Association between response kinetics and outcomes in relapsed/refractory multiple myeloma: analysis from TOURMALINE-MM1.
Association between response kinetics and outcomes in relapsed/refractory multiple myeloma: analysis from TOURMALINE-MM1.
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复发/难治性多发性骨髓瘤的反应动力学和结果之间的关联：来自Tourmaline-MM1的分析。
DOI：
10.1038/s41375-018-0091-3
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发表时间：
2018-09
期刊：
影响因子：
11.4
通讯作者：
Richardson PG
中科院分区：
文献类型：
--
作者：
Garderet L;Laubach JP;Stoppa AM;Hari P;Cavo M;Ludwig H;Mateos MV;Luptakova K;Lin J;Yung G;van de Velde H;Berg D;Moreau P;Richardson PG
多发性骨髓瘤（MM）的反应深度与长期预后之间的关系是公认的[1-3]。因此，当开始治疗时，临床医生和患者经常受到m蛋白快速下降的鼓舞，并且在初始诊断4个月时达到≥非常好的部分缓解（VGPR）与死亡率下降相关。然而，对反应动力学和结果之间的关系知之甚少。虽然一些报告表明，与晚期应答者相比，早期应答者可能会损害长期结果[5,6]，但这些研究是有限的，仅局限于一线环境，并且基于新药物可用之前的时代。在这里，我们通过反应深度和达到最佳反应的时间来评估无进展生存期（PFS）和反应持续时间（DOR），使用的数据来自于伊唑米那利度胺-地塞米松（IRd）与安慰剂- rd在复发/难固性MM (RRMM)[7]患者中的双盲3期TOURMALINE-MM1试验（NCT01564537）。该研究表明，IRd的PFS优于安慰剂-Rd（中位数为20.6个月vs 14.7个月，风险比[HR] 0.74； P= 0.01），并且附加毒性有限，因此批准ixazomib联合Rd用于至少接受过一次先前治疗的MM患者[8,9]。TOURMALINE-MM1研究（NCT01564537）此前已被报道。RRMM患者以1:1的比例随机接受IRd （n= 360）或安慰剂- rd (n= 362)，直到疾病进展（PD）或不可接受的毒性。每个周期根据中心实验室结果并由独立审查委员会（IRC）评估bbb评估反应。主要终点PFS在第一次预先指定的分析中达到，中位随访约15个月（中位PFS， IRd vs安慰剂- rd: 20.6 vs 14.7个月；HR 0.74, 95%可信区间0.59,0.94，P= 0.01）；这是PFS[7]的最终统计分析。在中位随访约23个月后进行了总生存期（OS）的后续分析，其中包括PFS的非推断敏感性分析（中位PFS， IRd vs安慰剂- rd: 20.0 vs 15.9个月；HR 0.82, 95%可信区间：0.67,1.0）[7]。本文报道的事后分析来自23个月的随访。在此分析中，两组患者的中位总生存期均未达到，该试验仍在以双盲、安慰剂对照的方式继续进行，以使生存期数据成熟。
The association between depth of response in multiple myeloma (MM) and long-term outcomes is well recognized [1–3]. Thus, clinicians and patients are often encouraged by a rapid decrease of M-protein when treatment is initiated, and achieving≥ very-good partial response (VGPR) by 4 months of initial diagnosis has been associated with decreased mortality [4]. However, little is known about the association between response kinetics and outcomes. While some reports suggest that early responders may have compromised long-term outcomes compared with late responders [5, 6], these studies were limited, confined to frontline setting only, and based in the era prior to novelagent availability.Here, we evaluated progression-free survival (PFS) and duration of response (DOR) by depth of response and time to best response using data from the double-blind phase 3 TOURMALINE-MM1 trial (NCT01564537) of ixazomiblenalidomide-dexamethasone (IRd) versus placebo-Rd in patients with relapsed/refractory MM (RRMM)[7]. The study demonstrated superior PFS with IRd versus placebo-Rd (median 20.6 versus 14.7 months, hazard ratio [HR] 0.74; P= 0.01) with limited additional toxicity [7], leading to the approval of ixazomib, in combination with Rd, for MM patients who had received at least one prior therapy [8, 9]. The TOURMALINE-MM1 study (NCT01564537) has been described previously [7]. Patients with RRMM were randomized 1: 1 to receive IRd (n= 360) or placebo-Rd (n= 362) until disease progression (PD) or unacceptable toxicity. Response was assessed every cycle based on central laboratory results and by Independent Review Committee (IRC) evaluation [10]. The primary endpoint PFS was met at the first prespecified analysis at a median follow-up of~ 15 months (median PFS, IRd versus placebo-Rd: 20.6 versus 14.7 months; HR 0.74, 95% confidence interval 0.59, 0.94, P= 0.01); this was the final statistical analysis of PFS [7]. A subsequent analysis for overall survival (OS) was performed after a median follow-up of~ 23 months, which included a non-inferential sensitivity analysis for PFS (median PFS, IRd versus placebo-Rd: 20.0 versus 15.9 months; HR 0.82, 95% confidence interval: 0.67, 1.0)[7]. The post-hoc analyses reported herein are from the 23-month follow-up. At this analysis, median OS was not reached in either arm, and the trial is continuing in a double-blind, placebo-controlled fashion to allow survival data to mature.
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