{"entity":{"id":"paper-cepheus-dara-vrd-natmed-2025","kind":"paper","name":"CEPHEUS: daratumumab quadruplet for newly diagnosed myeloma patients not having a transplant, with MRD-negativity as the main endpoint","aka":[],"tldr":"In patients who were transplant-ineligible or deferred transplant, the daratumumab quadruplet raised deep-remission rates from about 39% to 61% and cut progression risk by 43%.","summary":"CEPHEUS randomised 395 patients with newly diagnosed multiple myeloma who were transplant-ineligible or for whom transplant was deferred to daratumumab plus bortezomib, lenalidomide and dexamethasone (D-VRd) or VRd. Unusually, the primary endpoint was the overall MRD-negativity rate at 10^-5 sensitivity, reflecting the FDA advisory committee's 2024 acceptance of MRD as an endpoint supporting accelerated approval. MRD-negativity was 60.9% versus 39.4%, complete response or better 81.2% versus 61.6%, and PFS favoured D-VRd (hazard ratio 0.57). Toxicity was in line with other daratumumab quadruplets.","asOf":"2026-09-08","links":[{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=CEPHEUS%20daratumumab%20bortezomib%20lenalidomide%20transplant-ineligible%20Usmani%20Nature%20Medicine%202025"},{"label":"ClinicalTrials.gov NCT03652064","url":"https://clinicaltrials.gov/study/NCT03652064"}],"tags":[],"related":["paper-maia-daratumumab-rd-nejm-2019"],"cancers":["multiple-myeloma"],"sections":[],"technologies":["mrd-testing"],"targets":["cd38"],"drugs":["daratumumab","bortezomib","lenalidomide"],"companies":["johnson-johnson"],"institutions":[],"pathways":[],"terms":["mrd-negativity-myeloma","pfs"],"trials":["cepheus","imroz"],"people":["saad-usmani"],"bottlenecks":["b-trial-design","b-dormancy-mrd"],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2025,"doi":"10.1038/s41591-024-03485-7","pmid":"39910273","authors":"Usmani SZ, Facon T, Hungria V, et al.","paperType":"rct","findings":["395 transplant-ineligible or transplant-deferred patients; D-VRd vs VRd.","Primary endpoint, overall MRD-negativity at 10^-5: 60.9% vs 39.4%.","Complete response or better 81.2% vs 61.6%.","PFS hazard ratio 0.57 in favour of D-VRd.","Infection and cytopenia rates were higher with the quadruplet, consistent with PERSEUS."],"whatItMeans":"CEPHEUS extends the quadruplet standard to patients who are not going to transplant, closing the gap between transplant-eligible and ineligible populations. It is also one of the first phase 3 trials to be designed around MRD-negativity as the primary endpoint, which could shorten future myeloma trials by years. Frailer patients still need dose-adapted approaches.","caveats":["MRD-negativity is a surrogate; PFS and OS benefits need longer follow-up to confirm.","Included relatively fit transplant-deferred patients as well as truly ineligible ones.","Bortezomib-based induction is not ideal for very frail patients; the parallel IMROZ trial used a different quadruplet.","Cross-trial comparison with MAIA is indirect."],"changedPractice":true,"participants":395},"route":"/key-papers/paper-cepheus-dara-vrd-natmed-2025/","neighbours":{"paper":[{"id":"paper-maia-daratumumab-rd-nejm-2019","kind":"paper","name":"MAIA: adding daratumumab to lenalidomide-dexamethasone for older patients with newly diagnosed myeloma who cannot have a transplant","route":"/key-papers/paper-maia-daratumumab-rd-nejm-2019/"}],"cancer":[{"id":"multiple-myeloma","kind":"cancer","name":"Multiple myeloma","route":"/cancers/multiple-myeloma/"},{"id":"myeloma-transplant-ineligible","kind":"cancer","name":"Newly diagnosed multiple myeloma, transplant-ineligible","route":"/cancers/myeloma-transplant-ineligible/"}],"technology":[{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/"}],"target":[{"id":"cd38","kind":"target","name":"CD38","route":"/targets/cd38/"}],"drug":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"},{"id":"daratumumab","kind":"drug","name":"Daratumumab","route":"/drugs/daratumumab/"},{"id":"lenalidomide","kind":"drug","name":"Lenalidomide","route":"/drugs/lenalidomide/"}],"company":[{"id":"johnson-johnson","kind":"company","name":"Johnson & Johnson","route":"/companies/johnson-johnson/"}],"term":[{"id":"mrd-negativity-myeloma","kind":"term","name":"MRD negativity (myeloma, 10⁻⁵ / 10⁻⁶)","route":"/terms/mrd-negativity-myeloma/"},{"id":"pfs","kind":"term","name":"Progression-free survival (PFS)","route":"/terms/pfs/"}],"trial":[{"id":"cepheus","kind":"trial","name":"CEPHEUS","route":"/trials/cepheus/"},{"id":"imroz","kind":"trial","name":"IMROZ","route":"/trials/imroz/"}],"person":[{"id":"saad-usmani","kind":"person","name":"Saad Z. Usmani","route":"/people/saad-usmani/"}],"bottleneck":[{"id":"b-dormancy-mrd","kind":"bottleneck","name":"Dormant cells and minimal residual disease","route":"/bottlenecks/b-dormancy-mrd/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"}],"journal":[{"id":"nature-medicine","kind":"journal","name":"Nature Medicine","route":"/journals/nature-medicine/"}]}}