The matricellular protein SPARC (secreted protein acidic and rich in cysteine)/osteonectin was determined in patients with multiple myeloma and related disease to assess the hypothesized role of SPARC as a possible marker of tumor burden and disease progression. Soluble SPARC was measured by competitive enzyme-linked immunosorbent assay (ELISA) in plasma of 42 patients, including sequential measurements in individual patients, and in 20 healthy controls. SPARC values were heterogeneous in multiple myeloma patients showing a decline from baseline levels recorded in controls (456+/-195 vs 600+/-63 ng/ml, p=0.00023). A SPARC showed a significant positive correlation with platelet count (r=0.72, p=0.000000, n=42), hemoglobin (r=0.52, p=0.00037, n=42), and IgG level (r=0.43, p=0.0085, n=42) and negative correlation with beta(2)-microglobulin (r=-0.46, p=0.0023, n=42), aspartate aminotransferase (AST) (r=-0.42, p=0.0061, n=41), interleukin (IL)-6 (r=-0.41, p=0.008, n=42), lactate dehydrogenase (LDH) (r=-0.36, p=0.02, n=41), and percentage of plasma cells in bone marrow aspirate (r=-0.34, p=0.029, n=42). No correlation was found between SPARC and "M" component or disease stage. Investigations performed during the course of disease, including sequential measurements in individual patients, showed a trend to downregulation by disease progression, with the lowest level recorded in the terminal stage (217+/-107 ng/ml, n=11). Patients with established osteolytic lesions had lower plasma SPARC at diagnosis (309+/-197 vs 581+/-293, p=0.021), which correlated with osteocalcin by disease progression (r=0.31, p=0.026). The results of this pilot study revealed abnormalities in the level of humoral SPARC in multiple myeloma and an overall trend to downregulation in the advanced stage of the disease. The regulation of SPARC seems to be opposite to the markers of tumor burden and of aggressive multiple myeloma phenotype.