to help diagnose. 2 infiltration of bone marrow. Tumor cells proliferate in large amounts in the bone marrow, causing significant changes in bone marrow, decreased proliferation, active or markedly active. It is characterized by 10 to 90% of myeloma cells, varying in cell size, 15 to 30 μm in diameter, oval or round, rich in cytoplasm, dark blue or bright blue, with vacuoles, and transparent nucleus obvious. The nucleus is round or elliptical, which is on the side of the cell. The chromatin is coarsely reticular and contains 1 or 2 nucleoli, large and obvious. Sometimes there are 2 to 3 nuclei in a cell. Mature red blood cells are often arranged in a string. In the surrounding blood, it is characterized by progressive normal cells and normal pigmented anemia. In the smear, the red blood cells are in the form of a string. White blood cell and platelet counts can be normal or low, and late stage manifests as whole blood cell reduction. 3 infiltration of other organs. Due to the fracture of the spine or the compression of the spinal nerve root or the infiltration of the brain and spinal cord by the myeloma itself, it can cause neuralgia, paresthesia, and even paralysis. Due to the infiltration of tumor cells throughout the body, the liver, spleen and lymph nodes are enlarged, and the liver is more common. Can also invade other organs, causing the corresponding clinical team performance. Due to bone destruction and bone resorption, a large amount of calcium enters the blood, and the combination of M protein and calcium increases the bound calcium, which can cause hypercalcemia and increased urinary calcium. The clinical manifestations related to M protein have the following manifestations: 1 urinary protein, about 40 to 70% of patients with myeloma, Ig light chain in the urine, called Bens Jones protein, due to the synthesis of tumor cells In the Ig molecule, the light chain is more than the heavy chain, and the light chain molecule is small, which can be filtered out from the glomerulus and appears in the urine. When the amount of the light chain is small, it is difficult to detect, and the concentration of urine is high. 2 ESR increased, increasing to 100mm or more in the first hour. 3 bleeding tendency, thrombocytopenia and M protein-induced blood flow stagnation, vascular wall damage, platelet and clotting factor function disorders, patients often have bleeding tendency, table treatment is now mucosal oozing, skin purpura, late can have viscera or Intracranial hemorrhage has serious consequences. 4 renal failure, due to the deposition of light chain in the renal tubules, hypercalcemia and hyperuricemia, the function of renal tubular reabsorption is impaired, the infiltration of tumor cells into the kidney, etc., the domestic chronic renal insufficiency is the disease One of the salient features became. In the advanced stage of the disease, uremia can be the cause of many deaths. 5 susceptible to infection, the reduction of normal Ig content often leads to the award of immune dysfunction. Patients often have repeated infections, with lung and urinary tract infections more common. 6 high viscosity syndrome, a large number of monoclonal Ig improve blood viscosity, slow blood flow, cause microcirculatory disorders, retinal, brain, kidney and other organs are particularly vulnerable to damage, causing dizziness, visual impairment, numbness of hands and feet Seriously affecting brain function can lead to coma. This syndrome is more common in IgM type myeloma and macroglobulinemia. 7 Reynolds phenomenon, part of the patient's monoclonal Ig is cryoprecipitated globulin, in the case of cold globulin agglutination precipitation, causing microcirculatory disorders, the occurrence of hand and foot cyanosis, cold, numbness or pain, and symptoms relieved after heat. 8 amyloidosis, a small number of patients with amyloidosis, amyloid deposits widely in tissues, organs and tumors, causing peripheral nerve, kidney, heart, liver, spleen lesions leading to liver, splenomegaly, joint pain, nerve Clinical manifestations such as dysfunction. 1. Bone pain is one of the main symptoms of this disease. The degree of pain varies, and the early stage is often mild and temporary, and can become persistent and severe as the disease progresses. Severe or sudden increase in pain often indicates a pathological fracture. According to the analysis of 125 cases of MM initial symptoms in Peking Union Medical College Hospital, 80 cases (64.0%) were mainly complained of bone pain. The most common sites of bone pain were lumbosacral (28.0%), followed by thoracic ribs (27.0%), and the limbs were less long. (9.0%), a small number of patients have joint pain in the shoulder joint or limbs. The vast majority (90% to 93%) of patients have different degrees of bone pain symptoms throughout the course of the disease, but a small number of patients have no bone pain. In addition to bone pain and pathological fractures, bone masses can also appear. The tumor cells infiltrate from the bone marrow, invading the cortical bone, periosteum and adjacent tissues to form a mass. In multiple myeloma, this type of skeletal mass is often multiple, common in the chest ribs, clavicle, skull, nasal bone, mandible and other parts. Unlike solitary plasmacytoma, its lesions are not only multiple, but the bone marrow has long been violated, and a large number of monoclonal immunoglobulins are secreted. 2. Anemia and bleeding tendency Anemia is another common clinical manifestation of this disease. According to an analysis of 125 cases in Peking Union Medical College Hospital, the vast majority (90%) of patients experienced anemia of varying degrees in the course of the disease, and some (10.4%) of the patients were treated with anemia symptoms. The degree of anemia varies. The general course of disease is mild in the early stage and heavier in the late stage. Hemoglobin can be reduced to <50g/L. The main cause of anemia is malignant hyperplasia and infiltration of tumor cells in the bone marrow, which crowds out hematopoietic tissues and affects hematopoietic function. In addition, factors such as renal insufficiency, repeated infections, and malnutrition can also cause or aggravate anemia. Read more...