Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma

被引:33
|
作者
Kaiser, Martin F. [1 ,2 ,12 ]
Hall, Andrew [3 ]
Walker, Katrina [3 ]
Sherborne, Amy [1 ]
De Tute, Ruth M. [4 ]
Newnham, Nicola [5 ]
Roberts, Sadie [3 ]
Ingleson, Emma [3 ]
Bowles, Kristian [6 ]
Garg, Mamta [7 ]
Lokare, Anand [8 ]
Messiou, Christina [1 ,2 ]
Houlston, Richard S. [1 ]
Jackson, Graham [9 ]
Cook, Gordon [3 ,10 ]
Pratt, Guy [5 ]
Owen, Roger G. [4 ]
Drayson, Mark T. [5 ]
Brown, Sarah R. [3 ]
Jenner, Matthew W. [11 ]
机构
[1] Inst Canc Res, Div Genet & Epidemiol, London, England
[2] Royal Marsden Hosp, Dept Haematol, London, England
[3] Univ Leeds, Leeds Inst Clin Trials Res, Canc Res UK Clin Trials Unit, Leeds, England
[4] Leeds Teaching Hosp Trust, Leeds Canc Ctr, Haematol Malignancy Diagnost Serv, Leeds, England
[5] Univ Birmingham, Inst Immunol & Immunotherapy, Birmingham, England
[6] Norfolk & Norwich Univ Hosp NHS Trust, Dept Haematol, Norwich, England
[7] Leicester Royal Infirm, Dept Haematol, Leicester, England
[8] Birmingham Heartlands, Dept Haematol, Birmingham, England
[9] Newcastle Univ, Dept Haematol, Newcastle Upon Tyne, England
[10] Leeds Teaching Hosp Trust, Leeds Canc Ctr, Leeds, England
[11] Univ Hosp Southampton, Dept Haematol, Southampton, England
[12] Inst Canc Res, Div Genet & Epidemiol, Myeloma Mol Therapy Team, 123 Old Brompton Rd, London SW7 3RP, England
关键词
GENE-EXPRESSION; CLINICAL-TRIALS; SURVIVAL; SKY92; VALIDATION; DIAGNOSIS; STRATEGY; CRITERIA; DESIGNS; DETECT;
D O I
10.1200/JCO.22.02567
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
PURPOSEThe multicenter OPTIMUM (MUKnine) phase II trial investigated daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (Dara-CVRd) before and after autologous stem-cell transplant (ASCT) in newly diagnosed patients with molecularly defined ultra-high-risk (UHiR) multiple myeloma (NDMM) or plasma cell leukemia (PCL). To provide clinical context, progression-free survival (PFS) and overall survival (OS) were referenced to contemporaneous outcomes seen in patients with UHiR NDMM treated in the recent Myeloma XI (MyeXI) trial.METHODSTransplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of & GE;2 genetic risk markers t(4;14)/t(14;16)/t(14;20), del(1p), gain(1q), and del(17p), and/or SKY92 gene expression risk signature. Patients with UHiR MM/PCL were offered treatment with Dara-CVRd induction, V-augmented ASCT, extended Dara-VR(d) consolidation, and Dara-R maintenance. UHiR patients treated in MyeXI with carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide, or lenalidomide, dexamethasone, and cyclophosphamide, ASCT, and R maintenance or observation were identified by mirrored molecular screening. OPTIMUM PFS at 18 months (PFS18m) was compared against MyeXI using a Bayesian framework, and patients were followed up to the end of consolidation for PFS and OS.RESULTSOf 412 screened NDMM OPTIMUM patients, 103 were identified as UHiR or PCL and subsequently treated on trial with Dara-CVRd; 117 MyeXI patients identified as UHiR formed the external comparator arm, with comparable clinical and molecular characteristics to OPTIMUM. Comparison of PFS18m per Bayesian framework resulted in a 99.5% chance of OPTIMUM being superior to MyeXI. At 30 months' follow-up, PFS was 77% for OPTIMUM versus 39.8% for MyeXI, and OS 83.5% versus 73.5%, respectively. Extended post-ASCT Dara-VRd consolidation therapy was highly deliverable, with limited toxicity.CONCLUSIONOur results suggest that Dara-CVRd induction and extended post-ASCT Dara-VRd consolidation markedly improve PFS for UHiR NDMM patients over conventional management, supporting further evaluation of this strategy.
引用
收藏
页码:3945 / +
页数:12
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