MULTIPLE MYELOMA

Multiple Myeloma
Definition:
Multiple myeloma (MM), also sometimes called Kahler's disease, myelomatosis, or plasma cell myeloma, is cancer that originates in plasma cells. Multiple myeloma refers to a malignant tumor in hematological system, originating from plasma cells (a type of white blood cell generated in the bone marrow). Normal plasma cell is responsible for producing antibodies which can fight against infection, while malignant plasma cell---- myeloma cell proliferates in great numbers in the bone marrow.

Multiple Myeloma
Clinical manifestations are related to malignant behavior of plasma cells and abnormalities produced by M protein(monoclonal immunoglobulin)
plasma cell proliferation:
multiple osteolytic bone lesions hypercalcemia bone marrow suppression ( pancytopenia )

monoclonal M protein
decreased level of normal immunoglobulins hyperviscosity

Multiple Myeloma
Clinical symptoms: bone pains, pathologic fractures weakness and fatigue serious infection renal failure

C - calcium R - renal A anemia B - bone

Multiple Myeloma

Laboratory tests: ESR > 100 anaemia, thrombocytopenia rouleaux in peripheral blood smears marrow plasmacytosis > 10 -15% hyperproteinemia hypercalcemia proteinuria azotemia

Multiple Myeloma CAUSES

Is not known for sure Decline in the immune system Biological factors Certain occupations Exposure to certain chemicals Exposure to radiation Virus

Risk factors
Age. The majority of people who develop multiple myeloma are older than 50, with most diagnosed in their mid-60s. Few cases occur in people younger than 40. Sex. Men are more likely to develop the disease than are women. Race. Blacks are about twice as likely to develop multiple myeloma as are whites. History of a monoclonal gammopathy of undetermined significance (MGUS). Every year 1 percent of the people with MGUS in the United States develop multiple myeloma. Obesity. Your risk of multiple myeloma is increased if you're overweight or obese.

Other factors that may increase your risk of developing multiple myeloma include exposure to radiation and working in petroleum-related industries.

Anatomy and physiology related to multiple myeloma Multiple myeloma is a cancer of the plasma cells. Plasma cells are found in the bone marrow and other tissues and organs. They are a type of white blood cell that make antibodies. Multiple myeloma is considered a hematological or blood cancer because it affects blood cells.

Under normal circumstances, plasma cells are found in bone marrow, where blood cells are made. Normal bone marrow contains few plasma cells. A person with multiple myeloma often has many abnormal plasma cells (myeloma cells) in the bone marrow.
The myeloma cells can form tumours in bones called plasmacytomas. If there is only one tumour of myeloma cells in the bone, it is called a solitary plasmacytoma. When many plasmacytomas are found in the bones, the condition is called multiple myeloma. Plasmacytomas can also form outside of the bones and are called extramedullary plasmacytomas.

STRUCTURE Bone marrow is the soft, spongy substance in the centre of the bone where blood cells are made. In adults, the most active bone marrow is found in the pelvic and shoulder bones, spine (vertebrae), ribs, breastbone and skull. Plasmacytomas usually develop in the areas where bone marrow is active. Blood is made up of liquid (called plasma) and solid cells. Plasma is made up of water and chemicals, such as proteins, minerals and vitamins, that are dissolved in the water.

All our blood cells develop from stem cells. The process of blood cell development is called hematopoiesis. In the earliest stage of cell development, stem cells begin to develop along either the lymphoid cell line or the myeloid cell line. In both cell lines, the stem cells become blasts, which are still immature cells. During the last stage of cell development, the blasts mature into 3 types of blood cells.

Function Each of the 3 types of blood cells in the plasma has a specific role: Red blood cells carry oxygen from the lungs to the rest of the body and return carbon dioxide to the lungs. Platelets help the blood to clot when a blood vessel is damaged. White blood cells help prevent and fight infection by destroying bacteria, viruses and other foreign cells or substances.

White blood cells The immune system is the body's natural defence against infection. White blood cells are an important part of the immune system. Different types of white blood cells work in different ways to protect the body from infection. lymphocytes T cells recognize antigens and activate the B cells. They can also kill viruses and cancer cells. B cells develop into plasma cells, which produce antibodies to fight infection. Natural killer (NK) cells attack any foreign cells, including cancer cells.

 Neutrophils and monocytes fight infection by ingesting or engulfing foreign cells, such as bacteria. Eosinophils help control inflammation and allergic reactions. They attack and destroy certain parasitic organisms. Basophils play a role in certain allergic reactions.

Multiple myeloma starts in B cells. When B cells mature, they turn into plasma cells.

Antigens, antibodies and plasma cells Antigens are located on the surface of bacteria, viruses, cancer cells and other foreign invaders. An antigen triggers plasma cells (B cells) to produce antibodies. Antibodies, or immunoglobulins, are special proteins that fight infection and defend the body against harmful foreign invaders. They circulate in the blood and attach to specific antigens on the surface of bacteria, viruses or other foreign substances. Antibodies are specific to a particular antigen. When the immune system identifies a new antigen, a plasma cell makes a new antibody. Once plasma cells respond to an antigen, they will only make antibodies for that antigen.

In multiple myeloma, B cells are damaged and do not work properly. They begin to make many abnormal plasma cells (myeloma cells). The myeloma cells can collect in the bone marrow and crowd out the normal blood cells so they cant work properly. Normally, plasma cells make up about 1% of the cells in bone marrow. In people with multiple myeloma, abnormal plasma cells make up 10%30% of the cells in the bone marrow.

Immunoglobulins Immunoglobulins (Ig) are protein molecules called antibodies produced by plasma cells. There are 5 types of immunoglobulins IgG, IgA, IgM, IgD and IgE. Immunoglobulins are made up of 4 parts called chains. There are 2 light chains and 2 heavy chains. Each of the 5 types of immunoglobulins is named after the type of heavy chain that it contains. The 4 chains are attached to each other by special chemical bonds. Multiple myeloma and other plasma cell cancers are classified by the type of immunoglobulin produced by the myeloma cells and by the type of light or heavy chain.

 light chains kappa Lambda

heavy chains IgG IgA IgM IgD IgE

When damaged B cells develop into abnormal plasma cells (myeloma cells), they make large amounts of one type of immunoglobulin (called a monoclonal immunoglobulin) and release it into the blood. This monoclonal immunoglobulin is also called an M-protein. M-proteins can be measured in the blood and urine. Their presence indicates that there is a problem with the plasma cells.
Sometimes the myeloma cells do not release immunoglobulin properly and only release the light chains into the blood. The light chains that are not attached to heavy chains are called Bence Jones proteins.

Bone destruction Myeloma cells can damage the bone when they collect in the bone marrow. This is because they release chemicals called cytokines that cause other cells to dissolve bone. Cytokines also stimulate the growth of more myeloma cells and disrupt their normal life cycle.

The collection of myeloma cells can start to weaken and thin the bone. These areas of weakness, called osteolytic lesions, can be seen on an x-ray as dark circular spots in bones. Osteolytic lesions may mean a plasmacytoma or other disease of the bone is present. These weakened areas of the bone may cause it to break under normal stresses like walking, lifting and coughing. Thinning of the bone can also lead to osteoporosis.

DIAGNOSTIC TEST
Blood and urine tests. X-ray. Bone marrow biopsy and aspiration. Fat pad aspirate. Magnetic resonance imaging (MRI). Computed tomography (CT or CAT) scan. Positron emission tomography (PET) scan. Integrated PET-CT scan. Bence Jones Protein Urine Test

Blood and urine tests.

Myeloma cells secrete an antibody known as the M protein (monoclonal immunoglobulin). Levels of the M protein in a patient's blood and urine are used to determine the extent of the disease and to monitor the effectiveness of treatment. The levels of serum albumin (a blood protein made by the liver that is necessary for maintaining proper blood volume) and serum beta 2-microglobulin (2-M, a small protein that plays a role in immunologic defense) are measured using blood tests; these results are important for staging. Blood tests are also used to measure kidney function, calcium levels, and blood counts (for possible anemia).

X-ray. An x-ray is a way to create a picture of the structures inside of your body using a small amount of radiation. X-rays are typically the first step in evaluating bones when myeloma is suspected or diagnosed.

Bone marrow biopsy and aspiration.

These two procedures are similar and often done at the same time. Bone marrow has both a solid and a liquid part. A bone marrow biopsy is the removal of a small amount of solid tissue using a needle, and it is important to making a diagnosis of myeloma. An aspiration removes a sample of fluid with a needle. The sample(s) are then analyzed by a pathologist, a doctor who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose disease. A common site for a bone marrow biopsy and aspiration is the pelvic bone, which is located in the lower back by the hip. The skin in that area is usually numbed with medication beforehand, and other types of anesthesia (medication to block the awareness of pain) may be used.

Fat pad aspirate. If M proteins are deposited in body tissues, it can cause organ dysfunction. This condition is called amyloidosis. If amyloidosis is a consideration, it may be necessary to take a sample of the abdominal fat pad (the collection of fat around a person's abdomen) for examination under a microscope, called a biopsy.

Molecular testing of the tumor.

Your doctor may recommend running laboratory tests on a tumor sample to identify specific genes, proteins, and other factors unique to the tumor. Results of these tests may help guide your treatment options.

Magnetic resonance imaging (MRI). An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. An MRI can show replacement of normal bone marrow by myeloma cells or plasmacytoma (a plasma cell tumor growing in bone or soft tissue), especially in the skull, spine, and pelvis. The detailed images may also show compression fractures of the spine or a tumor pressing on nerve roots. A contrast medium (a special dye) may be injected into a patients vein to create a clearer picture.

Computed tomography (CT or CAT) scan. A CT scan creates a detailed, cross-sectional view that shows any abnormalities or tumors in soft tissues. A computer then combines these images into a three-dimensional picture of the inside of the body. Sometimes, a contrast medium is injected into a patients vein to provide better detail, but it is used cautiously in patients with multiple myeloma because of a risk of kidney failure.

Positron emission tomography (PET) scan. A PET scan is a way to create pictures of organs and tissues inside the body. A small amount of a radioactive substance is injected into a patients body. This substance is absorbed mainly by organs and tissues that produce the most energy. Because cancer tends to use energy actively, it absorbs more of the radioactive substance. A scanner then detects this substance to produce images of the inside of the body.

Integrated PET-CT scan. An integrated PET-CT scan combines the images from a positron emission tomography (PET) scan and a computed tomography (CT) scan, performed at the same time on the same machine. Together, the two scans create a more complete image than either test can offer alone.

Bence-Jones Protein (Urine) The lab may measure the amount of Bence-Jones protein in a 24-hour urine sample. To do this test, you will need to collect all the urine you pass during a 24-hour period. You will collect it in a container that your doctor or the lab gives you.

Staging of Multiple Myeloma

Clinical staging is based on level of haemoglobin, serum calcium, immunoglobulins and presence or not of lytic bone lesions correlates with myeloma burden and prognosis I. Low tumor mass II. Intermediate tumor mass III. High tumor mass subclassification A - creatinine < 2mg/dl B - creatinine > 2mg/dl

STAGING
Stage 1 Stage 2 Stage 3 A B
Low amount of myeloma Medium amount of myeloma High amount of myeloma

Normal kidney function

Abnormal kidney function

TREATMENT
The treatment of multiple myeloma (MM) is complex because of rapid advances in stem cell transplantation, medications, and better supportive care, which have led to improved survival for patients with multiple myeloma over the past thirty years. The main options for therapy include:

Standard chemotherapy drugs such as melphalan (Alkeran), cyclophosphamide (Cytoxan), Doxorubicin (Adriamycin) and liposomal doxorubicin (Doxil) Newer drugs such as thalidomide (Thalomid), lenalidomide (Revlimid), bortezomib (Velcade), carfilzomib (Kyprolis), and pomalidomide (Pomalyst) Corticosteroids such as prednisone or dexamethasone (Decadron) Stem cell (bone marrow) transplantation

Types of treatment There are four main types of treatment:

Chemotherapy In most people, chemotherapy partially controls multiple myeloma; rarely, chemotherapy leads to complete remission. Corticosteroids Corticosteroids include dexamethasone (Decadron) or prednisone. Newer Drugs Drugs such as thalidomide (Thalomid), lenalidomide (Revlimid), bortezomib (Velcade), carfilzomib (Kyprolis), and pomalidomide (Pomalyst) have emerged as important options for treatment of myeloma, both in newly diagnosed patients and in patients with advanced disease who have failed chemotherapy or transplantation. In most cases, these agents are used in combination with dexamethasone, with each other, or with standard chemotherapy agents.

 Stem cell transplantation Stem cell transplantation can be done using one's own stem cells (autologous) or using cells from a close relative or matched unrelated donor (allogeneic). In multiple myeloma, most transplants performed are of the autologous kind. Such transplants, although not curative, have been shown to prolong life in selected patients. They can be done as initial therapy in newly diagnosed patients or at the time of relapse. Sometimes, in selected patients more than one transplant may be recommended to adequately control the disease. Autologous transplants for multiple myeloma are very safe in centers with experience in the procedure.

MPT
Melphalan prednisone thalidomide (MPT) chemotherapy The combination of melphalan, prednisone, and thalidomide has been shown to be one of the most effective treatments of multiple myeloma for people who are not planning to undergo stem cell transplantation.

 Melphalan is a chemotherapy drug that functions to kill tumor cells Prednisone is a steroid that functions to kill tumor cells Thalidomide may work to slow the growth of new blood vessels to a tumor and may slow or stop the growth of tumor cells. Thalidomide is absolutely UNSAFE (contraindicated) for pregnant women.

Melphalan is not usually recommended for people who have kidney failure. In such situations, thalidomide/dexamethasone,bortezomib/dexamethasone, or bortezomib, thalidomide, dexamethasone (VTD) is preferred.

STEM CELL TRANSPLANTATION

Stem cell transplantation is a treatment option for some individuals with multiple myeloma. There are three types of transplantation, based on the source of the stem cells: Autologous transplantation: the stem cells are obtained from the individual with multiple myeloma. This is the type of transplantation that is most commonly recommended. Allogeneic transplantation: the stem cells or bone marrow are obtained from a donor with a tissue type matching that of the patient. This type of transplantation carries very high risks and is not recommended for most individuals with multiple myeloma. Syngeneic transplantation: the stem cells or bone marrow are obtained from an identical twin of the individual. This is the optimal form of transplantation, although few people with multiple myeloma have an identical twin who can serve as a donor.