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%; misdiagnosis. It should be given enough attention in the diagnosis and treatment.
Summary of cases
Case 1.
The patient, a 51-year-old female, was admitted to the hospital in December 2010 with the complaints of “increased urinary foam, back pain for more than one year, and dizziness for more than one month”. The patient was found to have increased foam in urine more than a year ago, and her blood sugar and urine were normal. He visited orthopedic departments of several hospitals, but his lumbar pain did not improve significantly. At the same time, the patient had pain in the waist and both sides of the ribs after going downhill, and was seen at a local hospital. One month ago, he became dizzy with weakness and poor circulation and came to the Hematology Department of Beijing Chaoyang Hospital for further treatment. Outpatient laboratory tests revealed anemia, high globulin, high creatinine, proteinuria, routine blood tests: hemoglobin 59g/l, globulin 103g/L, creatinine 315umol/l, urine occult blood ++, urine protein +. Past history: nothing special. Physical examination: pressure pain in the 3rd-5th vertebral body of the lumbar spine, the rest (-). Bone aspiration was performed on admission: 93.5% plasma cells, of which 60% were naïve plasma cells. Flow cytometry: 24.22%; cells (of all nucleated cells) were malignant monoclonal cells. CT showed: multiple bone destruction of lumbar vertebrae 2-5, bilateral ribs, and bilateral iliac bones. Immunoglobulin IgG84g/L, IgA and IgM were reduced, and immunofixation electrophoresis showed that the M component was IgG-λ. The diagnosis was “multiple myeloma IgG-λ type”.
Case 2.
The patient, a 76-year-old male, was admitted to the hospital in June 2011 with the chief complaint of “poor appetite, weakness and wasting for more than 6 months, aggravated for 20 days”. The patient had poor appetite with no obvious cause more than 6 months ago, eating less than one or two taels per meal, and feeling nauseous after eating, but no vomiting, accompanied by weakness and emaciation, which was not taken seriously. In the past 20 days, the above symptoms worsened and he was found to have decreased hemoglobin in the community hospital. He came to the Department of Hematology for further consultation and treatment. He had lost about 3 kg in the last half of his body weight and had no epistaxis or black stool. She was admitted to the ward as “anemia to be investigated”. No specific past history was recorded. On admission, physical examination: anemic appearance, pale conjunctiva, remainder (-). Routine blood count: hemoglobin 78g/L, average volume of red blood cells 68fl. Urine routine, stool routine and occult blood were (-). Bone marrow smear: 18.5% plasma cells; all were naïve plasma cells; M protein identification: IgA 34g/L, immunofixation electrophoresis showed that the M component was IgA-λ. Skull x-ray: multiple hypodense shadows in the skull. The diagnosis was “multiple myeloma IgA-λ type”.
Questions for consideration: Why did the above two patients take six months to a year to be diagnosed after the onset of symptoms? What are the lessons to be learned?
Mechanisms of multiple myeloma bone disease
Bone pain and osteolytic bone destruction are the prominent clinical manifestations of multiple myeloma. Bone pain is most common in the low back, followed by the sternum, ribs and lower extremity bones.
Mechanism: Once myeloma cells (MMC) infiltrate the bone marrow, adhesion of MMC to bone marrow stromal cells increases the production of IL-6, TNF a , MIP-1 a, OPN and DKK1, which enhances osteoclast activation, differentiation and maturation and diminishes 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-ray examination is 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. In advanced stages, the disease may progress to chronic renal insufficiency or uremia, which is one of the main causes of death in this disease. Approximately 50% of patients with myeloma are diagnosed with proteinuria and other renal damage, and 30% of MM patients have serum inosine >2 mg/dL at the time of diagnosis.
Foreign studies have found that patients with MM nephropathy have pathologically mild glomerular lesions 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.
Approximately 50%; of patients with moderate renal impairment, their renal impairment can be 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
(2) Inadequate production of erythropoietin (EPO) and a decrease in the number of erythroid cells in some MM patients due to renal insufficiency. Other mechanisms include the 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 below 85g/L.
How to avoid misdiagnosis of multiple myeloma
The rate of misdiagnosis 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
(International MM Working Group IMWG, 2003)
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, the presence of M-protein in the 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 ≥ 10% clonal plasma cells in the bone marrow
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 2 g/dl or < 10 g/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., usually with no more than 10% bone marrow plasma cells; and all 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 30 g/L, plasma cells in bone marrow is less than 10%;, without 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 hematological 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.
Reference answer to the reflection question
Why were the two patients above diagnosed only after six months to a year of symptoms? What are the lessons to be learned?
The patient in Case 1 was a middle-aged and elderly patient. More than a year before admission, he had a lot of foam in urine and no urine sugar or other abnormalities were found in the urine examination at the local hospital. It was only when he developed dizziness with weakness and poor nasal function 1 month before admission that he went to the hematology department.
Case 2 was an elderly male patient who presented with poor appetite, weakness and wasting six months before admission to the hospital.
Both patients were diagnosed with multiple myeloma after admission by bone marrow, M protein identification and bone imaging.
Therefore, for middle-aged and elderly patients with low back pain, proteinuria, anemia or recurrent fractures, recurrent pneumonia or infection, in addition to symptomatic management, the primary cause should be actively sought and routine admission for examination to exclude malignancies, including multiple myeloma.
Due to the clinical application of response stop, bortezomib and renalidomide targeted drugs, the average survival of multiple myeloma patients has improved from 3-5 years in the past to 5-7 years, and even up to 10 years or more in some patients.
The new annual American Society of Hematology (ASH) meeting in 2012 has clearly stated that multiple myeloma can already be considered a chronic disease like other malignancies. As the incidence of this disease increases, on the one hand, community and other primary care physicians will learn the reasons why this disease is easily misdiagnosed, improve the early and correct diagnosis rate, and save patients in a timely manner; on the other hand, the treatment of this disease is a comprehensive long-term process, which requires the cooperation of healthcare professionals and family members to reduce the occurrence of myeloma bone disease, nephropathy or infection, and further improve the survival and quality of life of patients.