Badros Ashraf, Goloubeva Olga, Fenton Robert, Rapoport Aaron P, Akpek Gorgun, Harris Carolynn, Ruehle Kathleen, Westphal Sandra, Meisenberg Barry
University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA.
Clin Lymphoma Myeloma. 2006 Nov;7(3):210-6. doi: 10.3816/CLM.2006.n.061.
In preclinical studies, bortezomib was shown to suppress tumor growth, sensitize malignant cells to apoptosis, and reverse chemotherapy resistance.
We evaluated the addition of escalating doses of bortezomib 0.7, 1, and 1.3 mg/m2 intravenously on days 1, 4, and 8 to DT-PACE (cisplatin 10 mg/m2, doxorubicin 10 mg/m2, cyclophosphamide 400 mg/m2, and etoposide 40 mg/m2 per day by intravenous continuous infusion on days 1-4) plus oral dexamethasone 40 mg on days 1-4 and thalidomide 200 mg on days 1-8 in newly diagnosed patients with multiple myeloma. Peripheral blood stem cells were collected after cycle 1. Twelve patients completed the study, and all received autologous stem cell transplantation (SCT).
Hematologic toxicities were predictable, with 3 episodes of neutropenic fever. Grade >/= 2 nonhematologic toxicities included diarrhea (n = 1), deep vein thrombosis (n = 2), hypotension (n = 2), syncope (n = 1), and peripheral neuropathy (n = 3). The median number of CD34+ cells collected was 20.57 x 10 superset6 CD34+ cells/kg. After 2 cycles, 10 of 12 patients exhibited a partial response or better. Best response after autologous SCT, complete response/near complete response was exhibited in 9 patients, and partial response was exhibited in 3 patients. At a median of 20 months, 4 patients experienced relapse and 1 had died. Bortezomib/DT-PACE compared favorably with DT-PACE with regard to leukapheresis days, total CD34+ cell collection, and engraftment.
This novel strategy of simultaneous proteasome inhibition in combination with thalidomide and chemotherapy was effective and safe, allowing for adequate stem cell collection and early autologous SCT; its impact on overall survival, especially in patients with high-risk myeloma, awaits further investigation.
在临床前研究中，硼替佐米被证明可抑制肿瘤生长，使恶性细胞对凋亡敏感，并逆转化疗耐药性。
我们评估了在新诊断的多发性骨髓瘤患者中，于第1、4和8天静脉注射递增剂量的硼替佐米（0.7、1和1.3mg/m²）加入到DT-PACE方案（顺铂10mg/m²、阿霉素10mg/m²、环磷酰胺400mg/m²以及依托泊苷40mg/m²，于第1 - 4天通过静脉持续输注），并在第1 - 4天口服地塞米松40mg以及在第1 - 8天口服沙利度胺200mg的效果。在第1周期后采集外周血干细胞。12名患者完成了研究，且均接受了自体干细胞移植（SCT）。
血液学毒性是可预测的，有3例中性粒细胞减少性发热。≥2级非血液学毒性包括腹泻（n = 1）、深静脉血栓形成（n = 2）、低血压（n = 2）、晕厥（n = 1）以及周围神经病变（n = 3）。采集的CD34⁺细胞中位数为20.57×10⁶个CD34⁺细胞/kg。2个周期后，12名患者中有10名表现出部分缓解或更好的效果。自体SCT后的最佳反应，9名患者表现为完全缓解/接近完全缓解，3名患者表现为部分缓解。在中位时间20个月时，4名患者复发，1名患者死亡。在白细胞分离天数、总CD34⁺细胞采集量和植入方面，硼替佐米/DT-PACE方案与DT-PACE方案相比更具优势。
这种将蛋白酶体抑制与沙利度胺和化疗同时联合的新策略是有效且安全的，能够进行充分的干细胞采集并早期进行自体SCT；其对总生存期的影响，尤其是对高危骨髓瘤患者的影响，有待进一步研究。
