Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
J Hematol Oncol. 2022 Aug 17;15(1):109. doi: 10.1186/s13045-022-01330-3.
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.
多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，具有异质性克隆扩增的特点。尽管抗 BCMA CAR-T 细胞疗法取得了有希望的缓解率，但患者仍可能复发，目前在 CAR-T 后尚无明确的治疗选择。在本报告中，我们报告了一例抗 BCMA CAR-T 复发/难治（RR）MM 患者，该患者存在皮肤髓外疾病（EMD），根据下一代测序和体外实验，采用了一种新型 MAPK 抑制联合策略。
一名 61 岁男性，患有 penta-（IgA lambda）五重难治性 MM，ISS 分期 3 期，伴超二倍体、1q21 增益和 13 号染色体缺失，接受了抗 BCMA CAR-T 细胞治疗，达到了最佳的 VGPR 缓解。6 个月后疾病进展，接受了自体干细胞移植短暂挽救。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均发现了 BRAF（V600E）优势亚克隆。根据体外实验和我们之前的研究，我们采用了三重 MAPK 抑制策略，患者在 110 天内获得了非常好的部分缓解，这使他能够桥接至后续临床试验，并最终获得严格的完全缓解（sCR）。
在这里，我们展示了三重 MAPK 抑制策略在特定亚组患者中在抗 BCMA CAR-T 失败背景下的适用性、有效性和耐受性。三重治疗使我们的一位处于终末期、BRAF（V600E）阳性的 RRMM 患者能够获得进一步的治疗选择，并最终达到 sCR。我们将在即将启动的一项精准医学临床试验中进一步评估 BRAF V600E 患者的三重 MAPK 抑制。
