Upfront Anti-CD38 Monoclonal Antibody-Based Quadruplet Therapy for Multiple Myeloma: A Systematic Review and Meta-Analysis of Clinical Trials

<b>Background:</b> Recently, the addition of anti-CD38 monoclonal antibodies (mAbs) to standard first-line triplet regimens, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD) and dexamethasone, has led to the introduction of quadruplets in clinical practice. <b>Methods:</b> A systematic search was conducted (end-of-search: 9 November, 2024) for clinical trials investigating first-line anti-CD38 mAb-based quadruplets in combination with a PI and an IMiD. Pooled proportions and effect-estimates along with 95% confidence intervals were calculated with common-effect and random-effects models and further subgroup and meta-regression analyses were performed. <b>Results:</b> The pooled 2-, 3- and 4-year progression-free survival (PFS) rates were 89%, 77% and 86%, respectively. Furthermore, patients treated with quadruplets demonstrated a 46% reduced risk for disease progression or death (HR = 0.54, 95% CI: 0.46-0.64) compared to those on triplets. Overall survival (OS) rates were consistently high, ranging from 83% to 96% between different regimens. High rates of deep responses that deepened over time were observed, with the pooled proportion of patients achieving at least complete response being 64%. Importantly, the pooled MRD negativity rate was 62%, whereas patients treated with quadruplet first-line therapy had 2.5 times the odds to be MRD negative at any point compared with those on triplets. Moreover, the odds for sustained 12-month MRD negativity were thrice as much with quadruplets compared to triplets. Finally, while no increase in serious adverse events was observed with quadruplet regimens compared to triplets, a 46% statistically significant increased risk for grade 3-4 neutropenia and thrombocytopenia was observed, along with a 14% increased risk for grade 3-4 infections. <b>Conclusions:</b> The addition of anti-CD38 mAbs to standard triplet regimens has shown particularly favorable outcomes, supporting their integration in the upfront treatment of patients with NDMM. However, close monitoring for hematological toxicity and infections is essential.