The CEPHEUS trial is the first to report outcomes when daratumumab is combined with VRd as a front-line strategy in transplant-ineligible and transplant-deferred newly diagnosed myeloma.— Saad Z. Usmani, MD, MBA, FACP, FASCO
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In the phase III CEPHEUS trial,1 the achievement of undetectable measurable residual disease (or MRD negativity)—the primary endpoint—was met by 61% of patients with transplant-ineligible or deferred newly diagnosed multiple myeloma treated with the monoclonal antibody daratumumab plus bortezomib, lenalidomide, and dexamethasone (VRd) as induction. “CEPHEUS complements the MAIA trial2 of daratumumab plus Rd, supporting a daratumumab-based quadruplet or triplet as the standard treatment” in this population, said Saad Z. Usmani, MD, MBA, FACP, FASCO, of Memorial Sloan Kettering Cancer Center, New York, who presented the findings at the 2024 International Myeloma Society (IMS) Annual Meeting.
“The CEPHEUS trial is the first to report outcomes when daratumumab is combined with VRd as a front-line strategy in transplant-ineligible and transplant-deferred newly diagnosed myeloma,” Dr. Usmani noted. MRD negativity was improved by an absolute 22% with daratumumab plus VRd, and the risk of disease progression or death was reduced by 43%.
“Throughout the IMS meeting, we heard how important MRD has become as an endpoint for clinical trials and how MRD negativity is associated with improvements in both progression-free and overall survival,” Dr. Usmani noted. “We are also aware of how daratumumab has become an important front-line strategy, with the PERSEUS data3 demonstrating both improved depth of response and progression-free survival benefit, and MAIA2 setting a new benchmark for median overall survival, 7.5 years. Triplet therapies, however, still remain the standard of care in the newly diagnosed transplant-ineligible population.”
About CEPHEUS
In the CEPHEUS trial, 395 patients were randomly assigned to receive standard induction with VRd followed by Rd as maintenance or the same with the addition of subcutaneous daratumumab both for induction and maintenance. The primary endpoint was overall MRD negativity at 10-5.
More than half the population was aged 70 or older, though only one-third were considered to be frail. High-risk cytogenetics were documented in 13%. Approximately 27% of patients in each arm had transplants deferred, and 73% were considered transplant-ineligible. Of note, the median treatment duration was much longer with daratumumab plus VRd (56.3 months) than with VRd alone (34.3 months).
High Rates of MRD Negativity
“The addition of daratumumab increased the overall MRD negativity rate as well as the rate of complete response or better by about 20%,” Dr. Usmani reported. He noted the following outcomes with daratumumab plus VRd induction compared with VRd alone:
- Complete response or better: 81.2% vs 61.6% (OR = 2.73;
P < .0001) - MRD negativity: 60.9% vs 39.4% (odds ratio [OR] = 2.37;
P < .0001) - MRD negativity at 10-6 sensitivity: 46.2% vs 27.3% (OR = 2.37;
P < .0001) - Sustained MRD negativity at 10-5 sensitivity: 46.2% vs 27.3%
(OR = 2.24; P = .0001) - Sustained MRD negativity ≥ 12 months: 48.7% vs 26.3%
(OR = 2.63; P < .0001).
At a median follow up of 58.7 months, the median progression-free survival has not been reached with daratumumab plus VRd but is 52.6 months with VRd alone—a statistically significant difference (hazard ratio [HR] = 0.57; P = .0005). The progression-free survival rates at 54 months were 68.1% and 49.5%, respectively, with a favorable trend for the use of the daratumumab combination in most prespecified subgroups.
KEY POINTS
- The phase III CEPHEUS trial is the first to report outcomes when the monoclonal antibody daratumumab is combined with bortezomib, lenalidomide, and dexamethasone (VRd) as a front-line strategy in transplant-ineligible and transplant-deferred newly diagnosed myeloma.
- With daratumumab, measurable residual disease (MRD) negativity was improved by an absolute 22%, and the risk of disease progression or death was reduced by 43%.
- MRD negativity was achieved by 61% of patients receiving daratumumab plus VRd and 39% of those treated with VRd alone for induction.
Overall survival data remain immature, but the curves begin separating after 3 years (HR = 0.85; 95% confidence interval [CI] = 0.58–1.24). “Given the fact that the majority of enrollment on this study occurred at the height of the pandemic, we censored for death due to COVID-19…and saw the hazard ratio drop (HR = 0.69; 95% CI = 0.45–1.05). That trend is a little more pronounced after 3 years—though again, these data are immature,” Dr. Usmani added.
Safety Data
With a median duration of treatment on the daratumumab arm of almost 22 months longer than for the VRd arm, Dr. Usmani noted more grade 3 or 4 treatment-related adverse events in the experimental arm—92.4% vs 85.6%—but fewer patients in that arm discontinued all study drugs because of toxicity—7.6% vs 15.9%, respectively. Non-COVID–related treatment-related deaths numbered 21 (10.7%) and 15 (7.7%), respectively, though after adjustment for the 2-year difference in treatment duration, these rates were comparable (0.39 and 0.31 per 100 patients, respectively).
The safety data were consistent with the established profile of each individual drug. Quality-of-life assessments, performed throughout the study, showed improvements in both arms, “highlighting the fact that the addition of daratumumab did not lead to a detriment in quality of life,” Dr. Usmani said.
EXPERT POINT OF VIEW
Nisha S. Joseph, MD
Nisha S. Joseph, MD, Associate Professor in the Department of Hematology and Medical Oncology at Winship Cancer Institute, Emory University, shared her thoughts on the CEPHEUS trial. “As we consider the context of the CEPHEUS trial and other recently published randomized studies in a similar patient population,” she began, “three main questions arise: (1) How do we define “transplant-eligible” vs “-ineligible”; (2) How do the outcomes in these trials compare with outcomes of patients who have undergone autologous stem cell transplant (ASCT); and (3) Can these data be extrapolated to a frail patient population?”
Dr. Joseph continued: “The definition of transplant eligibility outside the United States is highly dependent on age, whereas in the United States, it is dependent more on functional and performance status. In these trials, not only were patients enrolled who would largely be considered transplant-eligible at many U.S. centers, including patients opting for deferred transplant, but also frail, and therefore truly transplant-ineligible patients were specifically excluded. Thus, classifying these trials as ‘transplant-ineligible’ studies is not entirely accurate.”
Outcomes by Transplant Eligibility
In clinical trials, when comparing the progression-free survival benefit of transplant vs nontransplant, Dr. Joseph said the transplant arms consistently perform better. “The 4-year progression-free survival in PERSEUS3 [in transplant-eligible patients] for the daratumumab plus bortezomib, lenalidomide, and dexamethasone (VRd) arm was 84%, compared with approximately 70% in CEPHEUS,” she explained. “Though cross-trial comparisons are never ideal, this certainly suggests that if a patient is transplant-eligible based on performance status and comorbidity standpoint, upfront transplant should be offered.” Moreover, she added, the Emory group presented a comparative subgroup analysis in more than 1,300 patients aged 65 and older induced with either VRd or daratumumab plus VRd followed by ASCT and risk-stratified maintenance therapy. Equal benefit for the older and younger cohorts was demonstrated.4,5
“For the truly frail patient, we do not have data currently supporting quadruplets as the new standard. Four-drug regimens can be challenging in this population from a toxicity standpoint, and treatment selection should continue to be determined on a case-by-case basis,” Dr. Joseph concluded.
REFERENCES
DISCLOSURE: Dr. Usmani has served as a consultant to AbbVie, Amgen, Bristol Myers Squibb, Celgene, EdoPharma, Genentech, Gilead Sciences, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, Secura Bio, SkylineDx, Takeda, and TeneoBio. Dr. Joseph reported personal financial relationships with BMS and Janssen Oncology.
REFERENCES
1. Usmani SZ, Facon T, Hungria V, et al: Daratumumab + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: Results of the phase 3 CEPHEUS study. 2024 International Myeloma Society Annual Meeting. Abstract OA-63. Presented September 27, 2024.
2. Facon T, Kumar SK, Plesner T, et al: Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): Overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 22:1582-1596, 2021.
3. Sonneveld P, Dimopoulos MA, Boccadoro M, et al: Phase 3 randomized study of daratumumab + bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplantation: Primary results of the PERSEUS trial. 2023 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 12, 2023.
4. Joseph NS, Kaufman JL, Gupta VA, et al. Quadruplet therapy for newly diagnosed myeloma: Comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib and dexamethasone (RVd) versus daratumumab with RVd in transplant-eligible patients. Blood Cancer J 14:159, 2024.
5. Joseph NS, Kaufman JL, Gupta VA, et al: Efficacy of Dara-RVd induction therapy in newly diagnosed myeloma patients ≥ 65 years of age. 2024 International Myeloma Society Annual Meeting. Abstract OA-51. Presented September 26, 2024.
