Background: Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus lowdose dexamethasone (Rd) are standards of care for elderly untreated multiple myeloma patients. Methods: We did a phase 2b, parallel-group, multicentre, open-label randomised trial at 44 hospitals in Spain. We randomly assigned 242 patients (1:1) to receive 9 cycles of VMP followed by 9 cycles of Rd or alternating cycles of VMP and Rd for 18 cycles. The primary endpoints were 18-month progression-free survival and safety profile, which were similar between arms at an initial analysis after a median follow-up of 30·3 months. We did an updated pooled analysis of progression-free and overall survival, overall and by age, cytogenetic risk and minimal residual disease status. Findings: After a median follow-up of 51 months, the median progression-free survival and overall survival were 31·2 and 63·5 months, respectively. The median progression-free survival was 33, 32, and 24 months for patients aged 65-75, 75-80, and >80 years, respectively, (p=0·017); median overall survival was not reached vs 57 vs 33 months (p<0·0001). In patients with high-risk versus standard-risk cytogenetics the median progression-free survival was 26 versus 33 months (p=0·3). Patients who were minimal residual disease-negative had 5-year progression-free and overall survival rates of 57% and 76%, respectively. Interpretation: VMP plus Rd represents a feasible option for patients aged up to 80 years, with excellent outcomes in minimal residual disease-negative patients. Clinical Trial Number: This trial is registered with ClinicalTrials.gov (NCT01237249). Funding Statement: Spanish Ministry of Health; European Regional Development Fund; Asociacion Espanola contra el Cancer. The trial was sponsored by PETHEMA (Spanish Programme for the Treatment of Haematological Diseases) Declaration of Interests: MVM reports personal fees from Janssen, Celgene, Takeda and Amgen, outside the submitted work. EO reports personal fees from Novartis, Takeda, Abbvie, Pharmamar, Seattle Genetics, Amgen, Celgene, BMS, Janssen, Array Pharmaceuticals, Mundipharma and Sanofi, outside the submitted work. LR reports honoraria from Janssen, Celgene and Amgen. AO reports membership of advisory boards for Janssen and Amgen, participation in sponsored events for Amgen, Janssen and Takeda, and provision of expert opinion for Celgene. JPdO reports consultancy with Celgene and Janssen. BP reports personal fees from Amgen, grants and personal fees from Celgene, personal fees from BMS, personal fees from Janssen, grants and personal fees from Sanofi, personal fees from Novartis, grants from EngMab, and grants and personal fees from Takeda, during the conduct of the study. NP reports personal fees from Celgene and Janssen, outside the submitted work. JB has received honoraria for lectures from Celgene, Janssen and Amgen. JSM reports membership of advisory boards for Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, and Roche. All other authors declare no competing interests. Ethics Approval Statement: The institutional review board and/or independent ethics committee of each participating centre approved the study (See page 76, 77 of the report for the list of the IEC's). All patients provided written informed consent before screening in accordance with the Declaration of Helsinki. Data were monitored by an external contract research organisation and centrally assessed.