PDF(Pubmed)
Abstract：
Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront \"novel agents\" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with \"conventional\" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to \"outdated\" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront \"novel agents\".
摘要：
基于我们的HOVON-65/GMMG-HD4试验（德国部分；n=395）随机VAD诱导（长春瑞星/阿霉素/地塞米松）/串联移植/沙利度胺维持vs.PAD诱导（硼替佐米/阿霉素/地塞米松）/串联移植/硼替佐米维持，我们通过与增殖和治疗依赖性反应相关的不同模式来辨别染色体畸变如何决定长期预后,在预后方面，不同方案的反应是否相等，以及在资源有限的情况下，是否可以将患者亚群定义为无需预先“新型药物”即可治疗，例如，在低收入或中等收入国家。对395例患者的血清参数和危险因素进行了评估。对CD138纯化的浆细胞进行荧光原位杂交（n=354）和基因表达谱分析（n=204）。我们发现染色体畸变与存活有四种关系,扩散,和响应：删除（del）del17p13，del8p21，del13q14，（增益）1q21+，和易位t（4；14）（均为不良）与更高的增殖相关。其中,del17p与不良反应相关(模式1)，和1q21+，t(4;14)，和del13q14，具有治疗依赖性更好的反应（模式2）。超二倍体与较低的增殖相关而不影响反应或存活(模式3)。易位t(11;14)与生存无关,而是治疗依赖性不良反应(模式4)。与“常规”（VAD）相比，达到接近完全反应或更好的患者明显减少诱导或高剂量美法仑后以硼替佐米为基础的治疗。这些病人,然而,显示中位无进展生存期和总生存期明显更好。分子上，对两种治疗方案反应的患者在基因表达上不同，表明响应骨髓瘤细胞的独特生物学特性。肾功能正常的患者（89.4%），低细胞遗传学风险（72.5%），或低增殖率(37.9%)对基于硼替佐米的前期治疗的无进展生存期和总生存期均无益处.我们得出结论，响应水平，实现它的治疗方法，和分子背景决定了长期预后。染色体畸变以四种模式与增殖和治疗依赖性反应相关。在预后不良像差1q21和t（4;14）的情况下，具有更快和更深响应的关联可能具有欺骗性。远非提倡回归“过时”治疗，如果资源不允许最先进的治疗，正常的肾功能和/或分子谱分析可确定患者亚群在没有预先“新型药物”的情况下表现良好。
