Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial

Kumar, Shaji; Jacobus, Susanna; Cohen, Adam D.; Weiss, Matthias; Callander, Natalie S.; Singh, Avina K.; Parker, Terri L.; Menter, Alexander; Yang, Xinyun; Parsons, Benjamin M.; Kumar, Pankaj; Kapoor, Prashant; Rosenberg, Aaron S; Zonder, Jeffrey A.; Faber, Edward A.; Lonial, Sagar; Anderson, Kenneth C.; Richardson, Paul G.; Orłowski, Robert Z.; Wagner, Lynne I.; Rajkumar, S. Vincent

doi:10.1016/s1470-2045(20)30452-6

Cited by 187 publications

(211 citation statements)

References 34 publications

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“…At a median follow-up of nine months, the PFS was 34.6 months in the KRd group and 34.4 months in the VRd group (HR 1.04; p = 0.74). Median OS had not been reached in either group [21]…”

Section: Front-line Transplant Settingmentioning

confidence: 84%

“…According to authors' conclusions, KRd regimen did not show significant advantage and was associated with more toxicity. Therefore, VRd regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk NDMM, and is a suitable treatment backbone for the development of combinations of four drugs [21].…”

Section: Front-line Non-transplant Settingmentioning

confidence: 99%

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Recent Advances in the Treatment of Patients with Multiple Myeloma

Legarda

Cejalvo

Rubia

2020

Cancers

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In the past 20 years, few diseases have seen as great progress in their treatment as multiple myeloma. With the approval of many new drugs and the limited availability of clinical trials comparing head-to-head the different possible combinations, the choice of the best treatments at each stage of the disease becomes complex as well as crucial since multiple myeloma remains incurable. This article presents a general description of the novelties of the whole treatment of multiple myeloma, from induction in the newly diagnosed patient through the role of hematopoietic stem cell transplantation and maintenance treatment until early and late relapses, including a section on recently approved drugs as well as novel drugs and immunotherapy in advanced stages of research, and that will surely play a relevant role in the treatment of this devastating disease in the coming years.

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“…At a median follow-up of nine months, the PFS was 34.6 months in the KRd group and 34.4 months in the VRd group (HR 1.04; p = 0.74). Median OS had not been reached in either group [21]…”

Section: Front-line Transplant Settingmentioning

confidence: 84%

Section: Front-line Non-transplant Settingmentioning

confidence: 99%

Recent Advances in the Treatment of Patients with Multiple Myeloma

Legarda

Cejalvo

Rubia

2020

Cancers

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“…In our analysis, median PFS was not reached at a median follow‐up time of 8.1 months. In the recent phase 3 ENDURANCE trial of induction therapy for NDMM in standard or intermediate risk, transplant‐ineligible or transplant‐deferred patients, twice‐weekly KRd administered for nine cycles did not improve median PFS vs VRd (34.6 months vs 34.4 months; HR, 1.04 [95% CI, 0.8‐1.3]) 27 . Further studies are needed to evaluate whether once‐weekly KRd could improve outcomes vs twice‐weekly KRd or VRd.…”

Section: Discussionmentioning

confidence: 99%

A phase 1b study of once‐weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma

et al. 2020

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Twice-weekly carfilzomib with lenalidomide-dexamethasone (Rd) is an effective regimen for newly diagnosed multiple myeloma (NDMM). Here we evaluated onceweekly carfilzomib with Rd (once-weekly KRd) in NDMM patients. The NDMM patients were enrolled regardless of transplant eligibility. Patients received carfilzomib on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on carfilzomib days (also day 22 for cycles 1-8) for ≤18, 28-day cycles. Enrollment initiated in a carfilzomib 20/70 mg/m 2 (20 mg/m 2 on cycle one, day 1; 70 mg/m 2 thereafter) NDMM dose-expansion arm, which was suspended because of serious adverse events. After evaluation of dose-limiting toxicities in a two-step-up dose-evaluation cohort, an NDMM dose-expansion arm (carfilzomib 20/56 mg/m 2) was opened. Fifty-one NDMM patients were enrolled in dose-finding and dose-expansion cohorts. Results are presented for the carfilzomib 56 mg/m 2 NDMM dose-expansion arm (n = 33). The grade ≥ 3 treatment-emergent AE (TEAE) rate was 63.6%. Twenty-five patients underwent stem cell collection; 18 proceeded to auto stem cell transplant, and five resumed KRd on study after autoSCT. The overall response rate (ORR) based on best overall response by cycle four was 97.0% (≥very good partial response [VGPR], 69.7%) in the NDMM 20/56 mg/m 2 cohort. In patients who did not receive autoSCT (n = 15), the median number of cycles was 16.0; ORR was 93.3% (≥VGPR, 80.0%). At a median follow-up of 8.1 months, median progression-free survival was not reached. Onceweekly KRd (carfilzomib 56 mg/m 2) had a favorable safety profile and promising activity in NDMM, supporting the use of this regimen in this setting. 1 | INTRODUCTION Triplet combination regimens consisting of a proteasome inhibitor, an immunomodulatory agent, and dexamethasone are among the most active treatment options for patients with newly diagnosed multiple myeloma (NDMM). Triplet combination strategies have been associated with deep responses, 1-5 and randomized, phase three trials have demonstrated prolonged progression-free survival (PFS) with triplet

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“…The superiority of carfilzomib compared to bortezomib was demonstrated in patients with relapsed disease in the ENDEAVOR study [ 5 ]. The superiority of carfilzomib is not, however, supported by data from the recently reported ENDURANCE study [ 24 ], which examined the combination of carfilzomib with lenalidomide and dexamethasone (without cyclophosphamide) as induction treatment for newly diagnosed myeloma patients. This study did not identify a difference in outcome between patients receiving KRd or bortezomib, lenalidomide, and dexamethasone (VRd), but it was not carried out in the same population as Myeloma XI+, excluding patients with high-risk disease and those destined for stem cell transplantation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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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Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial

Cited by 187 publications

References 34 publications

Recent Advances in the Treatment of Patients with Multiple Myeloma

Recent Advances in the Treatment of Patients with Multiple Myeloma

A phase 1b study of once‐weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma

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

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