SummaryBackgroundPatients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses.MethodsThe Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1–21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, 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 Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18–50), median progression-free survival was 39 months (95% CI 36–42) with lenalidomide and 20 months (18–22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41–0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6–81·6) in the lenalidomide group and 75·8% (72·4–79·2) in the observation group (HR 0·87 [95% CI 0·73–1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3–90·7) in the lenalidomide group and 80·2% (76·0–84·4) in the observation group (HR 0·69 [95...

Disease factors such as tumor burden and molecular risk affect myeloma patient outcomes as well as patient factors that impact the capacity to deliver treatment. How the relative importance of these factors changes with patient age has not previously been investigated comprehensively. We analyzed data from 3894 patients of all ages uniformly treated in a large clinical trial of myeloma patients, Myeloma XI. Even with novel therapeutic approaches progression-free survival (PFS) and overall survival (OS) are affected by age with a stepwise reduction in PFS and OS with each decade increase. Renal function deteriorated with increasing age whilst the frequency of t(4;14) and del(17p) decreased and gain(1q) increased. The relative contribution of performance status, international staging score and molecular risk to progression-free and overall survival varied by age group. Molecular events have a larger effect on outcome in younger patients with their relative contribution diminishing in the elderly. Performance status is important for patient outcome at all ages suggesting that physical frailty may be a more important predictor of outcome than age itself. Significant differences in the factors driving patient outcomes at different ages are important to consider as we design disease segmentation strategies to deliver personalized treatment approaches.

We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4–1.0%), 2.3% (95% CI 1.6–2.7%) and 3.8% (95% CI 2.9–4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2–26.4%), compared with 6.5% (95% CI 0.2–12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.

Background Lenalidomide is an effective treatment for myeloma and has been studied in a range of combination regimens worldwide. The results of these studies have suggested that prolonged exposure to lenalidomide is important to improve outcomes both as a maintenance agent post-transplant (Attal M et al NEJM 2012, McCarthy et al NEJM 2012) and in the transplant ineligible population (Palumbo A et al NEJM 2012, Benboubker L et al NEJM 2014). In the Myeloma XI study, the largest of its kind, we explored the use of oral lenalidomide continued to disease progression compared to no therapy in both newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) populations. Here we present the results of this maintenance randomization, which demonstrate the efficacy and safety of maintenance lenalidomide. Methods The Myeloma XI study is a Phase III, UK-based, multicenter, open-label, parallel group, randomized controlled trial for newly diagnosed symptomatic myeloma patients of all ages and includes a maintenance comparison of lenalidomide versus no maintenance. Newly diagnosed symptomatic myeloma patients both TE and TNE were enrolled to the study. Induction treatment in both pathways was with thalidomide or lenalidomide plus cyclophosphamide and dexamethasone, with appropriate dose reductions for TNE patients. TE patients proceded to a standard melphalan 200mg/m2 transplant. Patients were randomized to either maintenance lenalidomide or observation after achieving maximum response (TNE) or at 100 days after transplant (TE). Lenalidomide was administered at a dose of 10mg daily in 21/28 day cycles until disease progression. Dose adjustments for renal impairment and following AEs were permitted. The primary endpoints for the maintenance randomization were progression-free (PFS) and overall survival. Secondary endpoints included response, toxicity and PFS2. Time-to-event endpoints were measured from maintenance randomization. This abstract summarizes a preliminary analysis, final data will be presented at the meeting. The median follow up in this analysis is 26 months [IQR 12-41]. Results A total of 1550 patients, 828 TE and 722 TNE, median age 61 and 74 years, respectively, were randomized between lenalidomide (n=857) and no maintenance (n=693). The arms were well-balanced for clinical features and response to induction therapy (e.g. ISS stage III: 27% vs 23%, VGPR/CR: 73% vs 73%). The maintenance randomization has met its primary endpoint demonstrating a 55% reduction in risk of progression or death for lenalidomide compared to no maintenance (HR 0.45 [95%CI 0.39-0.52], median PFS 37 vs 19 months, p<0.0001) This significant improvement was observed in each pathway TE: HR 0.46 [95%CI 0.36-0.58], median PFS 60 vs 28 months, p<0.0001. TNE: HR 0.44 [95%CI 0.36-0.53], median PFS 26 vs 12 months, p<0.0001. The benefit of lenalidomide maintenance on PFS persisted across risk subgroups and was independent of induction therapy and response. An exploratory analysis of 132 patients stopping lenalidomide treatment for reasons other than disease progression (91 toxicity, 28 patient choice and 13 clinician choice) shows that patients receiving greater than 12 months of treatment have an improved median PFS compared to those stopping earlier (HR 0.35 [95%CI 0.18-0.68], 49 vs 31 months, p<0.0015). At this time 445 patients continue to receive lenalidomide maintenance on study. Of patients who have stopped therapy, only 21.5% did so due to toxicity. Relevant grade 3/4 adverse events were: neutropenia 35%, thrombocytopenia 7.4%, anaemia 4.4%, peripheral neuropathy 1.4%. Venous thromboembolism occurred in 2.3%. Second primary malignancy (SPM) data was collected and the relationship with maintenance therapy reviewed. 72 SPM were observed (24 no maintenance, 48 lenalidomide). Haematologic malignancy crude incidence was 0.3% vs. 0.9%. While we found a slight excess of SPM in older patients these were mostly non-invasive and did not impact the outcome benefit demonstrated. Conclusion The use of maintenance lenalidomide treatment results in highly significant improvements in PFS for patients of all ages and should be standard of care. On behalf of the NCRI Haem-Onc CSG Disclosures Jackson: Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Davies:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Pawlyn:Takeda Oncology: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support. Jones:Celgene: Honoraria, Research Funding. Kishore:celgene: Other: travel grant. Garg:Janssen: Other: Travel support, Research Funding, Speakers Bureau; Takeda: Other: Travel support; Novartis: Other: Travel support, Research Funding. Williams:Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau. Karunanithi:Celgene: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding. Lindsay:Janssen: Consultancy; Novartis: Other: Travel support; Takeda: Other: Travel support; BMS: Consultancy, Other: Travel support; Celgene: Honoraria, Other: Travel support. Jenner:Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau. Kaiser:BMS: Consultancy, Other: Travel Support; Takeda: Consultancy, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Chugai: Consultancy. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Takeda: Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Other: Travel support. Morgan:Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding.

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...