CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies.
CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies.
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DOI：
10.1182/bloodadvances.2023010162
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发表时间：
2023-11-14
期刊：
影响因子：
7.5
通讯作者：
Sherbenou, Daniel W.
中科院分区：
文献类型：
--
作者：
de Acha, Olivia Perez;Reiman, Lauren;Jayabalan, David S.;Walker, Zachary J.;Bosma, Grace;Keller, Alana L.;Parzych, Sarah E.;Abbott, Diana;Idler, Beau M.;Ribadeneyra, Drew;Niesvizky, Ruben;Forsberg, Peter A.;Mark, Tomer M.;Sherbenou, Daniel W.
我们发现，患者在接受其他治疗时逐渐恢复CD38抗体敏感性。我们的结论是，再治疗的疗效可能会提高等待1年前再激发和交替抗CD38药物。靶向CD38的单克隆抗体对于新诊断和复发的多发性骨髓瘤（MM）的治疗都是重要的。达雷妥尤单抗和isatuximab是抗CD38抗体，已获得美国食品药品监督管理局批准，可用于多种不同的组合。尽管初始疗效良好，但患者不可避免地产生耐药性。患者是否可以在后续治疗中有效地用这些抗体重新治疗尚不清楚。到目前为止，研究大多局限于洗脱期较短的临床回顾。为了回答患者是否在较长时间洗脱后恢复敏感性，我们使用离体敏感性试验分离了从暴露于达雷妥尤单抗然后停用达雷妥尤单抗长达53个月的患者中获得的样本中的抗CD38抗体特异性细胞毒性。来自达雷妥尤单抗停药>1年的患者的MM细胞显示出比<1年的患者更高的敏感性，尽管它们仍然不如达雷妥尤单抗初治患者敏感。MM细胞上的CD38表达逐渐恢复，尽管再次未达到抗CD38抗体初治患者的水平。有趣的是，低MM CD38仅解释了45%确定的达雷妥尤单抗耐药病例。通过临床随访，我们发现体外敏感性可预测随后的临床反应，但CD38过表达不能。临床上再次接受抗CD38抗体治疗的患者具有<6个月的临床获益，但1例暴露于达雷妥尤单抗但不难治的患者实现了持续13个月的完全缓解。我们的结论是，暂时的疗效可以通过等待1年前CD38抗体再激发，但这种方法可能是最好的，作为一个桥梁，或后，嵌合抗原受体T细胞治疗。
We show that patients gradually recover CD38 antibody sensitivity while on other treatments. We conclude that re-treatment efficacy may improve by waiting 1 year before rechallenge and alternating anti-CD38 agents. Monoclonal antibodies targeting CD38 are important for treatment of both newly diagnosed and relapsed multiple myeloma (MM). Daratumumab and isatuximab are anti-CD38 antibodies with the US Food and Drugs Administration approval in multiple different combinations. Despite good initial efficacy, patients inevitably develop drug resistance. Whether patients can be effectively re-treated with these antibodies in subsequent lines of therapy is unclear. Thus far, studies have mostly been limited to clinical retrospectives with short washout periods. To answer whether patients regain sensitivity after longer washouts, we used ex vivo sensitivity testing to isolate the anti-CD38 antibody-specific cytotoxicity in samples obtained from patients who had been exposed to and then off daratumumab for up to 53 months. MM cells from patients who had been off daratumumab for >1 year showed greater sensitivity than those with <1 year, although they still were less sensitive than those who were daratumumab naïve. CD38 expression on MM cells gradually recovered, although, again, not to the level of anti-CD38 antibody–naïve patients. Interestingly, low MM CD38 explained only 45% of cases identified to have daratumumab resistance. With clinical follow-up, we found ex vivo sensitivity predicted subsequent clinical response but CD38 overexpression did not. Patients clinically re-treated with anti-CD38 antibodies had <6 months of clinical benefit, but 1 patient who was daratumumab exposed but not refractory achieved complete response lasting 13 months. We conclude that transient efficacy can be achieved by waiting 1 year before CD38 antibody rechallenge, but this approach may be best used as a bridge to, or after, chimeric antigen receptor T-cell therapy.
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