Multiple Myeloma

Alternative Name :Plasma cell myeloma or Kahler’s disease

Definition:
Multiple myeloma is a type of cancer. Cancer is a group of many related diseases. Myeloma is a cancer that starts in plasma cells, a type of white blood cell. It’s the most common type of plasma cell cancer.

click to see the picture

Multiple myeloma (from Greek myelo-, bone marrow), a type of white blood cell normally responsible for the production of antibodies. Collections of abnormal cells accumulate in bones, where they cause bone lesions, and in the bone marrow where they interfere with the production of normal blood cells. Most cases of myeloma also feature the production of a paraprotein, an abnormal antibody that can cause kidney problems and interferes with the production of normal antibodies leading to immunodeficiency. Hypercalcemia (high calcium levels) is often encountered

Health problems caused by multiple myeloma can affect your bones, immune system, kidneys and red blood cell count.

If some one has multiple myeloma but don’t have symptoms,the doctors may just monitor his or her condition. If experiencing symptoms, a number of treatments are available to help control multiple myeloma.

The disease develops in 1–4 per 100,000 people per year. It is more common in men, and is twice as common in blacks as it is in whites. With conventional treatment, the prognosis is 3–4 years, which may be extended to 5–7 years or longer with advanced treatments. Multiple myeloma is the second most common hematological malignancy (13%) and constitutes 1% of all cancers.

Signs and symptoms:
Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB: C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions. Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.

Bone pain
Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological bone fracture. Involvement of the vertebrae may lead to spinal cord compression. Myeloma bone disease is due to the overexpression of Receptor Activator for Nuclear Factor ? B Ligand (RANKL) by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. The resultant bone lesions are lytic in nature and are best seen in plain radiographs, which may show “punched-out” resorptive lesions (including the “pepper pot” appearance of the skull on radiography). The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.

Infection
The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S. pneumoniae, S. aureus, and K. pneumoniae, while common pathogens causing pyelonephritis include E. coli and other gram-negative organisms. The greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy. The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies. A selected group of patients may benefit from replacement immunoglobulin therapy to reduce the risk of infection.

Renal failure
Renal failure may develop both acutely and chronically. It is commonly due to hypercalcemia (see above). It may also be due to tubular damage from excretion of light chains, also called Bence Jones proteins, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.

Anemia
The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.

Neurological symptoms
Common problems are weakness, confusion and fatigue due to hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid). It may give rise to paraplegia in late presenting cases.

 

Causes:
Although the exact cause isn’t known, doctors do know that multiple myeloma begins with one abnormal plasma cell in our bone marrow — the soft, blood-producing tissue that fills in the center of most of our bones.

Normal blood cells
Most blood cells develop from cells in the bone marrow called stem cells. Bone marrow is the soft material in the center of most bones.

Stem cells mature into different types of blood cells. Each type has a special job:

*White blood cells help fight infection. There are several types of white blood cells.

*Red blood cells carry oxygen to tissues throughout the body.

*Platelets help form blood clots that control bleeding.

Plasma cells are white blood cells that make antibodies. Antibodies are part of the immune system. They work with other parts of the immune system to help protect the body from germs and other harmful substances. Each type of plasma cell makes a different antibody.

Myeloma cells
Myeloma, like other cancers, begins in cells. In cancer, new cells form when the body doesn’t need them, and old or damaged cells don’t die when they should. These extra cells can form a mass of tissue called a growth or tumor.

Myeloma begins when a plasma cell becomes abnormal. The abnormal cell divides to make copies of itself. The new cells divide again and again, making more and more abnormal cells. These abnormal plasma cells are called myeloma cells.

In time, myeloma cells collect in the bone marrow. They may damage the solid part of the bone. When myeloma cells collect in several of your bones, the disease is called “multiple myeloma.” This disease may also harm other tissues and organs, such as the kidneys.

Myeloma cells make antibodies called M proteins and other proteins. These proteins can collect in the blood, urine, and organs.
click to see the picture.

..Normal plasma cells help protect the body from germs and other harmful substances.

click to see picture.

…Myeloma cell (abnormal plasma cell) making M proteins.

 

Risk Factors:
Multiple myeloma isn’t contagious. Most people who develop multiple myeloma have no clearly identifiable risk factors for the disease.

Some factors that may increase your risk of multiple myeloma include:

*Age. Multiple myeloma is most common in people over 65, affecting men more than women. It rarely occurs in young people.

*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. 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 leather or rubber manufacturing or the petrol industry, obesity and radiation exposure may increase the risk of multiple myeloma.

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Diagnosis:
Doctors sometimes find multiple myeloma after a routine blood test. More often, doctors suspect multiple myeloma after an x-ray for a broken bone. Usually though, patients go to the doctor because they are having other symptoms.

To find out whether such problems are from multiple myeloma or some other condition, your doctor may ask about your personal and family medical history and do a physical exam. Your doctor also may order some of the following tests:

*Blood tests: The lab does several blood tests:

…#Multiple myeloma causes high levels of proteins in the blood. The lab checks the levels of many different proteins, including M protein and other immunoglobulins (antibodies), albumin, and beta-2-microglobulin.

…#Myeloma may also cause anemia and low levels of white blood cells and platelets. The lab does a complete blood count to check the number of white blood cells, red blood cells, and platelets.

…#The lab also checks for high levels of calcium.

…#To see how well the kidneys are working, the lab tests for creatinine.

*Urine tests: The lab checks for Bence Jones protein, a type of M protein, in urine. The lab measures the amount of Bence Jones protein in urine collected over a 24-hour period. If the lab finds a high level of Bence Jones protein in your urine sample, doctors will monitor your kidneys. Bence Jones protein can clog the kidneys and damage them.

*X-rays: You may have x-rays to check for broken or thinning bones. An x-ray of your whole body can be done to see how many bones could be damaged by the myeloma.

*Biopsy: Your doctor removes tissue to look for cancer cells. A biopsy is the only sure way to know whether myeloma cells are in your bone marrow. Before the sample is taken, local anesthesia is used to numb the area. This helps reduce the pain. Your doctor removes some bone marrow from your hip bone or another large bone. A pathologist uses a microscope to check the tissue for myeloma cells.

There are two ways your doctor can obtain bone marrow. Some people will have both procedures during the same visit:

...#Bone marrow aspiration: The doctor uses a thick, hollow needle to remove samples of bone marrow.
...#Bone marrow biopsy: The doctor uses a very thick, hollow needle to remove a small piece of bone and bone marrow.

Staging and classification:
These tests can help confirm whether you have multiple myeloma or another condition. If tests indicate you have multiple myeloma, the results from these tests allow your doctor to classify your disease as stage 1, stage 2 or stage 3. People with stage 3 myeloma are more likely to have one or more signs of advanced disease, including greater numbers of myeloma cells and kidney failure.

Treatment:
Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred.

In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat anemia.

Initial therapy
Initial treatment of multiple myeloma depends on the patient’s age and comorbidities. In recent years, high-dose chemotherapy with hematopoietic stem-cell transplantation has become the preferred treatment for patients under the age of 65. Prior to stem-cell transplantation, these patients receive an initial course of induction chemotherapy. The most common induction regimens used today are thalidomide–dexamethasone, bortezomib based regimens, and lenalidomide–dexamethasone.  Autologous stem cell transplantation (ASCT), the transplantation of a patient’s own stem cells after chemotherapy, is the most common type of stem cell transplantation for multiple myeloma. It is not curative, but does prolong overall survival. Allogeneic stem cell transplantation, the transplantation of a healthy person’s stem cells into the affected patient, has the potential for a cure, but is only available to a small percentage of patients. Furthermore, there is a 5-10% treatment-associated mortality rate.

Patients over age 65 and patients with significant concurrent illness often cannot tolerate stem cell transplantation. For these patients, the standard of care has been chemotherapy with melphalan and prednisone. Recent studies among this population   suggest improved outcomes with new chemotherapy regimens. Treatment with bortezomib, melphalan and prednisone had an estimated overall survival of 83% at 30 months, lenalidomide plus low-dose dexamethasone an 82% survival at 2 years and melphalan, prednisone and lenalidomide had a 90% survival at 2 years. Head-to-head studies comparing these regimens have not been performed.

A 2009 review noted “Deep venous thrombosis and pulmonary embolism are the major side effects of thalidomide and lenalidomide. Lenalidomide causes more myelosuppression, and thalidomide causes more sedation. Peripheral neuropathy and thrombocytopenia are major side effects of bortezomib.”

Treatment of related hyperviscosity syndrome may be required to prevent renal failure

Maintenance therapy
Sometimes after the initial treatment an ongoing maintenance therapy is offered. A 2009 review of maintenance therapy concluded “In younger patients, post-ASCT maintenance therapy with thalidomide appears to increase tumor burden reduction further, which translates in[to] prolonged PFS (progression free survival).”

Another 2009 review stated “the role of maintenance therapy with thalidomide, lenalidomide, or bortezomib for patients with multiple myeloma is not definitively established; such therapy should be performed only in the context of a clinical trial.”

Relapse
The natural history of myeloma is of relapse following treatment. Depending on the patient’s condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.

Later in the course of the disease, “treatment resistance” occurs. This may be a reversible effect,  and some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib (or Velcade) is a recent addition to the therapeutic arsenal, especially as second line therapy, since 2005. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is showing promise for treating myeloma.

Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.

Prognosis:
The International Staging System can help to predict survival, with a median survival of 62 months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease.

Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.

Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally “poor-risk” disease.

SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel. In MM, lack of a proliferative clone makes conventional cytogenetics informative in only ~30% of cases.

1.Virtual karyotyping identified chromosomal abnormalities in 98% of MM cases

2.del(12p13.31)is an independent adverse marker

3.amp(5q31.1) is a favorable marker

4.The prognostic impact of amp(5q31.1) over-rides that of hyperdiploidy and also identifies patients who greatly benefit from high-dose therapy.

Array-based karyotyping cannot detect balanced translocations, such as t(4;14) seen in ~15% of MM. Therefore, FISH for this translocation should also be performed if using SNP arrays to detect genome-wide copy number alterations of prognostic significance in MM.

The prognoses for patients with multiple myeloma, as those with other diseases, are not the same for everyone. The average age of onset is 70 years. Older patients often are experiencing other serious diseases, which affect survival. Younger patients might have much longer survival rates.

Some myeloma centers now employ genetic testing, which they call a “gene array.” By examining DNA oncologists can determine if patients are high risk or low risk. Myeloma patients identified as high risk are at high risk of having the cancer return more quickly following treatment. Low risk patients are at low risk of having the cancer return quickly following treatment.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose
Resources:
http://en.wikipedia.org/wiki/Multiple_myeloma
http://www.bbc.co.uk/health/physical_health/conditions/in_depth/cancer/myeloma1.shtml
http://www.mayoclinic.com/health/multiple-myeloma/DS00415
http://www.medicinenet.com/multiple_myeloma/article.htm
http://www.nature.com/nrc/journal/v2/n12/fig_tab/nrc952_F5.html

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