Interim Analysis of Dara VRD in the Treatment of TE-NDMM Patients with Standard Risk Who Refused to Accept ASCT As First Line in China

Background:

In China, the utilization rate of ASCT as front-line therapy is merely 10%. Many transplant-eligible (TE) patients decline ASCT for various subjective and objective reasons. Recent studies, such as GRIFFIN (D-VRd) and CASSIOPEIA (D-VTd), have shown promising results in TE-NDMM patients receiving ASCT as initial therapy. These findings have prompted us to investigate the potential efficacy of D-VRd in standard-risk patients. This interim analysis presents the first open-label, single-arm study evaluating the efficacy and safety of D-VRd in TE-NDMM patients with standard risk who declined ASCT in China (NCT 05088330).

Methods:

We enrolled NDMM patients, as per IMWG criteria, who were transplant-eligible but voluntarily declined ASCT. Patients with t(4;14), Del(17p), t(14;16), or R-ISS stage III were excluded. The D-VRd regimen consisted of: Daratumumab: 16 mg/kg I.V. weekly for 2 cycles, then every 3 weeks for 6 more cycles, bortezomib: 1.3 mg/m2 SC, Days 1, 4, 8, 11 for 8 cycles, lenalidomide: 25 mg P.O., Days 1-14 for 8 cycles, dexamethasone: 20 mg P.O., Days 1, 2, 4, 5, 8, 9, 11, 12 for 8 cycles. Patients then received Daratumumab 16mg/kg I.V. monthly for 1 year as maintenance therapy. The primary endpoint was NGS MRD negativity at 10^-5 after 8 cycles of D-VRd. Secondary objectives included ORR, sCR, ≥CR, ≥VGPR, AEs, TTR, and DOR. Stem cell collection was recommended after 4 cycles of D-VRd.

Result:

As of June 30, 2024, 46 patients were enrolled in the study. The median age was 62 years (range: 38-74), with 23 (50.0%) male patients. Cytogenetic analysis revealed 27 (58.7%) patients with 1q gain (3 copies) and 4 (8.7%) patients with t(11;14). Additionally, 8 (17.4%) patients presented with renal insufficiency, and 6 (13%) had extramedullary disease (EMD).

The overall response rate (ORR) was 97.4%, with 89.7% of patients achieving VGPR or better. Notably, 64.1% of patients attained CR or sCR. The median duration of treatment was 10 months (range: 1-21). The median number of treatment cycles was 9. Post-induction stem cell collection and storage was successful underwent in 19 (41.3%) patients.

With a median follow-up of 12 months (range: 1-23), 72.7% (16/22) of patients achieved NGS MRD negativity after 8 cycles. Subgroup analysis comparing patients with 1q gain versus those without showed ORR, CR+sCR, and 1-year progression-free survival (PFS) rates of 95.8%, 58.3%, and 88.2% versus 100%, 73.3%, and 100%, respectively (p>0.01).

Treatment-related adverse events (TRAEs) primarily consisted of hematological toxicities, occurring in all 46 (100%) patients. These included thrombocytopenia in 80.4% (n=37; 22 Grade 1-2, 15 Grade 3-4), lymphopenia in 58.7% (n=27; 17 Grade 1-2, 10 Grade 3-4), and neutropenia in 43.4% (n=20; 9 Grade 1-2, 11 Grade 3-4) of patients. Other adverse events (AEs) included ALT/AST elevation in 43.4% (n=20; 19 Grade 1-2, 1 Grade 3-4) and peripheral neuropathy (PN) in 45.7% (n=21; 12 Grade 1-2, 9 Grade 3-4) of patients. Infusion-related reactions were reported in 23.9% of patients (n=11, all Grade 1-2). Pneumonia occurred in 13.0% of patients (n=6, all Grade 3), with all cases resolving. One patient discontinued lenalidomide due to pulmonary embolism.

Conclusion:

Interim analysis of this study demonstrates that D-VRd treatment elicits rapid and deep responses in Chinese standard-risk, transplant-eligible newly diagnosed multiple myeloma (SR TE-NDMM) patients who declined ASCT, including those with 1q gain. The high rate of NGS MRD negativity (72.7%) before maintenance therapy underscores the regimen's efficacy. While hematological toxicities were the most common adverse events, they were generally manageable after the initial two cycles, indicating an acceptable safety profile. These promising results warrant further investigation to confirm the long-term efficacy and safety of D-VRd in this patient population.