Darzalex Regimen Boosts Rates of MRD Negativity in Newly Diagnosed, Transplant-Eligible Myeloma
Darzalex (daratumumab) plus Velcade (bortezomib), lenalidomide (Revlimid) and dexamethasone (D-VRd), followed by autologous stem cell transplant (ASCT), D-VRd consolidation (treatment after ASCT) and Darzalex plus Revlimid (DR) maintenance improved rates of sustained minimal residual disease (MRD; measure of remaining cancer cells after treatment) negativity compared with VRd induction, ASCT, VRd consolidation and Revlimid maintenance in transplant-eligible patients with newly diagnosed multiple myeloma, according to updated data from the phase 3 PERSEUS trial.
Findings, which were presented at the 2024 SOHO Annual Meeting, showed that among patients in the D-VRd arm (355 patients), 57.5% were MRD negative at a 10-5 sensitivity (extremely low) at the end of consolidation vs 32.5% of patients in the VRd arm (354 patients). In the experimental arm, the MRD-negative rates at the 10-5 threshold at up to 12 months, up to 24 months, and up to 36 months were 65.1%, 72.1% and 74.6%, respectively. These respective rates were 38.7%, 44.9% and 46.9% in the control arm.
At a 10-6 sensitivity, the MRD-negativity rates (no detectable cancer cells) in the D-VRd arm at the end of consolidation, up to 12 months, up to 24 months and up to 36 months were 34.4%, 43.9%, 57.7% and 63.9%, respectively. In the VRd arm, these respective rates were 16.1%, 20.9%, 27.4% and 30.8%.
Study Highlights:
- D-VRd significantly increased MRD negativity rates.
- Patients receiving D-VRd maintained MRD-negative status longer.
- D-VRd outperformed VRd in reducing residual cancer cells and improving survival.
- D-VRd could become a new standard of care for transplant-eligible patients.
- Treatment was tailored to individual patients’ MRD status.
Furthermore, 64.8% of patients in the D-VRd group sustained MRD negativity at the 10-5 threshold for at least 12 months compared with 29.7% of patients in VRd arm. The rates of patients who sustained MRD negativity for at least 18 months at 10-5 were 59.4% and 25.1%, respectively. At a 10-6 sensitivity, 47.3% of patients in the D-VRd arm sustained MRD negativity for at least 12 months vs 18.6% of patients in the VRd arm. The respective rates of patients who sustained MRD negativity for at least 18 months in these arms were 42% and 15%.
“These data further highlight the benefit of D-VRd and DR maintenance as a new standard of care for transplant-eligible patients with newly diagnosed multiple myeloma,” presenting study author Dr. Meletios A. Dimopoulos said during the presentation.
A New Treatment Option for Transplant-Eligible, Newly Diagnosed Myeloma
On July 30, 2024, the FDA approved D-VRd for induction and consolidation in patients with newly diagnosed multiple myeloma who are candidates for ASCT, based on prior data from PERSEUS.2
Previous findings demonstrated that D-VRd reduced the risk of disease or death by 58% compared with VRd alone. The 48-month progression-free survival (PFS; how long a patient with cancer lives without their disease getting worse) rate was 84.3% with D-VRd vs 67.7% with VRd.
PERSEUS Design and Goals
The phase 3 study included patients 18 to 70 years of age with newly diagnosed multiple myeloma who were eligible for ASCT.
Patients were randomly assigned to a specific treatment prior to the start of induction therapy. In the control arm, patients received VRd prior to ASCT. Those in the experimental arm received Darzalex plus the same VRd regimen prior to transplant. Induction therapy was given for four 28-day cycles. After ASCT, D-VRd or VRd were administered at the same dosages for two additional cycles.
During ongoing treatment, patients in the control arm received Revlimid until disease progression. In the experimental arm, ongoing therapy was based on MRD status; all patients initially received Darzalex plus Revlimid for a minimum of two years. Patients who were MRD positive continued DR. Those who were MRD negative for at least 12 months and achieved a complete response (CR; when a person’s disease cannot be detected by any tests or examinations) or better continued with Revlimid alone; they were permitted to restart Darzalex if they lost their CR without progressive disease or became MRD positive.
PFS served as the trial’s primary outcome. Secondary outcomes included overall CR or better rate, overall MRD-negativity rate and overall survival (OS; the time from the start of treatment when a patient with cancer is still alive).
Additional Updated Data from PERSEUS
Subgroup analyses showed that D-VRd improved MRD-negativity rates and sustained MRD-negativity rates compared with VRd across predefined groups.
The overall stringent CR (sCR; a more rigorous standard compared with traditional CR), CR, very good partial response (VGPR; cancer shrank significantly but still present) and PR rates in the D-VRd arm were 69.3%, 18.6%, 7.3% and 1.4%, respectively. These respective rates were 44.6%, 25.4%, 19.2% and 4.5% in the control arm. The CR or better rate was 87.9% in the D-VRd arm vs 70.1% in the VRd arm.
In the D-VRd arm, the respective sCR, CR, VGPR and PR rates at the end of induction were 9.6%, 13%, 62.3% and 9.3%. After ASCT, these rates were 10.7%, 17.2%, 57.5% and 8.7%, respectively. At the end of induction, the sCR, CR, VGPR and PR rates were 18.9%, 25.6%, 46.5% and 4.2%, respectively.
For the VRd arm, the sCR, CR, VGPR and PR rates at the end of induction were 7.1%, 14.1%, 51.4% and 18.1%, respectively. After ASCT, these respective rates were 8.2%, 15.3%, 50% and 17.5%. Following consolidation, the sCR, CR, VGPR and PR rates were 13%, 21.8%, 47.5% and 9.9%, respectively.
Among patients with high-risk disease, those treated with D-VRd (76 patients) achieved an MRD-negativity rate of 68.4% at the 10-5 threshold and 57.9% at the 10-6 threshold. Those rates were 47.4% and 30.8%, respectively, among patients with high-risk disease in the VRd arm (78 patients). In the experimental arm, 48.7% of patients maintained MRD negativity at a 10-5 sensitivity for at least 12 months and 30.3% remained MRD negative at the 10-6 threshold for at least 12 months. Those respective rates were 25.6% and 14.1% in the control arm.
D-VRd (44 patients) also trended toward improved PFS among patients with high-risk disease who achieved MRD negativity at a 10-6 sensitivity compared with those treated with VRd (24 patients)
Among patients in the D-VRd arm who were MRD positive at the end of consolidation (88 patients), 60.2% became MRD negative at the 10-5 threshold during maintenance compared with 40.5% of patients treated with VRd (121 patients). At the 10-6 threshold, these rates were 56.7% for D-VRd (134 patients) and 25.2% for VRd (155 patients). Among patients who became MRD negative at a 10-5 sensitivity, 38.6% in the D-VRd arm had sustained MRD negativity vs 17.4% in the control arm. At the 10-6 sensitivity, these respective rates were 31.3% and 10.3%.
Reaching MRD negativity at a 10-6 sensitivity was associated with improved long-term outcomes in both arms. Overall, 65.1% of patients in the D-VRd arm reached MRD negativity at the 10-6 threshold at any point compared with 32.2% of patients in the VRd arm.
“The percentage of patients achieving MRD negativity with D-VRd was significantly higher. This again speaks in favor of administering [D-VRd] up-front in order to increase the number of patients who will achieve MRD negativity, sustained MRD negativity, improved PFS and hopefully improved OS,” Dimopoulos concluded.
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