Phase I/Ii study of combination high-dose therapy with busulfan, thiotepa, and total body irradiation (TBI) for the treatment of aggressive multiple myeloma

Autologous stem cell transplantation (Tx) has been shown to be superior to conventional chemotherapy in patients with multiple myeloma (MM). However, the optimal preparative regimen prior to Tx has yet to be defined. Busulfan, thiotepa, and TBI have all been shown to possess single agent activity against MM. The aim of this study was to determine the toxicity, efficacy and maximum tolerated dose (MTD) of busulfan when given with fixed doses of TBI (900 cGy) and Thiotepa (400 mg/m2) as the preparative regimen. Sixteen patients (median age 52, range 38-64) with chemoresponsive intermediate or advanced stage MM received stem cell mobilization chemotherapy with (CED) cyclophosphamide (3 gm/ m2), etoposide (600mg/m2), dexamethasone (160mg) and G-CSF (10 mg/kg/day). CED mobilization resulted in adequate stem cell collection in 15 of 16 patients (mean 47.44 x 10" CD34+ cells/kg; range 2.4-250.9 x 10 CD34+ cells/kg; sd 66.3). One patient required bone marrow harvest to supplement her stem cell collection. No grade III/IV toxicity was seen with mobilization. For the preparative regimen busulfan dosing was started at 6mg/kg with 4 patients per dose cohort and escalated by 2 mg/kg per cohort until the MTD was defined. The first 2 patients at the 8mg/kg dose exhibited grade Ill/IV gastrointestinal (GI) toxicity and the MTD was defined as 6 mg/kg. The remainder of patients were treated at this dose level. The mean number of CD34+ cells infused was 17.62 x 10'/kg (range 2.4-50.75; sd 17.08). All patients exhibited neutrophil recovery in a median of 10 (range 8-19) days. Platelet engraftment occurred in a median of 9 (range 7d to > 6 months) days. One hundred day Tx related mortality was 18.8%. Dose limiting toxicity was gastrointestinal. Twelve patients had grade III/IV mucositis. Other grade III/IV toxicity included 4 GI; 3 hepatic; 2 renal; 1 pulmonary; 6 infection; 1 hemorrhage; 1 dermatologie; 3 circulatory; and 3 hématologie. As of 7/2000 median overall survival is 408 days. Ten patients have died (I VOD, 1 multi-organ failure, 2 infection, 6 disease progression). MM has relapsed in 3 additional patients. We conclude that a preparative regimen of busulfan, thiotepa, and TBI produces significant toxicity in patients with MM and does not impart a benefit in overall survival.