克服多发性骨髓瘤的应答平台期：一种新型硼替佐米为基础的二次诱导和高产量 CD34+干细胞动员策略。
Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization.
机构信息
Center of Excellence for Lymphoma and Myeloma, Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, New York 10021, USA.
出版信息
Clin Cancer Res. 2013 Mar 15;19(6):1534-46. doi: 10.1158/1078-0432.CCR-12-1429. Epub 2013 Jan 28.
PURPOSE
This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction.
EXPERIMENTAL DESIGN
Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers.
RESULTS
The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥ VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥ VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 10(6) cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥ 3 adverse events included thrombocytopenia (13%), hand-foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration.
CONCLUSION
Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield.
目的
本Ⅱ期研究评估了硼替佐米为基础的二线诱导和干细胞动员在 38 例适合移植的多发性骨髓瘤患者中的疗效，这些患者在先前基于免疫调节剂的诱导后存在不完全和停滞的反应或复发。
实验设计
患者接受最多 6 个 21 天周期的硼替佐米联合地塞米松治疗，对于在第 2 个周期未达到部分缓解或更好或在第 4 个周期达到非常好的部分缓解或更好（≥VGPR）的患者，加用地塞米松脂质体阿霉素（DoVeD），随后进行硼替佐米、高剂量环磷酰胺和非格司亭动员。在基于硼替佐米的动员后，对纯化的 CD34+细胞进行基因表达/信号通路分析，并与仅接受非格司亭±环磷酰胺的患者进行比较。同样对血浆样本进行分析，以定量检测相关蛋白标志物。
结果
与基线前的 DoVeD 相比，DoVeD 的反应率为 61%，其中 39%≥VGPR。在接受硼替佐米动员的 27 例患者中有 10 例获得了更深层次的反应；动员后反应率为 96%，其中 48%≥VGPR，与基线前相比。中位 CD34+细胞产量为 23.2×106 细胞/kg（中位数为 1 次单采）。中位随访 46.6 个月后，DoVeD 开始后中位无进展生存期为 47.1 个月；5 年总生存率为 76.4%。≥3 级不良事件包括血小板减少症（13%）、手足综合征（11%）、周围神经病变（8%）和中性粒细胞减少症（5%）。基于硼替佐米的动员与参与干细胞迁移的基因表达的调节有关。
结论
硼替佐米为基础的二线诱导和动员可能是一种替代策略，用于消除免疫调节剂耐药患者的肿瘤负担，而不会影响干细胞产量。
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