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
Data from the analysis of the transplant-ineligible subgroup—excluding patients who deferred transplant—showed that at a median follow-up of 76 months, patients who recieved 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
“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 in New York, New York, and the recipient of the
CEPHEUS was a randomized, open-label study that 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 the intent-to-treat population.
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 an 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 was 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 in total, 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%).
Common grade 3 or 4 TEAEs that occured 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%).
