Key Takeaways:
- Enhanced Progression-Free Survival (PFS) and Depth of Response: The study evaluated the efficacy and safety of subcutaneous daratumumab combined with VRd induction and consolidation therapy followed by lenalidomide maintenance therapy (D-VRd) compared with another VRd regimen in patients with newly diagnosed multiple myeloma (NDMM) who are eligible for transplantation. Results demonstrated that patients in the D-VRd group experienced significantly longer PFS at 48 months (84.3%) compared to those in the VRd group (67.6%).
- Higher Minimal Residual Disease (MRD)-Negative Rates: The addition of D-VRd induction and consolidation therapy resulted in a substantially higher percentage of patients achieving MRD-negative status, with the rate for 12 months being 64.8% in the D-VRd group compared to only 29.7% in the VRd group. MRD negativity is associated with improved long-term outcomes, highlighting the potential clinical significance of the D-VRd regimen in NDMM treatment.
- Manageable Safety Profile: Although both treatment regimens were associated with adverse events (AEs), the D-VRd regimen demonstrated a favorable benefit-risk profile. Although there was a slightly higher incidence of serious AEs in the D-VRd group, the overall safety profile was manageable, indicating that the addition of daratumumab to VRd induction therapy did not significantly increase treatment-related toxicity.
In patients with newly diagnosed multiple myeloma (NDMM) who are eligible for transplantation, induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem-cell transplantation, consolidation therapy with VRd, then maintenance therapy with lenalidomide is considered standard care. However, the approval of daratumumab for the treatment of patients with NDMM alongside other regimens allows for the treatment of both patients who are eligible (combined bortezomib, thalidomide, and dexamethasone) and ineligible for transplantation (lenalidomide plus dexamethasone and combination bortezomib, melphalan, and prednisone).
Authors of a study published in The New England Journal of Medicine evaluated the safety and efficacy of subcutaneous daratumumab combined with VRd induction and consolidation therapy with lenalidomide maintenance therapy (D-VRd), and compared it with VRd induction and consolidation therapy with lenalidomide maintenance therapy alone. This open-label, multicenter, randomized phase 3 trial, PERSEUS (NCT03710603), examined patients with NDMM across 115 sites in Europe and Australia. The patients enrolled in the study were 18 to 70 years of age who were eligible for a high-dose therapy and autologous stem-cell transplantation. Each patient had an Eastern Cooperative Oncology Group performance-status score of 0 to 2 on a scale of 0 to 5 (higher scores indicate greater disability).
Patients were randomly assigned to be in 1 of 2 treatment groups. The D-VRd group received subcutaneous daratumumab combined with VRd induction therapy prior to transplantation with VRd consolidation therapy after transplantation and with lenalidomide maintenance therapy, and the VRd group received VRd induction and consolidation therapy and lenalidomide maintenance therapy alone. Every patient received VRd in 6 28-day cycles (4 induction cycles plus 2 consolidation cycles).
VRd treatment consisted of subcutaneous bortezomib (1.3 mg per m2 of body surface area administered on days 1, 4, 8, and 11 of each cycle), 25 mg of oral lenalidomide (administered on days 1-21 of each cycle), and 40 mg of oral or intravenous dexamethasone (administered on days 1-4 and days 9-12 of each cycle). Patients in the D-VRd group had also received 1800 mg of subcutaneous daratumumab per week (administered during cycles 1 and 2) and then every 2 weeks (administered during cycles 3-6), which was then coformulated with 2000 U per mL of solution of recombinant human hyaluronidase PH20.
Within 6 weeks after completing induction therapy (cycle 4), stem-cell mobilization was performed, and a second round of stem-cell mobilization or bone marrow harvest was performed if the stem-cell yield was considered adequate by the investigators. Over a period of 24 to 48 hours, patients underwent conditioning with 200 mg per m2 of body surface area of melphalan, followed by autologous stem-cell transplantation, and after 30 to 60 days after transplantation, consolidation therapy began.
After consolidation therapy (cycle 6), all patients received lenalidomide in 28-day maintenance cycles, with oral lenalidomide starting at 10 mg per day and increasing to 15 mg per day after 3 cycles if advised by the investigators. This was administered until the disease progression or toxic effect-related treatment discontinuation. Further, patients in the D-VRd group had also received 1800 mg of subcutaneous daratumumab every 4 weeks until either disease progression or toxic effect-related treatment discontinuation.
In addition, after a minimum of 24 months of maintenance therapy, daratumumab therapy was discontinued in patients who either had a complete response (CR) or sustained minimal residual disease (MRD)-negative status for at least 12 months. These patients continued to undergo treatment with lenalidomide until either disease progression or toxic effect-related treatment discontinuation. Further, patients resumed daratumumab therapy if they were confirmed to have a loss of CR without disease progression, or a recurrence of MRD.
The study’s primary endpoint was progression-free survival (PFS), which was assessed by the time from randomization to disease progression or death, depending on which occurred first. In addition, key secondary endpoints included a CR or better, MRD-negative status with a CR or better, and overall survival (OS).
A total of 698 patients with NDMM—of which 351 were in the D-VRd group and 347 were in the VRd group—received at least 1 dose of the assigned treatment. As of the clinical cutoff date, 322 patients (91.7%) in the D-VRd group and 300 patients (86.5%) in the VRd group had progressed past the induction phase of treatment and moved on to the maintenance phase. Among these patients, 315 (89.7%) in the D-VRd group and 302 (87.0%) in the VRd group underwent autologous stem-cell transplantation. Approximately 25.9% of patients in the D-VRd group and 54.2% in the VRd group had discontinued treatment, most commonly due to adverse events (AEs; 9.1% and 22.5%, respectively) and progressive disease (8.3% and 20.7%, respectively).
At a median follow-up of 47.5 months (range: 0-54.4), disease progression or death had occurred in 50 patients (14.1%) in the D-VRd group and 103 (29.1%) in the VRd group. At 48 months, the estimated percentage of patients with PFS was 84.3% (95% confidence interval [CI], 79.5-88.1) in the D-VRd group and 67.7% (95% CI, 62.2-72.6) in the VRd group. Further, the percentage of patients with a CR or better was higher in the D-VRd group compared with the VRd group (87.9% vs. 70.1%, P < .001). In addition, the percentage of patients who remained MRD-negative for 12 months was 64.8% in the D-VRd group and 29.7% in the VRd group.
The most common grade 3 or 4 AEs were neutropenia (D-VRd group: 62.1%; VRd group: 51.0%), thrombocytopenia (D-VRd group: 29.1%; VRd group: 17.3%), diarrhea (D-VRd group: 10.5%; VRd group: 7.8%), pneumonia (D-VRd group: 10.5%; VRd group: 6.1%), and febrile neutropenia (D-VRd group: 9.4%; VRd group: 10.1%). Further, grade 3 or 4 peripheral neuropathies occurred in 6.0% of patients in the D-VRd group and 4.9% of patients in the VRd group. Serious AEs (SAEs) occurred in 57.0% of patients in the D-VRd group and 49.3% of those in the VRd group, with the most common SAE being pneumonia (D-VRd group: 11.4%; VRd group: 6.1%).
According to the investigators, this trial did not have a second randomization to maintenance therapy, unlike prior research that included patients with NDMM who were eligible for transplantation. Additionally, the authors note that this trial’s design allows for clearer interpretation of the benefit of adding daratumumab across the entire treatment regimen, which is standard care for this population; however, they acknowledge that the trial’s design may not properly determine the exact contribution of each component within the treatment regimens.
With nearly 4 years of follow-up, the PERSEUS trial indicates that the D-VRd treatment regimen plus consolidation therapy with lenalidomide maintenance therapy was significantly and clinically more meaningful in patients with NDMM. Patients who received treatment with this regimen demonstrated stronger PFS, the occurrence of a CR or stronger, as well as MRD-negative statuses and a favorable benefit-risk profile.
References
Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054
