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Background/Objectives: Although triplet regimens have been shown to be effective and safe in pivotal studies involving frail patients with multiple myeloma (MM), their use in frail patients is often avoided in real-world settings. As MM treatment progresses and options increase, it is crucial to clarify the efficacy and safety of triplet regimens in clinical practice. Methods: Patients who received anti-CD38 antibody-containing triplet regimens at our hospital from 2017 to 2024 were divided into frail and non-frail groups based on the IMWG simplified frailty scale and retrospectively analyzed. Results: In the 150 patients included, the median age was 76 years for the frail group and 69 years for the non-frail group. Daratumumab-containing triplet regimens were given to 108 (82 frail) patients, and isatuximab-containing triplet regimens were given to 42 patients (18 frail). Progression-free survival and overall survival for the frail and non-frail groups were 15.4 vs. 11.4 months and 45.6 vs. 40.7 months, respectively; the overall response rate was 76% vs. 68%, with no significant differences. Prognoses by regimen were also not significantly different. There were no significant differences in any adverse events and grade 3–4 hematological and non-hematological adverse events between the two groups. This analysis showed that, in frail MM patients who were eligible to receive triplet regimens, anti-CD38 antibody-containing triplet regimens were as effective and safe as in non-frail patients. Conclusions: In conclusion, these regimens may be viable options for frail patients, provided that appropriate management, including withdrawal of therapeutic agents, dose reduction, and infection control, is rigorously performed, as for non-frail patients.