Abstract
SummaryBackgroundMultiple 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.MethodsThe 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.FindingsBetween 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 patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related.InterpretationIntensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK.FundingCancer Research UK, Celgene, Amgen, Merck, Myeloma UK.
Highlights
The aetiology and progression of multiple myeloma are driven by the accumulation of acquired genetic events that affect clonal competition within the bone marrow microenvironment
Tumour cell diversity increases as genetic lesions accumulate, and the disease progresses from monoclonal gammopathy of undetermined signif icance to myeloma, leading to substantial subclonal heterogeneity at the time of diagnosis
The optimal timing for achieving maximum response is unclear, we found in our previous study, Myeloma IX, that patients with a complete response before autologous haemopoietic stem cell transplantation had better progression-free and overall survival than patients with a less than complete response
Summary
The aetiology and progression of multiple myeloma are driven by the accumulation of acquired genetic events that affect clonal competition within the bone marrow microenvironment. Tumour cell diversity increases as genetic lesions accumulate, and the disease progresses from monoclonal gammopathy of undetermined signif icance to myeloma, leading to substantial subclonal heterogeneity at the time of diagnosis. The aetiology and progression of multiple myeloma are driven by the accumulation of acquired genetic events that affect clonal competition within the bone marrow microenvironment.. Tumour cell diversity increases as genetic lesions accumulate, and the disease progresses from monoclonal gammopathy of undetermined signif icance to myeloma, leading to substantial subclonal heterogeneity at the time of diagnosis. Applying induction treatment designed to eliminate susceptible clones might provide selective pressure for the expansion of resistant clones, resulting in early or late relapse. Combination chemotherapies designed to maximise tumour cell death and eliminate resistant clones can improve clinical outcomes compared with single-agent chemotherapies. Strategies to deepen response after induction therapy include the use of autologous haemopoietic stem cell transplantation (in those eligible) and the use of posttransplant consolidation therapy. The optimal timing for achieving maximum response is unclear, in our previous study, Myeloma IX, patients with complete response before transplantation had better progressionfree survival and overall survival than patients without complete response, supporting an argument for early achievement of deep responses and the use of pretransplant intensification rather that post-transplant consolidation
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