Safety and efficacy of triple vs quadruple therapy in transplant ineligible multiplemyeloma patients – a meta-analysis of randomized controlled trials

Abstract Introduction In newly diagnosed multiple myeloma (NDMM), many patients are ineligible for stem cell transplant due to advanced age, frailty, or comorbidities. Triplet regimens, combining an immunomodulatory (IMiD) agent, low-dose dexamethasone, and either a proteasome inhibitor (PI) or a CD38-targeting antibody, have been the standard treatment. While quadruplet regimens have demonstrated improved outcomes in transplant-eligible patients, their role in transplant-ineligible (TIE) patients, who may be more vulnerable to treatment-related toxicity, remains unclear. This meta-analysis of randomized controlled trials (RCTs) evaluates the safety and efficacy of quadruplet versus triplet therapy in TIE NDMM. Methods This meta-analysis of phase 3 RCTs comparing triplet vs. quadruplet regimens in TIE NDMM was conducted according to PRISMA guidelines, using PubMed, Embase, and the Cochrane Library (up to May 2025). Studies that were non-clinical trials, non-human, non-English, or lacked full-text availability were excluded. A random-effects meta-analysis was performed using R software. Outcomes were reported as odds ratios (ORs) or hazard ratios (HRs), with 95% confidence intervals (CIs) and p<0.05 as the threshold for statistical significance. Heterogeneity was assessed using the I2 statistic, with an I2 value greater than 75% considered highly heterogeneous. Results Five RCTs (ALCYONE, CEPHEUS, IMROZ, BENEFIT, and OCTANS) with 2,037 patients met the inclusion criteria. The CEPHEUS trial evaluated the addition of daratumumab to the standard triplet regimen of bortezomib, lenalidomide, and dexamethasone (D-VRd vs. VRd). The IMROZ trial compared isatuximab plus VRd (Isa-VRd) against VRd triplet therapy. The OCTANS and ALCYONE trials assessed the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP against VMP), and the BENEFIT trial compared the addition of Bortezomib to Isatuximab, lenalidomide, and dexamethasone (Isa-VRd vs Isa-Rd). Sustained MRD negativity, PFS, OS, and grade 3–4 TEAEs could not be extracted from the BENEFIT trial due to immature/ incomplete or non-specific reporting, and the OCTANS trial included only the Asian population. Quadruplet therapy significantly reduced disease progression or death (HR 0.45, 95% CI 0.29–0.71; p = 0.01; I² = 65.2%) and improved overall survival (HR 0.69, 95% CI 0.56–0.85; p = 0.01; I² = 0%). Quadruplet therapy also demonstrated a higher likelihood of achieving complete response or better (OR 2.50, 95% CI 1.76–3.54; p <0.01; I² = 32.2%), overall response rate (OR 1.98, 95% CI 1.01– 3.87; p = 0.04, I² = 66.8%), minimal residual disease (MRD) negativity (OR 3.16, 95% CI 1.73–5.75; p <0.01; I² = 74.2%), and sustained MRD negativity at 12 months (OR 4.11, 95% CI 1.20–14.13; p = 0.04; I² = 60.5%). Additionally, quadruplet regimens reduced overall mortality (OR 0.67, 95% CI 0.52–0.88; p = 0.01; I² = 0%). While the incidence of grade 3–4 treatment-emergent adverse events (TEAE) was higher with quadruplet therapy, this result was not statistically significant (OR 1.34, 95% CI 0.94–1.90; p = 0.08; I² = 0%). Conclusion This meta-analysis demonstrates that quadruplet therapy significantly improves progression-free survival, overall survival, response depth, and MRD negativity compared to triple therapy in TIE NDMM. Although grade 3-4 TEAE appeared to increase, this difference was not statistically significant. These findings support the consideration of quadruplet regimens as a more effective upfront strategy in TIE NDMM patients, with attention to patient-specific tolerability and individualized risk–benefit profiles.