Chromosomal Abnormalities in Myeloma as Detected by FISH

描述（由申请人提供）：了解已知和新的遗传因素在新型治疗背景下的影响对于最佳定义多发性骨髓瘤（MM）患者的最佳治疗策略至关重要。我们的团队一直处于基于遗传因素的预后确定的最前沿。此外，我们最近发现，高达50%的MM病例通过多种基因突变具有NF-κ B通路的组成性激活，所有这些都导致非经典通路的活性增加。重要的是，我们已经证明这些患者对硼替佐米的敏感性大大增加。MM的治疗不能再以“一刀切”的方式进行，我们必须验证遗传预后和预测标记物以选择MM治疗。虽然新型治疗药物改善了患者的整体前景，但净效应可能因分子亚型而异。一些新的治疗方法和策略有可能改善“高危”MM（HR-MM）的结局。“标准风险”MM（SR-MM）患者可能受益于更简单、毒性更低的干预措施，而HR-MM患者将需要引入更强化的方案，如早期硼替佐米和/或非清髓性异基因干细胞移植（NM-SCT）策略。为了解决这些问题，在本项目提案的中心，我们提出以下问题：1。沙利度胺和来那度胺能否克服HR-MM的不良预后？2.我们能否在接受来那度胺和沙利度胺治疗的患者中发现与疾病进展时间长相关的新基因组标志物？3.硼替佐米能否改善HR-MM患者的疗效和结局？4. NF-kB过度活化或TRAF 3失活能否预测硼替佐米治疗的疗效改善？5. NM-SCT能否克服t（4;14）（p16;q32）的不良预后？为了解决这些问题，我们提出了以下实验，使用一组分子和遗传测定，采用与5项3期临床试验相关的临床样品。在全球范围内，这些试验包括超过1500例接受来那度胺、沙利度胺和硼替佐米各种组合治疗的患者。包括ECOG临床试验E1 A00、E4 A03、E1 A05和E1 A06。此外，我们建议在一项大型随机试验（n = 700）中研究t（4;14）（p16;q32）的预后意义，该试验旨在探讨NM-SCT对新诊断MM的作用。为此，我们将检查与临床试验BMT CTN 0102相关的研究样本。公共卫生相关性：该拨款提案旨在更好地定义应针对骨髓瘤的哪些遗传亚型给予哪些治疗，为患者提供最佳和风险适应性治疗。

DESCRIPTION (provided by applicant): Understanding the impact of known and new genetic factors in the context of novel therapies is paramount to best define the optimal treatment strategy for multiple myeloma (MM) patients. Our group has been at the forefront of prognosis determination based on genetic factors. In addition, we recently discovered that up to 50% of MM cases have constitutive activation of the NF-kB pathway, through multiple genetic mutations, all leading to increased activity of the non-canonical pathway. Importantly we have shown these patients have greatly increased sensitivity to bortezomib. The treatment of MM can no longer be conducted under a "one size fits all" approach, and it is imperative that we validate genetic prognostic and predictive markers for the selection of MM treatments. While novel therapeutic agents have improved the overall prospects for patients, the net effect might be different based on the molecular subtypes. Some of the novel therapies and strategies have the potential to improve the outcome of "high risk"-MM (HR-MM). Patients with "standard risk" MM (SR- MM) might benefit from simpler, less toxic, interventions, while HR-MM patients will need the introduction of more intensive regimens such as early bortezomib and/or non-myeloablative allogeneic stem cell transplant (NM-SCT) strategies. To address these issues, and at center of this project proposal, we ask the following questions: 1. Can thalidomide and lenalidomide overcome the negative prognosis of HR-MM? 2. Can we identify new genomic markers associated with long time to progression in patients treated with lenalidomide and thalidomide? 3. Can bortezomib result in better responses and outcome in patients with HR-MM? 4. Can NF-kB hyperactivation or TRAF3 inactivation predict improved outcome with bortezomib? 5. Can NM-SCT overcome the poor prognosis of t(4;14)(p16;q32)? To address these questions we propose the following experiments, using a panel of molecular and genetic assays employing clinical samples associated with five Phase 3 clinical trials. Globally these trials include over 1500 patient treated with various combinations of lenalidomide, thalidomide and bortezomib. They include the ECOG clinical trials E1A00, E4A03, E1A05 and E1A06. In addition we propose to study the prognostic significance of t(4;14)(p16;q32) in a large randomized trial (n = 700) addressing the role of NM-SCT for newly diagnosed MM. To do so we will examine research samples associated with the clinical trial BMT CTN 0102. PUBLIC HEALTH RELEVANCE: This grant proposal aims to better define which treatments should be given to which genetic subtypes of myeloma, to provide optimal and risk adapted therapy for patients.