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.
<h4>Background</h4>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.<h4>Met...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-01-01
|
| Series: | PLoS Medicine |
| Online Access: | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003454&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849693163212505088 |
|---|---|
| author | Graham H Jackson Charlotte Pawlyn David A Cairns Ruth M de Tute Anna Hockaday Corinne Collett John R Jones Bhuvan Kishore Mamta Garg Cathy D Williams Kamaraj Karunanithi Jindriska Lindsay Alberto Rocci John A Snowden Matthew W Jenner Gordon Cook Nigel H Russell Mark T Drayson Walter M Gregory Martin F Kaiser Roger G Owen Faith E Davies Gareth J Morgan UK NCRI Haemato-oncology Clinical Studies Group |
| author_facet | Graham H Jackson Charlotte Pawlyn David A Cairns Ruth M de Tute Anna Hockaday Corinne Collett John R Jones Bhuvan Kishore Mamta Garg Cathy D Williams Kamaraj Karunanithi Jindriska Lindsay Alberto Rocci John A Snowden Matthew W Jenner Gordon Cook Nigel H Russell Mark T Drayson Walter M Gregory Martin F Kaiser Roger G Owen Faith E Davies Gareth J Morgan UK NCRI Haemato-oncology Clinical Studies Group |
| author_sort | Graham H Jackson |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.<h4>Trial registration</h4>ClinicalTrials.gov ISRCTN49407852. |
| format | Article |
| id | doaj-art-7fe445c9d7494b4397c8fa9d9a9d2182 |
| institution | DOAJ |
| issn | 1549-1277 1549-1676 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj-art-7fe445c9d7494b4397c8fa9d9a9d21822025-08-20T03:20:30ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762021-01-01181e100345410.1371/journal.pmed.1003454Carfilzomib, 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.Graham H JacksonCharlotte PawlynDavid A CairnsRuth M de TuteAnna HockadayCorinne CollettJohn R JonesBhuvan KishoreMamta GargCathy D WilliamsKamaraj KarunanithiJindriska LindsayAlberto RocciJohn A SnowdenMatthew W JennerGordon CookNigel H RussellMark T DraysonWalter M GregoryMartin F KaiserRoger G OwenFaith E DaviesGareth J MorganUK NCRI Haemato-oncology Clinical Studies Group<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.<h4>Trial registration</h4>ClinicalTrials.gov ISRCTN49407852.https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003454&type=printable |
| spellingShingle | Graham H Jackson Charlotte Pawlyn David A Cairns Ruth M de Tute Anna Hockaday Corinne Collett John R Jones Bhuvan Kishore Mamta Garg Cathy D Williams Kamaraj Karunanithi Jindriska Lindsay Alberto Rocci John A Snowden Matthew W Jenner Gordon Cook Nigel H Russell Mark T Drayson Walter M Gregory Martin F Kaiser Roger G Owen Faith E Davies Gareth J Morgan UK NCRI Haemato-oncology Clinical Studies Group 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. PLoS Medicine |
| 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 |
| url | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003454&type=printable |
| work_keys_str_mv | AT grahamhjackson carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT charlottepawlyn carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT davidacairns carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT ruthmdetute carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT annahockaday carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT corinnecollett carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT johnrjones carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT bhuvankishore carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT mamtagarg carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT cathydwilliams carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT kamarajkarunanithi carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT jindriskalindsay carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT albertorocci carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT johnasnowden carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT matthewwjenner carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT gordoncook carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT nigelhrussell carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT marktdrayson carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT waltermgregory carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT martinfkaiser carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT rogergowen carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT faithedavies carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT garethjmorgan carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial AT ukncrihaematooncologyclinicalstudiesgroup carfilzomiblenalidomidedexamethasoneandcyclophosphamidekrdcasinductiontherapyfortransplanteligiblenewlydiagnosedmultiplemyelomapatientsmyelomaxiinterimanalysisofanopenlabelrandomisedcontrolledtrial |