CEPHEUS Highlights Efficacious, Safe Regimen for Transplant-Ineligible/Deferred Multiple Myeloma

The landscape of multiple myeloma care has advanced and developed in transformational ways and will continue to do so as leading experts push the bounds of research and therapy. The phase 3 CEPHEUS trial (NCT03652064)
evaluating subcutaneous daratumumab (D; Darzalex) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma is one of the more recent trials to highlight an efficacious and safe regimen in the landscape.

During a Between the Lines program hosted by CancerNetwork, Hans Lee, MD, the director of myeloma research at the Sarah Cannon Research Institute; and Andrew Yee, MD, an assistant professor of medicine at Harvard Medical School and the clinical director of the Center for Multiple Myeloma at Massachusetts General Hospital, gathered to speak about recent breakthroughs and discoveries in the multiple myeloma field.

CEPHEUS Results From the First Readout

“The cornerstone of therapy has been subcutaneous daratumumab [because], for me, that drug represents an amazing combination of both efficacy and tolerability,” Yee said.

With a median follow-up of 58.7 months, the overall minimal residual disease (MRD) negativity rate with a complete response (CR) or better was 60.9% with D-VRd vs 39.4% with VRd alone (OR, 2.37; 95% CI, 1.58-3.55; P < .0001).¹ The sustained MRD negativity rate at 12 months or more was 48.7% vs 26.3%, respectively (OR, 2.63; 95% CI, 1.73-4.00; P < .0001). Notably, the CR or better rate was 81.2% with daratumumab plus VRd vs 61.6% with VRd alone (OR, 2.73; 95% CI, 1.71-4.34; P < .0001).

The median progression-free survival (PFS) was not reached (NR) with D-VRd vs 52.6 months with VRd alone (HR, 0.57; 95% CI, 0.41-0.79; P = .0005); the overall survival HR trended in favor of D-VRd vs VRd alone (HR, 0.85; 95% CI, 0.58-1.24).

Updated results shared at the 2025 American Society of Clinical Oncology Annual Meeting spotlighted the combination through a cytogenetic subgroup analysis and a subgroup analysis of patients who are transplant ineligible.^2,3

Cytogenetic Risk Subgroup Results

“Particularly among the standard-risk patients and revised data-risk patients, there’s a significantly higher MRD negativity rate at a sensitivity of 10^-5 with D-VRd vs VRd [alone]. In the high-risk or revised high-risk groups, there are comparable MRD negativity rates of 10^-5 between the 2 groups,” Lee said.

The overall MRD negativity rate was 64% with D-VRd and 38% with VRd (P < .0001) in patients with standard cytogenetic risk, and in those with revised standard risk, it was 68% vs 38%, respectively (P < .0001). The 12-month or more sustained MRD negativity rate in the standard risk group was 51% vs 26% (P < .0001) and 54% vs 24% in the revised standard risk group (P < .0001).

In the high-risk group, the overall MRD negativity rate was 48% with D-VRd and 56% with VRd (P = .7816); in the revised high-risk group, it was 55% vs 45%, respectively (P = .2169). The 12-month or more sustained MRD negativity rate in the high-risk group was 40% vs 37% (P = 1.0000) and 43% vs 30% in the revised high-risk group (P = .0782).

In patients with standard cytogenetic risk, the median PFS was not evaluable (NE) with D-VRd compared with 60.6 months with VRd alone (HR, 0.61; 95% CI, 0.41-0.91; P = .0136); in the revised standard risk group, the median PFS was NE vs 60.6 months, respectively (HR, 0.54; 95% CI, 0.32-0.91; P = .0189).

In the high-risk subgroup, the median PFS with D-VRd was 39.8 months vs 31.7 months with VRd alone (HR, 0.88; 95% CI, 0.42-1.84; P = .7387); in the revised high-risk subgroup, it was NE vs 45.6 months, respectively (HR, 0.73; 95% CI, 0.46-1.15; P = .1739).

On whether attaining MRD negativity translated into a PFS benefit, Lee said, “Among the patients who are standard risk and revised standard risk, there was a significant benefit with D-VRd vs VRd alone. There would seem to be a trend toward some benefit to PFS in the high-risk and revised high-risk subgroups in those patients on D-VRd vs VRd [alone].”

Transplant-Ineligible Subgroup Results

“When you’re looking at more of a frailer, transplant-ineligible patient population, D-VRd is superior to VRd alone,” Lee said.

At a median follow-up of 58.7 months, the subgroup analysis for patients who were ineligible to receive transplant revealed an overall MRD negativity rate, with a specificity of 10^-6, was 45.8% with D-VRd vs 26.9% with VRd alone (OR, 2.28; 95% CI, 1.40-3.73; P = .001). With a specificity of 10^-5, the MRD negativity rate was 60.4% vs 39.3%, respectively (OR, 2.37; 95% CI, 1.47-3.80; P < .0001); the 12-month or more sustained MRD negativity was 46.5% vs 27.6% (OR, 2.27; 95% CI, 1.39-3.70; P = .0010).

The PFS was NR with D-VRd and 49.6 months with VRd alone; the 54-month PFS rate was 69.0% vs 48.0%, respectively (HR, 0.51; 95% CI, 0.35-0.74; P = .0003). The HR for overall survival was 0.66 (95% CI, 0.42-1.03), which, after censoring for COVID-19 deaths, became 0.55 (95% CI, 0.34-0.90).

“When you focused on the transplant-ineligible [population], the PFS curves were practically identical to the original overall data set. That provides further validation of incorporating this and using a 4-drug regimen,” Yee said.

Because the transplant-ineligible patient population tends to be older and frailer, Yee reduces the dose of lenalidomide from 25 mg to 15 mg and administers bortezomib once weekly instead of twice on a 28-day schedule. This serves to reduce the risk of peripheral neuropathy and makes the therapy more convenient for the patient. “Dialing down the lenalidomide a notch probably does help in terms of patient tolerability and success with the regimen,” he said.

“In the real world, all of us dose modify the lenalidomide and bortezomib, and we often deescalate the dexamethasone,” Lee said.

Safety

“There are no new unexpected safety signals seen with D-VRd vs VRd alone,” Lee said, regarding the safety profile of the agents.

The most common any-grade adverse effects (AEs) stemming from D-VRd were infection (91.9%), diarrhea (56.9%), peripheral sensory neuropathy (55.8%), neutropenia (55.8%), and thrombocytopenia (46.7%); of grade 3 or 4 AEs, the most common were neutropenia (44.2%), infection (40.1%), and thrombocytopenia (28.4%).

Although there are slight increases in the incidence of neutropenia, thrombocytopenia, and infections with the quadruplet, none are unexpected. “I don’t think daratumumab necessarily adds any additional toxicity to the regimen,” Yee said. He also added that it is the “easiest” of the 4 drugs, though it may add an increased risk of infection.

Yee also iterated that although many patients might not notice the increased risk of infection, they may notice the improvement in their quality of life and the rapid responses that the 4-drug regimen elicits.

Of note, the peripheral neuropathy was of concern, though, as noted earlier, reducing the bortezomib to once weekly from twice weekly helps manage that problem. Regarding the increased risk of infections, intravenous immunoglobulin was recommended to mitigate that issue.

Both doctors agreed that with the appropriate, unique dose modification, the daratumumab plus VRd regimen is “very tolerable” as a long-term treatment. “Ultimately, it is about individualizing the treatment to the patient,” Lee concluded.

References

1. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025;31(4):1195-1202. doi:10.1038/s41591-024-03485-7
2. Bahlis NJ, Usmani SZ, Facon T, et al. Daratumumab + bortezomib, lenalidomide, and dexamethasone (DVRd) vs VRd in transplant-ineligible (TIE)/transplant-deferred (TD) newly diagnosed multiple myeloma (NDMM): phase 3 CEPHEUS trial cytogenetic subgroup analysis.J Clin Oncol. 2025;43(suppl 16):7529. doi:10.1200/JCO.2025.43.16_suppl.7529
3. Facon T, Zweegman S, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) in patients with newly diagnosed multiple myeloma (NDMM): subgroup analysis of transplant-ineligible (TIE) patients in the phase 3 CEPHEUS study. J Clin Oncol. 2025;43(suppl 16):7516. doi:10.1200/JCO.2025.43.16_suppl.7516