Segawa, Fred

ABSTRACT Introduction Multiple myeloma is a malignant plasma cell disorder predominantly affecting older adults and poses a significant health burden due to its incurable nature, high relapse rate, and associated immune dysfunction. Daratumumab, when added to standard therapy, has shown promising results in large trials. This meta‐analysis compared clinical trials of daratumumab‐containing regimens with standard therapies in the treatment of multiple myeloma. The primary outcomes analyzed were overall response rate (ORR) and progression‐free survival (PFS). Methods A systematic search of PubMed, Scopus, Cochrane CENTRAL, and Google Scholar was performed from January 2015 through December 2024. After screening via Rayyan, data were extracted on an Excel spreadsheet. Quality was assessed using the Cochrane RoB 2.0 tool. Eligible randomized controlled trials (RCTs) were included and analyzed using RevMan 5.4. Outcomes assessed were ORR and PFS. Adverse effects were compared among therapies. Results Nine Phase III RCTs ( n = 4556) were included, with a mean follow‐up of 44.3 months. Daratumumab‐based regimens significantly improved PFS (HR 0.55, 95% CI 0.46–0.66) but did not confer a statistically significant overall survival advantage (RR 0.90, p = 0.25). ORR was inconsistent, with five trials favoring daratumumab and one favoring control. Safety analyses showed higher risks of pneumonia (RR 1.74, p < 0.0001), secondary malignancies (RR 1.46, p = 0.003), neutropenia (RR 1.25, p = 0.006), and thrombocytopenia (RR 1.17, p = 0.01). Lymphopenia showed a numerical increase but was not statistically significant. Conclusion Daratumumab plus standard therapy regimens significantly improve PFS in multiple myeloma, though the overall survival benefit remains unproven. While efficacy is notable, treatment is associated with increased risks of infections, hematological toxicities, and secondary malignancies, highlighting the need for careful patient selection and vigilant monitoring. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.