Real-world comparative effectiveness of quadruplet vs triplet induction in multiple myeloma

Abstract Background: The incorporation of anti-CD38 monoclonal antibodies such as Daratumumab into induction therapy has transformed the treatment landscape for newly diagnosed multiple myeloma (NDMM). While clinical trials have shown improved progression-free survival with quadruplet regimens, these trials often have strict inclusion criteria and may not reflect real-world populations. Furthermore, there is limited large-scale real-world evidence comparing triplet and quadruplet induction regimens in routine clinical practice. Understanding their comparative effectiveness and safety is critical to guide frontline treatment decisions. Methods: We conducted a retrospective cohort study utilizing the TriNetX global research network, which comprises 151 healthcare organizations across academic and community settings. Adult patients (≥18 years) with newly diagnosed multiple myeloma (ICD-10: C90.0) were identified between 2017 and 2024. Patients with relapsed/refractory disease or those treated with alkylators, thalidomide, pomalidomide, or elotuzumab were excluded to maintain parity. Two treatment cohorts were defined: triplet therapy (Bortezomib or Carfilzomib, Lenalidomide, Dexamethasone) and quadruplet therapy (Bortezomib or Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab). Propensity score matching (1:1) was performed based on age, race, chronic kidney disease, anemia, and history of cytogenetic procedures, yielding 1,653 patients per arm. Outcomes included 5-year all-cause mortality, incidence of sepsis, and relapse within the follow-up period. Results: Following propensity score matching, baseline demographic and clinical characteristics were well balanced between cohorts. Patients who received quadruplet induction therapy had significantly lower five-year all-cause mortality compared to those treated with triplet therapy (11.6% vs. 17.0%; risk difference 5.4%, 95% CI: 3.1–7.8; p<0.001), along with improved overall survival (72.3% vs. 67.0%; log-rank p=0.029). Sepsis incidence was also lower in the quadruplet group (6.3% vs. 9.1%; risk difference 2.9%, 95% CI: 1.0–4.7; p=0.003), although time-to-event analysis for sepsis did not reach statistical significance (p=0.064). No relapses were captured in either cohort during the study period, likely due to limited follow-up duration or underreporting in electronic health record data. Conclusion: In this large, multi-institutional real-world analysis, the addition of Daratumumab to triplet-based induction therapy significantly improved overall survival and reduced infectious complications in patients with newly diagnosed multiple myeloma. These findings support the routine use of Daratumumab-based quadruplet regimens as the preferred standard of care in eligible patients in real-world clinical practice. Additional studies are warranted to evaluate the long-term durability, toxicity profile, and cost-effectiveness of quadruplet therapy across diverse populations