Frerichs Kristine A, Verkleij Christie P M, Dimopoulos Meletios A, Marin Soto Jhon A, Zweegman Sonja, Young Mary H, Newhall Kathryn J, Mutis Tuna, van de Donk Niels W C J
Cancer Center Amsterdam, Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.
Cancers (Basel). 2021 May 18;13(10):2452. doi: 10.3390/cancers13102452.
Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance. The efficacy and safety of daratumumab and durvalumab in daratumumab-refractory relapsed/refractory MM patients was evaluated in this prospective, single-arm phase 2 study (NCT03000452). None of the 18 enrolled patients achieved PR or better. The frequency of serious adverse events was 38.9%, with one patient experiencing an immune related adverse event (grade 2 hyperthyroidism). No infusion-related reactions were observed. Analysis of tumor- and immune cell characteristics was performed on bone marrow samples obtained at baseline and during treatment. Daratumumab combined with durvalumab reduced the frequency of regulatory T-cells and decreased the proportion of T-cells expressing LAG3 and CD8 T-cells expressing TIM-3, without altering T- and NK-cell frequencies. Durvalumab did not affect tumor cell characteristics associated with daratumumab resistance. In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance.
达雷妥尤单抗作为单药以及与其他药物联合使用时，对多发性骨髓瘤（MM）患者均有活性。然而，大多数患者会发展为对达雷妥尤单抗难治的疾病，其预后较差。由于达雷妥尤单抗也具有免疫调节作用，在疾病进展时添加程序性死亡受体配体1（PD-L1）阻断抗体度伐利尤单抗可能会逆转对达雷妥尤单抗的耐药性。在这项前瞻性单臂2期研究（NCT03000452）中，评估了达雷妥尤单抗和度伐利尤单抗对达雷妥尤单抗难治的复发/难治性MM患者的疗效和安全性。18名入组患者中无一例达到部分缓解（PR）或更好疗效。严重不良事件的发生率为38.9%，有1例患者发生免疫相关不良事件（2级甲状腺功能亢进）。未观察到输液相关反应。对基线和治疗期间获得的骨髓样本进行了肿瘤和免疫细胞特征分析。达雷妥尤单抗联合度伐利尤单抗降低了调节性T细胞的频率，并降低了表达淋巴细胞活化基因3（LAG3）的T细胞和表达T细胞免疫球蛋白黏蛋白3（TIM-3）的CD8 T细胞的比例，而未改变T细胞和自然杀伤（NK）细胞的频率。度伐利尤单抗未影响与达雷妥尤单抗耐药相关的肿瘤细胞特征。总之，在出现对达雷妥尤单抗的耐药性后，将度伐利尤单抗添加到达雷妥尤单抗治疗中，毒性特征可接受，但无效。这表明在对达雷妥尤单抗耐药时抑制程序性死亡蛋白1（PD-1）/PD-L1信号通路不足以逆转对达雷妥尤单抗的耐药性。
