Currently, the use of radiotherapy alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. Single immune-checkpoint inhibitors, such as anti-programmed death-1 (anti-PD1), have not been successful. We aimed to evaluate the activity and safety of the combination of pembrolizumab and low-dose, single-fraction, hypofractionated radiotherapy to treat patients with relapsed or refractory multiple myeloma. For this prospective, single-centre, single-group, open-label, phase 2 trial, we recruited patients with relapsed or refractory multiple myeloma from the Winship Cancer Institute (Emory University, Atlanta, GA, USA). Key inclusion criteria were aged 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, relapsed or refractory multiple myeloma as indicated by progression under International Myeloma Working Group (IMWG) criteria, and adequate candidacy for both pembrolizumab and radiotherapy. Baseline and post-treatment assessments were serial bone-marrow biopsy, peripheral blood collections, staging, serial serum and urine paraprotein analysis, serial PET–CT imaging, and a physical examination. On day 1, patients received hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) radiotherapy to either symptomatic or progressing extra-osseous or osseous myeloma sites. Patients also received pembrolizumab (200 mg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Dose reduction and interruptions were not allowed. The primary outcome was acute toxicity defined as grade 3 or worse toxicity at 3 months within the radiated site when used in combination with pembrolizumab. All patients were analysed per protocol and included in safety analyses. This trial is registered on (); it is completed and closed to accrual. 32 patients were screened between June 1, 2018, and Sept 2, 2022, and 25 were enrolled in the trial and treated on protocol. Of the 25 treated patients, 11 (44%) were female and 14 (56%) were male. 19 (76%) patients were White and six (24%) were Black or African American. Toxicity, as the primary outcome, was deemed to be acceptable as no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response). There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths. Combination treatment of low-dose, single-fraction radiotherapy with pembrolizumab was safe, with early promise of response activity. Our approach could be an option for patients with relapsed or refractory multiple myeloma who have not responded to previous treatment. Larger trials to substantiate our findings are needed. Merck Sharp & Dohme.

中文翻译：

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派姆单抗和低剂量单次放疗治疗复发性或难治性多发性骨髓瘤患者：在美国进行的一项前瞻性、单中心、单组、开放标签、2 期试点试验


目前，对多发性骨髓瘤患者单独使用放射疗法仅限于缓解疼痛、治疗骨折和控制脊髓压迫。单一免疫检查点抑制剂，例如抗程序性死亡-1（抗PD1），尚未取得成功。我们的目的是评估派姆单抗与低剂量、单次大分割放疗联合治疗复发或难治性多发性骨髓瘤患者的活性和安全性。对于这项前瞻性、单中心、单组、开放标签的 2 期试验，我们从 Winship 癌症研究所（美国佐治亚州亚特兰大埃默里大学）招募了复发或难治性多发性骨髓瘤患者。主要纳入标准为年龄 18 岁或以上、东部肿瘤合作组 (ECOG) 表现评分为 0 或 1、根据国际骨髓瘤工作组 (IMWG) 标准进展表明复发或难治性多发性骨髓瘤，以及派姆单抗和帕博利珠单抗的充分候选资格放射治疗。基线和治疗后评估包括连续骨髓活检、外周血采集、分期、连续血清和尿液副蛋白分析、连续 PET-CT 成像和体检。第 1 天，患者接受大分割 8 灰分 1 次 (8 Gy/1 fx) 放射治疗，针对有症状或进展的骨外或骨骨髓瘤部位。患者还在第 2 或 3 天接受派姆单抗（200 mg 静脉注射），然后每 3 周（±7 天）一次，持续 2 年，或直至疾病进展、不可接受的毒性、撤回同意、失访或死亡。不允许减少剂量和中断。 主要结局是急性毒性，定义为与派姆单抗联合使用时，3 个月内辐射部位出现 3 级或更严重的毒性。所有患者均按照方案进行分析并纳入安全性分析。该试验已在 () 注册；它已完成并停止计提。 2018年6月1日至2022年9月2日期间对32名患者进行了筛查，其中25名患者参加了试验并按照方案进行治疗。在 25 名接受治疗的患者中，11 名（44%）为女性，14 名（56%）为男性。 19 名 (76%) 患者是白人，6 名 (24%) 患者是黑人或非裔美国人。作为主要结果的毒性被认为是可以接受的，因为没有观察到 4 级或 5 级不良事件。在 3 个月的随访中，25 名患者中有 8 名（32%）获得了治疗益处（一名患者病情稳定，三名患者部分缓解，两名患者部分缓解非常好，两名患者完全缓解）。受辐射体积内没有出现 3 级或更严重的辐射相关毒性。接受联合治疗的 25 名患者中，有 1 名 (4%) 出现 3 级派姆单抗相关不良事件。没有出现与治疗相关的死亡。低剂量、单次放疗与派姆单抗的联合治疗是安全的，并且有望尽早发挥缓解活性。我们的方法可能是对先前治疗没有反应的复发性或难治性多发性骨髓瘤患者的一种选择。需要更大规模的试验来证实我们的发现。默克夏普和多姆。