# CEPHEUS: daratumumab quadruplet for newly diagnosed myeloma patients not having a transplant, with MRD-negativity as the main endpoint

Source: https://onco.cc/key-papers/paper-cepheus-dara-vrd-natmed-2025/  
OnCo record `paper-cepheus-dara-vrd-natmed-2025` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Nature Medicine
- Year: 2025
- DOI: 10.1038/s41591-024-03485-7
- Authors: Usmani SZ, Facon T, Hungria V, et al.
- 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.
- What it means: 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.

## Sources

- PubMed search: https://pubmed.ncbi.nlm.nih.gov/?term=CEPHEUS%20daratumumab%20bortezomib%20lenalidomide%20transplant-ineligible%20Usmani%20Nature%20Medicine%202025
- ClinicalTrials.gov NCT03652064: https://clinicaltrials.gov/study/NCT03652064

## Connected records

- key papers: [MAIA: adding daratumumab to lenalidomide-dexamethasone for older patients with newly diagnosed myeloma who cannot have a transplant](https://onco.cc/key-papers/paper-maia-daratumumab-rd-nejm-2019/)
- cancers: [Multiple myeloma](https://onco.cc/cancers/multiple-myeloma/), [Newly diagnosed multiple myeloma, transplant-ineligible](https://onco.cc/cancers/myeloma-transplant-ineligible/)
- technologies: [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/)
- targets: [CD38](https://onco.cc/targets/cd38/)
- drugs: [Bortezomib](https://onco.cc/drugs/bortezomib/), [Daratumumab](https://onco.cc/drugs/daratumumab/), [Lenalidomide](https://onco.cc/drugs/lenalidomide/)
- companies: [Johnson & Johnson](https://onco.cc/companies/johnson-johnson/)
- terms: [MRD negativity (myeloma, 10⁻⁵ / 10⁻⁶)](https://onco.cc/terms/mrd-negativity-myeloma/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/)
- trials: [CEPHEUS](https://onco.cc/trials/cepheus/), [IMROZ](https://onco.cc/trials/imroz/)
- people: [Saad Z. Usmani](https://onco.cc/people/saad-usmani/)
- bottlenecks: [Dormant cells and minimal residual disease](https://onco.cc/bottlenecks/b-dormancy-mrd/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- journals: [Nature Medicine](https://onco.cc/journals/nature-medicine/)

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