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Recombinant human soluble tumor necrosis factor receptor fusion protein in patients with refractory multiple myeloma


, : Recombinant human soluble tumor necrosis factor receptor fusion protein in patients with refractory multiple myeloma. Blood 98(11 Part 2): 312b, November 16

Elevated serum and bone marrow TNF levels occur in some patients with MM and are associated with poor prognosis. Enbrel is a fusion protein consisting of the extracellular, ligand-binding domain of the human p75 TNF receptor linked to the Fc portion of human IgG1. This soluble TNFR-Fc fusion construct acts as a competitive inhibitor of TNF binding to cell surface TNF receptors. A pilot study to assess the activity of Enbrel in patients with refractory MM is being conducted. Eligibility criteria include primary resistance to gtoreq2 courses of induction chemotherapy, transient response, or relapsed disease, in a patient with quantifiable serum M-protein and bone marrow plasmacytosis >5%. Eleven patients have been entered on study to date. Patients were treated with Enbrel 25 mg SC twice weekly for a minimum of 8 doses. Patients without overt progression continued treatment at the same dose. Ten patients (8 male), 9 with performance status (PS) 0-1, and 1 with PS 2 are currently evaluable. Median age is 63 years (range, 43-76). Baseline median Hgb was 11g/dl (range, 8.9-13.8); median WBC 4.7X109/L (range, 2.9-5.6) median platelet count 199X109/L (range, 57-356); median creatinine 1.0mg/dl (range, 0.7-2.6), median beta2-Microglobulin 6.9 mg/L (range, 1.2-17.5) and median calcium 8.7mg/dl (range, 7.7-10.5). Seven patients had IgG and 3 IgA MM. Median number of prior treatments was 5 (range, 2-7). All patients had failed prior Thalidomide therapy, 6 had failed prior Hyper-CVAD, and 2 had failed prior autologous stem cell transplantation. The median follow-up is 33 weeks (range 3-45). The 10 evaluable patients have received a total of 25 cycles (4 weeks=1 cycle), median 2 (range 1-7). The median number of doses was 16 (range 3-55), total 191. Eight patients had stable disease (SD); one of whom had a 30% decrease in BM plasma cells and beta2-Microglobulin level. Two patients had progressive disease (PD) on study and were withdrawn after 18 and 30 days; both had PD on enrollment. Enbrel was associated with fever in 2 patients; flu-like syndrome in 2; grade 1 fatigue in 1; chest pain in 1; abdominal discomfort in 1; and grade 1 hyperbilirubinemia in 1. No patient was withdrawn from the study because of toxicity. The median survival has not been reached with 8% of the patients alive at 45 weeks. No patient on study had clinically meaningful response to therapy. Enbrel was well tolerated in this small group of patients with advanced, refractory MM. In particular, as this is a highly immunosuppressed population, no overt increase in infectious episodes was noted. Enbrel was not overtly associated with progressive disease in this cohort, but such an association is difficult to detect in a small cohort of patients, most of whom had progressive disease at time of study entry. Short-term exposure to Enbrel appears safe in patients with advanced MM and studies of more protracted therapy are indicated.

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