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Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.

ABSTRACT: High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide.Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to lenalidomide 25 mg on days 1-21 plus dexamethasone 40 mg on days 1-4, 9-12, and 17-20 of a 28-day cycle (high dose), or lenalidomide given on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (low dose). After four cycles, patients could discontinue therapy to pursue stem-cell transplantation or continue treatment until disease progression. The primary endpoint was response rate after four cycles assessed with European Group for Blood and Bone Marrow Transplant criteria. The non-inferiority margin was an absolute difference of 15% in response rate. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00098475.445 patients were randomly assigned: 223 to high-dose and 222 to low-dose regimens. 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients on low-dose therapy had complete or partial response within four cycles (odds ratio 1.75, 80% CI 1.30-2.32; p=0.008). However, at the second interim analysis at 1 year, overall survival was 96% (95% CI 94-99) in the low-dose dexamethasone group compared with 87% (82-92) in the high-dose group (p=0.0002). As a result, the trial was stopped and patients on high-dose therapy were crossed over to low-dose therapy. 117 patients (52%) on the high-dose regimen had grade three or worse toxic effects in the first 4 months, compared with 76 (35%) of the 220 on the low-dose regimen for whom toxicity data were available (p=0.0001), 12 of 222 on high dose and one of 220 on low-dose dexamethasone died in the first 4 months (p=0.003). The three most common grade three or higher toxicities were deep-vein thrombosis, 57 (26%) of 223 versus 27 (12%) of 220 (p=0.0003); infections including pneumonia, 35 (16%) of 223 versus 20 (9%) of 220 (p=0.04), and fatigue 33 (15%) of 223 versus 20 (9%) of 220 (p=0.08), respectively.Lenalidomide plus low-dose dexamethasone is associated with better short-term overall survival and with lower toxicity than lenalidomide plus high-dose dexamethasone in patients with newly diagnosed myeloma.National Cancer Institute, Rockville, MD, USA.

SUBMITTER: Rajkumar SV

PROVIDER: S-EPMC3042271 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.

Rajkumar S Vincent SV Jacobus Susanna S Callander Natalie S NS Fonseca Rafael R Vesole David H DH Williams Michael E ME Abonour Rafat R Siegel David S DS Katz Michael M Greipp Philip R PR

The Lancet. Oncology 20091021 1

<h4>Background</h4>High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide.<h4>Methods</h4>Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to lenalidomide 25 mg on days 1-21 plus dexamethasone 40 mg on days 1-4, 9-12, and 17-20 of a 28-day cycle (high dose), or ...[more]

PMID: 19853510

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Project description:BackgroundThe outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients.MethodsIn this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297.FindingsSixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment.InterpretationIxazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients.FundingJanssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.

Project description: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 < 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.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.

Dataset Information

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.

Publications

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.

Similar Datasets

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