Avelumab, a PD-L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma.
Avelumab, a PD-L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma.
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DOI：
10.1002/onco.13712
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
C Jones J
中科院分区：
文献类型：
--
作者：
Kazandjian D;Dew A;Hill E;Ramirez EG;Morrison C;Mena E;Lindenberg L;Yuan C;Maric I;Wang HW;Calvo K;Dulau-Florea A;Roswarski J;Emanuel M;Braylan R;Turkbey B;Choyke P;Camphausen K;Stetler-Stevenson M;Steinberg SM;Figg WD;C Jones J
尽管最初对使用免疫检查点抑制治疗多发性骨髓瘤持乐观态度，但随后的临床研究令人失望。临床前研究表明，除了检查点抑制之外，还可以用各种方式启动免疫系统，可以克服相对的T细胞衰竭或衰老;然而，在这个小数据集中，检查点抑制的放疗似乎并没有激活抗肿瘤免疫反应。髓外疾病（EMD）被认为是多发性骨髓瘤（MM）的一种侵袭性亚型，需要新的治疗方法。因此，我们设计了一项原理验证性初步研究，以评价抗PD-L1、avelumab和伴随的大分割放疗之间的协同作用。这是一项单臂II期Simon两阶段单中心研究，在入组4例患者后因COVID-19大流行而提前终止。关键合格性包括复发性/难治性多发性骨髓瘤（RRMM）患者，这些患者已用尽标准治疗或不是标准治疗的候选者，并且至少有一处病变适合放疗。患者在第2周期接受avelumab治疗，直至疾病进展或出现不可耐受的毒性，并对局灶性病变进行大分割放疗。考虑到既往研究的重要观察结果，即远位效应需要伴随治疗，因此将放疗延迟至第2周期，以使avelumab达到研究状态。在中位潜在随访10.5个月时，无客观缓解，1例极轻微缓解，2例疾病稳定为最佳缓解。中位无进展生存期（PFS）为5.3个月（95%置信区间[CI]：2.5-7.1个月），未发生死亡。无≥3级和5例1-2级治疗相关不良事件。Avelumab联合放疗治疗RRMM和EMD患者与非常适度的全身临床获益相关;然而，患者确实像往常一样从局部放疗中获益。此外，与历史RRMM治疗方案相比，该组合耐受性非常好。
Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing. Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T‐cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response. Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof‐of‐principle pilot study to evaluate the synergy between the combination of the anti–PD‐L1, avelumab, and concomitant hypofractionated radiotherapy. This was a single‐arm phase II Simon two‐stage single center study that was prematurely terminated because of the COVID‐19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect. At a median potential follow‐up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression‐free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5–7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1–2 treatment‐related adverse events. Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.
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DOI：
10.3324/haematol.2012.065698
发表时间：
2012-11-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Usmani, Saad Z.;Heuck, Christoph;Barlogie, Bart
通讯作者：
Barlogie, Bart
影响因子：
10.9
作者：
Gong J;Le TQ;Massarelli E;Hendifar AE;Tuli R
通讯作者：
Tuli R
影响因子：
2.1
作者：
Takezako, Naoki;Kosugi, Hiroshi;Suzuki, Kenshi
通讯作者：
Suzuki, Kenshi
影响因子：
45.3
作者：
Lesokhin, Alexander M.;Ansell, Stephen M.;Timmerman, John
通讯作者：
Timmerman, John
影响因子：
64.8
作者：
Twyman-Saint Victor, Christina;Rech, Andrew J.;Maity, Amit;Rengan, Ramesh;Pauken, Kristen E.;Stelekati, Erietta;Benci, Joseph L.;Xu, Bihui;Dada, Hannah;Odorizzi, Pamela M.;Herati, Ramin S.;Mansfield, Kathleen D.;Patsch, Dana;Amaravadi, Ravi K.;Schuchter, Lynn M.;Ishwaran, Hemant;Mick, Rosemarie;Pryma, Daniel A.;Xu, Xiaowei;Feldman, Michael D.;Gangadhar, Tara C.;Hahn, Stephen M.;Wherry, E. John;Vonderheide, Robert H.;Minn, Andy J.
通讯作者：
Minn, Andy J.