Monoclonal gammopathy of undetermined significance

INTRODUCTION

Multiple myeloma is a cancer caused by malignant plasma cells. This disease is a hematologic cancer that affects many people. There are a number of risks that are associated with multiple myeloma, although nothing strictly predisposes the disease. The number of multiple myeloma cases is increasing due to the ability to better diagnose the disease. The treatment of multiple myeloma has become very standard due to its elusive characteristics, but further advances are being made to combat this disease.

ETIOLOGY AND EPIDEMIOLOGY

Malignant plasma cells are the source of multiple myeloma. Plasma cells are part of the immune system, and they are derived from B-cells and they create the antibodies that fight foreign antigens. In multiple myeloma, plasma cells grow uncontrolled and form tumors in the bone marrow. This compromises the integrity of the bone along with the makeup of the blood. In multiple myeloma plasma cells produce only 1 of the 5 antibodies in large quantities instead of producing the antibody that the immune system detects.1 This can compromise the patient's immune system, and cause other side effects depending on the antibody produced. Such as the accumulation of a single antibody, IgG1 or IgG3, can cause hyperviscosity of the blood.2 Plasma cells are able to create these large quantities with the aid of surrounding stromal cells.

Plasma cells are able to grow uncontrolled and avoid apoptosis due to nonmalignant stromal cells. When malignant plasma cells adhere and become localized in the bone marrow an accumulation of cytokines begins to form.3 Surrounding stromal cells produce these cytokines. Interleukin-6 is the main cytokine produced and it promotes plasma cell growth. The production of interleukin-6 increases when the stromal cells actually contacts the plasma cell tumor.1 Interleukin-6 also promotes angiogenesis that further increases the tumor's growth.4

Changes induced by the bone marrow microenvironment are equally important in the pathogenesis of multiple myeloma.5 Osteoclastic activity factors are also an integral in the development of the disease. It is evident that the molecular classification of multiple myeloma will both direct and foster future therapeutic approaches to this disease.5,6

Multiple myeloma affects about 3 out of 100,000 per year and is the 15th leading cause of cancer death, causing approximately 2% of all cancer deaths. This disease affects about an equal number of men and women.7 Multiple myeloma affects nearly twice as many blacks than whites. Socioeconomic factors do not seem to be the reason for this statistic. There is some evidence that blacks may have a higher prevalence of this disease because they have higher number of antibodies than whites. This may represent a higher number of plasma cells from which multiple myeloma may develop.2 Some data shows that other ethnic groups like Hawaiians, female American Indians, female Hispanics, and Alaskan natives have higher disease rates than whites of the same geographic region. The data also shows that Chinese, Japanese, Filipino, male Hispanics, and male American Indians are almost the same as whites in the same geographic regions.8

To date multiple myeloma is an incurable disease and the prognosis is not good. The average survival rate is about 3 years after diagnosis.9 Some data shows that blacks have a slightly higher survival rate at about 5 years. The data also states that women have a higher survival rate than men regardless of the race. Survival is also higher among those with higher income and education. This seems to be dependent on the ability of the patient being able to travel to and receive treatment.8

There is no clear predisposing risk factor for multiple myeloma. There are many things that may cause multiple myeloma, but it is mainly an age dependent disease. Some of the risk factors associated with the disease include occupational exposure to wood, rubber, metal, textile, hair dyes, and petroleum. Exposure to ionizing radiation is more strongly linked to multiple myeloma.2

Most cases of multiple myeloma occur in people over the age of 60.2 Only about 2% of the cases are attributed to people under the age of 40.4 The average for developing the disease is 70. The median age of onset for other cancers in the United States is about 68 for males and 66 for females, while the median age for multiple myeloma is 69 for males and 71 for female.8

Multiple myeloma develops after a person has been exposed to high doses of radiation. There may also be risks of long-term lose dose exposure to radiation. Multiple myeloma has been studied in patients that were exposed to radiation from nuclear bomb blasts. The disease was studied in patients that entered Hiroshima City within 3 days after the bomb was dropped. These people were found to be at a 60% greater risk of developing multiple myeloma than those that did not enter the city. Almost one third of the deaths from multiple myeloma between 1950 and 1985 were among atomic bomb survivors.8

One disease, monoclonal gammopathy of undetermined significance (MGUS), can predispose to multiple myeloma. This disease causes an over production of antibody proteins from abnormal plasma cells like multiple myeloma. This disease usually has no affect on the patient's health. Studies have shown that about 20% of the people with MGUS will develop multiple myeloma.4

New studies are showing that a virus could cause some cases of multiple myeloma. This virus is the Herpesvirus-8 or Kaposi's Sarcoma Herpesvirus. The virus seems to be located in nonmalignant dendritic cells.9 The virus seems to encode the makings of an interleukin-6 derivative; thus it is able to stimulate the growth and avoidance of apoptosis by plasma cells. This virus may also play a role in the transformation of MGUS to multiple myeloma.10

SIGNS AND SYMPTOMS

Multiple myeloma causes problems in many parts of the body. This disease normally starts in the bone marrow and can cause problems in other organs. Bone disease is the most common complication of multiple myeloma. It occurs in about 75% to 80% of individuals affected by multiple myeloma.2 Bone pain is often severe and can result in pathologic fractures and spinal cord compression.11 Pathological fractures frequently occur in the spine, ribs, skull, pelvis, and proximal long bones. The fractures are a result of excess orthoclase activity. This also results in hypercalcemia. These two problems work together to cause pain and immobilize the patient. As these problems persist, they can cause pneumonia and other complications associated with immobility.5

Multiple myeloma can also affect the bone marrow. The blood cells derived from the bone marrow are compromised as the disease progresses. Anemia is common and can result in the patient being tired and weak. Thrombocytopenia can cause blood-clotting problems. Neutropenia can occur and further compromise the patient's ability to fight infection, namely urinary and respiratory infections. In extreme cases multiple myeloma can cause acute leukemia.5

Multiple myeloma can also affect the kidney. Renal problems occur in about 20% to 50% of individuals affected by multiple myeloma. Renal failure can result, and is aided by dehydration, infection, hyperuricemia, pyelonephritis, and hypercalcemia.5 The 4 main causes of renal insufficiency are amyloid deposits, myeloma kidney, hypercalcemia, and hyperviscosity syndrome. A myeloma kidney is caused by the accumulation of abnormal immunoglobulins in the renal tubules.2

Cardiac failure can also be caused by multiple myeloma. This is due to hyperviscosity syndrome, anemia, and the deposit of amyloids. Infection or renal failure usually causes death from multiple myeloma.5 Anemia is a prominent feature of multiple myeloma and is commonly associated with clinical progression of disease. Apparently the malignant plasma cell clone becomes cytotoxic for erythroid progenitors, which leads to destruction of the erythroid matrix.12

DIAGNOSIS

The diagnosis of multiple myeloma largely depends on the symptoms presented at examination. They also dictate the tests that will be performed to understand the etiology of the problem. Tests may include serum chemistries, complete blood counts, and serum protein electrophoresis. Immunoelectrophoresis is another test that is done to detect the presence of immunoglobins in the urine. Multiple myeloma can be confirmed by a bone marrow biopsy.2

If multiple myeloma is diagnosed it can be rated on a scale established by Durie, Salmon, and Moon. The scale is based upon the total calculated mass of myeloma cells in the body. It is divided into 3 stages. Stage I represents low cell mass, less than 0.6 x 10^sup 12^/m^sup 2^. Stage II is intermediate cell mass, 0.6 x 10^sup 12^m^sup 2^. Stage III is high cell mass, greater than 0.6 x 10^sup 12^m^sup 2^.2 Staging is also based on levels of calcium, hemoglobin, and abnormal M protein in the blood, as well as severity of bone disease based on radiography and scanning techniques.11

TREATMENT

To date there are a number of ways to treat multiple myeloma, but there is currently no cure. Due to the fact that multiple myeloma is a hematological disease, antineoplastic chemotherapy is the preferred treatment. If treatment is initiated early, survival can be extended from about 7 months to 2 or 3 years.2 With other chemotherapy there is also a standard. It consists of the combination of melphalan and prednisone. If these drugs are not effective other drugs are used such as vincristine, cyclophosphamide, carmustine, and doxorubicin. They may also be used in combination with the standard drugs. The choice of which drugs to use is based upon the presenting symptoms. These drugs target rapidly dividing cells, therefore, tissues like the intestine, bone marrow, lining of the mouth, and hair may be damaged. Care should be taken to alleviate as much pain and discomfort as possible during these procedures.4

Some other drugs are given to combat problems associated with multiple myeloma. A class of drugs called bisphosphonates inhibits the process of osteoclasts degrading bone. Diuretics are given to help the kidneys remove excess salt and fluids. Pain relievers are also given to improve the patient's quality of life. Interferon is another drug given, and it acts opposite of interleukin-6 by slowing down the growth of plasma cells. Interferon has flu like side effects in most cases.4 Despite the use of many drugs, multiple myeloma usually has a relapse period where it becomes unresponsive to chemotherapy and other courses of action are taken.2

Recently, autologous peripheral blood stem cell supported high dose melphalan has become the standard, particularly in young patients.13 Thalidomide and Revimil are also used. Cytogenic abnormalities which are present in 1/3 of newly diagnosed patients are poor prognosticators, but otherwise an 80% to 90 % 4-year survival can be obtained.13 Research should probably focus on the molecular and biologic mechanisms of treatment failure in the high-risk subgroup.

Thalidomide works via a path of antiangiogenesis, and the discovery that multiple myeloma is associated with new vessel formation makes this treatment attractive and represents a major breakthrough.14,15 However, thalidomide may work via a number of yet undetermined mechanisms, and there is opportunity to improve outcome. An idiotype protein secreted by the multiple myeloma cells has been the main target for immunotherapy as it is the most well-defined tumor specific antigen in this disease.14

Radiation therapy is another way that multiple myeloma is treated. It is used to treat lytic bone lesions, compression fractures, and to relieve pain. In the case of compression fractures surgery may be required to treat the loss of sensation, muscle weakness, or paralysis that may have resulted from a compression of the spinal cord.4 Recently, the injection of inflatable bone tamps into the vertebral body, allowing the area to fill in with bone cement, has been found to affect significant improvement in pain, physical function, vitality, and social functioning, measured by SF36 scores.16

REHABILITATION AND PHYSICAL THERAPY CONSIDERATIONS

The major cause of disability in multiple myeloma is due to the bone lesions that are so prevalent. Fractures may need to be evaluated by an orthopedist to determine stability and ability to withstand exercise and mobilization.11 Assessment of weight bearing status of long bones is paramount to decrease the risk of pathological fractures, which are all too common in this disease. A combination of pharmacotherapy, including adequate pain control, and physical exercise may enable patients to return to self dependence and work.17

The exact role of exercise in multiple myeloma has not been established definitively. Light active assisted exercise is useful in most patients, keeping the location and extent of boney lesions in mind. More strenuous strengthening exercises may not be tolerated well and may be contraindicated. The accompanying anemia may preclude such exercises. Mobilization of the patient out of bed is tantamount; and in advanced cases, transfer training and wheelchair training may be applicable. Orthotic devices are sometimes employed in painful areas to restrict motion and to provide support where the diseased skeleton may be unable to maintain stability, but tolerance of these devices is variable.

In preterminal and terminal stages, attention to supportive therapy and palliation are integral and can make a great impact on the quality of life. The physical therapist or other rehabilitation specialist should be in close attendance to provide this care, and in many cases their role may actually increase in late stages of the disease, where immobility and renal failure frequently complicate the clinical picture.

WORKS CITED

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13. Barglogie B, Shaughnessy JD, Tricot G, et al. Treatment of multiple myeloma. Blood. 2003 (in print).

14. Heffner LJ, Lonial S. Breakthroughs in the management of multiple myeloma. Drugs. 2003;63(16): 1621-1636.

15. Schey SA. Thalidomide ini the management of multiple myeloma. Hematology. 2002;7(5):291-299.

16. Dudney S, Lieberman IH, Reinhardty MK, Hussein M. Kyphoplasty in the treatment of osteolytic vertebral compression fractures as a result of multiple myeloma. J Clin Oncol. 2002;20(9):2382-2387.

17. Zyzek G, Zdiaeska B, Dolinska D. Rehabilitation of patients with myeloma and marked locomotor dysfunction. Pol Tyg Lek. 1991;46(30-31):553-554.

Bo Poulson, MD1

Stephen A. Gudas, PT, PhD2

1At the time this paper was written, Dr. Poulson was a medical student, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia. He is currently serving a one year internship in emergency medicine at the school

2Associate Professor, Department of Anatomy and Neurobiology, Physical Therapist, Cancer Rehabilitation, Massey Cancer Center, Virginia Commonwealth University, Medical College of Virginia

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