Article Title: A multi -centre phase -II trial of thalidomide in relapsed/refractory multiple myeloma reveals an adverse prognostic impact of advanced age Short Title: Thalidomide/interferon & myeloma

Background: Patients with relapsed or refractory multiple myeloma have a poor outlook. Thalidomide has activity in a proportion, however criteria for predicting response have not been conclusively identified. Methods: We initiated a prospective multi-centre Phase-II trial in patients with relapsed/refractory myeloma using thalidomide up to maximum dose 800 mg/day. Interferonα-2B (1.5-3.0MU,SC,TIW) was added at week 12 if disease was responsive or stable. Patients intolerant of interferon continued thalidomide alone. Thalidomide +/interferon was continued until disease progression. Objectives were to determine toxicity, response rate (RR), progression-free survival (PFS), overall survival (OS) and to elucidate relevant prognostic factors. Results: Seventy-five patients, with median age 64 (range 36-83), were enrolled. The median individual-maximum-tolerated dose of thalidomide was 600mg/day. 41% reached 800 mg/day. Overall RR was 28% with one complete response, and 55% stable disease (SD). The only predictor for response was age ≤ 65 (38% vs 17%;P=0.043). At 18 months median follow-up, the actuarial median PFS and OS were 5.5 and 14.6 months respectively. Multivariate analysis for OS demonstrated age >65 (median 9.2mo v >26mo;P=0.011), raised serum LDH (P=0.002), and raised serum creatinine (P=0.007) predicted inferior outcomes. Nineteen patients received interferon. 10 discontinued due to toxicity. Four of 12 patients who received >4 weeks interferon were converted from SD to partial response. Conclusions: Our findings confirm substantial activity of thalidomide in relapsed/refractory myeloma. Interferon may improve response in selected patients, but is often not tolerated. The inferior outcome demonstrated in those with the identified prognostic factors is important in planning management for these patients. Corresponding author: Miles.Prince@petermac.org