Daratumumab Plus VRd Continues to Demonstrate Durable Benefits in Transplant-Ineligible Newly Diagnosed Multiple Myeloma

The addition of anti-CD38 therapy to standard induction regimens has transformed treatment expectations for patients with newly diagnosed multiple myeloma (NDMM). However, transplant-ineligible patients continue to be a particularly important population, as these patients commonly undergo poorer outcomes and fewer opportunities for treatment intensification.

The final results from the phase 3 CEPHEUS study (NCT03652064), presented at the 2026 American Society of Clinical Oncology Annual (ASCO) Meeting, provided more than 6 years of follow-up data demonstrating that daratumumab (Darzalex; Janssen Biotech, Inc) plus bortezomib (Velcade; Takeda Pharmaceutical Company and Janssen Pharmaceutical Companies), lenalidomide (Revlimid; Celgene), and dexamethasone, otherwise known as DVRd, delivers deep, durable responses and prolonged progression-free survival (PFS) in comparison with VRd alone in transplant-ineligible patients with NDMM.¹

Deep Responses in Multiple Myeloma

Achieving minimal residual disease (MRD) negativity is emerging as one of the strongest prognostic markers in MM. Clinicians are increasingly viewing sustained MRD negativity as a key indicator of long-term disease control, especially in patients who may not undergo autologous stem cell transplantation.

Improvements in MRD negativity and PFS with DVRd in comparison with VRd (bortezomib, lenalidomide, and dexamethasone) in transplant-ineligible or transplant-deferred patients were demonstrated previously in the CEPHEUS study. Prior analyses showed that approximately 70% of transplant-ineligible patients receiving DVRd remained alive and progression-free at nearly 5 years of follow-up. The final analysis was intended to determine whether these benefits would persist with longer observation.¹

CEPHEUS Trial Design

CEPHEUS is a phase 3 study that evaluated DVRd vs VRd in patients with NDMM who were either transplant-ineligible or had deferred transplant. The final analysis focused on the transplant-ineligible population.

Among the 395 enrolled patients, 289 were transplant-ineligible patients who received either DVRd (n = 144) or VRd (n = 145). The researchers evaluated the primary end point of overall MRD negativity at a sensitivity threshold of 10⁻⁵ and assessed secondary end points including sustained MRD negativity, complete response or better (≥CR), and investigator-assessed PFS. Median follow-up reached 76.0 months, providing one of the longest follow-up periods reported for a quadruplet regimen in this patient population.¹

Deeper and More Durable Responses with DVRd

Substantial improvements across multiple efficacy end points were demonstrated with DVRd in comparison with VRd.

Overall MRD negativity at the 10⁻⁵ threshold was achieved in 61.1% of patients receiving DVRd in comparison with 40.0% of patients receiving VRd (OR, 2.35; 95% CI, 1.47-3.77; P = .0004). At the more stringent 10⁻⁶ threshold, MRD negativity rates were 46.5% and 27.6%, respectively (OR, 2.27; 95% CI, 1.39-3.71; P = .0010).¹

Crucially, these responses were also more durable. Sustained MRD negativity at the 10^-5 threshold occurred in 49.3% of patients treated with DVRd compared with 29.0% of patients receiving VRd (OR, 2.40; 95% CI, 1.47-3.91; P = .0005). At the 10⁻⁶ threshold, sustained MRD negativity rates were 37.5% and 16.6%, respectively (OR, 3.01; 95% CI, 1.73-5.24; P < .0001).¹

Depth of response also favored the daratumumab-containing regimen. Complete response or better was achieved in 80.6% of patients treated with DVRd compared with 61.4% of patients treated with VRd (OR, 2.64; 95% CI, 1.54-4.51; P = .0003).¹

Progression-Free Survival Benefit Maintained Beyond 6 Years

Notably, the PFS benefit observed in earlier analyses progressively deepened with longer follow-up.

Median PFS was not estimable for the DVRd arm, while patients receiving VRd experienced a median PFS of 50.2 months (HR, 0.55; 95% CI, 0.39-0.78; P = .0007). At 72 months, 59.3% of patients receiving DVRd remained alive and progression free compared with 38.3% of patients receiving VRd.¹

While overall survival data remain immature, outcomes numerically favored DVRd over VRd (HR, 0.84; 95% CI, 0.57-1.24). The data noted that COVID-19 significantly affected the study population, and analyses censoring for COVID-19-related events showed a more favorable HR of 0.74 (95% CI, 0.49-1.12).¹

Reinforcing a Standard of Care

The CEPHEUS study’s final analysis provided compelling long-term evidence supporting DVRd as a standard-of-care regimen for transplant-ineligible patients with NDMM. After more than 6 years of follow-up, patients receiving DVRd experienced higher rates of MRD negativity, greater durability of response, improved complete response rates, and substantially prolonged PFS in comparison with VRd alone.

For a patient population that may be unable to have access to the benefits of stem cell transplantation, accomplishing durable disease control is especially important. The persistence of these benefits over more than 6 years reinforces the value of frontline quadruplet therapy and further establishes DVRd as a foundational treatment approach for transplant-ineligible NDMM.

References

1. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) in patients with newly diagnosed multiple myeloma (NDMM): final analysis of transplant-ineligible (TIE) patients in the phase 3 CEPHEUS study. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 7513.