Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
Cancer. 2019 Sep 1;125(17):2991-3000. doi: 10.1002/cncr.32178. Epub 2019 May 15.
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.
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.
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.
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.
达雷妥尤单抗（DARA）在临床试验中作为单药以及与标准治疗方案联合治疗多发性骨髓瘤（MM）的疗效已得到证实。本文报告了 DARA 联合泊马度胺（POM）和地塞米松（即 DARA-POM-D）的安全性和疗效的回顾性分析，更重要的是，报告了一组首次接受 DARA 和 POM 治疗的患者以及一组在接受 DARA 和/或 POM 治疗后评估重新治疗效果的患者的长期随访情况。
2015 年 1 月至 2016 年 7 月，在埃默里大学温希普癌症研究所接受 DARA-POM-D 治疗的 34 例复发性和/或难治性 MM 患者纳入分析。该研究得到了埃默里大学机构审查委员会的批准。所有患者均接受过蛋白酶体抑制剂和免疫调节药物（IMiDs）治疗，且对最后一线治疗均耐药。
所有患者均对来那度胺耐药，91%的患者对硼替佐米耐药。根据患者先前是否接受过 DARA 和/或 POM 治疗，将患者分为两个队列。队列 1（12 例患者）为 DARA 和 POM 初治患者，队列 2（22 例患者）为 DARA 和/或 POM 耐药患者。队列 2 中有 12 例患者（队列 3）为 DARA 和 POM 双重耐药。该联合方案的耐受性与评估该联合方案的已发表的 1b 期研究（EQUULES）的结果一致，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 例部分缓解（PR）和 1 例非常好的 PR。在中位随访 41 个月时，队列 1 的中位无进展生存期（PFS）未达到，而队列 2 为 3.2 个月。DARA-POM-D 不仅对 DARA 和 POM 初治患者有效，而且对三分之一的再次接受这些药物治疗的患者也产生了临床反应。
与 EQUULEUS 试验（该试验导致美国食品和药物管理局批准 DARA-POM-D 联合方案）先前报告的获益相比，队列 1 观察到的 PFS 获益增加了四倍以上，这表明引入单克隆抗体联合策略和 IMiDs 作为早期治疗方案的选择，可能会带来更好的临床结局。当三分之一的患者对 DARA 和/或 POM 的单独治疗线产生耐药性时，他们重新接受联合治疗会产生应答，并且这产生了与其他可用于 DARA 耐药患者的抗骨髓瘤药物/联合方案相当的生存获益。
