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Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial

BACKGROUND: Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. METHODS AND FINDINGS: The Myelo...

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Autores principales: Jackson, Graham H., Pawlyn, Charlotte, Cairns, David A., de Tute, Ruth M., Hockaday, Anna, Collett, Corinne, Jones, John R., Kishore, Bhuvan, Garg, Mamta, Williams, Cathy D., Karunanithi, Kamaraj, Lindsay, Jindriska, Rocci, Alberto, Snowden, John A., Jenner, Matthew W., Cook, Gordon, Russell, Nigel H., Drayson, Mark T., Gregory, Walter M., Kaiser, Martin F., Owen, Roger G., Davies, Faith E., Morgan, Gareth J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799846/
https://www.ncbi.nlm.nih.gov/pubmed/33428632
http://dx.doi.org/10.1371/journal.pmed.1003454
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author Jackson, Graham H.
Pawlyn, Charlotte
Cairns, David A.
de Tute, Ruth M.
Hockaday, Anna
Collett, Corinne
Jones, John R.
Kishore, Bhuvan
Garg, Mamta
Williams, Cathy D.
Karunanithi, Kamaraj
Lindsay, Jindriska
Rocci, Alberto
Snowden, John A.
Jenner, Matthew W.
Cook, Gordon
Russell, Nigel H.
Drayson, Mark T.
Gregory, Walter M.
Kaiser, Martin F.
Owen, Roger G.
Davies, Faith E.
Morgan, Gareth J.
author_facet Jackson, Graham H.
Pawlyn, Charlotte
Cairns, David A.
de Tute, Ruth M.
Hockaday, Anna
Collett, Corinne
Jones, John R.
Kishore, Bhuvan
Garg, Mamta
Williams, Cathy D.
Karunanithi, Kamaraj
Lindsay, Jindriska
Rocci, Alberto
Snowden, John A.
Jenner, Matthew W.
Cook, Gordon
Russell, Nigel H.
Drayson, Mark T.
Gregory, Walter M.
Kaiser, Martin F.
Owen, Roger G.
Davies, Faith E.
Morgan, Gareth J.
author_sort Jackson, Graham H.
collection PubMed
description BACKGROUND: Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. METHODS AND FINDINGS: The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51–0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19–5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10(−5) bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world. CONCLUSIONS: The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN49407852.
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spelling pubmed-77998462021-01-22 Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial Jackson, Graham H. Pawlyn, Charlotte Cairns, David A. de Tute, Ruth M. Hockaday, Anna Collett, Corinne Jones, John R. Kishore, Bhuvan Garg, Mamta Williams, Cathy D. Karunanithi, Kamaraj Lindsay, Jindriska Rocci, Alberto Snowden, John A. Jenner, Matthew W. Cook, Gordon Russell, Nigel H. Drayson, Mark T. Gregory, Walter M. Kaiser, Martin F. Owen, Roger G. Davies, Faith E. Morgan, Gareth J. PLoS Med Research Article BACKGROUND: Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. METHODS AND FINDINGS: The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51–0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19–5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10(−5) bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world. CONCLUSIONS: The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN49407852. Public Library of Science 2021-01-11 /pmc/articles/PMC7799846/ /pubmed/33428632 http://dx.doi.org/10.1371/journal.pmed.1003454 Text en © 2021 Jackson et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Jackson, Graham H.
Pawlyn, Charlotte
Cairns, David A.
de Tute, Ruth M.
Hockaday, Anna
Collett, Corinne
Jones, John R.
Kishore, Bhuvan
Garg, Mamta
Williams, Cathy D.
Karunanithi, Kamaraj
Lindsay, Jindriska
Rocci, Alberto
Snowden, John A.
Jenner, Matthew W.
Cook, Gordon
Russell, Nigel H.
Drayson, Mark T.
Gregory, Walter M.
Kaiser, Martin F.
Owen, Roger G.
Davies, Faith E.
Morgan, Gareth J.
Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial
title Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial
title_full Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial
title_fullStr Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial
title_full_unstemmed Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial
title_short Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial
title_sort carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (krdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (myeloma xi+): interim analysis of an open-label randomised controlled trial
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799846/
https://www.ncbi.nlm.nih.gov/pubmed/33428632
http://dx.doi.org/10.1371/journal.pmed.1003454
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