Di Bacco Alessandra, Bahlis Nizar J, Munshi Nikhil C, Avet-Loiseau Hervé, Masszi Tamás, Viterbo Luísa, Pour Ludek, Ganly Peter, Cavo Michele, Langer Christian, Kumar Shaji K, Rajkumar S Vincent, Keats Jonathan J, Berg Deborah, Lin Jianchang, Li Bin, Badola Sunita, Shen Lei, Zhang Jacob, Esseltine Dixie-Lee, Luptakova Katarina, van de Velde Helgi, Richardson Paul G, Moreau Philippe
Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, MA, USA.
Southern Alberta Cancer Research Institute, University of Calgary, Calgary, AB, Canada.
Eur J Haematol. 2020 Jul;105(1):35-46. doi: 10.1111/ejh.13405. Epub 2020 Apr 15.
In the TOURMALINE-MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib-lenalidomide-dexamethasone (IRd) showed different magnitudes of progression-free survival (PFS) benefit vs placebo-Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).
RNA sequencing data were used to investigate the basis of these differences.
The PFS benefit of IRd vs placebo-Rd was greater in patients with tumors expressing high c-MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c-MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c-MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.
PFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c-MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE-MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537.
在复发/难治性多发性骨髓瘤的TOURMALINE-MM1 3期试验中，与安慰剂-来那度胺-地塞米松（Rd）相比，伊沙佐米-来那度胺-地塞米松（IRd）根据既往治疗的次数和类型显示出不同程度的无进展生存期（PFS）获益，在接受过>1线既往治疗或1线未进行干细胞移植（SCT）的既往治疗的患者中获益更大。
使用RNA测序数据来研究这些差异的基础。
与c-MYC低表达患者（中位无进展生存期20.6个月 vs 16.6个月；风险比[HR]0.75；95%置信区间[CI]，0.42，1.2）相比，c-MYC高表达肿瘤患者中IRd相对于安慰剂-Rd的PFS获益更大（中位无进展生存期未达到 vs 11.3个月；HR 0.42；95%CI，0.26，0.66；P <.001）。肿瘤中c-MYC的表达根据接受的既往治疗的次数和类型而有所不同，在接受过包括SCT在内的1线既往治疗的患者的肿瘤中观察到最低水平。这些肿瘤还具有较高的CD19和CD81表达水平。
PFS分析表明，来那度胺和伊沙佐米靶向c-MYC、CD19和CD81表达水平不同的肿瘤，从而为TOURMALINE-MM1研究中观察到的差异获益提供了潜在的理论依据。该试验在www.clinicaltrials.gov上注册为：NCT01564537。
