Presenter: Maria- Victoria Mateos
Session: 654. Multiple Myeloma: Pharmacologic Therapies: Optimizing Therapy in Newly Diagnosed Myeloma and Beyond
Date & Time: Sunday, December 8, 2024 5:45 PM–6:00 PM
Location: Pacific Ballroom Salons 21-22 (Marriott Marquis San Diego Marina)
Keywords: Daratumumab, CD38, MRD, Lenalidomide, Bortezomib, Carfilzomib, VMP, KRd, D-KRd, MRD-ve, DRd
Abstract Summary:
- The study met its primary endpoint, demonstrating significantly higher MRD-negative rates in the KRd (53.9%) and D-KRd (61.4%) groups compared to the VMP9-Rd9 control arm (26.6%).
- Consolidation with 4 DRd cycles improved MRD-negative rates in both the VMP9-Rd9 and KRd arms, with rates of 62.2% and 81.9%, respectively. The D-KRd arm achieved an MRD-negative rate of 85.3% without consolidation.
- Stringent complete response (sCR)/CR rates were higher in the KRd-DRd (81%) and D-KRd without consolidation (80.8%) groups compared to the VMP9-Rd9 with DRd (61.6%).
- At 48 months, progression-free survival was significantly higher in the KRd-DRd (71%) and D-KRd without consolidation (69%) groups compared to the control arm (52.2%).
- The safety profile was manageable, with neutropenia as the most common Grade 3/4 hematological adverse event, leading to dose reductions in 40% of patients in both consolidation arms.
Abstract
Background: In patients with newly diagnosed multiple myeloma (NDMM) who are not candidates for transplant, VMP (bortezomib, melphalan, prednisone) and Rd (lenalidomide, dexamethasone) have been standard treatments. The Spanish Myeloma Group combined 9 cycles of VMP and 9 cycles of Rd, yielding good results for “fit” patients aged 65-80. They achieved a complete response (CR) rate of 47%, with 20% of patients being minimal residual disease negative (MRD-ve). The median progression-free survival (PFS) was 34 months, and the 4-year overall survival (OS) was 70%.
Patients and Study Design: Building on these results, we conducted a study comparing VMP9-Rd9 (control arm) with KRd (carfilzomib, lenalidomide, dexamethasone) and D-KRd (daratumumab, carfilzomib, lenalidomide, dexamethasone). The induction phase included 18 cycles, with the primary endpoint being the MRD-ve rate after induction. This primary endpoint was met, with significantly higher MRD-ve rates observed in both the KRd group [53.9%, Odds Ratio (OR) = 1.74, 95% CI: 1.39-2.16, p<0.001] and the D-KRd group [61.4%, OR = 2.03, 95% CI: 1.61-2.57, p<0.001] compared to the VMP9-Rd9 arm [26.6% (41 patients)].
The trial design included 4 DRd consolidation cycles for the two arms that have not anti-CD38 as part of the induction (VMP9-Rd9 and KRd arms) to evaluate if DRd consolidation might compensate for the absence of a monoclonal antibody during induction. Subsequently, patients were stratified by MRD status (positive or negative) for maintenance therapy with D-R vs. observation.
Frailty was evaluated using the Geriatric Assessment in Hematology (GAH) scale, considering patients younger than 80 years and with a score between 0 and 42 as fit.
We report the efficacy of the four consolidation cycles in the group of patients who initiated the consolidation phase and compared results with that of patients who completed induction in the D-KRd group and did not receive consolidation per protocol.
Results: A total of 462 patients were randomized, 101/154 patients in the VMP-Rd arm (64%) and 109/154 (68%) in the KRd arm reached consolidation phase, 109/154 patients (71%) in the D-KRd were evaluable after induction.
In the VMP9-Rd9 arm, 24 patients converted from MRD+ve to MRD-ve with consolidation, compared to 11 patients in the KRd arm. The MRD-ve rate was 62.2% in the VMP 9-Rd 9/DRd and 81.9% in the KRd/DRd. The MRD-ve rate was 85.3% in the D-KRd arm without consolidation, which was superior to the VMP9-Rd9-DRd arm [OR 2.33, 95% CI: 1.50-3.62, p<0.001] though not the KRD-DRd arm [OR1.12, 95% CI: 0.89-1.42, p=0.19]. In terms of serological responses in the group of patients who received consolidation, the stringent complete response (sCR)/CR rate was higher for KRd-DRd (81%) and D-KRd without consolidation (80.8%) compared to the control VMP9-Rd9 with DRd (61.6%). At 48 month and in the Intent To Treat population the proportion of patients alive and progression-free remained significantly higher in KRd-DRd (71%, p=0.009) and D-KRd without consolidation (69%, p=0.032) compared to the control arm (52.2%).
Regarding hematological toxicity during consolidation, no significant differences were reported between the two arms that received 4 DRd cycles. The only Grade 3/4 hematological adverse event (AE) reported in ≥10% of patients was neutropenia, observed in 27% of patients after VMP9-Rd9 and 24% after KRd. None of the Grade 3/4 non-hematological AEs were reported in more than 10% of patients. Infections of any grade were reported with DRd in 29% of patients after VMP9-Rd9 and in 25% after KRd. Neutropenia led to dose reductions in 40% of patients in both arms.
Conclusion: The trial met its primary endpoint. Consolidation with 4 DRd cycles deepened the MRD-ve rate in both VMP 9-Rd 9 and KRd arms. Nevertheless, the control arm (VMP9-Rd9) continue to remain inferior to KRD+ DRd and D-KRd without consolidation, with the latter two schemes being equivalent. Further analysis may identify specific subgroups of patients would benefit more from each of the two latter combination. The safety profile is manageable, and the trial is ongoing to evaluate long-term outcomes.
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