Chromosomal Abnormalities in Myeloma as Detected by FISH

描述（由申请人提供）：了解在新疗法背景下已知和新的遗传因素的影响对于最好地定义多发性骨髓瘤（MM）患者的最佳治疗策略至关重要。我们的团队在基于遗传因素的预后判断方面一直走在前列。此外，我们最近发现，高达50%的MM病例具有NF-kB途径的组成性激活，通过多个基因突变，所有这些都导致非规范途径的活性增加。重要的是，我们已经表明这些患者对硼替佐米的敏感性大大增加。MM的治疗不能再按照“一刀切”的方法进行，我们必须验证MM治疗选择的遗传预后和预测标记。虽然新的治疗药物改善了患者的整体前景，但净效果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“高风险”mm （HR-MM）的预后。“标准风险”MM （SR- MM）患者可能受益于更简单、毒性更小的干预措施，而HR-MM患者将需要引入更强化的治疗方案，如早期硼替佐米和/或非清髓性异体干细胞移植（NM-SCT）策略。为了解决这些问题，也是本项目提案的核心，我们提出以下问题：沙利度胺和来那度胺能否克服HR-MM的不良预后？2. 我们能否确定与来那度胺和沙利度胺治疗的患者的长期进展相关的新的基因组标记？3. 硼替佐米能给HR-MM患者带来更好的疗效和预后吗？4. NF-kB过度激活或TRAF3失活能否预测硼替佐米改善的预后？5. NM-SCT能否克服t（4;14）的不良预后（p16;q32）？为了解决这些问题，我们提出以下实验，使用一组分子和遗传分析，采用与五个三期临床试验相关的临床样本。在全球范围内，这些试验包括使用来那度胺、沙利度胺和硼替佐米的各种组合治疗的1500多名患者。它们包括ECOG临床试验E1A00、E4A03、E1A05和E1A06。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，以解决NM-SCT对新诊断的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确定应为骨髓瘤的哪种遗传亚型提供哪种治疗，为患者提供最佳和风险适应治疗。

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.