Multiple Myeloma

Multiple myeloma Multiple myeloma (also plasma cell myeloma also known as MM, myeloma, plasma cell myeloma, or as Kahler’s disease) is a progressive hematologic (blood) disease. It is a cancer of the plasma cell, an important part of the immune system that produces immunoglobulins (antibodies) to help fight infection and disease. The immune system is made up of several types of cells that work together to fight infections. Lymph cells (called lymphocytes) are the main type of cell in the adaptive immune system. There are 2 types of lymph cells: T cells and B cells.

When B cells respond to an infection, they change into plasma cells. The plasma cells are found mainly in the bone marrow—the soft, inner part of some bones. The plasma cells make proteins called antibodies that attack and help kill germs. When plasma cells grow out of control, they can form a tumor, usually in the bone marrow. This type of tumor is called a myeloma, and if there are many tumors they are called multiple myeloma. If there is only one tumor, it is called solitary plasmacytoma. In many cases, this single tumor will go on to become multiple myeloma.

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Multiple myeloma is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal light chains). 1 Mechanism of developing malignant plasma cells: Normally, plasma cells make up a very small portion (less than 5%) of cells in the bone marrow. However, mostly multiple myeloma cell pathogenesis is based on bone marrow microenvironment. The subsets of bone marrow cell components including stromal cells, osteoclasts, and osteoblasts can modify growth advantage, survival and drug resistance of MM cells.

Myeloma plasma cells, however, have specific adhesion molecules on their surface allowing them to target the bone marrow where they attach to structural cells called stromal cells. 2Once myeloma cells attach to bone marrow stromal cells, several interactions cause myeloma cells to grow: Both myeloma cells and stromal cells produce chemical messengers called cytokines. These cytokines stimulate the growth of myeloma cells and inhibit (prevent) natural cell death (called apoptosis), leading to proliferation of myeloma cells and ltimately resulting in bone destruction. Myeloma cells also produce growth factors that promote angiogenesis, the creation of new blood vessels. These new blood vessels provide the oxygen and nutrients that promote tumor growth. A growth factor called vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. Angiogenesis encourages reproduction of myeloma cells, which increase in number and begin to infiltrate the bone marrow, eventually comprising more than 10% of the cells present.

Mature myeloma cells may fail to activate the immune system and may produce substances that decrease the body’s normal immune response to a foreign body. Thus, the cells can grow unchecked. 3 As tumors grow, they invade the hard outer part of the bone, the solid tissue. In most cases, the myeloma cells spread into the cavities of all the large bones of the body, forming multiple small lesions. This is why the disease is known as “multiple” myeloma. In some cases, collections of plasma cells arise either within bone or in soft tissues as masses or tumors.

These collections are called plasmacytomas, and may represent a more aggressive form of myeloma. Myeloma cells are identical and produce the same immunoglobulin protein, called monoclonal (M) protein or paraprotein, in large quantities. Although the specific M protein varies vary from patient to patient, it is always exactly the same in any one patient. When blood or urine is processed in a laboratory test called electrophoresis, these M proteins show up as a “spike” in the results. Unlike normal immunoglobulin, M protein does not benefit the body.

Instead, it crowds out normal, functional immunoglobulins. In addition, levels of functional immunoglobulin are depressed in individuals with myeloma. Although the process is not completely understood, it appears that the functional immunoglobulin made by existing normal plasma cells breaks down more quickly in patients with myeloma than in healthy individuals. 4 Clinical manifestations and Symptoms: Hypercalcemia, anemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulin are common clinical demonstrations of multiple myeloma.

MM is often also characterized usually in the pelvis, spine, ribs, and skull by diffuse osteoporosis. There are often no symptoms in the early stages of myeloma. In some cases, myeloma may be exposed by an accident in the course of routine blood testing and if symptoms are present they may be indistinct and related to those of other medical conditions. It is very rare to have any one patient with all of these symptoms below: Bone pain: Tiny fractures in the bones, causing bone pain often results due to the accumulation of plasma cells and weakened bone structures.

The most common sites of bone pain are back or the ribs, but usually any bone can be affected. Pain is usually worse with movement and at night. Fatigue: The growth and development of red blood cells in the bone marrow may be suppressed while having increase in the number of malignant plasma cells, which then cause low levels of red blood cells in the blood. This condition, know as anemia, can result in unusual fatigue or weakness. Recurrent Infections: The production of infection-fighting white blood cells also becomes reduced when number of malignant myeloma cell is elevated.

This leads to reduced immunity and the possibility of frequent recurrent infections, such as bacterial pneumonia, urinary-tract infections, and shingles Kidney Damage or Failure: Kidney damage and renal failure could happen due to excess protein in the blood, which is filtered through the kidneys hypercalcemia- a condition in which calcium concentration in the blood are elevated and overload the kidneys and can cause a variety of symptoms, including loss of appetite, fatigue, muscle weakness, restlessness, difficulty in thinking or confusion, constipation, increased thirst, increased urine production, and nausea and vomiting. Causes and risk factors of MM: Scientists have found a few risk factors that may make a person more likely to get multiple myeloma. These are the known risk factors for multiple myeloma: Age and gender: Age is the biggest risk factor for multiple myeloma. Very few cases are found in people younger than 35. Most people with this cancer are over 65 years old. The chances of getting multiple myeloma are slightly more in men than women. Race: The chances of getting MM are almost twice as common among black Americans as white Americans. However, the reason is unknown.

Radiation exposure: Exposure to radiation may increase the risk of multiple myeloma. At most, this accounts for a very small number of cases. Family history: This cancer seems to run in some families. If a person has a parent, brother, or sister with the disease, their risk of getting it is 4 times higher than that of other people. But this is rare. Exposure on the job: Some studies suggest that workers in some oil-related industries may be at a higher risk. Weight: A study by the American Cancer Society found that being overweight increases a person’s risk of getting this cancer.

Other plasma cell diseases: Many people with other plasma cell diseases will develop multiple myeloma later. 6 Exact causes are still unknown but scientists believe that cancer can be caused by changes (mutations) in the DNA that controls cell growth. Chromosomal changes including chromosomal translocations (generally involving the Ig heavy chain gene), and chromosomal gains and losses are very frequent in myeloma. These abnormalities have an important influence on disease outcome. Myeloma is not caused due to a single factor; it may be the result of several factors acting together. Diagnosis: A myeloma diagnosis is often based on the presence of an increased number of plasma cells in the bone marrow and, in most cases, the presence of excess protein (M protein) in the blood or urine. Patients are generally classified into stages based upon clinical and laboratory evaluation. Recently, a new staging system called the International Staging System for Multiple Myeloma has been developed. It divides cases of myeloma into 3 stages* based only on the serum beta-2 micro-globulin and serum albumin levels. 8 Stage Criteria Stage I

B2M 1 g of protein in 24 h is a major criterion for diagnosis of MM and quantification of creatinine clearance helps in identifying the severity of the patient’s renal injury. 9 Serum Viscosity: Check the serum viscosity in patients having nosebleeds, central nervous system symptoms, or very high M protein (another name for para-protein, an abnormal protein in the urine or blood) levels. 10 Serum protein electrophoresis: is often used as a screening tool to verify increase in monoclonal antibodies; it shows a narrow homogenous peak that indicates increased monoclonal production of immunoglobin.

Another procedure, immunofixation electrophoresis (IFU) is more sensitive and determines the class of immunoglobin. It is used to confirm the presence of monoclonal protein. The monoclonal protein usually contains one immunoglobin light chain and one heavy; IFE is used to detect light chains. 11 Quantitative immunoglobulins: In MM, the blood levels of the one type of immunoglobulin may be high while the others are low. Blood chemistry tests: These tests check the level of different chemicals and electrolytes (like calcium, potassium, and sodium) in the blood.

Calcium and potassium levels become elevated during Multiple myeloma, but plasma sodium levels would be low. 12 Bone marrow biopsy: People with multiple myeloma have too many plasma cells in their bone marrow. The test to check the bone marrow is called a bone marrow biopsy. Bone x-rays: Bone damage caused by the myeloma cells can be seen with x-rays. Often doctors will do a series of x-rays that includes most of the bones. This is called a bone survey. CT scan (computed tomography): A CT scan is a special type of x-ray that takes many pictures of the body.

A computer combines the x-rays to make a detailed picture. CT scans can help to tell if the patient’s bones have been damaged by myeloma. Some of the dyes used in CT scan, can damage the kidneys of people with myeloma. MRI (magnetic resonance imaging): This test uses radio waves and strong magnets instead of x-rays. The pattern of radio waves into cross-sectional pictures of the body is translated by a computer. MRI scans are very helpful in looking at soft tissues of brain, and the spinal cord. They may be able to find plasmacytomas that cannot be seen on regular x-rays.

PET scan (positron emission tomography): When a patient appears to have a solitary plasmacytoma, a PET scan may be used to look for other plasmacytomas. No single test is enough to tell for sure if a person has multiple myeloma. Doctors look at all factors: symptoms, physical exam, results of blood tests and x-rays, results of biopsies. Treatment, Prognostic indicators and Clinical Trials: Types of treatment: Chemotherapy Radiation Therapy Surgery Targeted Therapy Immunotherapy Antiangiogenesis Therapy Hyperthermia

Bone Marrow and Peripheral Blood Stem Cell Transplantation Gene Therapy13 The survival rate of multiple myeloma patients usually ranges from a few months period to more than ten years. The treatments for Multiple Myeloma also use several prognostic indicators that provide direct information on disease effects on an individual, risk groups and also clinical complications related to tumor cells. The prognosis is the forecast or likely outcome of a disease and it is usually based on the existence of different signs, symptoms, and circumstances.

They help determine how fast the tumor is growing, the extent of disease, tumor cell biology, response to therapy, and overall health status of the patient. 14 Prognostic indicators may also help determine when treatment should begin. Prognostic Indicators: – Test Description Values indicating a more favorable prognosis Beta 2-microglobulin (? 2-microglobulin or? 2-M) A protein normally found on the surface of cells; serum levels reflect the extent of disease

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