Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma.
Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma.
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达拉图珠单抗的功效和安全性与复发/难治性多发性骨髓瘤中的全反式视黄酸结合在一起。
DOI：
10.1182/bloodadvances.2021005220
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发表时间：
2021-12-14
期刊：
影响因子：
7.5
通讯作者：
van de Donk, Niels W. C. J.
中科院分区：
文献类型：
--
作者：
Frerichs, Kristine A.;Minnema, Monique C.;Levin, Mark-David;Broijl, Annemiek;Bos, Gerard M. J.;Kersten, Marie Jose;Mutis, Tuna;Verkleij, Christie P. M.;Nijhof, Inger S.;Maas-Bosman, Patricia W. C.;Klein, Saskia K.;Zweegman, Sonja;Sonneveld, Pieter;van de Donk, Niels W. C. J.
达雷妥尤单抗与ATRA联合治疗达雷妥尤单抗难治性MM患者是安全的，但活性有限。疗效有限的部分原因可能是ATRA治疗后CD 38表达一过性增加。达雷妥尤单抗的疗效部分取决于多发性骨髓瘤（MM）细胞上的CD 38表达。我们之前已经证明，全反式维甲酸（ATRA）上调CD 38表达和逆转达雷妥单抗体外耐药性。因此，我们在一项I/II期研究（NCT 02751255）中评价了达雷妥尤单抗联合ATRA治疗达雷妥尤单抗难治性MM患者的最佳剂量、疗效和安全性。在研究的A部分，63例患者接受了达雷妥尤单抗单药治疗。50例达雷妥尤单抗难治性MM患者随后入组B部分，接受达雷妥尤单抗（再强化方案）联合ATRA治疗，直至疾病进展。ATRA联合达雷妥尤单抗的推荐II期剂量定义为45 mg/m2。在该剂量下，总缓解率（ORR）为5%，表明未达到主要终点（ORR ≥15%）。然而，大多数患者（66%）至少达到了疾病稳定。中位随访43个月后，所有患者的中位无进展生存期（PFS）为2.8个月。与接受达雷妥尤单抗单药治疗后立即发生疾病进展的患者相比，既往接受达雷妥尤单抗单药治疗后达到至少部分缓解或极轻微缓解/疾病稳定的患者的PFS显著更长（中位PFS分别为3.4和2.8 vs 1.3个月）。中位总生存期为19.1个月。添加ATRA并没有增加不良事件的发生率。流式细胞仪分析显示，ATRA暂时增加免疫细胞亚群上的CD 38表达。总之，在达雷妥尤单抗难治性MM患者中，添加ATRA和重新强化达雷妥尤单抗的活性有限，这可能通过CD 38表达的短暂上调来解释。该试验在www.clinicaltrials.gov上注册为#NCT02751255。
The combination of daratumumab with ATRA is safe but has limited activity in patients with daratumumab-refractory MM. The limited efficacy may be partially explained by the transient increase in CD38 expression upon ATRA treatment. The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumab-refractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR ≥15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255.
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158.5
作者：
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Danhof S