Objective To analyze the clinical characteristics, treatment regimens, and prognosis of patients with macrofocal multiple myeloma (MFMM), providing critical evidence for clinical management and treatment of MFMM.Methods In this retrospective case-control study, 27 MFMM patients diagnosed at the Second Affiliated Hospital of Xi’an Jiaotong University (January 2019 to December 2024) were compared with 54 matched classical MM controls (1:2 ratio) sharing comparable induction regimens and diagnostic timelines. Comprehensive datasets encompassing demographics, clinicopathological profiles, cytogenetic abnormalities, treatment responses, and survival outcomes were analyzed. Nonparametric tests and chi-square tests were used for intergroup comparisons, and Kaplan-Meier analysis and log-rank tests were applied for survival analysis.Results The study included 27 MFMM cases and 54 classical MM controls. The median age at diagnosis in the MFMM group was significantly younger than in the classical MM group (Z=2.328, P=0.020). All MFMM patients were classified as ISS stage Ⅰ or Ⅱ, whereas the control group included 6 ISS stage Ⅰ (11.1%) and 23 ISS stage Ⅱ (42.6%) cases, with significant differences in ISS staging between the two groups (χ2=33.770, P<0.001). Stratification by mSMART3.0 revealed a significantly higher proportion of standard-risk patients in the MFMM group (χ2=10.408, P=0.005). Induction regimens and autologous stem cell transplantation rates were similar between the two groups, with no significant difference in complete response (CR) rates (59.3% vs 46.3%,P=0.067). Among MFMM patients, no statistically significant differences in efficacy were observed across proteasome inhibitor (PI), immunomodulatory drug (IMiD), or PI+IMiD(χ2=8.735, P=0.068). By December 2024, MFMM patients demonstrated significantly longer progression-free survival (PFS) (P=0.017) and overall survival (OS) (P=0.041) compared to classical MM controls.Conclusion MFMM represents a relatively indolent MM subtype characterized by younger age at diagnosis, lower tumor burden, and favorable prognosis in the era of novel therapies. Diverse induction regimens show comparable efficacy in MFMM patients