Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Finnish Leukemia Group

Abstract

High serum level of bioactive interleukin-6 (IL-6) is regarded as a predictor of poor prognosis in multiple myeloma (MM). On the other hand, the reported levels of immunoreactive IL-6 have been highly variable, and the prognostic value of immunoreactive IL-6 in MM is not clear. We have analyzed the prognostic significance of serum immunoreactive IL-6, as measured by a sensitive immunosorbent assay, in 210 patients with newly diagnosed MM subsequently treated with intermittent melphalan and prednisone. The serum levels of acute phase proteins C-reactive protein (CRP), alpha 1-antitrypsin (alpha 1AT), and acid alpha 1-glycoprotein (orosomucoid; OM) were evaluated as surrogates for IL-6. Serum IL-6, CRP, alpha 1AT, and OM levels were raised in 42%, 40%, 41%, and 24% of the patients, respectively. There was a significant correlation between the clinical stage of the patients and serum IL-6 (P = .006), alpha 1AT (P = .001), and OM (P = .004) levels at diagnosis. At 3 years, 52% of the patients were alive. Univariate logistic regression analysis showed that high levels of IL-6 (P = .002), CRP (P = .02), alpha 1AT (P < .001), OM (P = .007), beta 2- microglobulin (beta 2M; P < .001), and thymidine kinase (P < .05) were all associated with 3-year mortality. In multivariate regression analysis, beta 2M (P < .0001) and alpha 1AT (P = .01) had independent prognostic significance. The patients with high levels of both beta 2M and alpha 1AT or IL-6 were at very high risk of dying within 3 years from diagnosis (16% and 21% of the patients in these groups were alive, respectively). When the patients were stratified according to the clinical stage, the prognostic significance of serum IL-6 and alpha 1AT was especially evident in stage II patients. When the patients were divided into two groups according to normal or raised serum IL-6 levels, the patients with high IL-6 levels had more frequent osteolytic bone lesions (P = .03) and a more aggressive disease. We conclude that serum immunoreactive IL-6 is a significant prognostic marker in MM.

Deregulated cytokine network and defective Th1 immune response in multiple myeloma

“…These results prompted us to speculate that elevated serum IL-6 levels may inhibit the Th1 immune response in MM patients. Increased serum levels of IL-6 have been documented in active MM patients [32]. However, the data are discordant due to differences in assay sensitivity [38].…”

Serum interleukin‐6 has no discriminatory role in paraproteinaemia nor a prognostic role in multiple myeloma

“…The patients were either treatment-naive, had received treatment before or were undergoing treatment when serum IL-6 was measured. Secondly, cut-off values for the upper normal IL-6 level in serum were either not given (Brown et al, 1991;Thaler et al, 1994;Greco et al, 1994;Kyrtsonis et al, 1996) or ranged widely from 3´2 pg/ml (Pelliniemi et al, 1995) to 3300 pg/ml (Tienhaara et al, 1994). Each study reported a different range of values, even for normal controls (Table III).…”

Serum oncostatin M in multiple myeloma: association with prognostic factors

“…IL-6 is expressed by myeloma cells and mediates autocrine growth (see Kishimoto et al, 1995). High serum levels of IL-6 and CRP or 1AT as its surrogates have been associated with poor prognosis in MM patients (Pelliniemi et al, 1995). In addition, the raised concentration of sIL-6R is an independent prognostic factor and if both IL-6 and sIL-6R levels are elevated the patients have an even worse prognosis (Pulkki et al, 1996).…”

“…Raised serum concentrations of IL-6 as well as its surrogates, C-reactive protein (CRP) and 1-antitrypsin (1AT), are associated with poor prognosis in patients with multiple myeloma (MM) (Bataille et al, 1992;Pelliniemi et al, 1995). As OSM may simulate the effects of IL-6 we studied serum OSM concentration in relation to prognostic factors in 40 newly diagnosed MM patients.…”