Clinical efficacy of daratumumab, pomalidomide, and dexamethasone in patients with relapsed or refractory myeloma: Utility of re-treatment with daratumumab among refractory patients
Clinical efficacy of daratumumab, pomalidomide, and dexamethasone in patients with relapsed or refractory myeloma: Utility of re-treatment with daratumumab among refractory patients
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DOI：
10.1002/cncr.32178
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发表时间：
2019-09-01
期刊：
影响因子：
6.2
通讯作者：
Lonial, Sagar
中科院分区：
文献类型：
--
作者：
Nooka, Ajay K.;Joseph, Nisha S.;Lonial, Sagar
达雷妥尤单抗（达拉）作为单药治疗和与标准治疗方案联合治疗多发性骨髓瘤（MM）的疗效已在临床试验中得到证实。这篇文章介绍了达拉联合泊马度胺（POM）和地塞米松（即达雷妥尤单抗、泊马度胺和地塞米松[DARA-POM-D]）的安全性和疗效的回顾性分析，更重要的是，对DARA和POM初治队列以及在达拉和/或POM难治患者中评价再治疗效用的队列进行了长期随访。方法将2015年1月至2016年7月在埃默里大学Winship癌症研究所接受DARA-POM-D治疗的34例连续复发性和/或难治性MM患者纳入分析。这项研究得到了埃默里大学机构审查委员会的批准。所有患者既往均接受过蛋白酶体抑制剂和免疫调节药物（IMiD）治疗，且对最后一线治疗无效。结果所有患者均为来那度胺难治性，91%为硼替佐米难治性。根据既往暴露于达拉和/或POM确定了两个队列。队列1（12例患者）为达拉和POM初治患者，队列2（22例患者）为达拉和/或POM难治患者。队列2（队列3）中的12例患者亚组为达拉和POM难治性。该组合的耐受性与已发表的1b期研究（EQUULES）的结果一致，该研究评估了该组合，未观察到新的安全性信号。队列1、2和3的总体缓解率（ORR）分别为91.7%、40.9%和33.3%。在队列1中观察到深度缓解，包括4例严格完全缓解。在队列2中，ORR包括8个部分缓解（PR）和1个非常好的PR。在中位随访41个月时，队列1未达到中位无进展生存期（PFS），队列2为3.2个月。DARA-POM-D不仅在达拉和POM初治患者中有效，而且在三分之一再次接受这些药物治疗的患者中产生了临床反应。结论：与EQUULEUS试验中先前报告的获益（导致美国食品药品监督管理局批准DARA-POM-D组合）相比，队列1中观察到的PFS获益超过四倍，这突出了以下事实：引入单克隆抗体组合策略和IMiD作为早期治疗选择可能会提供更好的临床结局。三分之一对单独的达拉和/或POM线难治的患者在用组合重新治疗时有反应，并且这导致与可用于DARA难治性患者的其他抗骨髓瘤药物/组合等同的生存益处。
Background The efficacy of daratumumab (DARA) both as a monotherapy and in combination with standard-of-care regimens in multiple myeloma (MM) has been established in clinical trials. This article presents a retrospective analysis of the safety and efficacy of DARA in combination with pomalidomide (POM) and dexamethasone (ie, daratumumab, pomalidomide, and dexamethasone [DARA-POM-D]) and, more importantly, the long-term follow-up of a cohort that was naive to DARA and POM as well as a cohort in which the utility of re-treatment was evaluated among patients who were DARA- and/or POM-refractory. Methods Thirty-four consecutive patients with relapsed and/or refractory MM treated with DARA-POM-D at the Winship Cancer Institute of Emory University from January 2015 through July 2016 were included in the analysis. The study was approved by Emory University's institutional review board. All received prior proteasome inhibitors and immunomodulatory drugs (IMiDs) and were refractory to their last line of therapy. Results All patients were lenalidomide-refractory, and 91% were bortezomib-refractory. Two cohorts were identified on the basis of prior exposure to DARA and/or POM. Cohort 1 (12 patients) was DARA- and POM-naive, and cohort 2 (22 patients) was DARA- and/or POM-refractory. A subgroup of 12 patients in cohort 2 (cohort 3) was DARA- and POM-refractory. The combination's tolerability was consistent with the results of the published phase 1b study (EQUULES) that evaluated the combination and no new safety signals were observed. The overall response rates (ORRs) were 91.7%, 40.9%, and 33.3% in cohorts 1, 2, and 3, respectively. Deep responses, including 4 stringent complete responses, were observed in cohort 1. In cohort 2, the ORR comprised 8 partial responses (PRs) and 1 very good PR. The median progression-free survival (PFS) was not reached in cohort 1 at a median follow-up of 41 months, and it was 3.2 months in cohort 2. DARA-POM-D not only was effective in DARA- and POM-naive patients but also produced clinical responses in a third of patients re-treated with these drugs. Conclusions A better than quadrupled PFS benefit observed in cohort 1 in comparison with the previously reported benefit in the EQUULEUS trial (which led to US Food and Drug Administration approval of the DARA-POM-D combination) highlights the fact that the introduction of monoclonal antibody combination strategies and IMiDs as earlier lines of therapeutic options potentially could deliver better clinical outcomes. One-third of patients refractory to separate lines of DARA and/or POM responded when they were re-treated with a combination, and this resulted in survival benefits equivalent to those of other antimyeloma agents/combinations available for DARA-refractory patients.