Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma
PURPOSE: The 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.
METHODS: Transplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of ≥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.
RESULTS: Of 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.
CONCLUSION: Our 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:41 |
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| Enthalten in: |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology - 41(2023), 23 vom: 10. Aug., Seite 3945-3955 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kaiser, Martin F [VerfasserIn] |
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| Links: |
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| Themen: |
4Z63YK6E0E |
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| Anmerkungen: |
Date Completed 09.08.2023 Date Revised 13.03.2024 published: Print-Electronic ClinicalTrials.gov: NCT03188172 Citation Status MEDLINE |
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| doi: |
10.1200/JCO.22.02567 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35816902X |
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| 100 | 1 | |a Kaiser, Martin F |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma |
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| 500 | |a Date Completed 09.08.2023 | ||
| 500 | |a Date Revised 13.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03188172 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: The 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 | ||
| 520 | |a METHODS: Transplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of ≥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 | ||
| 520 | |a RESULTS: Of 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 | ||
| 520 | |a CONCLUSION: Our 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 | ||
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a De Tute, Ruth M |e verfasserin |4 aut | |
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| 700 | 1 | |a Roberts, Sadie |e verfasserin |4 aut | |
| 700 | 1 | |a Ingleson, Emma |e verfasserin |4 aut | |
| 700 | 1 | |a Bowles, Kristian |e verfasserin |4 aut | |
| 700 | 1 | |a Garg, Mamta |e verfasserin |4 aut | |
| 700 | 1 | |a Lokare, Anand |e verfasserin |4 aut | |
| 700 | 1 | |a Messiou, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Houlston, Richard S |e verfasserin |4 aut | |
| 700 | 1 | |a Jackson, Graham |e verfasserin |4 aut | |
| 700 | 1 | |a Cook, Gordon |e verfasserin |4 aut | |
| 700 | 1 | |a Pratt, Guy |e verfasserin |4 aut | |
| 700 | 1 | |a Owen, Roger G |e verfasserin |4 aut | |
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| 700 | 1 | |a Brown, Sarah R |e verfasserin |4 aut | |
| 700 | 1 | |a Jenner, Matthew W |e verfasserin |4 aut | |
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