Daratumumab in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials

Background: Treatment for transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) has improved with anti-CD38 monoclonal antibodies. Among them, daratumumab, combined with standard therapies, has shown promising results in clinical trials. This meta-analysis consolidates evidence on the effectiveness and safety of daratumumab-based treatments for this patient group from all available randomized controlled trials (RCTs). Methods: We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and clinical trial registries from inception to September 2025 for phase II and III RCTs comparing daratumumab-containing regimens to non-daratumumab controls in TIE NDMM patients. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included minimal residual disease (MRD) negativity rate and adverse events (AEs). Heterogeneity was assessed using I2 statistics, and subgroup analyses were performed to explore potential sources of heterogeneity. Results: Six RCTs involving 2478 patients were included. Daratumumab-based regimens significantly improved PFS (hazard ratio HR = 0.544, 95% confidence interval CI: 0.483–0.612, p < 0.001; I2 = 28.6%) and OS (HR = 0.693, 95% CI: 0.606–0.791, p < 0.001; I2 = 30.6%). The MRD negativity rate was significantly higher with daratumumab (risk ratio RR = 2.322, 95% CI: 1.486–3.627, p < 0.001). Furthermore, daratumumab-based regimens yielded a four-fold increase in the rate of sustained MRD negativity (≥12 months) (RR = 3.999, 95% CI: 1.094–8.403, p < 0.001). However, these regimens were associated with increased risks of serious adverse events (SAEs) (RR = 1.146, 95% CI: 1.064–1.233, p < 0.001), overall grade 3/4 AEs (RR = 1.075, 95% CI: 1.038–1.115, p < 0.001), neutropenia, lymphopenia, infections, pneumonia, and fatal AEs. No significant differences were observed in thrombocytopenia or anemia. Conclusions: Daratumumab-based regimens significantly improve survival outcomes and the depth/durability of treatment response in TIE NDMM patients, supporting their use as first-line therapy. However, the increased risk of specific AEs necessitates careful patient selection, proactive infection prevention, and vigilant monitoring. These findings provide robust evidence for clinical practice guidelines and underscore the need to balance efficacy with safety in this vulnerable population.