Barlogie B, Jagannath S, Desikan K R, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J
Myeloma and Transplantation Research Center (MTRC), University of Arkansas for Medical Sciences, Arkansas Cancer Research Center, Little Rock, AR 72205, USA.
Blood. 1999 Jan 1;93(1):55-65.
Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum beta-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy ("Total Therapy"). Remission induction utilized non-cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low beta-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and beta-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.
1990年8月至1995年8月期间，231例有症状的多发性骨髓瘤患者（中位年龄51岁，53%为Durie-Salmon III期，中位血清β2微球蛋白3.1 g/L，中位C反应蛋白4 g/L）参加了一个使用一系列诱导方案和两个周期大剂量治疗（“全程治疗”）的项目。缓解诱导采用非交叉耐药方案（长春新碱-阿霉素-地塞米松[VAD]、大剂量环磷酰胺及粒细胞-巨噬细胞集落刺激因子联合外周血干细胞采集，以及依托泊苷-地塞米松-阿糖胞苷-顺铂）。首次大剂量治疗包括美法仑200 mg/m²，若首次移植后维持完全缓解（CR）或部分缓解（PR）则重复进行；若缓解程度低于PR，则加用全身照射或环磷酰胺。第二次自体移植后使用干扰素-α2b维持治疗。14例有HLA相匹配供者的患者接受了异体移植作为其第二个大剂量治疗周期。88%的患者完成了诱导治疗，84%和71%的患者分别进行了首次和第二次移植（大多数分别在8个月和15个月内）。8例患者（3%）在诱导期间死于毒性反应，2例（1%）和6例（4%）在两次移植期间死亡。VAD治疗后5%（34%）达到真正的CR和至少PR（PR加CR），诱导结束时为15%（65%），首次移植后为26%（75%），第二次移植后为41%（83%）（意向性治疗）。中位总生存期（OS）和无事件生存期（EFS）分别为68个月和43个月。5年OS和EFS精算率分别为58%和42%。疾病进展或复发的中位时间为52个月。在94例达到CR的患者中，CR持续时间的中位数为50个月。多因素分析显示，在不存在不良核型（11q断点异常、-13或13q-）且诊断时β2微球蛋白水平低的情况下，EFS和OS更佳。CR持续时间在CR早期出现和核型良好时明显更长。时间依赖性协变量分析表明，及时进行第二次移植可显著延长EFS和OS，与细胞遗传学和β2微球蛋白无关。全程治疗是一种针对新诊断骨髓瘤患者的综合治疗方法，采用多方案诱导和串联移植，随后进行干扰素维持治疗。因此，随着治疗的持续，达到CR的患者比例逐渐增加。这一观察结果尤为重要，因为CR是长期疾病控制乃至治愈的必要条件。
