Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands;
Janssen Research & Development, Beerse, Belgium;
Blood. 2016 Aug 18;128(7):959-70. doi: 10.1182/blood-2016-03-703439. Epub 2016 Jun 15.
The anti-CD38 monoclonal antibody daratumumab is well tolerated and has high single agent activity in heavily pretreated relapsed and refractory multiple myeloma (MM). However, not all patients respond, and many patients eventually develop progressive disease to daratumumab monotherapy. We therefore examined whether pretreatment expression levels of CD38 and complement-inhibitory proteins (CIPs) are associated with response and whether changes in expression of these proteins contribute to development of resistance. In a cohort of 102 patients treated with daratumumab monotherapy (16 mg/kg), we found that pretreatment levels of CD38 expression on MM cells were significantly higher in patients who achieved at least partial response (PR) compared with patients who achieved less than PR. However, cell surface expression of the CIPs, CD46, CD55, and CD59, was not associated with clinical response. In addition, CD38 expression was reduced in both bone marrow-localized and circulating MM cells, following the first daratumumab infusion. CD38 expression levels on MM cells increased again following daratumumab discontinuation. In contrast, CD55 and CD59 levels were significantly increased on MM cells only at the time of progression. All-trans retinoic acid increased CD38 levels and decreased CD55 and CD59 expression on MM cells from patients who developed daratumumab resistance, to approximately pretreatment values. This resulted in significant enhancement of daratumumab-mediated complement-dependent cytotoxicity. Together, these data demonstrate an important role for CD38 and CIP expression levels in daratumumab sensitivity and suggest that therapeutic combinations that alter CD38 and CIP expression levels should be investigated in the treatment of MM. These trials were registered at www.clinicaltrials.gov as #NCT00574288 (GEN501) and #NCT01985126 (SIRIUS).
抗 CD38 单克隆抗体达雷妥尤单抗在经过大量预处理的复发和难治性多发性骨髓瘤（MM）中具有良好的耐受性和高单药活性。然而，并非所有患者都有反应，许多患者最终对达雷妥尤单抗单药治疗产生进展性疾病。因此，我们研究了预处理时 MM 细胞上 CD38 和补体抑制蛋白（CIP）的表达水平是否与反应相关，以及这些蛋白表达的变化是否有助于产生耐药性。在接受达雷妥尤单抗单药治疗（16mg/kg）的 102 例患者队列中，我们发现与未达到部分缓解（PR）的患者相比，至少达到 PR 的患者的 MM 细胞上的 CD38 表达水平显著更高。然而，CIP 蛋白（CD46、CD55 和 CD59）的细胞表面表达与临床反应无关。此外，在第一次达雷妥尤单抗输注后，骨髓局部和循环 MM 细胞中的 CD38 表达均减少。在达雷妥尤单抗停药后，MM 细胞中的 CD38 表达水平再次增加。相比之下，仅在进展时，MM 细胞上的 CD55 和 CD59 水平显著增加。全反式维甲酸增加了达雷妥尤单抗耐药患者 MM 细胞上的 CD38 水平，并降低了 CD55 和 CD59 的表达，使其接近预处理值。这导致达雷妥尤单抗介导的补体依赖性细胞毒性显著增强。总之，这些数据表明 CD38 和 CIP 表达水平在达雷妥尤单抗敏感性中起着重要作用，并表明应研究改变 CD38 和 CIP 表达水平的治疗联合用药，以治疗 MM。这些试验在 www.clinicaltrials.gov 上注册为 #NCT00574288（GEN501）和 #NCT01985126（SIRIUS）。
