Managed Care - July 2008 - (Page H10) vessels that support the proliferation of myeloma cells), osteoclast activation (which interferes with normal growth and repair of bone), and several myeloma-related immunodeficiencies. Cytokines also activate intracellular signaling pathways that further enhance the expression of adhesion molecules, reinforcing a cycle of antiapoptotic activity (Mitsiades 2007). Symptoms and diagnosis Myeloma cells produce monoclonal (M) proteins that interfere with normal bone remodeling and repair; thus, bone destruction is often a first indication of the disease, and the most common presenting complaint among patients is bone pain. Lytic bone lesions occur in almost 70 percent of patients, many of whom present with compression fractures in the spine and other areas. Anemia also is a common symptom, as is hypercalcemia, or the excess calcium in the blood that results from the resorption of bone. Kidney dysfunction frequently is caused by proteins secreted from myeloma cells, as well as by increased levels of calcium from bone resorption; renal failure is not unusual in patients with myeloma and is a poor prognostic factor. Patients also are at an increased risk for bacterial and viral infections for a variety of reasons, including reduced white blood cell count, inhibition of normal immunoglobulin production, impaired Tlymphocyte function, and eventually, as a result of treatment. Infection often accompanies the diagnosis, progression, and terminal stages of this disease. The diagnostic evaluation of myeloma patients typically involves a list of tests. With the adoption of the International Staging System (ISS), introduced in 2005 to replace the more complicated Durie-Salmon system, fewer tests are required for definitive diagnosis and staging. However, many laboratory tests remain useful for monitoring the disease because of significant interpatient variations in its manifestation and response to treatment. Moreover, data analyses of the results of currently indicated tests may eventually be used to predict which patients will respond to a particular type of therapy. A characteristic feature of most myeloma cells is their tendency to secrete M protein into the blood and urine; indeed, patients often are diagnosed with myeloma because this protein is discovered on routine assays before symptoms emerge. However, studies have shown that the amount of M protein secreted by myeloma cells varies considerably among patients; in fact, the lack of M protein excretion occurs in less than 10 percent of all patients (Kyle 2003). For each patient, a ratio of M protein to tumor burden must be established, and in some patients this ratio may change during treatment. More useful with regard to treatment implications is the identification of the particular subtype of monoclonal protein that is produced by a patient’s myeloma cells (eg, IgG, IgA, IgD, or IgA). This information is obtained by immuno- fixation and may predict clinical behavior and prognosis, and most important, can be used as a tumor marker to monitor disease status. The simplified diagnosis of myeloma begins with a bone marrow biopsy used to confirm the presence and number of myeloma cells. When these cells comprise less than 10 percent of all bone marrow cells, a patient is determined to have monoclonal gammopathy of undetermined significance (MGUS). The risk of transition from MGUS to myeloma is very low — only about 1 percent per year (Kyle 2002). When myeloma cells constitute between 10 and 30 percent of all bone marrow cells, and a patient has no other significant end-organ damaged (anemia, renal failure, etc.), he or she is classified as having indolent or smoldering myeloma. This asymptomatic form of the disease also is unlikely to rapidly progress to myeloma, but the risk for progression is higher — approximately 10 to 20 percent per year (Kyle 2007). Patients with inactive disease should be observed every 3 to 6 months (NCCN 2008). If signs of disease progression emerge (≥25 percent increase in M protein, evidence of lytic disease or hypercalcemia, or ≥50 percent increase in tumor volume in patients with plasmacytoma) patients should undergo treatment for active disease. There is no evidence that early treatment of these asymptomatic forms is advantageous (Rajkumar 2006a), but many of these patients do elect to participate in clinical trials to assess early treatment options. Initial treatment considerations One of the most important clinical challenges associated with the management of myeloma is determining the goal of treatment. Myeloma is an incurable disease and long-term complete remissions are relatively rare. Thus, although improving the complete response (CR) rate among patients is typically the goal in clinical trials, but under a physician’s care, this may not always be practical, especially given a patient’s functional status or comorbid conditions. Treatment must be tapered to fit the needs of each individual patient, with quality of life (QoL) serving as an important consideration. No single treatment for myeloma presently is recognized as standard therapy. At every stage of treatment, clinicians encounter multiple options and generally choose from the same selection of agents. Significant patient variations require that clinicians draw on whatever information is available about the treatment of similar patients, with an ever-increasing focus on determining the optimum combination and sequencing of agents. To assist in decision making, the National Comprehensive Cancer Network (NCCN) compiles guidelines based on recommendations of an expert committee charged with reviewing existing clinical trial data and forming a consensus for treatment. These guidelines, published once a year, are the most comprehensive available. 10 MANAGED CARE / SUPPLEMENT
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