dc.contributor.author | Jackson, GH | |
dc.contributor.author | Pawlyn, C | |
dc.contributor.author | Cairns, DA | |
dc.contributor.author | de Tute, RM | |
dc.contributor.author | Hockaday, A | |
dc.contributor.author | Collett, C | |
dc.contributor.author | Jones, JR | |
dc.contributor.author | Kishore, B | |
dc.contributor.author | Garg, M | |
dc.contributor.author | Williams, CD | |
dc.contributor.author | Karunanithi, K | |
dc.contributor.author | Lindsay, J | |
dc.contributor.author | Rocci, A | |
dc.contributor.author | Snowden, JA | |
dc.contributor.author | Jenner, MW | |
dc.contributor.author | Cook, G | |
dc.contributor.author | Russell, NH | |
dc.contributor.author | Drayson, MT | |
dc.contributor.author | Gregory, WM | |
dc.contributor.author | Kaiser, MF | |
dc.contributor.author | Owen, RG | |
dc.contributor.author | Davies, FE | |
dc.contributor.author | Morgan, GJ | |
dc.contributor.author | UK NCRI Haemato-oncology Clinical Studies Group, | |
dc.date.accessioned | 2021-01-25T14:53:43Z | |
dc.date.issued | 2021-01-01 | |
dc.identifier.citation | PLoS medicine, 2021, 18 (1), pp. e1003454 - ? | |
dc.identifier.issn | 1549-1277 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4312 | |
dc.identifier.eissn | 1549-1676 | |
dc.identifier.doi | 10.1371/journal.pmed.1003454 | |
dc.description.abstract | 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. | |
dc.format | Electronic-eCollection | |
dc.format.extent | e1003454 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | PUBLIC LIBRARY SCIENCE | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | UK NCRI Haemato-oncology Clinical Studies Group | |
dc.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. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-11-23 | |
rioxxterms.versionofrecord | 10.1371/journal.pmed.1003454 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2021-01-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | PLoS medicine | |
pubs.issue | 1 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Myeloma Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Myeloma Group | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Myeloma Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Myeloma Group | |
pubs.publication-status | Published | |
pubs.volume | 18 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Myeloma Biology and Therapeutics | |
icr.researchteam | Myeloma Group | |
dc.contributor.icrauthor | Pawlyn, Charlotte | |
dc.contributor.icrauthor | Kaiser, Martin | |