Barlogie B
Division of Hematology/Oncology, Arkansas Cancer Research Center, Little Rock, 72205, USA.
Clin Cancer Res. 1997 Dec;3(12 Pt 2):2605-13.
This paper traces the lack of progress, until recently, in the treatment of multiple myeloma (MM) to having ignored the principles that led to cure in acute leukemia more than 2 decades ago. Only in the mid-1980s did investigation begin to consider complete remission (CR) a research objective, representing a necessary first step toward cure. The experience with autologous and allogeneic stem cell-supported high-dose therapy is reviewed, demonstrating, in both historically controlled and randomized studies, the validity of the dose-response concept in MM in terms of increased CR rates as well as extended event-free (EFS) and overall survival (OS). Avoidance of hematopoietic stem cell-damaging agents, especially melphalan, nitrosoureas, and ionizing radiation to marrow-containing sites, assures the ability of peripheral stem cell collection of high quality and quantity, providing rapid engraftment so that mortality is well under 5% following high-dose melphalan (200 mg/m2). This treatment can be applied safely to patients even >70 years of age and in the presence of renal failure. Tandem autotransplants after multiregimen induction have yielded CR rates in the 40% range with median durations of EFS and OS of 43 and 62 months, respectively. Certain chromosomal abnormalities (11 and 13; and translocations) represent the dominant adverse prognosticator for EFS and OS, confirmed in over 500 patients including those with prior therapy. Allogeneic transplants, possible in less than 10% of MM patients, are associated with a 50% mortality during the first year and, unfortunately, late relapses; thus, this approach should be reserved for patients with high-risk disease early in their management. A risk-based treatment algorithm that matches a patient's disease risk with the risk of intervention is presently used, followed by bisphosphonate therapy, not only to delay the onset of MM-related bone disease but also to induce tumor cell apoptosis, indirectly or directly, by down-regulation of cytokines with antiapoptotic activities. Although many patients relapse, this author subscribes to his mentor's motto: "Be Prepared for Success!".
本文追溯了直到最近多发性骨髓瘤（MM）治疗方面缺乏进展的原因，即忽视了20多年前使急性白血病得以治愈的原则。直到20世纪80年代中期，研究才开始将完全缓解（CR）视为一个研究目标，这是迈向治愈的必要第一步。本文回顾了自体和异基因干细胞支持的高剂量疗法的经验，在历史对照研究和随机研究中均表明，就提高CR率以及延长无事件生存期（EFS）和总生存期（OS）而言，MM中的剂量反应概念是有效的。避免使用损害造血干细胞的药物，尤其是美法仑、亚硝基脲类药物以及对含骨髓部位进行电离辐射，可确保高质量、高数量地采集外周干细胞，实现快速植入，从而使高剂量美法仑（200mg/m²）治疗后的死亡率远低于5%。这种治疗方法甚至可以安全地应用于70岁以上的患者以及存在肾衰竭的患者。多方案诱导后的串联自体移植产生的CR率在40%左右，EFS和OS的中位持续时间分别为43个月和62个月。某些染色体异常（11号和13号染色体；以及易位）是EFS和OS的主要不良预后因素，这在包括曾接受过治疗的患者在内的500多名患者中得到了证实。异基因移植在不到10%的MM患者中可行，第一年的死亡率为50%，不幸的是还会出现晚期复发；因此，这种方法应仅用于疾病处于高危阶段且在治疗早期的患者。目前采用一种基于风险的治疗算法，将患者的疾病风险与干预风险相匹配，随后进行双膦酸盐治疗，这不仅可以延迟MM相关骨病的发生，还可以通过下调具有抗凋亡活性的细胞因子间接或直接诱导肿瘤细胞凋亡。尽管许多患者会复发，但本文作者赞同其导师的座右铭：“为成功做好准备！”
