Treatment of transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) remains challenging due to age, frailty, and comorbidities. Anti-CD38 monoclonal antibodies, particularly daratumumab, have emerged as promising additions to frontline regimens. However, the long-term outcomes of these therapies are still uncertain. This systematic review and meta-analysis aimed to compare the survival outcome of anti-CD38 antibodies in TIE-NDMM patients.

We systematically searched PubMed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) published up to April 2025 comparing anti-CD38 mAbs based regimens versus standard therapy in transplant-ineligible NDMM patients. A random-effects model was used to calculate pooled hazard ratios (HRs) with 95 % confidence intervals (CIs).

A total of six RCTs with 2,625 patients were included in the analysis. Of these, 1,390 (52.9 %) patients received anti-CD38-based regimens. The follow-up duration varied from 41.2 to 86.7 months across the studies. Compared to standard therapy, anti-CD38-based regimens significantly improved both overall survival (OS) (HR 0.70; 95 % CI 0.58–0.84; p=0.0002; I² = 46 %) and progression-free survival (PFS) (HR 0.57; 95 % CI 0.51–0.65; p < 0.00001; I² = 15 %). The pooled results demonstrated that non-frail patients had a longer PFS than frail patients (HR = 0.46; 95 % CI, 0.34–0.63 and HR = 0.55; 95 % CI, 0.45–0.67, respectively), although the difference between the subgroups was not statistically significant (p = 0.36).

In transplant-ineligible NDMM patients, the addition of anti-CD38 monoclonal antibodies to standard regimens significantly improves clinical outcomes. These findings support the integration of anti-CD38 therapy into first-line treatment for this vulnerable patient population .