BACKGROUND: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual. FINDINGS: Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4-9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2-88·1) versus 85·0% (76·8-90·5; hazard ratio [HR] 1·22; 95% CI 0·67-2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).