Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial

Abstract

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...

Ixazomib maintenance therapy in newly diagnosed multiple myeloma: An integrated analysis of four phase I/II studies

“…6 Similarly, in the recently concluded Myeloma XI trial, a median PFS of 26 months was reported with lenalidomide maintenance vs 11 months with observation in transplantineligible patients. 36 The PFS results reported in our analysis are also consistent with the PFS outcomes observed with single-agent ixazomib maintenance in the phase III TOURMALINE-MM3 study, although differences in patient populations exist between the two studies. 23 The benefit of long-term PI administration to transplant-ineligible patients with NDMM has been reported in two earlier trials incorporating bortezomib-based doublet maintenance.…”

Venous thromboembolism risk with contemporary lenalidomide‐based regimens despite thromboprophylaxis in multiple myeloma: A systematic review and meta‐analysis

“…Singleagent Len maintenance was received by 1557 patients (17%). Two maintenance trials did not mandate thromboprophylaxis in their protocol, 9,70 which is in accordance with current IMWG guidelines. The combination of Rd with a proteasome inhibitor, which is the current standard of care in ND MM and is widely used in the R/R setting, was tested in one-quarter of trials, including 15% of patients.…”

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

“…Although progression free survival improved with lenalidomide versus observation in all patients in the maintenance randomisation, patients receiving no CVD appeared to have an even greater benefit than those who had CVD or were not randomly assigned (no CVD HR 0·26 [95% CI 0·17-0·40] vs CVD HR 0·48 [0·30-0·76] vs not randomly assigned HR 0·49 [0·43-0·57] p heterogeneity =0·011). 8 The benefit of CVD therapy in terms of progressionfree survival was consistent across subgroups and persisted after autologous haemopoietic stem cell transplantation in transplantationeligible patients. The response rates after transplantation for the CVD and no CVD patients show that autologous haemopoietic stem cell transplantation alone can improve suboptimal initial response, but this can be significantly further improved by the use of pretransplant intensifi cation.…”

“…This Article reports the results of the randomisation to induction intensification treatment. Results of the induction and maintenance randomisations have been, 8 or will, be presented elsewhere. The trial recruited from 110 National Health Service hospitals in England, Wales, and Scotland (appendix p 15).…”