The phase 3 CEPHEUS trial (NCT03652064) assessed daratumumab (DARA, Darzalex; Janssen Biotech, Inc) in combination with bortezomib (Velcade; Millennium: The Takeda Oncology Company), lenalidomide (Revlimid; Celgene), and dexamethasone (D-VRd) as a frontline therapy for patients with newly diagnosed multiple myeloma (NDMM) who were transplant-ineligible or for whom transplant was deferred. At the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California, lead trial investigator Sonja Zweegman, MD, PhD, presented results of an analysis of minimal residual disease (MRD) from the CEPHEUS trial.1,2
A vector representation of multiple myeloma cells. Image Credit: © sovova - stock.adobe.com
CEPHEUS is multicenter, open-label, randomized, phase 3 trial, and its primary end point focused on MRD negativity, which is increasingly recognized as a strong prognostic factor in multiple myeloma, as it correlates with improved long-term survival outcomes. Further, MRD negativity has increasingly become a key clinical end point in clinical trials as the FDA's Oncology Drug Advisory Committee has supported MRD as an early end point for accelerated approvals for multiple myeloma therapies, Zweegman explained.1,2
“CEPHEUS is the first phase 3 DARA trial with MRD as a primary end point, and it showed that the addition of DARA to VRd in patients who are transplant ineligible or for whom transplant was deferred led to superior overall and sustained MRD negative [complete response (CR)], and it significantly improved progression free survival [PFS],” said Zweegman, head of the Department of Hematology at VU Medisch Centrum in Amsterdam, Netherlands, during the ASH presentation.1
The study included 395 patients who were randomized to receive either standard VRd or D-VRd. Patients with NDMM were enrolled if there was no intent for transplant based upon their age (≥70 yrs), presence of comorbid conditions likely to hinder transplant or high-dose chemotherapy tolerance, or had deferred first-line transplant. The patients were stratified by International Staging System (ISS) disease stage and age/transplant eligibility (<70 yrs ineligible, <70 yrs and transplant deferred, ≥70 yrs) and randomized 1 to 1 to D-VRd or VRd.1,2
The primary end point was the rate of MRD negativity at a sensitivity threshold of 10-5, with patients who did not achieve CR or were evaluable considered MRD positive. MRD was assessed using next-generation sequencing at several time points, including at 12, 18, 24, 30, and 36 months, with the aim of determining the depth of response.1,2
The results from the CEPHEUS trial demonstrated that the addition of DARA to VRd significantly increased MRD negativity rates compared to VRd alone. At the 10-5 threshold, 60% of patients in the D-VRd group achieved MRD negativity, compared to 40% in the VRd group. When the sensitivity threshold was raised to 10-6, the MRD negativity rate in the D-VRd group was 46.2%, compared to 27.3% in the VRd group. This increase in MRD negativity translated into a substantial improvement in PFS, with the D-VRd group showing a 43% reduction in the risk of disease progression or death compared to VRd alone. At 45 months, 68.1% of patients treated with D-VRd were progression-free, compared to 49.5% in the VRd group.1,2
Further analysis revealed that improvement in MRD negativity with D-VRd was consistent across subgroups, regardless of age, performance status, or ISS disease stage. Additionally, the study found that patients treated with D-VRd reached MRD negativity more rapidly than those receiving VRd alone, with the difference in MRD-negativity rates widening over time at up to 3 years.1,2
Importantly, sustained MRD negativity, defined as MRD negativity lasting for at least 12 months, was strongly associated with superior PFS. D-VRd almost doubled the sustained MRD negativity rates at 12, 24, and 36 months compared to VRd, indicating that deeper, longer-lasting responses were achieved with DARA added to VRd. This finding underscores the implication of sustained MRD negativity, which has been shown to be a predictor of long-term survival.1,2
The impact of achieving MRD negativity at the 10-6 threshold was particularly pronounced in terms of PFS. Patients who achieved MRD negativity at this threshold with D-VRd had the strongest PFS outcomes, with 86.2% of them being progression-free at 54 months. This was in contrast to the VRd group, where the rate of PFS was significantly lower. The addition of DARA to VRd resulted in improved outcomes regardless of whether patients achieved MRD negativity or not, with better PFS observed in patients who were MRD-negative in both treatment arms.1,2
Overall, the CEPHEUS trial demonstrated that the addition of DARA to the standard VRd regimen significantly improved both the depth and duration of MRD negativity in transplant-ineligible or transplant-deferred patients with NDMM. This deeper and more sustained MRD negativity translated into significantly improved PFS, with D-VRd showing a clear benefit over VRd alone. These findings support the use of D-VRd as a new standard of care for patients with NDMM who are transplant-ineligible or for whom transplant is deferred, providing strong evidence for the use of DARA in combination with VRd as a frontline treatment. The results of this trial also further validate MRD negativity as a valuable end point in multiple myeloma therapy, according to Zweegman.1,2
“CEPHEUS is the fifth phase 3 trial in NDMM showing that the addition of DARA to standard of care regimens improved the depth and the duration of response, leading to improved PFS,” Zweegman said. “These data underscore that the use of DARA in combination with VRD is another standard of care for patients with NDMM who are transplant ineligible or in whom transplant is deferred.”1
REFERENCES
Zweegman S. 653. Multiple Myeloma: Clinical and Epidemiological: Advancing Minimal Residual Disease (MRD): Detection, Impact on Prognosis and Treatment Decisions. Presented at: 66th ASH Annual Meeting and Exposition; San Diego, California; December 7-10, 2024.
Zweegman S, Facon T, Hungria V, et al. 362 Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide and Dexamethasone (VRd) Versus Alone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma or for Whom Transplant Is Not Planned As Initial Therapy: Analysis of Minimal Residual Disease in the Cepheus Trial. American Society of Hematology. 2024. Accessed December 7, 2024. https://ash.confex.com/ash/2024/webprogram/Paper200871.html