Background

Retrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial.

Methods

The primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m² followed by pharmacokinetically adjusted doses on days −7, −6, −5, and −4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m² per day on days −2 and −1 (total melphalan dose 140 mg/m²), or a melphalan dose of 200 mg/m² on day −2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov, number NCT01413178.

Findings

Between Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22·6 months (IQR 15·2–47·1) and 20·2 months (IQR 8·8–46·6) in the melphalan alone group. Median progression-free survival was 64·7 months (32·9–64·7) with busulfan plus melphalan versus 43·5 months (19·9–not estimated) with melphalan alone (hazard ratio 0·53 [95% CI 0·30–0·91]; p=0·022). There were no treatment-related deaths by day 100 in either group. Grade 2–3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group.

Interpretation

These findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma.

Funding

This study was funded in part by the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant (CA016672).

中文翻译：

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多发性骨髓瘤自体造血细胞移植前白消安加美法仑与单独美法仑的调理：一项开放标签、随机、3期试验

背景

回顾性研究表明，在接受自体造血细胞移植 (auto-HCT) 的多发性骨髓瘤患者中，与单独使用美法仑相比，使用白消安加美法仑进行预处理可以延长无进展生存期。我们的目的是在一项随机试验中检验这一假设。

方法

该研究的主要目的是在多发性骨髓瘤患者中比较白消安加美法仑与单独美法仑的无进展生存期。符合细胞移植条件的新诊断多发性骨髓瘤患者，年龄在 70 岁或以下，至少病情稳定，被随机分配 (1:1) 接受治疗。患者接受白消安加美法仑，白消安试验剂量为 32 mg/m ²，然后在第 -7、-6、-5 和 -4 天进行药代动力学调整剂量，以达到目标每日曲线下面积 (AUC)第-2天和第-1天每天5000 mmol-分钟和马法兰70 mg/m ^{2 （总马法兰剂量140 mg/m 2}），或马法兰剂量200 mg/m ²第-2天。随机化是通过德克萨斯大学 MD 安德森癌症中心的临床试验实施网站进行的。应计已完成，最终结果显示在此处。该研究已在 ClinicalTrials.gov 注册，编号为 NCT01413178。

发现

在 2011 年 10 月 12 日至 2017 年 3 月 22 日期间，对 205 名患者进行了资格评估并随机分配接受治疗。对 202 名接受治疗的患者进行了无进展生存期的初步分析：白消安加美法仑组 104 名患者和美法仑单独组 98 名患者。在 auto-HCT 后 90 天，104 名接受白消安加美法仑的患者中有 102 名（98%）和 98 名单独接受美法仑的患者中有 95 名（97%）达到部分缓解或更好。白消安加美法仑组的中位随访时间为 22·6 个月（IQR 15·2-47·1）和单独美法仑组的 20·2 个月（IQR 8·8-46·6）。白消安加美法仑的中位无进展生存期为 64·7 个月（32·9–64·7），而单独使用美法仑的无进展生存期为 43·5 个月（19·9-未估计）（风险比 0·53 [95% CI 0 ·30–0·91]；p=0·022)。到第 100 天，两组均未出现与治疗相关的死亡。白消安加美法仑组 104 名患者中有 77 名（74%）观察到 2-3 级粘膜炎，而美法仑单独组 98 名患者中有 14 名（14%）观察到。

解释

这些发现如果在其他正在进行的研究中得到证实，则表明白消安加美法仑可以替代单独的美法仑作为新诊断骨髓瘤患者自身 HCT 的预处理方案。

资金

这项研究部分由美国国立卫生研究院 (NIH) 通过MD 安德森癌症中心支持拨款 (CA016672) 资助。