Mina Roberto, Musto Pellegrino, Rota-Scalabrini Delia, Paris Laura, Gamberi Barbara, Palmas Angelo, Aquino Sara, de Fabritiis Paolo, Giuliani Nicola, De Rosa Luca, Gozzetti Alessandro, Cellini Claudia, Bertamini Luca, Capra Andrea, Oddolo Daniela, Vincelli Iolanda Donatella, Ronconi Sonia, Pavone Vincenzo, Pescosta Norbert, Cea Michele, Fioritoni Francesca, Ballanti Stelvio, Grasso Mariella, Zamagni Elena, Belotti Angelo, Boccadoro Mario, Gay Francesca
Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy; Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
Department of Precision and Regenerative Medicine and Ionian Area, "Aldo Moro" University School of Medicine, Bari, Italy; Hematology and Stem Cell Transplantation Unit, AOU Consorziale Policlinico, Bari, Italy.
Lancet Oncol. 2023 Jan;24(1):64-76. doi: 10.1016/S1470-2045(22)00693-3. Epub 2022 Dec 14.
Patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities (HRCA) represent an unmet medical need. In the FORTE trial, lenalidomide and dexamethasone plus carfilzomib (KRd) induction resulted in a higher proportion of patients with at least a very good partial response as compared with carfilzomib, cyclophosphamide, and dexamethasone (KCd), and carfilzomib plus lenalidomide maintenance prolonged progression-free survival compared with lenalidomide maintenance. In this prespecified analysis of the FORTE trial, we described the outcomes of enrolled patients according to their cytogenetic risk.
The UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done at 42 Italian academic and community practice centres, which enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 18-65 years. Eligible patients had newly diagnosed multiple myeloma based on standard International Myeloma Working Group criteria, a Karnofsky performance status of at least 60%, and had not received any previous treatment with anti-myeloma therapy. At enrolment, patients were stratified according to International Staging System stage (I vs II/III) and age (<60 years vs 60-65 years) and randomly assigned (1:1:1) to KRd plus autologous stem-cell transplantation (ASCT; four 28-day induction cycles with KRd, melphalan at 200 mg/m and ASCT [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), 12 28-day KRd cycles, or KCd plus ASCT (four 28-day induction cycles with KCd, MEL200-ASCT, and four 28-day KCd consolidation cycles), using a web-based system (block randomisation, block size of 12). Carfilzomib was administered at 20 mg/m on days 1 and 2 of cycle 1, followed by 36 mg/m intravenously administered on days 8, 9, 15, and 16 of cycle 1, and then 36 mg/m intravenously administered for all subsequent doses on days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg was administered orally on days 1-21; cyclophosphamide 300 mg/m was administered orally on days 1, 8, and 15; and dexamethasone 20 mg was administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. After the consolidation phase, patients were stratified according to induction-consolidation treatment and randomly assigned (1:1; block size of 8) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m was administered intravenously on days 1-2 and days 15-16, every 28 days for up to 2 years, and lenalidomide 10 mg was administered orally on days 1-21 every 28 days until progression or intolerance in both groups. The primary endpoints were the proportion of patients with at least a very good partial response after induction with KRd versus KCd and progression-free survival with carfilzomib plus lenalidomide versus lenalidomide alone as maintenance treatment. In this preplanned analysis, we included patients enrolled in the FORTE trial with complete cytogenetic data on del(17p), t(4;14), t(14;16), del(1p), gain(1q) (3 copies), and amp(1q) (≥4 copies) assessed by fluorescence in-situ hybridisation analysis on CD138-positive sorted cells. We assessed progression-free survival, overall survival, minimal residual disease negativity, and 1-year sustained minimal residual disease negativity according to the presence of zero, one, and two or more HRCA across treatment groups. The FORTE trial is ongoing, and registered with ClinicalTrials.gov, NCT02203643.
Between Feb 23, 2015, and April 5, 2017, 477 patients were enrolled, of whom 396 (83%) had complete cytogenetic data and were analysed (176 [44%] of whom were women and 220 [56%] were men). The median follow-up from first randomisation was 51 months (IQR 46-56). 4-year progression-free survival was 71% (95% CI 64-78) in patients with zero HRCA, 60% (95% CI 52-69) in patients with one HRCA, and 39% (95% CI 30-50) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of progression or death was similar in patients with one HRCA (hazard ratio [HR] 1·33 [95% CI 0·90-1·97]; p=0·15) and higher in patients with two or more HRCA (HR 2·56 [95% CI 1·74-3·75]); p<0·0001) across the induction-intensification-consolidation groups. Moreover, the risk of progression or death was also higher in patients with two or more HRCA versus those with one HRCA (HR 1·92 [95% CI 1·34-2·76]; p=0·0004). 4-year overall survival from the first randomisation was 94% (95% CI 91-98) in patients with zero HRCA, 83% (95% CI 76-90) in patients with one HRCA, and 63% (95% CI 54-74) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of death was significantly higher in patients with one HRCA (HR 2·55 [95% CI 1·22-5·36]; p=0·013) and two or more HRCA (HR 6·53 [95% CI 3·24-13·18]; p<0·0001). Patients with two or more HRCA also had a significantly higher risk of death than those with one HRCA (HR 2·56 [95% CI 1·53-4·28]; p=0·0004). The rates of 1-year sustained minimal residual disease negativity were similar in patients with zero HRCA (53 [35%] of 153] and with one HRCA (57 [41%] of 138) and were lower in patients with two or more HRCA (25 [24%] of 105). The median duration of follow-up from second randomisation was 37 months (IQR 33-42). 3-year progression-free survival from the second randomisation was 80% (95% CI 74-88) in patients with zero HRCA, 68% (95% CI 59-78) in patients with one HRCA, and 53% (95% CI 42-67) in patients with two or more HRCA. The risk of progression or death was higher in patients with one HRCA (HR 1·68 [95% CI 1·01-2·80]; p=0·048) and two or more HRCA (2·74 [95% CI 1·60-4·69], p=0·0003) than in patients with zero HRCA.
This preplanned analysis of the FORTE trial showed that carfilzomib-based induction-intensification-consolidation regimens are effective strategies in patients with standard risk (zero HRCA) and high-risk (one HRCA) myeloma, resulting in similar rates of progression-free survival and 1-year sustained minimal residual disease negativity. Despite promising progression-free survival, patients with ultra-high-risk disease (those with 2 or more HRCA) still have an increased risk of progression and death and therefore represent an unmet medical need.
Amgen and Celgene/Bristol Myers Squibb.
新诊断的多发性骨髓瘤且伴有高危细胞遗传学异常（HRCA）的患者存在未被满足的医疗需求。在FORTE试验中，与卡非佐米、环磷酰胺和地塞米松（KCd）方案相比，来那度胺、地塞米松联合卡非佐米（KRd）诱导方案使至少达到非常好的部分缓解的患者比例更高；与来那度胺维持治疗相比，卡非佐米加来那度胺维持治疗可延长无进展生存期。在对FORTE试验的这项预先设定的分析中，我们根据患者的细胞遗传学风险描述了入组患者的结局。
UNITO-MM-01/FORTE是一项在42个意大利学术和社区实践中心进行的随机、开放标签的2期试验，入组年龄在18 - 65岁、适合移植的新诊断多发性骨髓瘤患者。符合条件的患者基于国际骨髓瘤工作组的标准被诊断为新发性多发性骨髓瘤，卡氏评分至少为60%，且之前未接受过任何抗骨髓瘤治疗。入组时，患者根据国际分期系统分期（I期与II/III期）和年龄（<60岁与60 - 65岁）进行分层，并通过基于网络的系统（区组随机化，区组大小为12）随机分配（1:1:1）至KRd联合自体干细胞移植（ASCT；四个28天的KRd诱导周期，200mg/m²的美法仑和ASCT [MEL200 - ASCT]，随后是四个28天的KRd巩固周期）、12个28天的KRd周期或KCd联合ASCT（四个28天的KCd诱导周期，MEL200 - ASCT，以及四个28天的KCd巩固周期）。卡非佐米在第1周期的第1天和第2天以20mg/m²给药，随后在第1周期的第8、9、15和16天静脉注射36mg/m²，然后在所有后续剂量的第1、2、8、9、15、16天静脉注射36mg/m²；来那度胺25mg在第1 - 21天口服；环磷酰胺300mg/m²在第1、8和15天口服；地塞米松20mg在第1、2、8、9、15、16、22和23天口服或静脉注射。在巩固期后，患者根据诱导 - 巩固治疗进行分层，并随机分配（1:1；区组大小为8）至卡非佐米加来那度胺或单独使用来那度胺进行维持治疗。卡非佐米36mg/m²在第1 - 2天和第15 - 16天静脉注射，每28天一次，最多2年，来那度胺10mg在第1 - 21天每28天口服一次，直至两组出现疾病进展或不耐受。主要终点是KRd与KCd诱导后至少达到非常好的部分缓解的患者比例，以及卡非佐米加来那度胺与单独使用来那度胺作为维持治疗的无进展生存期。在这项预先计划的分析中，我们纳入了在FORTE试验中通过对CD138阳性分选细胞进行荧光原位杂交分析评估了del(17p)、t(4;14)、t(14;16)、del(1p)、gain(1q)（3拷贝）和amp(1q)（≥4拷贝）完整细胞遗传学数据的患者。我们根据各治疗组中HRCA为零、一个和两个或更多的情况评估了无进展生存期、总生存期、微小残留病阴性率和1年持续微小残留病阴性率。FORTE试验正在进行中，并已在ClinicalTrials.gov注册，注册号为NCT02203643。
在2015年2月23日至2017年4月5日期间招募了477名患者，其中396名（83%）有完整的细胞遗传学数据并进行了分析（其中176名[44%]为女性患者，220名[56%]为男性患者）。从首次随机分组开始的中位随访时间为51个月（四分位间距46 - 56个月）。HRCA为零的患者4年无进展生存率为71%（95%置信区间64 - 78），HRCA为一个的患者为60%（95%置信区间52 - 69），HRCA为两个或更多的患者为39%（95%置信区间30 - 50）。与HRCA为零的患者相比，HRCA为一个的患者进展或死亡风险相似（风险比[HR] 1.33 [95%置信区间0.90 - 1.97]；p = 0.15），而HRCA为两个或更多的患者风险更高（HR 2.56 [95%置信区间1.74 - 3.75]；p < 0.0001），在整个诱导 - 强化 - 巩固组中均如此。此外，HRCA为两个或更多的患者与HRCA为一个的患者相比，进展或死亡风险也更高（HR 1.92 [95%置信区间1.34 - 2.76]；p = 0.0004）。从首次随机分组开始计算，HRCA为零的患者4年总生存率为94%（95%置信区间91 - 98），HRCA为一个的患者为83%（95%置信区间76 - 90），HRCA为两个或更多的患者为63%（95%置信区间54 - 74）。与HRCA为零的患者相比，HRCA为一个的患者死亡风险显著更高（HR 2.55 [95%置信区间1.22 - 5.36]；p = 0.013），HRCA为两个或更多的患者死亡风险更高（HR 6.53 [95%置信区间3.24 - 13.18]；p < 0.0001）。HRCA为两个或更多的患者与HRCA为一个的患者相比，死亡风险也显著更高（HR 2.56 [95%置信区间1.53 - 4.28]；p = 0.0004）。HRCA为零的患者（153名中的53名[35%]）和HRCA为一个的患者（138名中的57名[41%]）1年持续微小残留病阴性率相似，而HRCA为两个或更多的患者（105名中的25名[24%]）较低。从第二次随机分组开始的中位随访时间为37个月（四分位间距33 - 42个月）。从第二次随机分组开始计算，HRCA为零的患者3年无进展生存率为80%（95%置信区间74 - 88），HRCA为一个的患者为68%（95%置信区间59 - 78），HRCA为两个或更多的患者为53%（95%置信区间42 - 67）。HRCA为一个的患者（HR 1.68 [95%置信区间1.01 - 2.80]；p = 0.048）和HRCA为两个或更多的患者（2.74 [95%置信区间1.60 - 4.69]，p = 0.0003）进展或死亡风险高于HRCA为零的患者。
对FORTE试验的这项预先计划的分析表明，基于卡非佐米的诱导 - 强化 - 巩固方案是标准风险（HRCA为零）和高风险（HRCA为一个）骨髓瘤患者的有效策略，导致无进展生存率和1年持续微小残留病阴性率相似。尽管无进展生存期前景良好，但超高风险疾病患者（HRCA为两个或更多）仍有更高的进展和死亡风险，因此存在未被满足的医疗需求。
安进公司和新基公司/百时美施贵宝公司。
