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DSMM XI study: dose definition for intravenous cyclophosphamide in combination with bortezomib/dexamethasone for remission induction in patients with newly diagnosed myeloma.

ABSTRACT: A clinical trial was initiated to evaluate the recommended dose of cyclophosphamide in combination with bortezomib and dexamethasone as induction treatment before stem cell transplantation for younger patients with newly diagnosed multiple myeloma (MM). Thirty patients were treated with three 21-day cycles of bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 plus dexamethasone 40 mg on the day of bortezomib injection and the day after plus cyclophosphamide at 900, 1,200, or 1,500 mg/m(2) on day 1. The maximum tolerated dose of cyclophosphamide was defined as 900 mg/m(2). At this dose level, 92% of patients achieved at least a partial response. The overall response rate [complete response (CR) plus partial response (PR)] across all dose levels was 77%, with a 10% CR rate. No patient experienced progressive disease. The most frequent adverse events were hematological and gastrointestinal toxicities as well as neuropathy. The results suggest that bortezomib in combination with cyclophosphamide at 900 mg/m(2) and dexamethasone is an effective induction treatment for patients with newly diagnosed MM that warrants further investigation.

SUBMITTER: Kropff M

PROVIDER: S-EPMC2745621 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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DSMM XI study: dose definition for intravenous cyclophosphamide in combination with bortezomib/dexamethasone for remission induction in patients with newly diagnosed myeloma.

Kropff Martin M Liebisch Peter P Knop Stefan S Weisel Katja K Wand Hannes H Gann Claudia-Nanette CN Berdel Wolfgang E WE Einsele Herrmann H

Annals of hematology 20090310 11

A clinical trial was initiated to evaluate the recommended dose of cyclophosphamide in combination with bortezomib and dexamethasone as induction treatment before stem cell transplantation for younger patients with newly diagnosed multiple myeloma (MM). Thirty patients were treated with three 21-day cycles of bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 plus dexamethasone 40 mg on the day of bortezomib injection and the day after plus cyclophosphamide at 900, 1,200, or 1,500 mg/m(2) on day 1. ...[more]

PMID: 19274460

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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

DSMM XI study: dose definition for intravenous cyclophosphamide in combination with bortezomib/dexamethasone for remission induction in patients with newly diagnosed myeloma.

Publications

DSMM XI study: dose definition for intravenous cyclophosphamide in combination with bortezomib/dexamethasone for remission induction in patients with newly diagnosed myeloma.

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