Clinical trialPhase 3Multiple myeloma

Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial.

Nat Med · 2025395 patients

Usmani SZ, Facon T, Hungria V, et al. Nat Med. 2025. 31:1195-1202

Study type: Clinical trial
Study name: CEPHEUS
Phase: Phase 3
Design: Randomised trial
Sample size: 395 patients
Source: Nat Med · 2025
Trial registration: NCT03652064

In plain words

This study was for people with newly diagnosed myeloma for whom a bone marrow (stem cell) transplant was not suitable or not planned for now. One group received a common three-drug regimen (bortezomib, lenalidomide and dexamethasone) and the other group received the same three drugs plus daratumumab given under the skin. With daratumumab added, more patients had no trace of the disease left even on very sensitive tests (about 61% versus 39%), and the risk of the disease getting worse or of death was 43% lower. The side effects were the known side effects of these drugs.

Key results

60.9% vs 39.4%

MRD negativity (10⁻⁵)

Odds ratio 2.37 (95% CI 1.58–3.55); P < 0.0001; median follow-up 58.7 months

81.2% vs 61.6%

Complete response or better

P < 0.0001

48.7% vs 26.3%

Sustained MRD negativity (at least 12 months)

P < 0.0001

43% reduction

Risk of progression or death

HR 0.57 (95% CI 0.41–0.79); P = 0.0005

Drugs in this study:Bortezomib (Velcade)Lenalidomide (Revlimid)Daratumumab (Darzalex)

Dose and schedule cards

D-VRd in transplant-ineligible patients (CEPHEUS trial)

Newly diagnosed myeloma, transplant-ineligible or with no planned transplantation; in the EHA-EMN guideline, for patients under 80 years of age without significant frailtyOn the page “Multiple myeloma” · Newly diagnosed myeloma: transplant-ineligible patients

Newly diagnosed myeloma, transplant-ineligible or with no planned transplantation; in the EHA-EMN guideline, for patients under 80 years of age without significant frailty

Drug	Dose	Route	Schedule
Subcutaneous daratumumab	1,800 mg	SC	Weekly in Weeks 1–6, every 3 weeks in Weeks 7–24, every 4 weeks from Week 25
Cycles 1–8 (21-day)
Bortezomib	1.3 mg/m²	SC	Days 1, 4, 8 and 11
Lenalidomide	25 mg once daily	Oral	Days 1–14
Dexamethasone	20 mg (age over 75 years or BMI below 18.5: 20 mg on Days 1, 4, 8 and 11)	Oral	Days 1, 2, 4, 5, 8, 9, 11 and 12
Cycle 9 onward (28-day)
Lenalidomide	25 mg once daily	Oral	Days 1–21
Dexamethasone	40 mg (age over 75 years or BMI below 18.5: 20 mg)	Oral	Days 1, 8, 15 and 22

Cycle length: Cycles 1–8 every 21 days; from Cycle 9 every 28 days
Duration: 8 cycles of D-VRd, then daratumumab + lenalidomide + dexamethasone until progression

Doses from the FDA label for DARZALEX FASPRO (CEPHEUS section); results from CEPHEUS; place in therapy from the EHA-EMN guideline.

On the page “Multiple myeloma” · Newly diagnosed myeloma: transplant-ineligible patients

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Daratumumab + bortezomib + lenalidomide + dexamethasone (D-VRd)

Daratumumab 1800 mg subcutaneously weekly in weeks 1 to 6, every 3 weeks in weeks 7 to 24 and every 4 weeks from week 25 until disease progression. Cycles 1 to 8 (21 days): bortezomib 1.3 mg/m² subcutaneously on days 1, 4, 8 and 11; lenalidomide 25 mg orally on days 1 to 14; dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 (in patients over 75 years or with BMI below 18.5: 20 mg on days 1, 4, 8 and 11). From cycle 9 (28 days): lenalidomide 25 mg on days 1 to 21 and dexamethasone 40 mg on days 1, 8, 15 and 22 (or 20 mg weekly in patients over 75 years or with BMI below 18.5) with daratumumab, until disease progression.

2Bortezomib + lenalidomide + dexamethasone (VRd)

Eight cycles of VRd at the same doses and schedule, then lenalidomide + dexamethasone (Rd) until disease progression.

Source of the regimen details: FDA label for DARZALEX FASPRO (Clinical Studies section, CEPHEUS)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with newly diagnosed multiple myeloma who were transplant-ineligible or for whom transplant was not planned as initial therapy (transplant deferred); 395 patients (55% in the D-VRd group aged 70 years or older).

Endpoints

Primary endpoint: overall rate of minimal residual disease (MRD) negativity at a threshold of 10^-5 by next-generation sequencing.

Key secondary endpoints: rate of complete response or better, progression-free survival and rate of sustained MRD negativity at 10^-5.

Safety and side effects

The most common grade 3 or 4 adverse events (D-VRd vs VRd): neutropenia 44.2% vs 29.7% and thrombocytopenia 28.4% vs 20.0%. Peripheral neuropathy of any grade 61.9% vs 66.2%, grade 2: 31.5% vs 36.9%, and grade 3 or 4: 11.2% vs 10.8%. Adverse events were consistent with the known safety profiles of daratumumab and VRd (full paper).

Clinical significance and place in guidelines

CEPHEUS showed that adding subcutaneous daratumumab to VRd in transplant-ineligible or transplant-deferred patients produces deeper responses (MRD negativity) and better progression-free survival. The authors regard D-VRd as a new standard of care in this group.

Limitations

The primary endpoint was MRD negativity (a surrogate endpoint), and the abstract gives no overall survival data. The study population mixed transplant-ineligible and transplant-deferred patients. Adverse-event figures and doses are not given in the abstract.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.