Introduction: High-risk multiple myeloma (HRMM) is primarily defined by adverse cytogenetic abnormalities that are associated with inferior outcomes despite contemporary treatment with novel induction agents and autologous stem cell transplantation (ASCT). While the accumulation of high-risk lesions has been proposed to further stratify prognosis, the relative impact of single-hit versus double-hit HRMM on post-transplant outcomes in real-world clinical practice remains incompletely characterized. Methods: We conducted a multicenter retrospective cohort study of transplant-eligible adults with HRMM undergoing upfront ASCT between 2009 and 2024 at three U.S. academic centers. Patients were categorized as single-hit HRMM or double-hit HRMM based on the number of high-risk cytogenetic abnormalities at diagnosis. Response rates, progression-free survival (PFS), and overall survival (OS) were compared between groups using standard statistical methods. Results: A total of 154 patients were included, of whom 63 had SH-HRMM, and 91 had DH-HRMM. Following induction therapy, overall response rates (ORR) were high and comparable between groups. After ASCT, ORR was significantly higher in SH-HRMM compared with DH-HRMM (97% vs. 82%, p = 0.006), although depth of response did not differ significantly. With a median follow-up of 150 months, median OS was 103 months in SH-HRMM and 94 months in DH-HRMM (p = 0.40). Median PFS was 36 months and 31 months, respectively (p = 0.20). Restricted mean survival time analyses similarly demonstrated no significant differences in OS or PFS between groups. Although ORR differed, depth of response and long-term survival did not. Conclusions: In this real-world cohort of transplant-treated HRMM, single-hit disease was associated with a higher likelihood of achieving post-ASCT response; however, no significant differences in long-term survival outcomes were observed between single-hit and double-hit HRMM. These findings suggest that cytogenetic hit burden alone may be insufficient to predict post-transplant survival, highlighting the need for refined risk stratification incorporating additional biological and response-based markers.