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