Dara-vd vs vrd: A breakthrough in newly diagnosed multiple myeloma treatment — superior survival and safety profiles

Abstract Effective induction regimens are critical for improving outcomes in newly diagnosed multiple myeloma (NDMM). Bortezomib, lenalidomide, and dexamethasone (VRd) is currently a standard option, but it has certain limitations, including limited efficacy in high-risk patients, significant side effects, and restricted applicability in elderly or frail patients. Thus, there is an urgent need to find more widely effective first-line treatment regimens. The Dara-Vd regimen has been proven to be significantly effective in relapsed/refractory myeloma patients. However, its efficacy and safety in NDMM have not been verified in real-world settings. This study directly compared the efficacy and safety of Dara-Vd and VRd in NDMM patients. This multicenter prospective trial was approved by the Ethics Committee (No. 2025PS795K) and registered with the Chinese Clinical Trial Registry (ChiCTR2500102869). A total of 206 NDMM patients were enrolled from March 2023 to March 2025. All received Bortezomib and Dex (VD) in the first cycle; from the second cycle, patients were divided into two groups: Dara-Vd or VRd, Dara or lenalidomide was added due to suboptimal responses or physician decision. Efficacy was evaluated per cycle according to IMWG criteria. Adverse events (AEs) were graded using NCI CTCAE V5.0, focusing on peripheral neuropathy, infection, and hematological toxicity. Baseline characteristics showed that in Dara-Vd group the patients were older than those in VRd group (mean age: 63.90±9.37 vs 61.19±8.92, p=0.034), and with higher rates of concomitant renal impairment (57.14% vs 25.25%, p<0.001) and high-risk cytogenetic abnormalities (HRCA: 56.98% vs 44.44%, p=0.105). After 5 cycles, the overall response rate (ORR) was 97.85% in the Dara-Vd group, and 96.91% in VRd group. Deep remission rates were comparable: MRD negativity (5.38% vs 5.15%), and sCR/CR (32.26% vs 31.96%). Thus, Dara-Vd achieved high remission and favorable deep responses despite older patients, more renal impairment, and HRCA in its cohort. Subgroup analyses (by genetic risk, bone destruction, extramedullary lesions) showed similar efficacy in the two groups. For renal response, 78.0% (39/50) in Dara-Vd and 92.0% (23/25) in VRd achieved response (renal-CR: 36.0% vs 72.0%; renal-PR: 16.0% vs 12.0%; renal-MR: 26.0% vs 8.0%), but baseline renal function significantly differed. In the Dara-Vd group, the mean baseline eGFR of patients with renal impairment was 22.93 ml/min/1.73m², with 72% having severe renal impairment (eGFR<30ml/min/1.73m²) and 44% having renal failure (eGFR<15ml/min/1.73m²). In the VRd group, the mean baseline eGFR was 32.80 ml/min/1.73m², with 52% having severe renal impairment and only 20% having renal failure. Therefore, evaluating the impact of the two regimens on renal response solely based on renal response status was not precise. When objectively comparing the increase in eGFR after 5 induction cycles in patients with renal impairment between the two groups, the Dara-Vd group showed an increase of 15.21 ml/min/1.73m² and the VRd group an increase of 12.69 ml/min/1.73m²(p=0.48), indicating no statistical significance. At the end of June 2025, the median PFS for both regimens has not been reached yet. Log-rank test (Chi-square=3.377, df=1, p=0.066) showed no statistical difference in PFS, the mean survival time of Dara-Vd group was 33.339±1.111 months (95%CI:31.162-35.517) vs 31.361±1.548 months (95%CI:28.327-34.395) in VRd. Kaplan-Meier curves showed higher cumulative survival probability, and risk function curves indicated lower cumulative risk in Dara-Vd. Safety profiles were manageable. Hematological toxicities (grade 3-4 neutropenia, anemia, thrombocytopenia) were less frequent in Dara-Vd than in VRd group (11.11% vs 27.78%, 33.33% vs 66.67%, 33.33% vs 55.00%). Non-hematological AEs: Dara-Vd had higher rates of diarrhea(3.09% vs 0.93%), nausea(4.12% vs 0.93%), fever(11.34% vs 6.54%), and herpes zoster(3.09% vs 0.93%), but all were 1-2 grade; VRd had higher rates of muscle spasm(0% vs 2.80%), AST elevation(5.14% vs 8.41%), thrombosis(0% vs 1.87%), and peripheral neuropathy(4.12% vs 7.48%). Peripheral edema(1.03% vs 0.93%) and pneumonia rates(4.12% vs 4.67%) were similar. In conclusion, Dara-Vd may be superior to VRd in NDMM, particularly in older patients and those with renal insufficiency, offering favorable deep remission, better PFS trends, and manageable safety.