Schroeder Mark A, Fiala Mark A, Huselton Eric, Cardone Michael H, Jaeger Savina, Jean Sae Rin, Shea Kathryn, Ghobadi Armin, Wildes Tanya, Stockerl-Goldstein Keith E, Vij Ravi
BMT and Leukemia Program, Washington University School of Medicine, St Louis, Missouri.
Hematology/Oncology Division, University of Rochester Medical Center, Rochester, New York.
Clin Cancer Res. 2019 Jul 1;25(13):3776-3783. doi: 10.1158/1078-0432.CCR-18-1909. Epub 2019 Apr 5.
Pegylated liposomal doxorubicin (PLD) combined with bortezomib is an effective salvage regimen for relapsed refractory multiple myeloma (RRMM). Carfilzomib, a second-generation proteasome inhibitor, has clinical efficacy even among bortezomib-refractory patients.
We performed a phase I/II trial of carfilzomib, PLD, and dexamethasone (KDD) with the primary endpoints being safety and efficacy (NCT01246063). Twenty-three patients were enrolled in the phase I portion and the MTD of carfilzomib was determined to be 56 mg/m (days 1, 2, 8, 9, 15, and 16) when combined with PLD (30 mg/m on day 8) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, and 16). Seventeen additional patients were enrolled in the phase II portion.
KDD was determined to be well tolerated with the only common grade 3/4 nonhematologic adverse events of infection. Grade 3/4 hematologic toxicity included lymphopenia (63%), thrombocytopenia (40%), anemia (40%), and neutropenia (28%). In the cohort of patients treated at the MTD, where median prior therapies were 2% and 42% were refractory to bortezomib, the overall response rate was 83% (20/24) with 54% (13/24) having a very good partial response or better. The median progression-free survival was 13.7 months (95% CI, 5.0-21.7).
This trial is the first to report outcomes using a triplet regimen of high-dose carfilzomib. KDD was well tolerated and appears efficacious in RRMM. Additional study is needed to more precisely determine patient outcomes with this regimen and its utility compared with other carfilzomib containing salvage regimens.
聚乙二醇化脂质体阿霉素（PLD）联合硼替佐米是复发难治性多发性骨髓瘤（RRMM）的一种有效挽救方案。卡非佐米作为第二代蛋白酶体抑制剂，即使在对硼替佐米耐药的患者中也具有临床疗效。
我们开展了一项卡非佐米、PLD及地塞米松（KDD）的I/II期试验，主要终点为安全性和疗效（NCT01246063）。23例患者入组I期试验，卡非佐米与PLD（第8天30mg/m）及地塞米松（第1、2、8、9、15及16天20mg）联合使用时，其最大耐受剂量（MTD）确定为56mg/m（第1、2、8、9、15及16天）。另外17例患者入组II期试验。
KDD耐受性良好，唯一常见的3/4级非血液学不良事件为感染。3/4级血液学毒性包括淋巴细胞减少（63%）、血小板减少（40%）、贫血（40%）及中性粒细胞减少（28%）。在接受MTD治疗的患者队列中，既往治疗的中位数为2次，42%对硼替佐米耐药，总缓解率为83%（20/24），其中54%（13/24）达到非常好的部分缓解或更好。无进展生存期的中位数为13.7个月（95%CI，5.0 - 21.7）。
本试验首次报告了使用高剂量卡非佐米三联方案的结果。KDD耐受性良好，在RRMM中似乎有效。需要进一步研究以更精确地确定该方案的患者预后及其与其他含卡非佐米的挽救方案相比的效用。
