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

Martin F. Kaiser; Andrew Hall; Katrina Walker; Amy Sherborne; Ruth M. De Tute; Nicola Newnham; Sadie Roberts; Emma Ingleson; Kristian Bowles; Mamta Garg; Anand Lokare; Christina Messiou; Richard S. Houlston; Graham Jackson; Gordon Cook; Guy Pratt; Roger G. Owen; Mark T. Drayson; Sarah R. Brown; Matthew W. Jenner

doi:10.1200/JCO.22.02567

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

Martin F. Kaiser^*, Andrew Hall, Katrina Walker, Amy Sherborne, Ruth M. De Tute, Nicola Newnham, Sadie Roberts, Emma Ingleson, Kristian Bowles, Mamta Garg, Anand Lokare, Christina Messiou, Richard S. Houlston, Graham Jackson, Gordon Cook, Guy Pratt, Roger G. Owen, Mark T. Drayson, Sarah R. Brown, Matthew W. Jenner

^*Corresponding author for this work

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Abstract

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.

Original language	English
Pages (from-to)	3945-3955
Number of pages	11
Journal	Journal of Clinical Oncology
Volume	41
Issue number	23
Early online date	14 Jun 2023
DOIs	https://doi.org/10.1200/JCO.22.02567
Publication status	Published - Aug 2023

Bibliographical note

Funding Information:
The authors thank the Myeloma XI trial team, with lead statistical work by David Cairns, for their support. M.F.K. is supported by a Jacquelin Forbes-Nixon Fellowship via Myeloma UK. The molecular risk stratification strategy was designed by the Myeloma Molecular Therapy Team at the Institute Cancer Research, London. The authors acknowledge Sidra Ellis, Amy Price, and Kim Sharp for their work on central molecular screening. Molecular studies were supported through grants of the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden Hospital. The authors acknowledge Suvi Savola and Lilit Atanesyan from MRC-Holland and the team at SkylineDx for technical discussions and support. The authors thank the myeloma patient representatives giving anonymous advice on the patient-focused design and delivery of the OPTIMUM trial via Myeloma UK. The authors thank Eric Low for his support from concept to study delivery.

Publisher Copyright:
© American Society of Clinical Oncology.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Kaiser, M. F., Hall, A., Walker, K., Sherborne, A., De Tute, R. M., Newnham, N., Roberts, S., Ingleson, E., Bowles, K., Garg, M., Lokare, A., Messiou, C., Houlston, R. S., Jackson, G., Cook, G., Pratt, G., Owen, R. G., Drayson, M. T., Brown, S. R., & Jenner, M. W. (2023). Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma. Journal of Clinical Oncology, 41(23), 3945-3955. https://doi.org/10.1200/JCO.22.02567

@article{1726b465dd77401b91a07e42fa675a8e,

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

abstract = "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.",

author = "Kaiser, {Martin F.} and Andrew Hall and Katrina Walker and Amy Sherborne and {De Tute}, {Ruth M.} and Nicola Newnham and Sadie Roberts and Emma Ingleson and Kristian Bowles and Mamta Garg and Anand Lokare and Christina Messiou and Houlston, {Richard S.} and Graham Jackson and Gordon Cook and Guy Pratt and Owen, {Roger G.} and Drayson, {Mark T.} and Brown, {Sarah R.} and Jenner, {Matthew W.}",

note = "Funding Information: The authors thank the Myeloma XI trial team, with lead statistical work by David Cairns, for their support. M.F.K. is supported by a Jacquelin Forbes-Nixon Fellowship via Myeloma UK. The molecular risk stratification strategy was designed by the Myeloma Molecular Therapy Team at the Institute Cancer Research, London. The authors acknowledge Sidra Ellis, Amy Price, and Kim Sharp for their work on central molecular screening. Molecular studies were supported through grants of the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden Hospital. The authors acknowledge Suvi Savola and Lilit Atanesyan from MRC-Holland and the team at SkylineDx for technical discussions and support. The authors thank the myeloma patient representatives giving anonymous advice on the patient-focused design and delivery of the OPTIMUM trial via Myeloma UK. The authors thank Eric Low for his support from concept to study delivery. Publisher Copyright: {\textcopyright} American Society of Clinical Oncology.",

year = "2023",

month = aug,

doi = "10.1200/JCO.22.02567",

language = "English",

volume = "41",

pages = "3945--3955",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "23",

}

Kaiser, MF, Hall, A, Walker, K, Sherborne, A, De Tute, RM, Newnham, N, Roberts, S, Ingleson, E, Bowles, K, Garg, M, Lokare, A, Messiou, C, Houlston, RS, Jackson, G, Cook, G, Pratt, G, Owen, RG, Drayson, MT, Brown, SR & Jenner, MW 2023, 'Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma', Journal of Clinical Oncology, vol. 41, no. 23, pp. 3945-3955. https://doi.org/10.1200/JCO.22.02567

TY - JOUR

T1 - Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma

AU - Kaiser, Martin F.

AU - Hall, Andrew

AU - Walker, Katrina

AU - Sherborne, Amy

AU - De Tute, Ruth M.

AU - Newnham, Nicola

AU - Roberts, Sadie

AU - Ingleson, Emma

AU - Bowles, Kristian

AU - Garg, Mamta

AU - Lokare, Anand

AU - Messiou, Christina

AU - Houlston, Richard S.

AU - Jackson, Graham

AU - Cook, Gordon

AU - Pratt, Guy

AU - Owen, Roger G.

AU - Drayson, Mark T.

AU - Brown, Sarah R.

AU - Jenner, Matthew W.

N1 - Funding Information: The authors thank the Myeloma XI trial team, with lead statistical work by David Cairns, for their support. M.F.K. is supported by a Jacquelin Forbes-Nixon Fellowship via Myeloma UK. The molecular risk stratification strategy was designed by the Myeloma Molecular Therapy Team at the Institute Cancer Research, London. The authors acknowledge Sidra Ellis, Amy Price, and Kim Sharp for their work on central molecular screening. Molecular studies were supported through grants of the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden Hospital. The authors acknowledge Suvi Savola and Lilit Atanesyan from MRC-Holland and the team at SkylineDx for technical discussions and support. The authors thank the myeloma patient representatives giving anonymous advice on the patient-focused design and delivery of the OPTIMUM trial via Myeloma UK. The authors thank Eric Low for his support from concept to study delivery. Publisher Copyright: © American Society of Clinical Oncology.

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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