Chapter 106. Plasma Cell Disorders (Part 7) Serum β 2 -microglobulin is a protein of 11,000 mol wt with homologies with the constant region of immunoglobulins that is the light chain of the class I major histocompatibility antigens (HLA-A, -B, -C) on the surface of every cell. Serum β 2 -microglobulin is the single most powerful predictor of survival and can substitute for staging. Patients with β 2 -microglobulin levels <0.004 g/L have a median survival of 43 months and those with levels >0.004 g/L only 12 months. Serum β 2 -microglobulin and albumin levels are the basis for a three-stage International Staging System (ISS). It is also felt that once the diagnosis of myeloma is firm, histologic features of atypia may also exert an influence on prognosis. IL-6 may be an autocrine and/or paracrine growth factor for myeloma cells; elevated levels are associated with more aggressive disease. High labeling index and high levels of lactate dehydrogenase are also associated with poor prognosis. Other factors that may influence prognosis are the number of cytogenetic abnormalities including hyperploidy, chromosome 13q and 17p deletion, t(4;14) and t(11;14); % plasma cells in the marrow; circulating plasma cells; performance status; as well as serum levels of soluble IL-6 receptor, C-reactive protein, hepatocyte growth factor, C-terminal cross-linked telopeptide of collagen I, transforming growth factor (TGF) β, and syndecan-1. Microarray profiling and comparative genomic hybridization have formed the basis for RNA- and DNA- based prognostic staging systems, respectively. The ISS system is the most widely used method of assessing prognosis (Table 106-3). Multiple Myeloma: Treatment About 10% of patients with myeloma will have an indolent course demonstrating only very slow progression of disease over many years. Such patients only require antitumor therapy when the disease becomes symptomatic with development of anemia, hypercalcemia, progressive lytic bone lesions (including vertebral compression fractures), progressive rise in serum myeloma protein levels and/or Bence Jones proteinuria, or recurrent infections. Patients with solitary bone plasmacytomas and extramedullary plasmacytomas may be expected to enjoy prolonged disease-free survival after local radiation therapy to a dose of around 40 Gy. There is a low incidence of occult marrow involvement in patients with solitary bone plasmacytoma. Such patients are usually detected because their serum M component falls slowly or disappears initially only to return after a few months. These patients respond well to systemic chemotherapy. Patients with symptomatic and/or progressive myeloma require therapeutic intervention. In general such therapy is of two sorts: systemic therapy to control the progression of myeloma, and symptomatic supportive care to prevent serious morbidity from the complications of the disease. Therapy can significantly prolong survival and improve the quality of life for myeloma patients. The initial standard treatment for newly diagnosed myeloma is dependent on whether or not the patient is a candidate for high-dose chemotherapy with autologous stem cell transplant. In patients who are transplant candidates, alkylating agents such as melphalan should be avoided since they damage stem cells, leading to decreased ability to collect stem cells for autologous transplant. High-dose pulsed glucocorticoids have been used either alone (dexamethasone 40 mg for 4 days every 2 weeks) or in combination VAD chemotherapy (vincristine, 0.4 mg/d in a 4-day continuous infusion; doxorubicin, 9 mg/m 2 per day in a 4-day continuous infusion; dexamethasone, 40 mg/d for 4 days per week for 3 weeks) for initial cytoreduction. However, two studies have combined thalidomide with dexamethasone as initial therapy for newly diagnosed multiple myeloma in transplant candidates and reported rapid responses in two-thirds of patients, while allowing for successful harvesting of peripheral blood stem cells for transplantation. A randomized phase III trial showed statistically significantly higher response rates for thalidomide (200 mg PO qhs) plus dexamethasone (40 mg for 4 days every 2 weeks) compared to dexamethasone alone, setting the stage for use of this combination as standard therapy in newly diagnosed patients. Initial therapy is continued until maximal cytoreduction. Importantly, novel agents bortezomib, a proteasome inhibitor, and lenalidomide, an immunomodulatory derivative of thalidomide, have similarly been combined with dexamethasone and obtained high response rates without compromising collection of stem cells for transplantation. In patients who are not transplant candidates, therapy has consisted of intermittent pulses of an alkylating agent, L-phenylalanine mustard (L-PAM, melphalan) and prednisone administered for 4–7 days every 4–6 weeks. The usual doses of melphalan/prednisone (MP) are melphalan, 8 mg/m 2 per day, and prednisone, 25–60 mg/m 2 per day for 4 days. Doses may need adjustment due to unpredictable absorption and based on marrow tolerance. Patients responding to therapy generally have a prompt and gratifying reduction in bone pain, hypercalcemia, and anemia, and often have fewer infections. The serum M component lags substantially behind the symptomatic improvement, often taking 4–6 weeks to fall. This fall depends on the rate of tumor kill and the fractional catabolic rate of immunoglobulin, which in turn depends on the serum concentration (for IgG). Light chain excretion, with a functional half-life of ~6 h, may fall within the first week of treatment. However, since urine light chain levels may relate to renal tubular function, they are not a reliable measure of tumor cell kill. Calculations of tumor cell kill are made by extrapolation of the serum M component level and rely heavily on the assumption that every tumor cell produces immunoglobulin at a constant rate. About 60% of patients will achieve at least a 75% reduction in serum M component level and tumor cell mass in response to melphalan and prednisone. Although this is a tumor reduction of <1 log, clinical responses may last many months. The important feature of the level of the M protein is not how far or how fast it falls, but the rate of its increase after therapy. Efforts to improve the fraction of patients responding and the degree of response have involved adding other active agents to the treatment program. In patients >65 years, combining thalidomide with MP (MPT) obtains higher response rates and overall survival than MP alone, and MPT is the standard therapy for patients who are not transplant candidates. . Chapter 106. Plasma Cell Disorders (Part 7) Serum β 2 -microglobulin is a protein of 11,000 mol wt with homologies. including hyperploidy, chromosome 13q and 17p deletion, t(4;14) and t(11;14); % plasma cells in the marrow; circulating plasma cells; performance status; as well as serum levels of soluble IL-6 receptor,. reliable measure of tumor cell kill. Calculations of tumor cell kill are made by extrapolation of the serum M component level and rely heavily on the assumption that every tumor cell produces immunoglobulin