Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial

Abstract

Background Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design.Methods The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m² subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for pati...

Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials

“…Methods and results from both trials have been published previously. [31][32][33][34][35] In brief, transplant-eligible patients in Myeloma IX were randomly assigned either to cyclophosphamide, thalidomide, and dexamethasone (CTD) or to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) before autologous stem cell transplantation (ASCT). Transplant-ineligible patients were randomly assigned either to attenuated CTD (CTDa) or to melphalan plus prednisolone (MP) induction chemotherapy.…”

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

“…Myeloma XI+ was only for transplant-eligible patients and was designed and opened before Myeloma XI data had matured; as such, the primary outcome was the comparison between KRdc and the triplet approaches studied in Myeloma XI and continued into Myeloma XI+. Results of the Tdc versus Rdc randomisation in transplant-eligible patients from Myeloma XI showed a small, but statistically significant improvement in PFS and overall survival (OS) associated with receiving Rdc [ 8 ]; results of the cyclophosphamide, bortezomib, and dexamethasone (CVD) intensification randomisation and the maintenance randomisation are also published [ 9 , 10 ]. This paper reports only patients contemporaneously randomised between KRdc and Rdc/Tdc as per the statistical analysis plan for the study.…”

Guidelines on the diagnosis, investigation and initial treatment of myeloma: a British Society for Haematology/UK Myeloma Forum Guideline

“…The Myeloma XI trial data demonstrated that patients achieving less than a VGPR following CTD or CRD induction benefit from switching to a bortezomib-based regimen. 96 However, most patients will now receive bortezomib as initial therapy. Many units use DT-PACE (with or without bortezomib) or similar regimens in fit patients to achieve a deeper response prior to transplant, although there is a lack of data in this area.…”