Triple MAPK inhibition salvaged a relapsed post-BCMA CAR-T cell therapy multiple myeloma patient with a BRAF V600E subclonal mutation.
Triple MAPK inhibition salvaged a relapsed post-BCMA CAR-T cell therapy multiple myeloma patient with a BRAF V600E subclonal mutation.
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DOI：
10.1186/s13045-022-01330-3
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发表时间：
2022-08-17
影响因子：
28.5
通讯作者：
Lagana, Alessandro
中科院分区：
文献类型：
--
作者：
Elnaggar, Muhammad;Agte, Sarita;Restrepo, Paula;Ram, Meghana;Melnekoff, David;Adamopoulos, Christos;Stevens, Mark M.;Kappes, Katerina;Leshchenko, Violetta;Verina, Daniel;Jagannath, Sundar;Poulikakos, Poulikos, I;Parekh, Samir;Lagana, Alessandro
关键词：
多发性骨髓瘤（MM）是一种进行性浆细胞肿瘤，其特征是异质性克隆性扩增。尽管抗BCMA CAR-T细胞疗法实现了有希望的缓解率，但患者仍可能复发，目前在CAR-T后环境中没有明确的治疗选择。在这份报告中，我们介绍了一例BCMA CAR-T后复发/难治性（RR）MM患者伴皮肤髓外疾病（EMD）的病例，其中基于下一代测序和体外实验实施了一种新型MAPK抑制组合策略。一名患有五难治性MM五（伊加λ）、ISS 3期伴超二倍体、获得1 q21和del 13的61岁男性接受抗BCMA CAR-T细胞治疗，达到VGPR的最佳缓解。他在6个月后进展，并通过自体干细胞移植短期挽救。最终，他进展为髓外疾病，表现为皮下结节。基于全外显子组测序，我们在骨髓和皮肤浆细胞瘤中鉴定了BRAF（V600 E）显性亚克隆。在体外实验之后，根据我们以前的研究，我们实施了三重MAPK抑制策略，在该策略下，患者在110天内获得了非常好的部分应答，这使得他能够进入后续的临床试验，并最终获得严格的完全应答（sCR）。在这里，我们展示了三重MAPK抑制策略在特定患者亚组中BCMA后CAR-T失败的背景下的适用性、有效性和耐受性。三联疗法可以将我们的BRAF（V600 E）临终关怀RRMM患者与实现sCR的进一步治疗选择联系起来。我们将在即将启动的精准医学临床试验中进一步评估BRAF V600 E患者的三重MAPK抑制作用。在线版本包含补充材料，可通过10.1186/s13045-022-01330-3获得。
Multiple Myeloma (MM) is a progressive plasma cell neoplasm characterized by heterogeneous clonal expansion. Despite promising response rates achieved with anti-BCMA CAR-T cell therapy, patients may still relapse and there are currently no clear therapeutic options in post-CAR-T settings. In this report, we present a case of a post-BCMA CAR-T relapsed/refractory (RR) MM patient with skin extramedullary disease (EMD) in which a novel MAPK inhibition combinatorial strategy was implemented based on next-generation sequencing and in vitro experiments. A 61-year-old male with penta-refractory MM penta- (IgA lambda), ISS stage 3 with hyperdiploidy, gain of 1q21 and del13 was treated with anti-BCMA CAR-T cell therapy, achieving a best response of VGPR. He progressed after 6 months and was salvaged for a short period with autologous stem cell transplantation. Eventually, he progressed with extramedullary disease manifested as subcutaneous nodules. Based on whole-exome sequencing, we identified a BRAF (V600E) dominant subclone in both bone marrow and cutaneous plasmacytoma. Following in vitro experiments, and according to our previous studies, we implemented a triple MAPK inhibition strategy under which the patient achieved a very good partial response for 110 days, which allowed to bridge him to subsequent clinical trials and eventually achieve a stringent complete response (sCR). Here, we show the applicability, effectiveness, and tolerability the triple MAPK inhibition strategy in the context of post-BCMA CAR-T failure in specific subset of patients. The triple therapy could bridge our hospice bound RRMM patient with BRAF (V600E) to further therapeutic options where sCR was achieved. We will further evaluate triple MAPK inhibition in patients with BRAF V600E in a precision medicine clinical trial launching soon. The online version contains supplementary material available at 10.1186/s13045-022-01330-3.
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影响因子：
28.2
作者：
Adamopoulos C;Ahmed TA;Tucker MR;Ung PMU;Xiao M;Karoulia Z;Amabile A;Wu X;Aaronson SA;Ang C;Rebecca VW;Brown BD;Schlessinger A;Herlyn M;Wang Q;Shaw DE;Poulikakos PI
通讯作者：
Poulikakos PI
影响因子：
3.2
作者：
Banks M;Crowell K;Proctor A;Jensen BC
通讯作者：
Jensen BC
DOI：
10.1038/nrc.2017.79
发表时间：
2017-11
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Karoulia Z;Gavathiotis E;Poulikakos PI
通讯作者：
Poulikakos PI
影响因子：
48
作者：
Caravagna G;Giarratano Y;Ramazzotti D;Tomlinson I;Graham TA;Sanguinetti G;Sottoriva A
通讯作者：
Sottoriva A
影响因子：
28.2
作者：
Corcoran RB;Ebi H;Turke AB;Coffee EM;Nishino M;Cogdill AP;Brown RD;Della Pelle P;Dias-Santagata D;Hung KE;Flaherty KT;Piris A;Wargo JA;Settleman J;Mino-Kenudson M;Engelman JA
通讯作者：
Engelman JA