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multiple myeloma paraprotein

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multiple myeloma paraprotein

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Multiple myeloma diagnosis and treatment of
Multiple myeloma (multiple myeloma, MM) is the abnormal proliferation of monoclonal plasma cell malignancy, to secrete monoclonal immunoglobulin (M protein) as the main feature. Clinical features of tumor cells of bone marrow infiltration, bone damage, immunoglobulin abnormalities. Serum protein electrophoresis shows a single peak protruding M protein, anemia, infection and renal dysfunction and so on. Because of this disease tumor cell doubling time is long, five patients could be longer-term symptoms, and some even up to several years, this early period is called multiple myeloma, common in the elderly, aged 60 to 50 - more than 40 years old The following are rare, more men than women.
First, the diagnosis
(A) Domestic Diagnostic criteria:
1. Bone marrow plasma cells> 15%, and abnormal plasma cells (myeloma cells) or tissue biopsy confirmed plasmacytoma.
2. A large number of serum monoclonal immunoglobulin (M protein), IgG> 35g / L, IgA> 20g / L, IgD> 2.0g / L, IgM> 2.0g / L, IgM> 15g / L, or urine of monoclonal immunoglobulin light chain (Week protein), 1.0g / d, a small number of cases, there may be two-or three clones cloned.
3. No osteolytic lesions or other causes generalized osteoporosis. IgM-MM diagnosis, in addition to compliance and 2, but still need to have the typical clinical manifestations of MM and multiple parts of osteolytic lesions. Only 1 and 3 is not secreted by MM, for further identification is not synthetic and not synthetic or secretory subtypes. Only 1 and 2 of those (especially the original immature bone marrow plasma cells are not), shall be excluded from an increase in reactive plasma cells, such as connective tissue disease, chronic infection, chronic liver disease, tuberculosis, cancer and so on. Generally mature plasma cells <10%.
(B) of the World Health Organization (WHO) in 2001 proposed diagnostic criteria for MM
1. Main criteria
A bone marrow plasma cells increased (30%)
B biopsy proven plasmacytoma
CM components: serum 1gG> 3.5g/dl or 1gA> 2.0g/dl, this week, protein, 1g/24h
2. Secondary Standard
A bone marrow plasma cells increased (10% -30%)
BM components, but lower than the level of presence
C with osteolytic lesions
D reduction of normal immunoglobulin 50%, 1gG <600mg/dl, 1gA <100mg/dl, 1gM <50mg/dl diagnosis of MM with at least? Major criteria and one minor criteria, or have three minor criteria and including at least one and two, patients should progress with the diagnosis of related diseases
Exhibition, Pi symptoms. Solitary plasmacytoma of the diagnostic criteria: â‘  X ray, nuclear magnetic resonance (MRl) inspection showed a single osteolytic tumor; â‘¡ tumor biopsy confirmed plasmacytoma; â‘¡ many parts of the bone marrow of normal bone marrow biopsy; â‘£ generally not associated with monoclonal immunoglobulin increased. Extramedullary plasmacytoma is primary in the bone marrow and bone than other plasma cell tumors, the best part is the upper respiratory tract issued, followed by lymph nodes, thyroid, skin, stomach and brain are rare. Extramedullary plasmacytoma diagnostic criteria: â‘  biopsy proven plasmacytoma; â‘¡ normal bone marrow; â‘¡ X ray and MRI were normal; â‘£ generally not accompanied by increased monoclonal immunoglobulin.
Second, the differential diagnosis
As MM more insidious onset, clinical manifestations, more complex and diverse, often misdiagnosed, according to Li Shoujing reported 2547 cases of MM and other clinical misdiagnosis rate as high as 69.1% and the hospital has reported 29 cases 17 cases of misdiagnosis, misdiagnosis rate was 58,6 %. Therefore, MM is the differential diagnosis of clinical physicians should pay special attention to important issues.
1. Plasma cell histiocytosis reaction itself does not cause clinical symptoms, clinical manifestations depending on the primary disease, such as connective tissue disease, chronic liver disease, tuberculosis, cancer, etc. can cause an increase in pulp fine Qu, usually mature plasma cells> 3% <10% No bone destruction and blood and urine monoclonal immunoglobulin by the non-appear.
2. Bone marrow metastases, there may be fever, anemia, bleeding, bone pain, elevated ESR, peripheral blood appeared immature red and (or) promyelocytic, X-ray examination may have bone destruction, most likely to be confused with the MM, in particular malignant primary tumor is unclear, when bone marrow aspiration and biopsy, serum protein electrophoresis and urine protein helps to distinguish this week.
3. Primary macroglobulinemia, also known as Waldenstom macroglobulinemia, bone marrow, similar to lymphoid plasma cells, serum immunological tests increased mainly 1gM, X-ray examination in general no osteolytic bone damage.
4. Low back pain disorders, low back pain common to muscle strain, spinal tuberculosis, counter disc herniation, osteoporosis and other diseases, while the MM is the main symptom of low back pain, the patient if the clinician when treatment was no vigilance or awareness of the lack of MM, especially the X-ray examination revealed no vertebral compression lesions, prone to misdiagnosis or missed diagnosis. Therefore, clinicians should pay particular attention to the chief complaint of low back pain in elderly patients to treatment, especially when persistent or low back pain was aggravated after the event, accompanied by anemia or elevated ESR, although no X-ray examination of osteolytic lesions or compression fractures, bone marrow biopsy should also be other tests and serum protein electrophoresis.
Third, treatment
Multiple myeloma is still an incurable disease. Available treatments only prolong survival and improve quality of life, elderly and frail patients to consider another immune deficiency, chemotherapy, dose and duration, must be properly controlled, and must strengthen the supportive care and treatment of complications.
1. Chemotherapy, multiple myeloma is still the main method of treatment, combination chemotherapy alone is clearly more than a drug effect.
(1) MP solution: currently the treatment of early treatment of people used melphalan (melpnalan, M) and prednisone (prednison, P). Usage: M 68mg / d, orally, once every 4-5 days, P 45mg ~ Omgtd for 7 days, repeated every 46 weeks for a course of treatment, because the MM, Emotion progress slower to react more slowly to treatment to a number of general hum process to determine the efficacy rate was 50% of the reported -60%
(2) M2 program: the MP, based on the use case, vincristine (VCR), cyclophosphamide dipped by (CTX) BCNU (BCNu) better results than the MP. It is reported that the effective rate was 75%, use: VCR 2mg/m2d1 iv CTX400mg/m2 d1iv BCNU 20 mg/m2 d1 iv M 8 mg/m2 d14 P20-40mg/m2d114, intermittently for 5 weeks, can be reused.
(3) VAD program: the VCR, adriamycin (ADM) and dexamethasone (Dex) composition. In recent years, alkylating agent using this program on drug-resistant MM have a certain effect. Usage: VCRO. 4mg / d, continuous infusion used in conjunction 4 days; ADM9mg/m2, continuous infusion qd for 4 days. Dex20mg/m2dl- 4, d9-12, d17-20, repeated every 28-35 days.
The program's advantages: â‘  VCR doxorubicin by continuous infusion, administration method can increase the myeloma cells in the S phase of the destruction, to quickly lower the tumor burden; â‘¡ no damage to stem cells; â‘¢ outside of drug excretion by the kidney and renal function incomplete without dosage adjustment; â‘£ lesser degree of bone marrow suppression, faster recovery. These special
Point for renal insufficiency, pancytopenia, need to quickly lower the tumor burden, such as hypercalcemia, nerve compression in patients with the application.
Prepared to do for the body in patients with hematopoietic stem cell transplantation, the fear of applications include alkylating agents, including melphalan drugs can affect the quality of hematopoietic stem cells collected, VAD programs often can be used as the preferred treatment. Can be applied to other anthracycline drugs, alternatives such as epirubicin adriamycin (EPl) and idarubicin (1DA). (4) VAMP program VCR, ADM dose and administration of the program with the VAD only alternative to methylprednisolone and dexamethasone, usage: VCRO. 4mg / d continuous infusion d1-4, ADM9mg/m2/d continuous intravenous infusion of dl-4, methylprednisolone 1g/m2 ~ d1-4, can be repeated for each on the 28th. (5) MDP program: for refractory MM, patients use: to care anthraquinone (MIT) 4mg/m2iv, d1-4VCR 0,4 mg / d intravenous infusion of dl-4, P 45mg/d1-4, d17-20 After 4 weeks, repeat.
Ⅰ M protein of the patients disappeared after chemotherapy, up to 12-24 months or more, you can not give maintenance therapy. Ⅱ Ⅲ of MM patients on already in the stable phase, whether spinning holding therapy, remains controversial, based on clinical trial summary, long-term maintenance chemotherapy does not appear to delay recurrence, prolong progression-free survival, so researchers do not claim to more chemotherapy, maintenance therapy, and can be used low-dose α-interferon and thalidomide. For refractory and relapsed MM patients, in addition to use of chemotherapy, but also reverse the resistance to agents such as the addition of cyclosporine A, PSC833 and calcium channel blockers and so on.
2, radiation therapy
(1) for solitary bone plasmacytoma and extramedullary plasmacytoma, radiotherapy is the preferred method of treatment. Radiation dose 40 - 45Gy, 20 minutes to give a course of 4 weeks, rates were 94% and 93%.
(2) of MM patients with local radiotherapy to relieve pain, reduce fractures and spinal compression symptoms may occur after radiation therapy of bone regeneration, fracture healing and oppression lifted, vertebral involvement paraplegic who may recover. Prevention and edema caused by radiation therapy may be given dexamethasone.
Three, target therapy
Target therapy, a new method to treat MM. Changes in drug treatment by bone marrow micro-environment in which the myeloma cells can not survive in the bone marrow microenvironment and therapeutic purposes.
(1), thalidomide (1halidomide, thalidomide) is glutamic acid derivative, has been used for early pregnancy vomiting of 50 years, and found the baby teratogenic, after being disabled in 1997, approved for the treatment of leprosy drugs, to obtain better results. In recent years, due to tumor angiogenesis in the role of science and thalidomide has significant anti-angiogenic role in the treatment of some solid tumors and hematological tumor treatment, to obtain efficacy in the treatment of multiple myeloma in particular gained a gratifying progress.
Mechanism of thalidomide: â‘  can inhibit the vascular endothelial growth factor (VEGF) induced angiogenesis, reduced VEGF-induced mitogenic protein kinase {MAPK) signal path. â‘¡ could directly inhibit the proliferation of myeloma cells and kill tumor cells. â‘¢ can regulate the expression of adhesion molecules, preventing tumor cell growth and proliferation-related cytokine secretion, interference with bone marrow tumor cells aiming microenvironment interactions. â‘£ on T cells and NK cells in vivo has a direct stimulating effect, enhancing its activity against myeloma cells and the quantity, and promote IL-2 and IFN-r secretion, strengthen the immune myeloma cells in vitro.
Reaction disable method: using increasing doses, starting amount? 100mg / d ,1-2 weeks, gradually increasing to 200mg / d to 400-600mg / d, but the optimal dose therapy has not been established, according to clinical reports> 400mg / d of Most patients are still capable of dose tolerance. However, some patients can not tolerate, it was reported that low dose thalidomide therapy, can achieve better effect. There are also reports of about 30-45% of refractory / relapsed MM patients with thalidomide in the treatment of partial remission. Thalidomide combined with dexamethasone or in combination with chemotherapy side effects often constipation, drowsiness, secondary menopause, skin rash and peripheral neuropathy, rare side effects such as neutropenia, hypothyroidism, bradycardia and intravenous thrombosis.
(2) a proteasome inhibitor PS-341
PS-341 is a synthetic protease inhibitor with high selectivity borate, studies confirm that it can directly inhibit myeloma cells, and can inhibit the bone marrow microenvironment in the bone marrow through a paracrine mechanism of tumor growth can be directly on the bone marrow resistant tumor cells induced apoptosis of myeloma cells, IL-6 gram fishy on myeloma cells, protection, and enhanced anti-tumor effect of dexamethasone, is foreign has entered clinical trials. It is reported that 25 cases of MM patients with PS-341 alone condition to obtain a stable condition after treatment, except for 1 after dexamethasone exceptions, the rest have received anti-MM effect.
(3) arsenic trioxide (As203)
As203 treatment of newly diagnosed, relapsed and refractory acute promyelocytic leukemia (APL) achieve amazing results. In recent years, not only through the study found that arsenic trioxide can induce apoptosis, cell differentiation, but also on the cell cycle and have a role in tumor angiogenesis. Through direct inhibition of bone marrow microcirculation and survival of tumor growth curve factors to mediate the production of anti-myeloma cells.
In vitro experiments show that vitamin C can reduce the concentration of intracellular glutathione myeloma cells enhanced the sensitivity of As203, Bahlis such reports 6 cases of refractory / relapsed myeloma patients with As203 0,25 mg / kg · d plus mouth with vitamin C1000mg / d, 25 days after administration, 2 were effective, 4 stable disease. Munshi et al reported 14 cases of high-dose chemotherapy with autologous stem cell transplantation with refractory / relapsed patients treated with As203 0.15mg/kg · d Used for 2 hours intravenous infusion of 60 days, effective three cases, stable in 8 cases, disease progression 3 cases.
4, immunotherapy
(1) α-interferon (1FN-α): α-interferon as a multifunctional cytokine with anti-virus and anti-tumor cell proliferation and modulate immune function. Studies have shown, α-interferon in the inhibition of alkylating agent and Boni Song proliferation of myeloma cells have synergistic effect. In recent years, α-interferon has been used in the treatment of myeloma patients, especially IFN-α in combination with chemotherapy drugs can improve efficacy, the effective rate of 75-82%, patients with remission after chemotherapy can be dose interferon alone 300-500 million U/m2, 3 times Ti, intramuscular or subcutaneous injection.
Side effects: Most patients have initial application of interferon can be flu-like symptoms, rare mild bone marrow suppression, dizziness, nausea, vomiting, headache and mild hair loss, loss of appetite and so on.
(2), interleukin -2 (1L-2)
D cells are the main source of 1L-2, 1L-2's role: ① to stimulate T cell proliferation and differentiation; ⑦ cytotoxic T lymphocytes induced; ③ promote increase in the number and activity of NK cells increased; ④ activated LAK cells generated; ⑤ stimulation on cell proliferation, differentiation, secretion of antibodies; ⑥ induction of T cells to secrete IFN-r and TNF-α; ⑦ produce graft-versus-tumor effect.
1L-2 application: â‘  immunotherapy after transplantation; â‘¡ radiotherapy and chemotherapy treatment. 1L-2 and melatonin (MLT) may enhance the anti-tumor effect with advanced MM were treated with IL-2 300   U / d subcutaneously 6 days per week for 4 weeks MLT 20mg / d, orally available treatment. Side effects: fever, hypotension, tachycardia, rash, thrombocytopenia, nausea, vomiting and other side effects, usually self-limiting after stopping.
(3) CD20 monoclonal antibody
Only the former B surface antigen CD20 cells and mature B cells, CD20 antigen and antibody binding does not occur modification, loss or neutralization, is therefore considered ideal for monoclonal antibody diagnostic and therapeutic targets. Rituximab is the use of recombinant DNA technology developed by anti-human mouse hybrid monoclonal antibody leukocyte cluster of differentiation CD. Study confirmed that rituximab in combination with chemotherapy can achieve good results.
Usage: Rituximab 375mg/m2, 1 times / week × 4, 4 times for one cycle of sharing, giving the first 35 days of rituximab given melphalan 0.25mg/kg, oral administration of dl-4, Boni Song 100mg, oral d1-4, each 4-6 weeks, repeat, low toxicity, rituximab, only mild nausea, myalgia and so on.
5, hematopoietic stem cell transplantation: the current of MM patients the primary means is still the chemotherapy, but for the "60-year-old patient, consider the use of high dose therapy (HDT) plus autologous hematopoietic stem cell transplantation (ASCT), can be used as treatment strategies component, while the> 60-year-old patient, the general situation is better, it can be considered, but for> 70 years were not considered. For the "50-year-old line can be considered in patients with allogeneic hematopoietic stem cell transplantation, which is the only hope that a thorough cure.
6, supportive therapy, and complications
(1) to lose red blood cell anemia, severe anemia, and addition of androgen stimulation of hematopoietic stem cell anemia, stanozolol {Stanozolol) 2mg / time, 3 times / d; testosterone undecanoate 40mg / time ,2-3 / d, but also can be used erythropoietin (EPO) therapy, EPO is a safe and effective drug, can improve the quality of life of patients, 50% -60% efficiency. The initial dose or every other day subcutaneous 3000u 10000u (weekly 300-450u/kg) increasing to weekly 900u/kg ,4-6 weeks can occur treatment, EPO adverse reactions were mild, few patients with mild increase in blood pressure after treatment.
(2) infection: once infected, anti-infective therapy should be actively used to select appropriate drug, and should be deemed to have throat swabs, sputum, urine and blood culture, choice of antibiotics based on susceptibility testing, if the choice of fungal infection fluconazole and itraconazole and other drugs. In the event of a serious infection, or WBC count <1.0x109 / L, can be intravenous immune globulin, a dose of 0.4/kg · d, for 5 days and granulocyte colony-stimulating
Factor (G-CSF).
(3) hypercalcemia
MM patients with hypercalcemia, according to statistics up to 30-60% of patients in Europe and America, about 16% of China's statistics. The occurrence of hypercalcemia may be due to excessive activation of osteoclast caused bone destruction causes the release of Ca2 from the bones, the other myeloma patients with impaired renal function lead to reduced glomerular filtration rate, reduced Ca2 removal. Treatment of hypercalcemia hypocalcemia barrier drink lots of water daily urine output should be maintained at 2000mi above, such as body fluids are complementary, can be used diuretics such as furosemide, Lee urea, helps calcium excretion, Boni Song 30-60mg / d, oral or intravenous dexamethasone. Hormone has a rapid effect in reducing hypercalcemia, the mechanism can reduce intestinal calcium absorption and inhibit osteoclast activity and act directly on myeloma cells. Bisphosphonate drugs, can induce osteoclast apoptosis in tumor cells and bone marrow of myeloma cells have a direct anti-tumor effect, and can effectively reduce the serum calcium, reduce bone pain.
(4), renal failure, dialysis can be treated with VAD chemotherapy program, because of its markedly faster, and has little effect on renal function in emergency situations can be a single dexamethasone as initial therapy. Allopurinol can be taken orally 0.1 / time, 3 times / d, can reduce blood uric acid, may protect renal function.
(5) hyperviscosity syndrome
Hyperviscosity syndrome is a complication of MM, the incidence of myeloma patients t0%, because a large number of M protein in the blood viscosity increase, leading to disorders of blood circulation occurs, it may present with a series of blood viscosity increase of the clinical symptoms, such as decreased visual acuity, retinal hemorrhage and exudation sudden disturbance of consciousness or other symptoms of central nervous system disorders. At this point with plasma exchange therapy on M protein-induced hyperviscosity syndrome is an effective treatment. Each replacement takes about 2500-3000m, plasma ,2-3 hours to complete, serum monoclonal immunoglobulin decreased 35.5%, if the exchange capacity of 5000ml, you can clear the 80% of the immune serum globulin. Because the efficacy of plasma exchange is short, should be based on M protein reduction after replacement of the situation and to improve the situation hyperviscosity syndrome in 1 week and then decide whether the line replacement. Line plasma exchange for the same time, as soon as possible MP or VAD patients undergoing chemotherapy, inhibition of tumor cells and reduce the M protein.
Fifth, the prognosis
MM is still no cure, treatment response and duration of disease, individual differences, outcomes and total amount of M protein, clinical stage, immunophenotype, osteolytic damage, anemia, the degree of severity of renal dysfunction, and some survival shorter, less than 1 year, 3-5 years, but the individual and some can be up to 10 years, mainly cause of death was infection, hemo
rrhage, renal failure and so on.
VI Conclusion
Multiple myeloma is a kind of in the elderly population of the disease, the population is gradually aging, and medical diagnosis and treatment of rapid development, and the people of this disease awareness raising the level of the past 10 years, MM incidence increased significantly, people of this disease gradually in-depth research, have begun to use in the diagnosis of immunoglobulin heavy chain (lgH) and light chain (1gL) translocation and the expression of specific genes and gene expression methods such as rapid and accurate diagnosis
Off MM, the application in the treatment of a variety of treatment methods include administration of chemotherapy, radiotherapy and hematopoietic stem cell transplantation, target therapy (thalidomide, arsenic, etc.) as well as immune therapy achieved a certain effect, but MM is still a difficult to cure disease, I believe the future will be working on through the efforts of even greater success.
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