Introduction
Multiple myeloma(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 and secretion of monoclonal plasma cellsMonoclonal 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.
Cause
(1) Causes of the disease
The cause of MM has not been fully understood so far. 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
(two) pathogenesis
The origin of myeloma cells, originally based on cell morphology and the characteristics of secretory immunoglobulins, is believed to be due to malignant transformation of plasma cells. 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.
symptom
Clinical manifestation
Slow onset, some patients can be asymptomatic for a long time, but serum protein electrophoresis found a monoclonal immunoglobulin (IG) peak, or urine light chain positive, called "pre-myeloma", this period can be up to 3 ~5 years. The main clinical manifestations are divided into the following two categories:
Myeloma cells infiltrate one tissue to infiltrate the bone. 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.
The tendency to hemorrhage is not uncommon in this disease. Among the 125 patients in Peking Union Medical College Hospital, 8 patients were treated with bleeding as the first symptom, and the bleeding tendency in the course of the disease was 10% to 25%. The degree of bleeding is generally not serious, and it is often characterized by mucosal oozing and purpura. The common sites are nasal cavity, gums, and skin. In the late stage, visceral hemorrhage and intracranial hemorrhage may occur. The cause of bleeding is thrombocytopenia and coagulopathy. Thrombocytopenia is caused by the inhibition of bone marrow hematopoietic function. Coagulation disorders are caused by a large number of monoclonal immunoglobulins covering the surface of platelets and the surface of blood coagulation factors (fibrinogen, prothrombin, factors V, VII, VIII, etc.), affecting their functions. Causes coagulopathy. Abnormal increase in immunoglobulin increases blood viscosity, slow blood flow, damage to capillaries, and can also cause or aggravate bleeding.
3. Repeated infection of this disease is prone to infection, especially pneumococcal pneumonia, followed by urinary tract infection and sepsis. Herpes zoster and varicella are common in viral infections. In 125 cases of Peking Union Medical College Hospital, 18 cases (14.4%) were treated with fever and infection, and most of them were pulmonary infections. Some patients were hospitalized for repeated pneumonia, and further examination was confirmed as MM complicated with pneumonia. For patients with advanced MM, infection is one of the leading causes of death. The reason for the infection of this disease is that the proliferation, differentiation and maturation of normal polyclonal B cells, plasma cells are inhibited, the production of normal polyclonal immunoglobulin is reduced, and the abnormal monoclonal immunoglobulin lacks immunological activity, resulting in decreased immunity. The pathogenic bacteria take advantage of it. In addition, the number and function of T cells and B cells, as well as the use of chemotherapy drugs and adrenocortical hormones, also increase the chance of infection.
4. Renal damage Renal lesions are a common and characteristic clinical manifestation of this disease. Due to the abnormal production of abnormal monoclonal immunoglobulin and the imbalance between the synthesis of heavy and light chains, excessive light chain formation, the light chain with a relative molecular mass of only 23,000 can be filtered from the glomerulus and reabsorbed by the renal tubule. Excessive light chain reabsorption causes tubular damage. In addition, hypercalcemia, hyperuricemia, hyperviscosity syndrome, amyloidosis, and tumor cell infiltration can cause kidney damage. Patients may have proteinuria, Ben-Ben's proteinuria, and microscopic hematuria, which are easily misdiagnosed as "nephritis." The final development is renal insufficiency. Renal failure is one of the causes of death in MM. In most cases, renal failure is chronic, progressive, but in a few cases acute renal failure can occur, the main cause is hypercalcemia and dehydration, if treated promptly, this acute renal failure can also reverse.
5. Hypercalcemia The increase in blood calcium is due to the destruction of blood calcium in the blood, the reduction of calcium exocrine in the renal tubules and the binding of monoclonal immunoglobulin to calcium. The incidence of hypercalcemia is different. The incidence of hypercalcemia in patients with MM in Europe and America is 10% to 30%, and can reach 30% to 60% when the disease progresses. The incidence of hypercalcemia in MM patients in China is about 16%, which is lower than that in Western countries. Hypercalcemia can cause headache, vomiting, polyuria, constipation, and severe cases can cause arrhythmia, coma and even death. Calcium deposits cause kidney damage in the kidneys, and severe cases can cause acute renal failure, which is life-threatening and requires urgent treatment.
6. Hyperviscosity syndrome The abnormal increase of monoclonal immunoglobulin in the blood, one wrapped red blood cells, reduced the repulsive force between the negative charges on the surface of red blood cells, resulting in the accumulation of red blood cells, and the second, increased blood viscosity, especially serum viscosity, blood flow Poor, causing microcirculatory disorders, causing a series of clinical manifestations called hyperviscosity syndrome. Common symptoms include dizziness, headache, vertigo, visual impairment, limb numbness, renal insufficiency, and severely affecting cerebral blood circulation, which can lead to disturbance of consciousness, epileptic seizures, and even coma. Fundus examination showed that the retinal veins were dilated and formed like a "sausage" with oozing and bleeding. Because immunoglobulin encapsulates the surface of platelets and clotting factors, affecting its function, and blood flow stagnation damages the capillary wall, it often has bleeding tendency, especially mucosal oozing (nasal cavity, oral cavity, gastrointestinal mucosa). In elderly patients, increased blood viscosity, anemia, and expansion of blood volume can lead to congestive heart failure. The Raynaud phenomenon can also occur.
The occurrence of hyperviscosity syndrome is related to both the concentration of immunoglobulin in the blood and the type of immunoglobulin. When the blood viscosity (plasma or serum viscosity) exceeds 3 times normal and the concentration of monoclonal immunoglobulin in the blood exceeds 30 g/L, high viscosity syndrome is prone to occur. Among various immunoglobulin types, IgM is relatively high in molecular mass, asymmetrical in shape, and has a tendency to aggregate, so it is most likely to cause high-viscosity syndrome. Secondly, IgA and IgG3 are prone to form multimers, so they are more likely to cause hyperviscosity syndrome.
7. Hyperuricemia, elevated blood uric acid> 327μmol / L is common in MM. Of the 91 patients with MM in Peking Union Medical College Hospital, 61 (67%) had hyperuricemia. Elevated blood uric acid is the result of increased uric acid production by the breakdown of tumor cells and reduced uric acid excretion by the kidneys. Although elevated blood uric acid rarely causes obvious clinical symptoms, it can cause kidney damage and should be prevented and treated.
8. Neural system damage tumor cell infiltration, tumor block compression, hypercalcemia, high viscosity syndrome, amyloidosis and mechanical compression caused by pathological fractures can all be the cause of neurological diseases and symptoms. The symptoms of the nervous system are diverse and can manifest as peripheral neuropathy and nerve root syndrome, as well as central nervous system symptoms. Compressive pathological fractures of the thoracic and lumbar spine can cause paraplegia. Among the 125 patients in Peking Union Medical College Hospital, 12 had neurological lesions, 3 had peripheral neuropathy, 3 had nerve root damage, 2 had intracranial lesions, and 4 had paraplegia due to spinal cord compression.
9. The complexation of the light chain and polysaccharide of amyloid immunoglobulin is precipitated in tissues and organs and is the amyloidosis of the disease. The affected tissues and organs are often extensive, and the tongue, parotid gland, skin, heart muscle, gastrointestinal tract, peripheral nerve, liver, spleen, kidney, adrenal gland, lung, etc. can be involved, which can cause hypertrophy of the tongue, swollen parotid gland, skin mass or Moss, cardiac hypertrophy, enlarged heart, diarrhea or constipation, peripheral neuropathy, hepatosplenomegaly, renal insufficiency, etc. The diagnosis of amyloidosis depends on tissue biopsy pathology, including morphology, Congo red staining, and immunofluorescence. European and American countries report that the incidence of amyloidosis in MM is 10% to 15%, while the incidence in China is 1.6% to 5.6%. Carpal tunnel syndrome caused by amyloidosis damage to the median nerve is more common in Western countries, but no report has been reported in China.
10. Hepatosplenomegaly and other tumor cell infiltration, amyloidosis leading to hepatosplenomegaly. The liver is seen in more than half of the patients, the spleen is found in about 20% of patients, usually the liver and spleen are slightly enlarged. Lymph nodes are generally not enlarged. A small number of patients may have joint pain, and even joint swelling, rheumatoid-like nodules, amyloidosis of the bones and joints. Skin damage such as itching, erythema, gangrenous pyoderma, and hairy are only seen in a small number of patients. Individual patients have xanthomatosis, which is believed to be the result of binding of monoclonal immunoglobulins to lipoproteins.
diagnosis
The main basis for the diagnosis of this disease are: M protein peaks appearing in serum protein electrophoresis; bone X-ray examination shows multiple osteolytic changes; a large number of myeloma cells are found in bone marrow smears. If two of the three are positive, combined with clinical manifestations, a diagnosis can be made.
The clinical manifestations of multiple myeloma are diverse and multivariate, which is easily confused with other diseases, and the incidence of misdiagnosis and missed diagnosis is high. Therefore, the development of diagnostic criteria for multiple myeloma has important clinical implications. The diagnosis of multiple myeloma needs to be based on a comprehensive analysis of the patient's clinical symptoms, signs and related laboratory tests (with emphasis on bone marrow, M components and bone lesions). After the diagnosis of multiple myeloma is determined, in order to develop a correct treatment strategy, the classification and clinical stage of multiple myeloma need to be further clarified, and the prognostic factors should be evaluated.
In 2001, the World Health Organization (WHO) organized experts to review the diagnostic criteria for multiple myeloma (MM) after reviewing and referencing existing diagnostic criteria for multiple myeloma.
1.WHO diagnostic MM standard
(1) Diagnostic MM requirements have at least one primary criterion and one secondary criterion, or have at least three secondary criteria and must include one and two. The patient should have progressive symptoms associated with the diagnostic criteria.
(2) Main criteria:
1 Increased plasma cells in the bone marrow (>30%).
2 tissue biopsy confirmed plasmacytoma.
3M components: serum IgG>3.5g/dl or IgA>2.0g/d1, urinary-peripheral protein>1g/24h.
(3) Secondary criteria:
1 Increased plasma cells in the bone marrow (10% to 30%).
The 2M component is present but the level is below the above level.
3 have osteolytic lesions.
4 normal immunoglobulin decreased by more than 50%: IgG <600mg / dl, IgA <100mg / dl, IgM <50mg / dl.
2. Diagnostic criteria of domestic MM in China The hematologists in China are based on the results of domestic clinical research and with reference to foreign diagnostic criteria.
(1) Plasma cells in the bone marrow > 15% with abnormal plasma cells (myeloma cells) or tissue biopsy confirmed as plasmacytoma.
(2) A large amount of monoclonal immunoglobulin (M component) appears in serum: IgG>35g/L, IgA>20g/L, IgD>2.0g/L, IgE>2.0g/L, IgM>15g/L, or The monoclonal immunoglobulin light chain (pre-week protein) in urine is >10g/24h. Biclonal or triple clonal immunoglobulins can occur in a few cases.
(3) osteolytic lesions or extensive osteoporosis without other causes.
If you meet the above 3 items or meet the requirements of (1) (2) or (1) (3), you can diagnose it as MM. However, in the diagnosis of IgM type MM, in addition to items (1) and (2), typical MM clinical manifestations and multi-site osteolytic lesions are required. Only those with (1) and (3) are non-secretory MM, and further identification is not synthetic or synthetic but not secreted. For those with only (1) and (2) (especially those without protoplasm and larval cells in the bone marrow), reactive plasma cell enlargement and undefined monoclonal immunoglobulinemia (MGUS) should be excluded.
Looking at the domestic and foreign MM diagnostic criteria can be summarized into three aspects: 1 abnormal proliferation of plasma cells in the bone marrow, must emphasize not only the increase in the number of plasma cells, but also the presence of myeloma cells (prime pulp, young plasma cells). Because the plasma cells in the bone marrow of reactive plasmacytosis may be >10% and reach 20% to 30%, no myeloma cells will appear. 2 Monoclonal immunoglobulin or its light chain appears in blood and urine and has a high level. 3 bone changes, namely diffuse osteoporosis and multiple osteolytic lesions. A lesion that meets the above three aspects or that meets the 1st or 2nd or 1st and 3rd lesions can be diagnosed as MM.
3. Classification The application of serum protein electrophoresis, immunoelectrophoresis, and light chain quantification methods can determine whether myeloma cells secrete monoclonal immunoglobulins and the types of monoclonal immunoglobulins secreted. Multiple myeloma can be divided into the following eight types depending on whether the myeloma cells secrete and secrete different types of monoclonal immunoglobulins:
(1) IgG type: the heavy chain of the monoclonal immunoglobulin is a γ chain, and the light chain is a κ chain or a λ chain. The IgG type is the most common MM subtype, accounting for about 50% of MM. This type has typical clinical manifestations of MM. In addition, normal immunoglobulin reduction is particularly pronounced in this type, with secondary infections being more common.
(2) Type IgA: the heavy chain of the monoclonal immunoglobulin is an alpha chain, and the light chain is a kappa chain or a lambda chain. IgA type accounts for about 15% to 20% of MM. In addition to the general performance of MM, there are still myeloma cells in a flaming state, IgA easy to aggregate into multimers and cause hyperviscosity, easy to have hypercalcemia and hypercholesterolemia. On serum protein electrophoresis, the M component formed by monoclonal IgA is often in the α2 region rather than the γ region.
(3) Light chain type: The monoclonal immunoglobulin is a monoclonal kappa chain or a monoclonal lambda chain, and the heavy chain is absent. This type accounts for about 15% to 20% of MM. Since the molecular weight of the light chain is only 23,000, which is much smaller than serum albumin (molecular weight 69,000), no M component appears on the serum protein electrophoresis. Immunoelectrophoresis and light chain quantitative determination must be used to detect a large number of single blood and urine in patients. Cloned light chain (urinary-peripherin positive). This type of tumor cells are often poorly differentiated, proliferate rapidly, bone destruction is common, and renal function damage is heavier.
(4) IgD type: the heavy chain of the monoclonal immunoglobulin is a δ chain, and the light chain is a κ chain or a λ chain. Foreign reports that this type only accounts for 1% to 2% of MM. However, domestic reports of this type account for about 8% to 10% of MM, which is not uncommon. This type has the general performance of MM. It has the characteristics of relatively young age, extramedullary infiltration and osteoporosis.
(5) IgM type: the heavy chain of the monoclonal immunoglobulin is a μ chain, and the light chain is a kappa chain or a lambda chain. This type is rare, accounting for only about 1% of MM. In addition to the general clinical manifestations of MM, because of its large molecular weight (molecular weight 950,000) and easy formation of pentamers, blood viscosity is increased, so it is easy to occur high viscosity syndrome.
(6) IgE type: the heavy chain of the monoclonal immunoglobulin is a δ chain, and the light chain is a κ chain or a λ chain. This type is rare. There are only a few reports in the world so far, and no reports have been reported in China. According to foreign reports, the serum IgE of this type of patients can be as high as 45 ~ 60g / L, light chain is mostly λ chain, osteolytic lesions are rare, but the peripheral blood plasma cells increased, can show signs of plasma cell leukemia.
(7) Double clone or polyclonal type: This type is rare, accounting for less than 1% of MM. Double clones are often monoclonal IgM combined with monoclonal IgG, or monoclonal IgM combined with monoclonal IgA. The light chains of double-cloned immunoglobulins are mostly of the same type (κ or λ chain), and even two light chains, ie, κ chain and Lambda chain. Double-cloned light chain MM (ie, monoclonal kappa chain combined with monoclonal λ chain) is rare, although it has been reported in cases. Polyclonal (triple or quad clone) type MM is rare. Double-cloned immunoglobulins can be derived either from the secretion of single clonal (tumor) cells or from the secretion of two clonal (tumor) cells.
(8) Non-secretion type: This type accounts for about 1% of MM. The patient has typical clinical manifestations of MM in the bone marrow in which the plasma (tumor) cells proliferate significantly, bone pain, bone destruction, anemia, normal immunoglobulin is reduced, and infection is prone to occur. However, there is no M component in the serum, and there is no monoclonal light chain in the urine (urinary-peripherin negative). This type of myeloma can be further divided into non-synthetic type and non-secretory type by immunofluorescence. The former tumor cells do not synthesize immunoglobulin. Protein, the latter tumor cells have monoclonal immunoglobulin synthesis, but can not be secreted.
Because the classification of MM is related to the clinical diagnosis of MM, and also to the treatment and prognosis of MM, when the diagnosis of MM is determined, the classification should also be clarified.
4. Clinical stage The clinical stage reflects the course of the disease, and the morning and evening of the MM course depends mainly on the total number of myeloma cells (tumor load) in the patient. When the number of tumor cells is limited, it does not cause clinical symptoms, and the patient may be unaware of it, which is called preclinical. This period is generally 1 to 2 years, and the preclinical period of a few cases can be as long as 4 to 5 years or longer. When the total number of tumor cells is ≥1×1011, clinical symptoms begin to appear. As the number of tumor cells increases, the condition gradually worsens. When the number of tumor cells increases to a considerable extent, it will lead to death.
The number of tumor cells can be determined either by direct assay or by indirect algorithm. The direct measurement method is to firstly measure the synthesis rate and decomposition rate of monoclonal immunoglobulin in vivo by radioimmunoassay, and then measure the immunoglobulin synthesis rate of a single tumor cell by tissue culture method, and then calculate the tumor cells in the patient's body. total. Although this method is direct and accurate, it is difficult to apply to clinical practice. The indirect algorithm is based on the total number of tumor cells in the patient and the level of serum monoclonal immunoglobulin, urinary monoclonal light chain level, hemoglobin level, bone destruction degree, blood calcium level, and the above relevant indicators can be determined. Indirectly calculate the total number of tumor cells, and judge the patient's disease period sooner or later. This method is simple and easy to use, so it is widely used in clinical practice. Durie and Salmon. According to the principle of indirect algorithm. The clinical staging criteria for multiple myeloma were presented in 1975, as shown in Table 1.
Clinical practice confirms that Durie and Salmon's staging criteria have a positive application value. According to the results of a foreign multicenter study of 135 MM patients, the median survival of stage I patients according to Durie and Salmon staging criteria was 48 months, phase II was 32 months, and stage III was 20 months. It indicates that clinical stage is related to prognosis.
Recent studies have found that serum β2-microglobulin levels are associated with tumor cell mass and prognosis. 2-2-microglobulin is a component of the class I (class I) major histocompatibility antigen (MHC) light chain, and myeloma cells also secrete β2-microglobulin, therefore, β2-microglobulin levels and myeloma cells total The amount is related. Since the molecular weight of β2-microglobulin (12000) is small, mainly discharged and reabsorbed by the kidney, factors such as renal insufficiency should be excluded when judging the amount of tumor in vivo based on the level of β2-microglobulin. In addition, in recent years, studies have also found that the degree of bone destruction and the degree of destruction have no significant correlation with the amount of tumor in vivo, so Alexanian and Dimopoulos proposed a new classification criteria for multiple myeloma tumors in 1995 (Table 2).
In addition, Bataille et al., based on the relationship between the level of β2-microglobulin and the amount of tumor cells in vivo, proposed a simpler staging standard for β2 microglobulin and serum albumin levels as tumor mass fractionation (Table 3).
In the above staging criteria, the Durie and Salmon staging criteria are the earliest and most widely used in clinical practice, and they are effective. Therefore, the Durie and Salmon staging standards are used in China, but the β2-microglobulin level should be referred to as the staging standard. .
5. Diagnostic evaluation
(1) MM is a malignant tumor originating from bone marrow, so the discovery of myeloma cells in the bone marrow is a basic requirement for the diagnosis of MM. Myeloma cells are malignant plasma cells that differ in morphology from normal mature plasma cells and are similar to primitive or immature plasma cells. Increased normal mature plasma cells in the bone marrow are seen in a variety of diseases (see differential diagnosis), but myeloma cells are found only in MM. Therefore, it is not possible to rely solely on the increase of plasma cells in the bone marrow as a basis for diagnosing MM, and it is necessary to find myeloma cells as a basis for diagnosis.
(2) The appearance of monoclonal immunoglobulin or monoclonal immunoglobulin light chain is one of the characteristics of MM, but it is not unique to MM, because other diseases (see differential diagnosis) may also be accompanied by monoclonal immunoglobulin or single The immunoglobulin light chain was cloned. Furthermore, the non-secretory form of MM does not show monoclonal immunoglobulin or its light chain in serum. Therefore, the emergence of monoclonal immunoglobulin or its light chain is an important feature and diagnostic basis of MM, but it cannot be diagnosed or excluded based solely on this.
Regarding the detection of monoclonal immunoglobulins or monoclonal immunoglobulin light chains, it is not sufficient to rely solely on serum protein electrophoresis. Because the molecular weight of the light chain is much smaller than that of albumin, the "M" band does not appear on the serum protein electrophoresis when it moves faster than albumin and escapes the electrophoresis gel. IgD and IgE are extremely low in serum, and even if there is an increase in monoclonal IgD or IgE in serum, it is difficult to form a distinct "M" band on the electrophoresis gel. However, if serum immunoelectrophoresis and blood and urine light chain quantification, monoclonal IgD or IgE with low serum levels can be detected and the presence or absence of a monoclonal light chain can be determined. In addition, serum protein electrophoresis does not identify the type of monoclonal immunoglobulin, and immunoelectrophoresis can clarify the type of monoclonal immunoglobulin and its light chain. Therefore, to determine the presence or absence of monoclonal immunoglobulin or its light chain, and to identify its type, serum protein electrophoresis, immunoelectrophoresis, blood and urine immunoglobulin light chain quantification must be performed simultaneously. It should be noted that the previous method of detecting the light chain in urine (urinary-peripherin assay) has been replaced by urinary light chain quantification because of its poor specificity and sensitivity.
(3) Extensive osteoporosis and/or osteolytic lesions are another important feature of MM. Among them, skull perforation-like osteolytic lesions and thoracolumbar vertebral compression fractures are the most representative. However, osteoporosis and bone destruction can also be seen in other diseases (see differential diagnosis), and not all of the MM patients have the above-mentioned typical bone changes. Therefore, it is not only possible to determine whether or not to exclude MM from the presence or absence of extensive osteoporosis and/or osteolytic lesions, but to determine whether there are other two diagnostic criteria.
Multiple myeloma is one of the more common medical conditions that are misdiagnosed. Clinically, it is often misdiagnosed as "osteoporosis", "bone metastasis cancer", "lumbar tuberculosis", "kidney disease", "recurrent pneumonia", "urinary tract infection" and other diseases. In the diagnosis, it is required to be associated with reactive plasmacytosis, unexplained monoclonal immunoglobulinemia, primary macroglobulinemia, primary systemic amyloidosis, and accompanying non-plasma disease. Identification of clonal immunoglobulins, bone metastases, primary bone tumors, primary nephropathy, hyperparathyroidism and other diseases. It has been reported in China that the clinical misdiagnosis rate of 2547 cases of MM is as high as 69%. It can be seen that the differential diagnosis of MM is an important issue that clinicians should pay attention to.
1. Reactive plasmacytosis, therefore, a variety of pathogens (viruses, tuberculosis, etc.), antigens (drugs, tumors, etc.), immune dysfunction (Sjogren's syndrome, rheumatoid arthritis, etc.) can cause Reactive plasmacytosis and elevated levels of immunoglobulin need to be differentiated from multiple myeloma. The main points of identification are as follows:
(1) The increase of plasma cells in myeloma is limited: generally ≥3% but <10% and both are normal mature plasma cells, while MM bone marrow plasma cells are often >15% and there are naive plasma cells (myeloma cells).
(2) Reactive plasmacytosis: the secreted immunoglobulin is normally polyclonal and the level is limited (eg IgG<30g/L), while the immunoglobulin secreted by MM is monoclonal (ie, M component) And the level rises significantly (eg IgG > 30g / L).
(3) Reactive plasmacytosis itself does not cause clinical symptoms: its clinical manifestations depend on the primary disease, so there is no anemia, bone pain, bone destruction, hypoalbuminemia, normal immunoglobulin reduction, hypercalcemia Clinical manifestations of MM, such as high-viscosity syndrome.
(4) Reactive plasmacytosis has clinical manifestations of its primary disease.
2. Unknown meaning Monoclonal immunoglobulinemia MGUS MGUS and MM are both senile diseases, and there are increased monoclonal immunoglobulins, which have similarities and are easily confused. However, MGUS does not require treatment, only need to be followed up, and MM is a malignant tumor, should be treated, and the prognosis is poor, so you need to pay attention to the identification of both (Table 4).
It should be emphasized that a significant proportion of patients who meet the MGUS diagnostic criteria will eventually develop MM or other malignant plasma cell disease or B lymphocyte malignancy. Kyle et al reported that 1384 cases of MGUS were diagnosed at Mayo Clinical Medical Center from 1960 to 1999, 12% after 10 years of follow-up, 20% after 20 years of follow-up, and 25% of MGUS developed to MM or other after 30 years of follow-up Plasma cell disease (macroglobulinemia, systemic amyloidosis) or B lymphocyte malignant proliferative disease (chronic lymphocytic leukemia, non-Hodgkin's lymphoma), ie MGUS is converted to malignant disease at a rate of 1% per year , which is mainly converted to MM. Cesana et al reported 1104 cases of MGUS, with a median follow-up time of 65 months (12-239 months), 64 cases (5.8%) developed into MM, 1 case developed extramedullary plasmacytoma, and 12 cases developed into Waldenstr?m Macroglobulinemia, 6 cases developed as non-Hodgkin's lymphoma, and 1 case developed as chronic lymphocytic leukemia. Gregerson et al reported that 1324 cases of MGSU were diagnosed in North Jutland of Denmark from 1978 to 1993. Of these, 97 (9.3%) eventually developed MM or other malignant plasma cell diseases.
The mechanism by which MGUS is converted to MM or other malignant plasma cell disease has not been elucidated. Studies by Rasillo and Konigsherg suggest that chromosome 13q- is related to the conversion of MGUS to MM, but the results of Fouseca et al have not found a correlation between 13q- and MGUS conversion to MM. Loveras et al believe that chromosome 18 monomer (monosoml18) may be related to the conversion of MGUS to MM, but has not been confirmed by other studies. Ablaski et al. showed that MGUS to MM conversion has no relationship with HHV-8 (human herpes virus-8).
Since the mechanism of MGUS conversion to MM is unknown, and the prognostic factors of MGUS are not clear, the long-term follow-up of MGUS patients is emphasized, and the relevant indicators are regularly checked. If the patient's PCLI is increased, M protein is on the rise, there are nucleolar plasma cells in the bone marrow, or patients with MM-related symptoms (anemia, bone pain, etc.), should be alert to MGUS in the conversion to MM.
3. Kidney disease Kidney damage is one of the important clinical manifestations of MM. MM patients often have proteinuria, microscopic hematuria, hypoproteinemia, edema, renal insufficiency, anemia and other manifestations, easy to be confused with "chronic glomerulonephritis", "nephropathy syndrome", and was misdiagnosed.
Identifying kidney disease (nephritis, kidney disease, etc.) and MM is not difficult, the key is whether the clinician can think of the possibility of MM. If the clinician thinks that MM is one of the diseases that cause kidney damage and is vigilant, especially in elderly patients with kidney damage, there are bone pain or anemia that is not parallel with renal insufficiency (renal anemia and renal insufficiency) When parallel, perform MM examinations such as bone marrow aspiration and (or) bone marrow biopsy, protein electrophoresis and/or immunoelectrophoresis, bone X-ray examination, etc., to detect the presence or absence of myeloma cells, M components, osteolytic lesions, And determine or exclude MM. In general, when kidney damage occurs, MM is not in the early stage of the disease, and the above examination can be performed to confirm the diagnosis and avoid misdiagnosis.
4. Primary macroglobulinemia This disease is characterized by the presence of a large amount of monoclonal immunoglobulin IgM in the serum, and lymphoplasmacytoid cells in the bone marrow proliferate and infiltrate. Similar to MM, it is mostly in the elderly, and there are a large number of monoclonal IgM in serum, so it needs to be differentiated from IgM type MM. There has been controversy over the existence of IgM-type MM. It is currently believed that there is indeed IgM type MM, and its identification points with primary macroglobulinemia are as follows:
(1) Primary macroglobulinemia is lymphocyte-like plasma cell proliferation in the bone marrow: the cell morphology resembles that of lymphocytes than similar plasma cells, and in a few cases, similar to plasma cells, but similar to lymphocytes, but still different In naive plasma cells (myeloma cells). In MM bone marrow, plasma cell proliferation is observed, and myeloma cells (primary plasma cells, immature plasma cells, and plasma cells) can be seen.
(2) multiple osteolytic lesions are common in MM: primary macroglobulinemia is generally no osteolytic lesions.
(3) Hypercalcemia and renal insufficiency are more common in MM and less common in primary macroglobulinemia.
5. Primary systemic amyloidosis Primary systemic amyloidosis and MM belong to the category of malignant plasma cell disease, MM can be associated with systemic amyloidosis, and the two have similarities in clinical manifestations, but treatment And the prognosis is different, so it should be identified.
However, no myeloma cells infiltrated in the bone marrow of patients with primary systemic amyloidosis, and bones were not osteolytic. No hypercalcemia, high viscosity syndrome, is the difference with light chain MM, bone marrow puncture, bone X-ray examination, blood biochemical examination can be identified. It should be emphasized that MM is often complicated by systemic amyloidosis. When diagnosed with MM, its systemic amyloidosis is secondary, rather than primary systemic amyloidosis.
6. Heavy chain disease Clinical manifestations and laboratory examinations are all different depending on the type of heavy chain. The identification of heavy chain disease and MM mainly relies on immunoelectrophoresis to find that only the monoclonal immunoglobulin heavy chain exists in the blood, and no monoclonal immunoglobulin light chain exists. Quantitative determination of immunoglobulin light chain in blood and urine can help identify heavy chain disease and MM. The former has no blood and urine, while the latter has a monoclonal immunoglobulin light chain in the blood and urine.
7. Increased monoclonal immunoglobulin associated with non-plasma cell disease The increase in monoclonal immunoglobulin is an important feature of malignant plasma cell disease, but it can also be seen in non-plasma cell diseases. Such as: chronic infection (tuberculosis, osteomyelitis, cytomegalovirus infection, hepatitis C, AIDS). Autoimmune disease (systemic lupus erythematosus,Rheumatoid arthritis, Sjogren's syndrome (sjogren's syndrome), polymyositis,scleroderma, nodular periarteritis, pemphigus), hematologic malignancies (acute lymphocytic leukemia, myelodysplastic syndrome, myeloproliferative disorders), non-malignant hematological disease (vascular hemophilia, pure red blood cell aplasia Anemia), a non-hematological malignancy (cholangiocarcinoma,Breast cancer, liver cancer,Lung cancerOvarian cancer,Prostate cancerUterine cancer,Melanoma, Kaposi sarcoma, oligodendroglioma, angiosarcoma), neurological diseases (peripheral neuropathy,POEMS syndrome, motor neuron disease), skin disease (disc lupus, mossy mucinous edema, gangrenous pyoderma, diffuse discoid xanthomatosis, periodic systemic capillary leak syndrome), organ transplantation (kidney transplantation) , liver transplantation) and other diseases (biliary disease, acutePorphyrin,Gaucher disease, sarcoidosis, Paget osteitis, etc.).
The main points of identification are as follows:
(1) The level of monoclonal immunoglobulin associated with non-plasma disease is limited: usually IgG<35g/L, IgA>20g/L, IgM<10g/L, and the monoclonal immunoglobulin level of MM is usually high. At the above levels, and continue to increase trend.
(2) The increase in monoclonal immunoglobulin associated with non-plasma cell disease does not itself cause any clinical symptoms: its clinical manifestations depend entirely on the primary disease. MM has related symptoms caused by the increase of monoclonal immunoglobulin: high viscosity syndrome, kidney damage, bleeding tendency, bone pain, fracture, anemia, hypercalcemia, hyperuricemia, secondary infection, etc. .
(3) Myeloma cells were found by bone marrow puncture, and osteolytic lesions were found by X-ray examination.
8. Low back pain Multiple myeloma is often misdiagnosed as "lumbar muscle strain", "disc herniation", "lumbar tuberculosis", "osteoporosis" and other diseases. Because low back pain is one of the main symptoms of multiple myeloma, it is often one of the main complaints of patients seeking medical treatment, and may choose general surgery or orthopedics. If the clinician is not vigilant or cognitively aware of multiple myeloma, especially if the lumbar spine X-ray does not show lumbar vertebral compression fractures, it is prone to missed diagnosis or misdiagnosis. It should be emphasized that when elderly patients are mainly treated with low back pain, especially low back pain is persistent and post-activity aggravation, local tenderness, accompanied by anemia or significant increase in erythrocyte sedimentation rate, although X-ray examination has no osteolytic lesions or compressibility. Fractures should also be examined (bone marrow puncture, protein electrophoresis, immunoelectrophoresis, etc.) to rule out or affirm the diagnosis of multiple myeloma.
9. Bone metastases, lung cancer, gastric cancer, colon cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer and other malignant tumors are prone to bone metastasis, causing bone pain, osteolytic lesions, anemia and other clinical manifestations, and multiple myeloma There are similarities that need to be identified.
(1) There is a significant increase in monoclonal immunoglobulin (M component) in the blood of multiple myeloma, while bone metastases generally have no M component in the blood. Even if the bone metastasis cancer is accompanied by an increase in monoclonal immunoglobulin, its level of increase is limited.
(2) Bone marrow puncture or biopsy can be seen in piles of metastatic cancer cells: the morphology and distribution of the cells are significantly different from those of myeloma cells. Immunophenotypic examination can help identify myeloma cells, plasma cells CD38, CDl38, CD56 positive, while metastatic cancer (mostly adenocarcinoma tumors, as mentioned above) is AE1/AE3 positive.
(3) Patients with bone metastases have clinical manifestations of primary tumors, which is different from the clinical manifestations of multiple myeloma.
10. Other diseases that need to be differentiated from MM and other violations of bone diseases. Hyperparathyroidism is associated with hypercalcemia, bone and joint pain, osteoporosis, pathological fractures and other clinical manifestations similar to MM. Identification points: 1 bone hyperplasia of hyperparathyroidism is characterized by extensive decalcification, fibrocystic osteitis and bone cyst formation, which is different from MM's perforated osteolytic lesions; 2 hyperparathyroidism of blood and urine There is no monoclonal immunoglobulin or its light chain, and no myeloma cells in the bone marrow.
complication
1. Fractures Pathological fractures are common in skull, pelvis, ribs, and spine bone fractures.
2. Hypercalcemia The incidence of myeloma with hypercalcemia in European and American patients can reach 30% to 60%, clinical manifestations of loss of appetite, nausea, vomiting, polydipsia, polydipsia, coma.
3. Renal damage is a common and important complication of MM and one of the leading causes of death. Acute and chronic renal failure is one of the important complications of multiple myeloma, and it is also an important clue in diagnosis. It can occur at any stage of multiple myeloma.
4. The incidence of high-viscosity syndrome in MM patients is 10%, often showing decreased vision, disturbance of consciousness, central nervous system disorders, heart failure and so on.
5. Hematological complications Anemia, bleeding, thrombosis.
6. Infection can cause repeated infections and fever during the course of the disease. Such as skin infections, lung infections, etc.
7. Amyloidosis causes corresponding clinical manifestations, including hypertrophy of the tongue, enlargement of the parotid gland, hypertrophy of the heart, enlargement of the heart, diarrhea, peripheral neuropathy, hepatosplenomegaly, and the like.
8. The incidence of neurological damage to MM with neurological damage is 28.6% to 40%, including spinal cord compression and nerve root spinal cord compression.
treatment
(a) treatment
1. Supporting treatment and supportive therapy plays an important role in the treatment of this disease and cannot be ignored.
Long-term bedridden patients are prone to bone decalcification, hypercalcemia, and renal insufficiency. Encouraging patients to perform appropriate regular activities can help improve these conditions. If the bone pain restricts the activity, the analgesic or local radiation can be used to achieve an analgesic effect. Patients with chest ribs or thoracolumbar spine should be protected with a lightweight corrective stent. It can reduce pain and prevent pathological fractures. For patients with severe thoracic and/or lumbar vertebral compression fractures that may damage the spinal cord and paraplegia, activities need to be restricted. Patients with thoracic vertebrae and lumbar vertebrae with osteolytic lesions should sleep on a padded hardwood bed to prevent the spine from causing a fracture and damage the spinal cord.
Anemia should be improved or corrected. The red blood cells maintain the hemoglobin concentration above 80g/L to improve the general condition of the patient and tolerate chemotherapy. Subcutaneous or intravenous injection of erythropoietin (EPO) helps to improve anemia. When thrombocytopenia causes bleeding, a concentrated platelet suspension can be delivered. When the high-viscosity syndrome is severe, the plasma exchange method can be used to rapidly remove abnormally large amounts of immunoglobulin, reduce plasma viscosity, and relieve symptoms. Hypercalcemia with intravenous injectionCalcitonin(calcitonin) 5 ~ 10U / (kg · d), intravenous infusion of pamidronate disodium (Boning, Ada) 60 ~ 90mg / d, oralPrednisone(60mg / d) can effectively reduce blood calcium. Hyperuricemia patients with allopurinol (allopurinol) 300 ~ 600mg / d can effectively reduce blood uric acid levels. Dehydration is caused by increased urinary calcium, polyuria, tubular insufficiency caused by polyuria and hypercalcemia caused by vomiting. In the treatment, the rehydration is given to make the urine volume reach 1500-2000ml/d. Treat hypercalcemia. For patients with renal insufficiency, according to the principle of renal insufficiency treatment.
1 hemoglobin is less than 60g / L, infusion of red blood cells; 2 hypercalcemia: isotonic saline hydration, prednisone: 20mg, oral, 3 ~ 4 times / d; 3 hyperuricemia: allopurinol: 0.2 Mg, oral, 3 times / d; 4 hyperviscosity: plasma exchange therapy; 5 renal failure: hemodialysis; 6 infection: combined antibiotic treatment, combined injection of penicillin, gamma globulin in patients with repeated infections effective.
Patients with this disease are prone to infection, should pay attention to prevent colds and maintain oral hygiene. Once an infection occurs, effective antibiotics should be selected for the pathogen to try to control the infection early. Intramuscular injection of human gamma globulin is difficult to achieve effective prevention of infection. The role of intravenous infusion of large doses of human gamma globulin in the prevention and treatment of infections in this disease is still under investigation.
2. Chemotherapy and chemotherapy is the main treatment for this disease. The application of new chemotherapeutic drugs and the improvement of drug administration methods are the key factors for improving the efficacy of this disease in recent years.
As a monotherapy, phenylalanine mustard (mil flange, L-phenylalanine mustard),Cyclophosphamide, nitrogen (formyl lysin, N-methyl), procarbazine (Methyl benzamidine), carmustine (dichloroethyl nitrosourea, carmustine, BCNU), lomustine (chloroethylcyclohexyl nitrosourea, sulphate, CCNU),VincristineDoxorubicin (doxorubicin),Etoposide(Episema, VPl6) and other effects.
(1) Program: The longest-time application and better efficacy are the application of combined chemotherapy.
1MP regimen: phenylalanine mustard (Malfran) 8mg/m2, oral, 1st to 4th days (or 4mg/m2, oral, 1st to 7th days); prednisone 60-80mg, oral, first 1 to 7 days, 4 weeks for a course of treatment. The effective rate of MP is about 50%, the median survival time is 24 to 30 months, and 80% of patients die within 5 years.
2M2 regimen: carmustine (carmustine) 00.5mg/kg, intravenous, day 1; cyclophosphamide 10mg/kg, intravenous, day 1; phenylalanine mustard (Malflang) 0.25 Mg/kg, oral, day 1-4 days; prednisone 1 mg/kg, orally, day 1 to 7, 0.5 mg/kg, orally, day 8 to 14; vincristine 0.03 mg/kg, intravenous injection On the 21st day, 5 weeks is a course of treatment.
3VBMCP regimen: vincristine 1.2 mg/m2, intravenous injection, day 1; carmustine (carmustine) 20 mg/m2, intravenous injection, day 1; phenylalanine mustard (Marfan) 8 mg /m2, oral, 1st to 4th day; cyclophosphamide 400mg/m2, intravenous injection, day 1; prednisone 40mg/m2, oral, 1st to 7th day, 20mg/m2, oral, 8th to 14th Days, 5 weeks is a course of treatment.
4VMCP/VBAP protocol: vincristine 1mg/m2, intravenous injection, day 1, phenylalanine mustard (Malfran) 6mg/m2, oral, 1-4 days, cyclophosphamide 125mg/m2, oral On days 1-4, prednisone 60 mg/m2, orally, on days 1-4, 3 weeks for a course of treatment; vincristine 1 mg/m2, intravenous, day 1; carmustine 30mg/m2, intravenous injection, day 1; doxorubicin (doxorubicin) 30mg/m2, intravenous injection, day 1; prednisone 60mg/m2, oral, 1-4 days, 3 weeks 1 course of treatment. The two schemes are used interchangeably.
(2) Currently, refractory cases are often treated with a VAD regimen or a high-dose phenylalanine mustard (Melphi) (HDM) regimen.
1VAD regimen: vincristine 0.4mg/24h continuous intravenous infusion for 4 days, doxorubicin (doxorubicin) 10mg/(m2·24h) continuous intravenous infusion for 4 days, dexamethasone 40mg, oral, first ~ 4 days, 9th to 12th day, 17th to 20th day, 25 days is a course of treatment. The effective rate of this program for refractory cases is 45% to 66%, and the median survival time is 11 to 16 months. The main side effect is secondary infection caused by high-dose dexamethasone. For refractory cases with high expression of multidrug resistance genes, MDR reversal agents can be added at the same time as chemotherapy, ie verapamil (isoprodine) 40-80 mg orally, 3 times/d, or cyclosporine 4mg/kg, intravenous, 2 times / d, 1st to 3rd day, 2.5mg / kg intravenous, 2 times / d, 4th to 5th day. It can also be taken in 1:3, cyclosporine (CsA) 5 mg / (kg · d).
2 large doses of phenylalanine mustard (Malflan) protocol: phenylalanine mustard (Malfran) 50 ~ 100mg / m2, intravenous, day 1. The effective rate of this program is about 40%. The main side effect is myelosuppression, which needs attention.
In addition to the above VAD, VAD plus MDR reversal agent and HDM regimen, CBV (cyclophosphamide, carmustine (carbazate), etoposide (Etoposide)) regimen can be selected for refractory cases or EDAP (etoposide)Dexamethasone, doxorubicin (doxorubicin), cisplatin) program. Both are about 40% efficient. It has been reported that the macrolide antibiotic clarithromycin 500mg, 2 times / d is effective for this disease, and even cases resistant to chemotherapy may work. oralThalidomide(Reaction stop) gradually increased from 200mg / d to 400 ~ 800mg / d, medication for more than 6 weeks, the effective rate is about 30%, side effects such as drowsiness, constipation, fatigue, peripheral neuropathy.
Regarding maintenance therapy, in the late 1970s and 1980s, intermittent treatment with MP or a combination regimen was used as a long-term maintenance treatment after complete remission of chemotherapy, but none of them achieved a significant positive effect of prolonging the remission period. This is because the residual tumor cells are multi-lineage resistant cells, so chemotherapy is not effective. In recent years, immunotherapy has been studied. For example, a patient's tumor cells are fused with dendritic cells (Dendritic cells) in vitro to prepare a tumor vaccine, which is inoculated into a patient in remission, and it is desired to activate the immune effector cells of the patient and kill residual MM cells.
3. Interferon and other biological response modifiers Interferon is a cytokine that has antiviral effects, affects (suppresses or stimulates) cell growth, regulates immunity, and the like. The effect of interferon on the growth of cells (including tumor cells) is mostly inhibited. At the same time, interferon also activates natural killer cells, activates cytotoxic T cells, stimulates B cells to synthesize immunoglobulins, and is used for tumors. Including the treatment of this disease. Interferon alpha (3 ~ 5) × 106U subcutaneous injection, 3 times a week, at least 6 weeks, the effective rate of single-agent treatment of patients with this disease is 10% to 20%, mostly partial remission. If combined with chemotherapy, whether it is better than chemotherapy alone is still controversial, although more reports that chemotherapy combined with interferon alpha can improve the remission rate and prolong the remission period, but some reports that the addition of interferon alpha has no effect on the efficacy. As for refractory cases, each report believes that interferon alpha is difficult to work. For patients with maintenance therapy after complete remission of chemotherapy, although some studies have a negative attitude, most studies certainly use interferon alpha [(3 ~ 5) × 106U subcutaneous injection, 3 times a week, long-term injection] as maintenance therapy, The effect of prolonging the remission period can be obtained. This debate remains to be further clarified.
Interleukin 6 (IL-6) is an important cytokine that induces B cell differentiation and stimulates B cell-plasma cell growth. IL-6 is required for in vitro culture of human myeloma cells, and IL-6 levels in bone marrow and serum of myeloma patients are also significantly increased, suggesting that IL-6 plays an important role in the pathogenesis of this disease, so there is research application. Anti-IL-6 monoclonal antibody treatment of this disease, preliminary report has a certain effect, but needs further research to confirm.
Bone pain is one of the main symptoms of this disease. Pamidronate disodium (Boning, Ada) reduces bone pain and osteolytic lesions by inhibiting osteoclast activity. The usage is 60-90 mg, intravenous drip. , once a month, can be reused. The use of OAF inhibitors (SD-7784, Statins) for the treatment of osteolytic lesions has recently been reported and has entered clinical trials.
Studies have reported that retinoic acid can achieve certain effects by inhibiting the growth of myeloma cells through negative regulation of IL-6 receptor. The study of oral retinoic acid in patients with elevated serum IL-6 levels is still ongoing.
4. Radiotherapy Radiation therapy is suitable for the treatment of isolated orthoplasmic plasma cell tumor and extramedullary plasmacytoma which are not suitable for surgical resection. It is also an effective treatment for relieving local severe bone pain. In addition, the use of half-body radiotherapy or half-body radiotherapy plus chemotherapy in patients with relapsed or drug-resistant relapses is about 50% effective. The radiation dose is generally 625 cGy in the upper body or 850 cGy in the lower body. In recent years, due to the progress of bone marrow transplantation, peripheral body radiotherapy has been used as one of pre-transplant pretreatment measures, and is not used alone.
5. Surgical treatment When the osteolytic lesions occur in the thoracic or lumbar vertebrae, the patient may be bedridden and may have paraplegia due to a compression fracture, and the diseased vertebra resection and artificial vertebral body replacement fixation may be performed. Successful surgery will prevent patients from paraplegia, restore mobility to a certain extent, and improve quality of life.
6. Although hematopoietic stem cell transplantation chemotherapy has achieved remarkable curative effect in this disease, it has not cured the disease. Therefore, since the 1980s, bone marrow transplantation has been used in combination with overdose chemotherapy and radiation to cure this disease. Allogeneic, allogeneic, autologous bone marrow (including peripheral blood stem cells) transplantation has been applied to the clinical treatment of this disease.
Pretreatment before bone marrow transplantation aims to remove tumor cells from the patient and inhibit the patient's immunity to make the bone marrow easy to mobilize. For this disease, a large dose of phenylalanine mustard (Malfran) 140-200 mg/m2 (-2 days) and peripheral body radiation (TBI) 850 cGy (-1 day) were used as pretreatment. Also used is carmustine (carbazate) 120mg/m2 (-8 days), etoposide (Etoposide) 250mg/m2 (-8 days, -6 days), phenylalanine mustard (Mar Flange) 140 mg/m2 (-2 days) and TBI 850cGy (-1 day) as pretreatment. In recent years, summative studies have shown that the use of phenylalanine mustard (Malflon) 200mg/m2 as a pretreatment effect is relatively good. 1 Isogenic bone marrow transplantation: The Seattle Research Center reported that 7 patients with this disease had the same gene bone marrow transplant of identical twin brothers, 2 of whom had survived disease-free for 8 years and more than 15 years (1994). Sweden reported 6 cases of syngeneic bone marrow transplantation, 3 of which have survived for more than 6 years. It indicates that bone marrow transplantation may cure this disease. 2 Allogeneic bone marrow transplantation: 90 cases of European bone marrow transplantation tissue, 50 cases of Seattle group report, 27 cases of Italy report, 17 cases of this disease were reported by Canada. Allogeneic bone marrow transplantation was performed. The results were similar: the 4-year survival rate was about 30%. The 10-year survival rate is about 20%, but the transplant-related mortality rate is as high as 40% to 50%. Infusion of donors to CD8 T lymphocytes in patients with relapse after allogeneic bone marrow transplantation, the development of graft anti-tumor effect (GVL) may rehabilitate some patients. It is generally believed that allogeneic bone marrow transplantation has a positive effect on this disease and is expected to cure some patients, but this therapy has certain risks, especially the incidence of graft-versus-host disease (GVHD) and the mortality rate of bone marrow transplantation. High, it should be noted that appropriate cases should be selected for allogeneic bone marrow transplantation. Most scholars advocate that patients with this age who are under 55 years of age with HLA-related blood donors and poor prognosis should strive for bone marrow transplantation as soon as possible. For patients with the above conditions but good prognosis, they should be postponed to the first. Bone marrow transplantation was performed at the time of recurrence. 3 autologous bone marrow transplantation: Because the current pretreatment program is difficult to ensure the complete elimination of tumor cells in patients, and lack of effective methods for purifying bone marrow in vitro, the recurrence rate after autologous bone marrow transplantation is high, and the curative effect is limited. Although studies have confirmed that autologous bone marrow transplantation can improve the remission rate, it is inconclusive as to whether the remission period can be extended. The improvement of the efficacy of autologous bone marrow transplantation depends on the improvement of pretreatment regimen and the progress of in vitro bone marrow purification research. 4 autologous peripheral blood stem cell transplantation: only a small number of tumor cells in the peripheral blood of patients with this disease is the advantage of using this method to treat this disease. Usually, after the chemotherapy, the bone marrow hematopoietic function is restored early, and the cytokines such as G-CSF are used to mobilize the bone marrow hematopoietic stem cells to escape into the peripheral blood to collect and store the peripheral blood stem cells. After the patients receive high-dose chemotherapy and TBI, they are returned to the patient. The efficacy reported by different medical centers is different. It is generally believed that autologous peripheral blood stem cell transplantation may be superior to chemotherapy alone in terms of remission rate or disease-free survival, but it is inevitable that recurrence will eventually occur. Research on this therapy is currently under active development.
7.CD20 monoclonal antibody treatment of multiple myeloma Rituximab(Mervaic) 375mg/m2, 1 time/week × 4 weeks, sharing 4 times for 1 cycle, intermittent 6 months for the 2nd cycle, a total of 6 cycles, giving rituximab (Merocal) 35th Tianyu phenylalanine mustard (Malfran) 0.25mg/kg, orally, on days 1 to 4, prednisone 100mg, orally, on days 1 to 4, repeated once every 4 to 6 weeks.
Judgment criteria: The important indicators for judging the curative effect of this disease are: serum M protein and/or urinary-peripheral protein decreased by more than 50%, plasmacytoma two diameters reduced by more than 50% and bone osteolytic lesions improved. Secondary standard, the pulp in the bone marrow (tumor) cells decreased by <5%, hemoglobin increased by 20g / L, blood calcium and urea nitrogen decreased to normal levels, after treatment, M protein disappeared, other indicators can reach normal The level is at least 1 for complete remission, and the main indicator and at least 2 secondary indicators are partial remission. The sum of complete response rate and partial response rate is always effective.
(two) prognosis
The factors associated with the prognosis of this disease are: clinical stage (including renal function), immunoglobulin typing, plasma (tumor) cell differentiation, serum β2-microglobulin levels, serum lactate dehydrogenase levels, and plasma cell marker index. . The median survival of clinical stage IA is up to 5 years, while the median survival of clinical stage IIIB is shorter than 2 years. Immunoglobulin types also have an impact on prognosis. The light chain type has a poor prognosis, and the IgA type prognosis is also inferior to the IgG type. The prognosis of patients with poor differentiation of plasma (tumor) cells is inferior to those with better differentiation of plasma (tumor) cells. 2-2-microglobulin (β2-M) is a low molecular weight (11800) protein, which is a light chain part of HLA-A, B, C histocompatibility antigen complexes, and normal serum β2-M content. <2.7 mg/L, almost all excreted by the kidney, the proximal tubules are taken in the form of pinocytosis, and the lysosomes of the renal tubular cells are degraded into amino acids. In this disease, blood and urine β2-M levels are elevated due to tumor cell proliferation, accelerated cell turnover, and impaired renal function. It is currently recognized that β2-M is an important prognostic factor for this disease, and serum β2-M is significantly elevated as one of the high risk factors. Elevated serum lactate dehydrogenase (LDH) levels are caused by tissue necrosis, which is seen in a variety of inflammation, tissue or tumor necrosis. Although not specific, LDH is significantly elevated as another risk factor for this disease. Plasma cell labeling index (PCL1) represents the synthesis of DNA in plasma (tumor) cells, reflecting the progression of myeloma, PCLI <1.0 is a low-risk group, PCLI <3.0 indicates the progression of myeloma, is a high-risk group. In addition, there are different opinions on whether C-reactive protein (CRP) and thymidine kinase (TK) are independent prognostic factors, and there is no conclusion.
The course of the disease varies widely between patients. According to the above prognostic factors, patients with this disease can be divided into low-risk group, intermediate-risk group and high-risk group. There is currently no recognized and uniform classification standard, and the following classification criteria are for reference only. In the low-risk group, the clinical stage was stage I, such as β2-M<2.7mg/L, PCLI<1%, the median survival time of this group was >5 years; the clinical stage of the middle-risk group was II stage, β2 -M≥2.7mg/L or PCLI≥1%, the median survival period of this group is about 3 years; the high-risk group at the time of diagnosis is clinical stage III, β2-M≥2.7mg/L, and PCLI≥1%, The lifetime of this group is about one and a half years. As far as the disease is concerned, the median survival time of patients with this disease is 30 to 36 months under the current conditions of chemotherapy. The main cause of death is infection, renal failure, peripheral failure caused by myeloma progression, or multiple organ failure, and a small number of patients die from gastrointestinal or intracranial hemorrhage. About 5% of patients are converted to acute leukemia, mostly acute plasma cell leukemia, but can also be acute monocytic leukemia, acute granulocyte-mononuclear leukocytes or acute myeloid leukemia.
prevention
The occurrence of this disease is related to the environment, diet and other factors, so prevention of the disease, enhance the patient's physical condition, actively treat chronic diseases, avoid contact with radiation and chemical poisons, and have important significance for the prevention and treatment of diseases.
First of all, contact with carcinogenic factors should be avoided. If there is a history of contact or a suspicious condition, regular physical examination should be conducted to seek early treatment and timely treatment. Patients should participate in appropriate regular activities to reduce decalcification. Pay attention to personal hygiene and prevent infection, especially pay attention to the cleansing of the oral mucosa and skin to prevent colds.
Chinese medicine methods should pay attention to conditioning emotions, to prevent the seven emotions too much, so as to maintain blood and smooth, yin and yang balance, prevent disease. After getting sick, keep optimistic, do not be angry, do not feel sad, and build confidence in the fight against disease, is an important part of the fight against disease. Pay attention to physical exercise, adjust the body in four seasons, you can take qigong, Tai Chi and other methods to enhance physical fitness, prevent disease, or cooperate with this disease treatment. Pay attention to the daily life, work and rest, cold and warm, avoid evil spirits, especially for house sex, to prevent kidney essence. Should not smoke alcohol, pay attention to diet, avoid overeating, diet preference. Avoid spicy and savory products. After the disease, it can be used to supplement blood, strengthen bones and reduce splenomegaly.
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