Multiple myeloma is a malignant disease of the most mature form of B lymphocyte, the plasma cell. It is not classified as a lymphoma. Plasma cells secrete immunoglobulins, proteins necessary for anti-body production to fight infection.
In myeloma, the malignant plasma cells produce an increased amount of a specific immunoglobulin that is nonfunctional. Func-tional types of immunoglobulin are still produced by nonmalignant plasma cells, but in lower-than-normal quantity. The specific im-munoglobulin secreted by the myeloma cells is detectable in the blood or urine and is referred to as the monoclonal protein, or M protein. This protein serves as a useful marker to monitor the ex-tent of disease and the patient’s response to therapy. It is measured by serum or urine protein electrophoresis. Moreover, the patient’s total protein level is typically elevated, again due to the production of M protein. Malignant plasma cells also secrete certain substances to stimulate the creation of new blood vessels to enhance the growth of these clusters of plasma cells; this process is referred to as angio-genesis. Occasionally the plasma cells infiltrate other tissue, in which case they are referred to as plasmacytomas. Plasmacytomas can occur in the sinuses, spinal cord, and soft tissues. Median sur-vival time is 3 to 5 years. Death usually results from infection.
The classic presenting symptom of multiple myeloma is bone pain, usually in the back or ribs. Bone pain is reported by two thirds of all patients at diagnosis. Unlike arthritic pain, the bone pain associated with myeloma increases with movement and de-creases with rest; patients may report that they have less pain on awakening but the pain intensity increases during the day. In myeloma, a substance secreted by the plasma cells, osteoclast ac-tivating factor, as well as other substances (eg, interleukin-6 [IL-6]) are involved in stimulating osteoclasts. Both mechanisms appear to be involved in the process of bone breakdown. Thus, lytic lesions as well as osteoporosis may be seen on bone x-rays. (They are not well visualized on bone scans.) The bone destruc-tion can be severe enough to cause fractures, including spinal fractures, which can impinge on the spinal cord and result in spinal cord compression. It is this bone destruction that causes significant pain.
If the bone destruction is fairly extensive, excessive ionized cal-cium is lost from the bone and enters the serum; patients may there-fore become hypercalcemic (frequently manifested by excessive thirst, dehydration, constipation, altered mental status, confusion, and perhaps coma). Renal failure may also be seen; the configura-tion of the circulating immunoglobulin molecule (particularly the shape of lambda light chains) can damage the renal tubules.As more and more malignant plasma cells are produced, the marrow has less space for RBC production, and the patient can become anemic. This anemia is also caused to a great extent by a diminished production of erythropoietin (a glycoprotein necessary for RBC production) by the kidney. Patients may complain of fatigue and weakness due to the anemia. In the late stage of the disease, a reduced number of WBCs and platelets may also be seen because the bone marrow is infiltrated by malignant plasma cells.
When plasma cells secrete excessive amounts of immunoglob-ulin, particularly IgA, the serum viscosity can be elevated. Hyper-viscosity may be manifested by bleeding from the nose or mouth, headache, blurred vision, paresthesias, or heart failure.
Finding an elevated monoclonal protein spike in the serum (via serum protein electrophoresis) or urine (via urine protein elec-trophoresis) or light chain in the urine (sometimes referred to as Bence Jones protein) is considered to be a major criterion in the diagnosis of multiple myeloma. The presence of lytic bone lesions on x-ray aids in the diagnosis, as does the presence of anemia or hypercalcemia. The diagnosis of myeloma can be confirmed by bone marrow biopsy; the presence of sheets of plasma cells is the hallmark diagnostic criterion. Because the infiltration of the mar-row by these malignant plasma cells is not uniform, the extent of plasma cells may not be increased in a given sample (a false-neg-ative result).
The incidence of multiple myeloma increases with age; the disease rarely occurs in patients younger than 40 years of age. Because of the increasing older population, more patients are seeking treat-ment for this disease. BMT or PBSCT is an option that can pro-long remission and potentially cure some patients. However, it is unavailable to most because of age limitations. Back pain, which is often a presenting symptom in this disease, should be closely in-vestigated in elderly patients.
There is no cure for multiple myeloma. Even BMT or PBSCT is considered by most authorities to extend remission rather than pro-vide a cure. However, for many patients, it is possible to control the illness and maintain their level of functioning quite well for several years or longer. Chemotherapy is the primary treatment; cortico-steroids, particularly dexamethasone (Decadron), are especially effective and are often combined with other agents (such as melphalan (Alkeran), cyclophosphamide (Cytoxan), doxorubicin (Adriamyein), vincristine (Oncouin), and BCNU (Carmustine).
Radiation therapy is very useful in strengthening a specific bone lesion, particularly one at risk for bone fracture or spinal cord compression. It is also useful in relieving bone pain and reducing the size of plasma cell tumors that occur outside the skeletal sys-tem. However, because it is a nonsystemic form of treatment, it does not diminish the source of the bone problems (ie, the pro-duction of malignant plasma cells). Therefore, radiation therapy is typically used with systemic treatment such as chemotherapy.
The biologic agent alpha-interferon has been used successfully to maintain remission in selected types of myeloma, particularly IgA type; however, its role in prolonging survival is controversial. Newer forms of bisphosphonates, such as pamidronate (Aredia) and zoledronic acid (Zometa), have been shown to strengthen bone in this disease (by diminishing the secretion of osteoclast activating factor) (Terpos et al., 2000), controlling bone pain and potentially preventing bone fracture. They are also effective in managing and preventing hypercalcemia. Some evidence suggests that bisphosphonates may actually have activity against the mye-loma cells themselves by inhibiting a growth factor necessary for myeloma cell survival (Berenson, 2001) (see later discussion).
When patients manifest signs and symptoms of hyperviscosity, plasmapheresis may be used to lower the immunoglobulin level. Symptoms may be more useful than serum viscosity levels in de-termining the need for this intervention.
Recent advances in the understanding of the process of angio-genesis have resulted in new therapeutic options. The sedative thalidomide (Thalomid), initially used as an antiemetic, has sig-nificant antimyeloma effects. It inhibits cytokines necessary for new vascular generation, such as, vascular endothelial growth fac-tor (VEGF) and for myeloma cell growth and survival, such as IL-6 and tumor necrosis factor), by boosting the body’s immune response against the tumor and by creating favorable conditions for apoptosis of the myeloma cells. Thalidomide is effective in re-fractory myeloma and in “smoldering” disease states, and may pre-vent progression to a more active state. Thalidomide is not a typical chemotherapeutic agent and has a unique side effect pro-file. Fatigue, dizziness, constipation, rash, and peripheral neu-ropathy are commonly encountered; myelosuppression is not (Goldman, 2001). Thalidomide is contraindicated in pregnancy because of associated severe birth defects.
Pain management is very important in this patient population. NSAIDs can be very useful for mild pain, or in combination with opioid analgesics. However, care needs to be taken, because NSAIDs can cause renal dysfunction. Patients need to be educated about activity restrictions (eg, lifting no more than 10 pounds, use of proper body mechanics). Braces are occasionally needed to pro-vide support to the spinal column.
Patients also need to be instructed about the signs and symp-toms of hypercalcemia. Maintaining mobility and hydration is important to diminish exacerbations of this complication; how-ever, the primary cause is the disease itself. Renal function should also be monitored closely. Renal failure can become severe, and dialysis may be needed. Maintaining high urine output (3 L/day) can be very useful in preventing this complication.
Because antibody production is impaired, infections, particu-larly bacterial infections, are common and can be life-threatening. Patients need to be instructed in appropriate infection prevention measures (see Chart 33-8) and should be advised to contact their health care provider immediately if they have a fever or other signs and symptoms of infection. Patients should receive Pneumovax and flu vaccines. Prophylactic antibiotics are sometimes used. In-travenous gamma globulin (IVIG) can be useful for patients with recurrent infections.
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