Multiple myeloma (MM) is a malignant plasma cell disease that occurs in B-lymphocytes. It predominantly occurs in middle-aged and elderly people, but in recent years the incidence has increased and the age of onset has tended to advance. The etiology and pathogenesis are not clear. It may be associated with high expression of oncogenes such as C-MYC, N-RAS or K-RAS or H-RAS induced by ionizing radiation, chronic antigenic stimulation, EBV or herpesvirus infection associated with Karls Sarcoma.
Early signs and symptoms of multiple myeloma are atypical, and patients may be first seen in orthopedics, nephrology, respiratory medicine or hematology for bone pain, proteinuria or anemia. There are a lot of misdiagnosis and mistreatment in primary hospitals, almost 50-80% of which are misdiagnosed. It should be given sufficient attention in the diagnosis and treatment.
Mechanisms of the formation of multiple myeloma bone disease
Bone pain and osteolytic bone destruction are the prominent clinical manifestations of multiple myeloma. Bone pain sites are most common in the low back, followed by the sternum, ribs and lower limb bones.
Mechanism: Once myeloma cells (MMC) infiltrate the bone marrow, the adhesion of MMC to bone marrow stromal cells increases the production of IL-6, TNFa, MIP-1a, OPN and DKK1, resulting in enhanced activation, differentiation and maturation of osteoclasts and diminished bone formation by osteoblasts, causing the development of myeloma bone disease.
Since patients with this disease often have severe osteoporosis, pathological fractures often occur with a little force or inadvertently, which can cause neurological symptoms due to mechanical compression and, in severe cases, paraplegia. If the paraplegia is prolonged, even after effective treatment, it is difficult for the patient to resume walking, which greatly affects the patient’s quality of life. Skeletal masses may also appear, with tumor cells infiltrating the bone, periosteum and adjacent tissues from the bone marrow outward to form masses.
X-rays are important in the diagnosis of this disease. Positive lesions are mainly found in the skull, pelvis, ribs and vertebrae, but also in the bones of the extremities. The typical manifestations are as follows: ① Penetrating osteolytic lesions, which are multiple round-like translucent areas, are the special X-ray manifestations of the disease. The skull and pelvis are the most easily detected. (ii) Diffuse osteoporosis. ③Pathological fractures, most commonly in the lower thoracic and upper lumbar vertebrae, but also in the ribs and other places. PET-CT or MRI is feasible for suspected cases to clarify the site of osteolytic lesions.
Mechanism of multiple myeloma nephropathy
Renal disease is a common and important lesion in this disease. Proteinuria is the most common clinical manifestation, followed by hematuria. Chronic renal insufficiency or uremia may develop in advanced stages and is one of the main causes of death in this disease. About 50% of patients with myeloma are diagnosed with proteinuria and other renal damage, and 30% of MM patients have serum inosine >2mg/dL at the time of diagnosis.
Foreign studies have found that patients with MM nephropathy have mild pathological glomerulopathy and severe tubulointerstitial lesions, so patients rarely develop hypertension clinically.
Myeloma nephropathy is caused by a variety of factors. Damage to renal tubules by light chain proteinuria and amyloidosis caused by deposition of light chain in glomeruli are the main causes, in addition to myeloma cell infiltration, hypercalcemia and hyperuricemia are also involved in the pathogenesis. Immunophenotyping is closely related to renal damage, with the highest rate of renal damage in the light chain type.
About 50% of patients with moderate renal impairment can have their renal impairment reversed after treatment with hydration, chemotherapy, diuretics and treatment of hyperuricemia.
Mechanism of formation of anemia in multiple myeloma
Mechanism: The causes of MM anemia are multiple.
(1) It is mainly related to a variety of cytokines associated with myeloma, such as IL-1, TNFa, TGF-β and IFN, which can cause insufficient production of erythropoietin (EPO) and a decrease in the number of red lineage cells.
(ii) Inadequate EPO production due to renal insufficiency in some MM patients.
(iii) Myeloma cells themselves can cause anemia by affecting the production of normal erythrocytes.
④Anaemia can be caused by apoptosis of erythroid progenitor cells induced by intercellular contacts and Fas/Fas-L interactions.
⑤ Other mechanisms include toxic side effects of chemotherapy, impaired iron utilization (functional iron deficiency), folic acid deficiency, shortened erythrocyte life span and increased plasma volume caused by M protein (dilutional anemia).
The combination of these factors results in an average Hb of around 100g/L in MM patients, with about 25% of patients having less than 85g/L.
How to avoid misdiagnosis of multiple myeloma
The misdiagnosis rate of multiple myeloma is high. Patients may be misdiagnosed as bone disease, nephritis and respiratory infection due to back and leg pain, urinary changes and fever, which may delay the disease.
Some clinical manifestations that are easily misdiagnosed.
I. Myeloma bone disease
Patients may not pay attention to bone pain or low back and leg pain, or visit orthopedic department and be misdiagnosed as sprain, fracture, bone tuberculosis or bone tumor and delay the condition.
Therefore, for middle-aged and elderly patients with severe osteoporosis or fractures, this disease should be considered in the diagnosis. Pay attention to the blood immunoglobulin and serum protein electrophoresis, etc. to clarify the diagnosis at an early stage.
II. Myeloma nephropathy
Patients may consult the nephrology or Chinese medicine departments for hematuria or proteinuria, and be misdiagnosed as nephritis, etc. without effective treatment for a long time, which may lead to advanced disease or development of uremia.
Therefore, for middle-aged and elderly patients who cannot be clearly diagnosed with long-term proteinuria and hematuria, renal biopsy, bone marrow aspiration or myeloma-related tests such as bone marrow, blood immunoglobulin and serum protein electrophoresis should be performed promptly.
III. Infection
Due to the decrease of normal immunoglobulins and increase of abnormal immunoglobulins without immune activity; leukopenia, anemia and radiotherapy affect normal immune function, so it is easy to have recurrent infections. Patients can be seen with fever as the first symptom. Patients are prone to respiratory tract infections such as epiglottitis, pneumonia or urinary tract infections, and female patients are more prone to urinary tract infections. In the late stage of the disease, infection is one of the main causes of death.
Therefore, for middle-aged and elderly patients with recurrent infections, they should not be limited to anti-infection treatment only, but should be treated with anti-infection treatment while actively looking for the presence of primary diseases. If the patient has combined bone pain, anemia and bleeding, the possibility of this disease should be considered.
Diagnostic criteria of multiple myeloma
The International MM Working Group (IMWG) redefined MM in 2003 as symptomatic and asymptomatic MM according to the presence or absence of organ damage.
I. Symptomatic MM
1. Presence of M-protein in blood or urine
(a narrow bottom peak in the gamma or beta region)
2, clonal plasma cells or plasmacytoma in bone marrow
3, associated organ or tissue damage (end-organ damage, including bone damage)
Second, asymptomatic MM
1, M-protein ≥ 30g/L
2, and/or clonal plasma cells in bone marrow ≥ 10%
3, no associated organ or tissue damage (end-organ damage, including bone damage) or asymptomatic
MM-related organ or tissue damage (ROTI, IMWG 2003)
1, blood calcium levels: serum calcium > 0.25 mmol/L or > 2.75 mmol/L upper limit of normal
2, renal insufficiency: creatinine > 173 mmol/L
3, anemia: Hb < normal low limit 2g/dl or < 10g/dl
4, bone damage: osteolytic bone damage or osteoporosis with combined compression fractures
5, other: symptomatic hyperviscosity syndrome, amyloidosis, recurrent bacterial infections (>2 episodes within 12 months)
In addition, attention needs to be paid to the differential diagnosis with the following diseases.
1, reactive plasmacytosis: seen in tuberculosis, typhoid fever, autoimmune diseases, etc. Generally, bone marrow plasma cells do not exceed 10% and are mature plasma cells.
2, other diseases that produce M protein: chronic liver disease, autoimmune disease, malignant tumors such as lymphoma, etc. can produce a small amount of M protein.
3, monoclonal immunoglobulinemia of undetermined significance (MGUS): M protein in serum is less than 30g/L, plasma cells in bone marrow is less than 10%, no osteolytic lesions, anemia, hypercalcemia and renal insufficiency. About 5% of patients eventually develop into multiple myeloma.
4.Bone metastatic carcinoma: mostly accompanied by osteogenesis, with increased bone density around the osteolytic defect and significantly elevated serum alkaline phosphatase. There is the presence of primary lesion.
Clinically, asymptomatic MM can be temporarily observed, and chemotherapy is needed to control the deterioration of the disease when it develops into symptomatic MM.
Summary
Multiple myeloma is a malignant hematologic disease that occurs in middle-aged and elderly people. Multiple myeloma is a malignant plasma cell disease with common complications of bone disease, nephropathy, anemia, and infection.
Therefore, for middle-aged and elderly patients with severe osteoporosis or fracture, proteinuria or hematuria, recurrent pneumonia and other respiratory tract infections or urinary tract infections, and poor treatment by orthopedics, nephrology or respiratory medicine, especially those with combined anemia, the cause should be actively investigated, especially the possibility of multiple myeloma diagnosis should be considered, and timely blood immunoglobulin and serum protein electrophoresis, bone marrow aspiration and bone biopsy should be performed if necessary. The diagnosis of multiple myeloma should be actively investigated, especially the possibility of diagnosis of multiple myeloma.
Currently, the clinical application of targeted drugs such as reactive stop, bortezomib and ranadolamide, as well as the combination of traditional chemotherapy drugs such as melphalan and cyclophosphamide, especially the combination of bortezomib and traditional chemotherapy regimen, most patients with multiple myeloma can rapidly reduce tumor load in 1-2 courses, creating favorable surgical timing for orthopedic surgery or combined with hemodialysis for patients with uremia. If the diagnosis and treatment are timely, many paraplegic patients can resume walking and some dialysis patients can get off dialysis, which has increased the average survival period of patients from 3-5 years in the past to 5-7 years, and some patients can even survive for more than 10 years. Therefore, early or accurate diagnosis is more important for multiple myeloma.