Multiple myeloma

Multiple myeloma (myelomatosis; plasma cell myeloma) is a plasma cell tumor that produces a monoclonal immunoglobulin that implants and destroys nearby bones.

The most frequent manifestations of the disease are bone pain, kidney failure, hypercalcemia, anemia, recurrent infections. For diagnosis, the presence of M-protein (often present in the urine and absent in the serum), destructive changes in the bones, the detection of light chains in the urine, an increased content of plasma cells in the bone marrow is necessary. A bone marrow biopsy is usually required. Specific therapy includes standard chemotherapy (usually with alkylating drugs, glucocorticoids, anthracyclines, thalidomide) and high-dose melphalan with autologous transplantation of peripheral blood stem cells.

The incidence of multiple myeloma ranges from 2 to 4 per 100 000 population. The ratio of men and women is 6: 1, most patients older than 40 years. The incidence of blacks is 2 times greater than that of whites. Etiology is unknown, although a certain role is played by chromosomal and genetic factors, irradiation, chemical compounds.

[1], [2], [3], [4], [5], [6]

Pathophysiology of multiple myeloma

Plasma cell tumors (plasmacytomas) produce IgG in approximately 55% and IgA in approximately 20% of patients with multiple myeloma. In 40% of these patients, Bens-Jones proteinuria is detected, which is the presence of free monoclonal to or X light chains in the urine. In 15-20% of patients, plasma cells secrete only Bence-Jones protein. These patients have a higher incidence of osteodestruction, hypercalcemia, renal failure and amyloidosis, compared to other patients with myeloma. Myeloma IgD occurs in about 1% of cases.

Diffuse osteoporosis or local destruction of bone tissue develop more often in pelvic bones, spine, ribs and skull. Damage is caused by replacement of bone tissue with a spreading plasmacytoma or activation of osteoclasts by cytokines, which are secreted by malignant plasma cells. As a rule, osteolytic lesions are of a multiple nature, but sometimes solitary intraosseous tumors are found. Extrinsic plasmacytomas are rare, but can be found in any tissues, especially the tissues of the upper respiratory tract.

Usually there is hypercalcemia and anemia. Often there is a renal failure (myeloma kidney), which is caused by the filling of the renal tubules with protein masses, atrophy of tubular epithelial cells and the development of interstitial fibrosis.

Increased sensitivity to bacterial infections is due to a decrease in the production of normal immunoglobulin and other factors. Secondary amyloidosis occurs in 10% of patients with myeloma, most often in patients with Bence-Jones proteinuria.

Symptoms of multiple myeloma

Persistent pain in the bones (especially in the spine and thorax), kidney failure, recurrent bacterial infections are the most typical manifestations of multiple myeloma. Often there are pathological fractures. The destruction of vertebral bodies can lead to compression of the spinal cord and paraplegia. The predominant symptom is often anemia, which can serve as the sole reason for examining the patient, some patients have manifestations of hyperviscosity syndrome (see below). Often there are peripheral neuropathy, carpal tunnel syndrome, abnormal bleeding, symptoms of hypercalcemia (eg, polyuria, polydipsia). Lymphadenopathy and hepatosplenomegaly are not typical for patients with multiple myeloma.

Diagnosis of multiple myeloma

Multiple myeloma is suspected in patients older than 40 with unexplained pain in the bones (especially at night or during rest), other typical symptoms or laboratory abnormalities such as elevated levels of protein in the blood and urine, hypercalcemia, renal failure, or anemia. The examination consists of the definition of standard blood indicators, protein electrophoresis, X-ray examination and bone marrow examination.

Variants of manifestations of multiple myeloma

The form	Characteristic
Extramedullary plasmacytoma	Plasmacytomas are found outside the bone marrow
The solitary bone plasmacytoma	A single bone focus of the plasmacytoma, which usually produces M-protein
Osteosclerotic myeloma (POEMS syndrome)	Polyneuropathy (chronic inflammatory polyneuropathy), organomegaly (hepatomegaly, splenomegaly, lymphadenopathy), endocrinopathy (for example, gynecomastia, testicular atrophy), M-protein, skin changes (eg, hyperpigmentation, increased hair growth)
Non-concluding myeloma	Absence of M-protein in serum and urine, the presence of M-protein in plasma cells

Standard blood counts include a general blood test, an ESR and a biochemical blood test. Anemia is present in 80% of patients, usually normocyte-normochromic with the formation of a multitude of agglutinates, usually consisting of 3 to 12 erythrocytes.

The number of leukocytes and platelets is usually normal. Often there is an increase in the level of urea, serum creatinine and uric acid, ESR can exceed 100 mm / h. The anion interval is sometimes low. Hypercalcemia is present at the time of diagnosis in 10% of patients.

Protein electrophoresis is performed and in the absence of a definite result, the proteins of the 24-hour urine concentrate are electrophoresed. In 80-90% of patients with the electrophoresis of whey proteins, M-protein is determined. The remaining 10-20% of patients usually have free monoclonal light chains (Bens-Jones protein) or IgD. In these patients, M-protein is almost always determined by electrophoresis of urine proteins. Electrophoresis with immunofixation identifies the class of M-protein immunoglobulin and often determines the light chain protein if immunoelectrophoresis of serum proteins was false-negative. Electrophoresis with immunofixation is recommended to be performed in cases when whey protein electrophoresis was negative in the presence of strong bases for suspicion of myeloma.

Radiographic examination includes a survey of skeletal bone. In 80% of cases, there is diffuse osteoporosis or lytic changes of rounded bones. Radionuclide scanning of bones is usually not informative. MRI can provide a more detailed picture and is recommended in the presence of pain and neurologic symptoms and the lack of data on conventional radiography.

Aspiration and bone marrow biopsy are also performed, in which a diffuse distribution or accumulation of plasma cells is detected, which indicates the presence of a bone marrow tumor. The defeat of the bone marrow is usually uneven and the increased number of plasma cells with a different degree of maturation is more often determined. Sometimes the number of plasma cells is normal. The morphology of plasma cells does not depend on the class of synthesized immunoglobulin.

A patient with M protein in the blood serum has reason to suspect myeloma at a level of Bens-Jones proteinuria of more than 300 mg / 24 h, osteolytic damage (no signs of metastatic cancer or granulomatous disease) and an increased plasma cell content in the bone marrow.

[7], [8], [9], [10], [11], [12], [13], [14], [15]

Treatment of multiple myeloma

Patients need serious maintenance treatment. Ambulatory maintenance therapy helps to maintain bone density. Analgesics and palliative doses of radiotherapy (18-24 Gy) can relieve pain in the bones. However, radiation therapy may interfere with the conduct of course chemotherapy. All patients should also receive bisphosphonates, which reduce the risk of developing complications from the skeleton, relieve bone pain and have antitumor activity.

Adequate hydration is the prevention of kidney damage. Even patients with prolonged, massive Bens-Jones proteinuria (10-30 g / day) can maintain kidney function if they maintain diuresis more than 2000 ml / day. In patients with Bence-Jones proteinuria, the dehydration accompanying the administration of a highly osmolar intravenous contrast may cause acute renal failure.

To treat hypercalcemia, abundant hydration and bisphosphonates are used, sometimes together with prednisolone 60-80 mg orally per day. Although most patients do not need to take allopurinol, taking 300 mg per day is indicated if there is kidney failure or symptoms of hyperuricemia.

Preventive vaccination against pneumococcal infection and influenza has been shown. The administration of antibiotics is performed with documented bacterial infection and the routine preventive administration of antibiotics is not recommended. Prophylactic administration of intravenous immunoglobulin can reduce the risk of infectious complications, usually prescribed to patients with frequent recurrent infections.

Recombinant erythropoietin (40,000 units subcutaneously 3 times a week) is used in patients with anemia that is not curable by chemotherapy. If anemia leads to violations from the cardiovascular system, transfusion of erythrocyte mass is used. With the development of hyperviscosity syndrome, plasmapheresis is performed. Conduction of chemotherapy is indicated to reduce serum or urinary M-protein. Post-cystostatic neutropenia can contribute to the development of infectious complications.

Standard chemotherapy usually consists of oral melphalan [0.15 mg / (kg x day)) and prednisolone (20 mg 3 times a day) every 6 weeks, with a response rate of 3-6 months. Polychemotherapy can be performed with the use of various regimes with intravenous administration of drugs. These regimens do not improve long-term survival compared to the combination of melphalan and prednisolone, but may provide a faster response in patients with renal dysfunction. Autologous transplantation of hematopoietic stem cells has been shown to patients younger than 70 years with an adequate function of the heart, liver, lungs and kidneys with a stable course of the disease or a good response after several courses of standard chemotherapy. These patients undergo initial chemotherapy with vincristine, doxorubicin and dexamethasone or dexamethasone with thalidomide. If it is necessary to prescribe a myeloid growth factor, drugs that inhibit bone marrow function, alkylating agents and nitrosoureas are not prescribed. Carrying out allogeneic transplantation with non-myeloablative regimens of conditioning (eg, low doses of cyclophosphamide and fludarabine or radiation therapy) in some patients can improve disease-free survival up to 5-10 years due to a decrease in toxicity and the presence of an immune allogeneic anti-myeloma effect. This method is indicated for patients younger than 55 years with a good physiological reserve. With relapse or refractory myeloma, new drugs (thalidomide, immunomodulatory drugs, proteasome inhibitors) are used, the effectiveness of these drugs as first-line therapy is being studied.

Supportive therapy is provided by non-chemotherapeutic drugs, including interferon, which provide a lasting effect, but have some side effects. The use of glucocorticoids as maintenance therapy is being studied.

Prognosis for multiple myeloma

Multiple myeloma continuously progresses, the median survival with standard chemotherapy is about 3-4 years, with high-dose chemotherapy with stem cell transplantation - about 4-5 years. Treatment improves quality and longevity in 60% of patients. Adverse prognostic signs at the time of diagnosis are high levels of M-protein in serum or urine, elevated serum beta- _2- microglobulin levels (> 6 μg / ml), diffuse bone lesions, hypercalcemia, anemia and kidney failure.