Thalidomide and Dexamethasone as Salvage Therapy after First Relapse in Multiple Myeloma: Analysis of Long-Term Outcomes.

Abstract 4933

Bortezomib and lenalidomide have been approved in the U.S. and Europe for the treatment of patients with advanced refractory/relapsed multiple myeloma (MM). In this setting, both these agents effected the highest activity among patients who relapsed after a single line of prior therapy. In particular, with early introduction of bortezomib at first relapse median TTP was 7 months vs 4.9 months with use of the same drug as third, or more, line of therapy; 1-year OS rates were 89% vs 73%, respectively. Similarly, reported median PFS and OS with lenalidomide and dexamethasone at first relapse were 14.1 and 42 months, respectively. Since the first report of single agent thalidomide (thal) for the treatment of MM patients who had failed multiple lines of prior therapy, including autologous stem-cell transplantation (ASCT), a large number of studies have investigated this drug further in the setting of advanced relapsed/refractory disease, most frequently combined with dexamethasone (dex).Aim of the present analysis was to evaluate the long-term outcomes of a series of 100 patients who received thal-dex as salvage therapy at first relapse after prior ASCT or conventional chemotherapy. By study design, thal was started at the dose of 100 mg/daily for two weeks and then escalated to 200 mg/daily, provided that the initial tolerance was acceptable. Otherwise, thal was continued at the initial dose until progression. Dex was given at a monthly dose of 160 mg. The first 60 patients did not receive any thromboprophylaxis, while fixed low-dose warfarin (0.25 mg/day) was added to thal-dex in the subsequent 40 patients. Median age of the patients was 62 years. Median time from start of first-line therapy to thal-dex was 34 months. Up-front therapy for MM had included ASCT, either single (30%) or double (42%), while the remaining 28 patients had previously received conventional chemotherapy. 59% of the patients were treated with a fixed thal dose of 100 mg/daily, while in the remaining 41% of patients the dose was increased up to 200 mg/daily. Overall, median duration of thal-dex therapy was 14 months. 65% of the patients stayed on treatment beyond the achievement of the best response or plateau phase; median duration of thal in these patients was 22 months (range 1-79). The most frequent adverse events were constipation (42%, grade III 8%), peripheral neuropathy (58%, grade III 5%), bradycardia (20%, grade III 0%) and skin rash (11%, grade III 1%). Venous thromboembolism was recorded in 7 patients (3 not receiving any thromboprophylaxis), at a median of 8 months (range 3-11) from the start of thal-dex therapy. The frequency of grade III neuropathy was significantly higher in patients receiving thal 200 mg/daily in comparison with those treated with 100 mg/daily (8.5% vs 1%, respectively, P = 0.01). Discontinuation of thal due to toxicity was recorded in 8 patients after a median of 12 months. On an intention to treat basis, 46% of patients achieved at least a partial response at a median time of 3 months from the start of thal-dex treatment; the response rate was not significantly different between patients receiving thal 100 mg/daily and those treated with 200 mg/daily. The median duration of response (DOR) was 28 months, while the median time to next therapy was 15.5 months. With a median follow up of 25 months, median OS, TTP and PFS were 43, 22 and 21 months, respectively. TTP and PFS were significantly longer for patients responding to thal-dex therapy (TTP: 34 months vs 15 months for nonresponders, P = 0.005; PFS: 28 months vs 12 months for nonresponders, P = 0.001, respectively). Median survival after relapse from thal-dex therapy was 26 months. In conclusion, low-dose thal-dex was an effective treatment of MM at first relapse. Although cross-trial comparisons are not adequate, results herein reported with thal-dex in terms of DOR, OS and EFS were similar to those previously seen with other novel agents when used in the same setting of patients. Low-dose thal-dex was generally well tolerated, as reflected by the long stay on treatment in the absence of disease progression (median: 25 months) and a low discontinuation rate due to toxicity (8%).