Overview
Myeloma is a cancer that develops in cells of the bone marrow called plasma cells. Plasma cells develop from B lymphocytes and are an important part of the immune system. Their primary function is to produce antibodies – targeted immunoglobulin proteins that help protect the body against infections. Normally, plasma cells are produced as needed. When B cells are exposed to pathogens, they mature into plasma cells and begin to produce antibodies. They share space in the bone marrow with maturing red blood cells (RBCs), platelets, and several types of white blood cells (WBCs). Sometimes, however, a plasma cell may become malignant and begins to divide uncontrollably, forming tumours in the bone marrow, eroding the surrounding bone and producing soft spots and holes known as lytic lesions. Myeloma can develop wherever there is bone marrow, including the pelvis, spine and ribcage. As it can occur in several places in the body, it is often called multiple myeloma.
Since the malignant cells are derived from a single plasma cell, they all produce an identical antibody – an abnormal monoclonal immunoglobulin (also termed an M-protein or paraprotein) that is released into the blood and sometimes lost in the urine. The abnormal antibody does not work properly and is not able to fight infections while the growth of malignant cells can affect the production of normal antibodies (immunosuppression), causing susceptibility to infection.
Normally, the body makes five different types of immunoglobulins - IgG, IgA, IgM, IgE and IgD - that have slightly different immune system functions. Each type of immunoglobulin is composed of four protein chains. Plasma cells choose different arragements of these protein chains to make up antibodies that recognise different pathogens. A normal antibody (immunoglobulin) has 2 heavy and 2 light chains. To make it more complicated the light chains can be of kappa or lambda type.
In patients with multiple myeloma, the malignant plasma cells produce only one type of intact (whole) immunoglobulin in large amounts. However, in about 75% of myeloma patients, the balance in production of light and heavy chains is disturbed and light chains are produced in excess. The surplus free light chains are released into the bloodstream and, because they are relatively small molecules, they are filtered by the kidneys and excreted into the urine, as a protein known as Bence-Jones protein. Rarely, the monoclonal protein produced consists only of light chains or, very rarely, heavy chains. Though the type of M protein produced by malignant cells may vary from one patient to the next, within one particular patient it usually stays the same since it is produced by identical or cloned plasma cells. Some patients have more than one malignant cell type and they can have more than one paraprotein.
The type of myeloma a patient has is often referred to by the type of M protein or paraprotein produced, whether an intact immunoglobulin or light chain. Patients with IgG and IgA myelomas are the most common, with IgG types comprising about 60-70% of myelomas and IgA types making up about 20% of myelomas. Cases of IgE and IgD are only rarely reported. Some patients who produce monoclonal IgM may have a related but different condition called Waldenstrom‘s macroglobulinaaemia.
Monoclonal Gammopathy of Undetermined Significance (MGUS): Sometimes people will produce abnormal amounts of identical copies of the same immunoglobulin (also known as monoclonal gammopathy) but not have any of the symptoms or complications of multiple myeloma. This condition is referred to as monoclonal gammopathy of undetermined significance or MGUS. Often, this condition is only discovered when routine tests reveal abnormal amounts of protein in the blood. About 20 to 30% of individuals with MGUS if followed up for a very long time will go on to develop myeloma or some other related disease such as lymphoma. Generally, these patients do not require any treatment, but they are closely monitored. Some of the tests used to diagnose and/or follow multiple myeloma are used to monitor patients with MGUS.
Many patients with multiple myeloma may show no symptoms for many years. Eventually, most patients develop some evidence of the disease either related to weakened bones (bone pain or fractures), decreased numbers of red or white blood cells (anaemia, infections), or kidney failure. As bones weaken fractures may develop without obvious injury. Destruction of the bone frequently increases the level of calcium in the blood, leading to symptoms of hypercalcaemia such as loss of appetite, nausea, thirst, fatigue, constipation, and confusion. A decrease in the number of normal white blood cells, red blood cells and platelets can result in frequent infections, anaemia, bleeding, and bruising. Bence-Jones proteins can lodge in the kidneys and may permanently damage them. In some cases, an increase in the thickness (viscosity) of the blood may lead to headaches.
Risks
Multiple myeloma is relatively uncommon. According to Cancer Research UK, there were 5,540 new cases reported in 2015, that’s around 15 every day It is the 19th most common cancer in the UK , accounting for 2% of all new cancer cases (2015). The cause of multiple myeloma is not yet known. The risk of developing it increases with age, with the majority of cases being diagnosed in patients 60 years or older. Genetic factors may play a role; people with a parent, brother, sister, or child with myeloma or MGUS are 2 or 3 times as likely to develop myeloma or MGUS compared to people with no close family members with these illnesses.
Serum Protein Electrophoresis (SPE): This test is used to diagnose and monitor multiple myeloma. Protein electrophoresis separates the proteins in a blood sample into several groups based on their electrical charge and size. In most patients with multiple myeloma, large amounts of an abnormal immunoglobulin protein (M-protein) will show up as an abnormal band on the electrophoresis strip. The amount of normal immunoglobulins in the sample may be visibly decreased.
Serum free light chains (SFLC):This blood test measures the amount of free light chains in the blood. Even in healthy individuals there is usually a small amount of free light chains released into the bloodstream that can be detected. Most patients with multiple myeloma produce high levels of either kappa or lambda free light chains, which can be measured in blood. This test may be used to monitor progression and/or treatment.
Immunofixation: if the SPE is abnormal, this is a technique used to identify the specific type of abnormal protein that is being produced by the malignant plasma cells. The amount of protein produced may vary throughout the course of the disease, but the type will usually remain the same.
Bone marrow aspiration and biopsy: Multiple myeloma is a disease of the bone marrow. Patients usually require a bone marrow evaluation to confirm the diagnosis, evaluate how many malignant plasma cells are present in the marrow, and to what degree they have affected the production of normal white or red blood cells and platelets.
Other Laboratory Tests
Bence-Jones protein (free light chains) can be detected in the urine of some patients with multiple myeloma. Some laboratories will test urine for Bence-Jones protein, rather than serum for free light chains if a sample is available. Usually an early morning sample of a few millilitres is adequate.
Other tests that may be done as part of an initial diagnostic workup, to monitor the progress of the disease, and to help detect and address complications include renal profile, calcium level, uric acid level and full blood count, beta2-microglobulin and LDH.
Non-Laboratory Tests
The large numbers of plasma cells being made in the bone marrow can cause damage to the hard outer covering of the bones. Your doctor will ask you to have X-rays of all your long bones, and your spine, pelvis and skull, to find any areas of damage. This is termed a skeletal survey.
MRI (Magnetic Resonance Imaging) can be more sensitive than X-ray for evaluating bone destruction and is occasionally resorted to.
Staging
The stage of a cancer tells your doctor how far it has grown or spread. Staging is based on information obtained from the tests and scans you have when diagnosing your myeloma, such as abnormal immunoglobulin being produced, the serum calcium level, the amount of normal proteins and ß-2 microglobulin in blood and the extent and severity of the bone damage. Staging helps to determine a patient’s prognosis and allows your specialist plan the treatment that is most appropriate for you.
Depending on the age and other health problems of a patient, and the stage of disease, treatment may be to induce complete or partial remission of disease. The other goals of treatment are to relieve pain and other symptoms, to slow the progress of the disease, and to detect and minimise complications as they occur. Doctors generally recommend that patients with multiple myeloma stay as active as possible to help preserve the calcium in their bones and drink plenty of fluids to help with kidney function. Complications such as infections, anaemia and bleeding should be promptly addressed with measures such as antibiotics and, when necessary, transfusions. Patients who do not have significant symptoms are monitored but may not receive any treatment. In early multiple myeloma, the side effects of the available treatments frequently outweigh the benefits.
Chemotherapy, steroids and biological therapies are the main treatments for myeloma. Radiotherapy is also used to help control pain. Stem cell transplant and Thalidomide and related agents are more recent therapeutic options. You may also be prescribed bisphosphonates to help prevent bone damage and relieve pain. If you are fit enough, your specialist may suggest intensive treatment using high dose chemotherapy with a bone marrow or stem cell transplant.
Your doctor may suggest a treatment called plasmapheresis if the level of abnormal immunoglobulin protein is too high in your blood. Too much protein in the blood can make it too thick and plasmapheresis can remove the excess protein.