Melphalan 200 mg/m2 has remained the standard of care as a preparative regimen for patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). Higher doses of melphalan are associated with unacceptable gastrointestinal toxicity. Preliminary studies suggested that administration of the cytoprotective agent amifostine could protect patients with MM undergoing ASCT from excessive toxicity from doses of melphalan as high as 280 mg/m2. We conducted a prospective, multicenter, randomized trial comparing melphalan 200 mg/m2 (mel200) v. 280 mg/m2 (mel280) using amifostine pretreatment in patients with MM undergoing ASCT.
The primary endpoints of the trial were grades 3–4 toxicity and near complete response (nCR) or better 60–120 days after ASCT. Eligibility included age ≤70, no prior ASCT, acceptable organ function, measurable monoclonal protein in serum or urine by protein electrophoresis and adequate stem cells for ASCT. Patients were stratified by ß2 microglobulin >5 at study entry, del 13 by FISH and response (<≥PR) to the last cytoreductive regimen prior to ASCT. Amifostine 710 mg/m2, with appropriate hydration and pre-medications, was given by intravenous push the day prior to and again 15 minutes prior to mel200 or mel280 given as a single infusion over 30 minutes.
Of 134 patients consented, consent was withdrawn for 4 patients, 1 patient who had abnormal renal function, one after a hypotensive episode following the first amifostine infusion, and 2 for other reasons. Manageable toxicities associated with amifostine infusion were hypotension (18), hypertension (3), dizziness (4), and nausea (33). Of 130 patients, 64 randomized to 200 mg/m2 and 66 280 mg/m2; 26 had del 13, and 55 had <PR to their last therapy; no patient had a ß2 microglobulin >5. Their median age was 60 years (range 42–70), they had received a median of 2 regimens (range 1–8) prior to stem cell collection, and 28 (22%) had received local radiation prior to ASCT. A total of 21 patients had grade 3–4 toxicity, 11% who received mel200 and 21% who received mel280 (p=0.11). Four of the seven in the mel200 group had a single grade 3–4 toxicity, while 3 had 2 grade 3–4 toxicities. Eight of the 14 in the mel280 group had a single toxicity, and 6 patients had two toxicities. By organ systems respectively, for mel200 v. mel 280, they were cardiac 1 v. 0, gastrointestinal 6 v. 11, mucositis 3 v. 7, CNS 0 v. 1 and pulmonary 0 v. 1. Hospitalization occurred in 94 patients 106 times; among the group receiving mel200 40 (62%) patients were hospitalized compared to 54 (82%) in the mel280 group, p=0.01. The mean total days of hospitalization were 7.3 and 10.2 days for mel200 and mel280, respectively (p=0.06); 3 patients in the mel200 group required 2 hospitalizations, 2 were admitted 3 times, while 5 patients in the mel280 group were admitted twice. The primary reasons for hospitalization for patients in receiving mel200 v mel280, respectively were, conditioning and transplant 9 v. 12, mucositis 2 v. 12, nausea and vomiting 8 v. 12, fever and infection 21 v. 18 and other 6 v. 6. No treatment related deaths occurred in this study. Responses following ASCT by EBMT criteria were for mel200 v. mel 280, respectively, ≥nCR 22% v. 39%, p=0.04, ≥PR 56% v. 70%, p= 0.09. The estimated progression-free survival at 1 and 3 years was 86% and 48%, respectively, for mel200 and 77% and 53%, respectively, for mel280. The risk of failure (death or progression) was similar (hazard ratio (mel280 vs. mel200) 1.12; 95% CI 0.64–1.95, p=0.69). The median follow-up among patients alive without progression was 524 and 555 days for mel200 and mel280, respectively. The estimated overall survival at 1 and 3 years was 96% and 83%, respectively, for mel200 and 89% and 73% for mel280, respectively. The risk of death was similar in the mel280 group relative to mel200 (HR=0.86; 95% CI 0.40–1.84; p=0.70).
In summary the combination of amifostine and mel280 was generally well tolerated although there were more grade 3–4 regimen-related toxicities, primarily mucositis and gastrointestinal. This resulted in slightly more frequent and longer hospitalizations (by 3 days) compared to amifostine + mel200. Mel280 resulted in a higher major response rate (CR + nCR) and warrants further study.
Off Label Use: amifostine.
Asterisk with author names denotes non-ASH members.