Differential Diagnosis

The required investigations detailed above assure the gathering of sufficient information for making the diagnosis. In most patients with symptomatic, progressive myeloma, the diagnosis is readily made by the presence of marked bone marrow plasmacytosis, monoclonal protein in serum and/or urine, and osteolytic bone lesions, all the major criteria for myeloma. Minor criteria, including anemia, hypercalcemia, renal insufficiency, and suppression of nonparaproteins, help establish the diagnosis in cases where bone disease is not obvious.124 The myeloma-related disorders, however, are a heterogeneous group, including multiple myeloma, smoldering myeloma, indolent myeloma, MGUS, solitary plasmacytoma of the bone, extramedullary plasmacytoma, and plasma cell leukemia. In addition, systemic AL amyloidosis, Waldenstrom's macroglobulinemia, and heavy-chain diseases also share the features of the neoplasia of Ig-secreting cells (see Chapters 88 and 90). The distinction among some of these disorders is not precise, and the diagnostic criteria used vary among experts. A number of classification systems are often used, including that by Durie-Salmon,125 by the Mayo group,2126 the Southwest Oncology Group (SWOG),127 and by the British Columbia Cancer Agency.128 A comparison of these classification systems in 157 patients with plasma cell dyscrasias showed that 80% of the cases could be classified by all systems, and in 64%, the diagnosis was concordant. Not unexpectedly, the discrepancies occurred primarily among the smoldering myeloma, indolent myeloma, and multiple myeloma stage I groups.124 Thus, currently, the selection of a particular diagnosis and classification system makes relatively little difference in treatment approach.

Recent efforts by international groups aim at simplifying the classification for uniform application.123129 Recognizing that myeloma-related disorders have a wide spectrum of overlapping features, the proposed classification emphasizes the importance of myeloma-related organ or tissue impairment (end-organ damage) in the clinical course of patients and in decision making for systemic therapy. The proposed diagnostic criteria, not greatly different from current classifications, have greater clarity.123'129 Tables 82.4-82.6 list the criteria for (symptomatic) multiple myeloma, MGUS, smoldering (indolent or asymptomatic) myeloma, nonse-cretory myeloma, solitary plasmacytoma of the bone, and extramedullary plasmacytoma. In addition, plasma cell leukemia is defined by the presence of monoclonal plasma cells of >2000/^L in the peripheral blood and >20% plasma cells in WBC differential count.

The biological basis for various classifications of myeloma-related disorders is unclear. Molecular studies have shown that similar genetic alterations occur in all variants of myeloma,130 and in gene expression profiling, MGUS is not distinguishable from early

Table 82.5 Diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS), smoldering or indolent or asymptomatic myeloma (SM), and non-secretory myeloma (NSMM)
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