PLoS Medicine (Jan 2021)

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.

  • 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

DOI
https://doi.org/10.1371/journal.pmed.1003454
Journal volume & issue
Vol. 18, no. 1
p. e1003454

Abstract

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BackgroundCarfilzomib 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 findingsThe 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 ConclusionsThe 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 registrationClinicalTrials.gov ISRCTN49407852.