Daratumumab Combo Exhibits Sustained Efficacy in Transplant-Ineligible NDMM

Daratumumab (Darzalex) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (DVRd) produced significantly higher rates of minimal residual disease (MRD)-negativity and improved progression-free survival (PFS) vs bortezomib, lenalidomide, and dexamethasone (VRd) in patients with transplant-ineligible, newly diagnosed multiple myeloma, according to data from a post-hoc analysis of the phase 3 CEPHEUS trial (NCT03652064), which were presented at the 2026 American Society of Clinical Oncology Annual Meeting (ASCO).¹

Data from the analysis of the transplant-ineligible subgroup in the trial, showed that a median follow-up of 76 months, patients who received DVRd (n = 144) achieved an overall MRD-negativity rate at 10^-5 sensitivity of 61.1% vs 40.0% with VRd (n = 145'; odds ratio [OR], 2.35; 95% CI, 1.47–3.77; P = .0004). The rate of sustained MRD-negativity for 12 months or longer 49.3% vs 29.0% with DVRd and VRd, respectively (OR, 2.40; 95% CI, 1.47–3.91; P = .0005). Moreover, the 24-month sustained MRD-negativity rate in each of the respective arms was 44.4% vs 23.4% (OR, 2.62; 95% CI, 1.58–4.36; P = .0002).

Prior data from CEPHEUS led to the January 2026 FDA approval of DVRd for patients who are with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant.²

“After a median follow-up of over 6 years, the final analysis of the CEPHEUS trial demonstrated that DVRd continues to show superior efficacy over VRd across key end points in transplant-ineligible patients,” said Saad Z. Usmani, MD, MBA, FACP, FASCO, in a presentation of the data.¹

Usmani is chief of Myeloma Service at Memorial Sloan Kettering Cancer Center.

How was CEPHEUS designed?

CEPHEUS was a randomized, open-label study enrolled patients who were transplant-ineligible or transplant-deferred, had an ECOG performance status of 2 or less, and an International Myeloma Working Group frailty score of 1 or less.

If patients had received prior therapy for multiple myeloma, invasive malignancies within the 5 years prior or grade 2 or higher peripheral neuropathy they were not included in the trial.³

Patients were randomly assigned to DVRd or VRd for cycles 1 through 8 on 21-day cycles, followed by daratumumab plus lenalidomide and dexamethasone for patients in the DVRd arm or lenalidomide and dexamethasone for patients in the VRd on 28-day cycles until disease progression or unacceptable toxicities were experienced.

Overall MRD-negativity was the primary end point of the trial. Key secondary end points included progression-free survival, sustained MRD-negativity, and complete response (CR) or better rate.

Baseline characteristics for the transplant-ineligible subpopulation (n = 289), which represented approximately 75% of the overall CEPHEUS enrollment, revealed that patients had a median age of 72 years, with approximately 76% of patients aged 70 years or older and approximately 30% aged 75 years or older. Usmani noted that this population was an older, frailer patient group with distinct clinical characteristics compared with patients in the intent-to-treat population.

What were the additional data for DVRd vs VRd in transplant-ineligible multiple myeloma?

The median PFS was not reached with DVRd compared with 50.2 months with VRd (HR, 0.55; 95% CI, 0.39–0.78; P = .0007), representing a 45% reduction in the risk of disease progression or death. Furthermore, the 72-month PFS rate for the DVRd arm was 59.3% compared with 38.3% in the VRd arm.

Overall survival (OS) rates in the analysis showed a hazard ratio (HR) of 0.84 (95% CI, 0.57–1.24). When deaths due to COVID-19 were censored, the OS HR improved to 0.74 (95% CI, 0.49–1.12).

The leading cause of death in each arm were unrelated adverse effects (AEs), with these deaths occurring in 16% of patients in the DVRd arm and 10.6% of the VRd arm. Eleven COVID-19 deaths occurred across each arm, 8 of which were in the DVRd arm and 3 were in the VRd arm. Progressive disease deaths were higher in the VRd arm (12%) vs the DVRd arm (5.6%).

Any-grade treatment-emergent AEs (TEAE) occurred in all patients in the analysis. Grade 3 or 4 TEAEs were reported in 93.8% and 88.7% of patients in DVRd and VRd arms, respectively. Grade 5 TEAEs unrelated to COVID-19 occurred in 12.5% vs 9.2% of patients, and COVID-19-related grade 5 TEAEs were experienced by 4.2% and 0.7% of patients in each of the respective arms. Serious TEAEs occurred in 75.7% of patients in the DVRd arm compared with 69.7% of patients in the VRd arm. TEAEs leading to treatment discontinuations were lower with DVRd (9.7%) vs VRd (23.2%).

Grade 3 or 4 TEAEs that occurred in at least 5% of patients included neutropenia (DVRd, 45.1%; VRD, 33.1%), thrombocytopenia (30.6%; 23.2%), anemia (11.1%; 9.9%), diarrhea (13.9%; 10.6%), fatigue (9.0%; 10.6%), COVID-19 (9.7%; 3.5%), and pneumonia (18.1%; 13.4%). Peripheral sensory neuropathy of any grade occurred in 59.7% of the DVRd arm vs 64.1% of the VRd arm; grade 3 or 4 peripheral sensory neuropath were reported in 9.7% vs 8.5% of each arm, respectively. Second primary malignancies occurred at a similar rate in both arms (13.9%; 14.1%).

References

1. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) in patients with newly diagnosed multiple myeloma: final analysis of transplant-ineligible (TIE) patients in the phase 3 CEPHEUS study. J Clin Oncol. 2026;44(suppl 16):7513. doi:10.1200/JCO.2026.44.16_suppl.7513

2. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. January 27, 2026. Accessed May 31, 2026. https://tinyurl.com/mvex2bfa

3. A study comparing daratumumab, Velcade (bortezomib), lenalidomide, and dexamethasone (D-VRd) with Velcade, lenalidomide, and dexamethasone (VRd) in participants with untreated multiple myeloma and for whom hematopoietic stem cell transplant is not planned as initial therapy. ClinicalTrials.gov. Updated January 20, 2026. Accessed May 31, 2026. https://tinyurl.com/3wdamt5u