Risk stratification models based on cytogenetics and disease burden help identify high-risk patients with newly diagnosed multiple myeloma (NDMM). However, some high-risk patients remain undetected. This study evaluated the prognostic utility of the proportion of clonal plasma cells in the S-phase of the cell cycle for NDMM. Patients with active multiple myeloma diagnosed between 01/01/2013 and 01/31/2023 who underwent S-phase assessment were included. The S-phase proportion was calculated by analyzing DNA content between G0/G1 and G2/M peaks. Among 823 patients, 16% (135) had S-phase ≥2% at diagnosis. Patients with S-phase ≥2% exhibited significantly worse median progression-free survival (PFS) of 1.4 years (95% CI: 1.2-1.9) compared to 2.9 years (95% CI: 2.6-3.3) for those with S-phase <
2% (HR 1.6, p <
0.0001). Median overall survival (OS) was also significantly lower at 3.9 years (95% CI: 2.9-5.7) versus 9.2 years (95% CI: 7.9-not reached
HR 2.2, p <
0.0001). Multivariate analysis confirmed S-phase ≥2% as an independent predictor of inferior PFS (HR 1.56, p = 0.001) and OS (HR 2, p <
0.0001) after adjusting for R2-ISS risk, age, renal function, and treatment strategies. Among patients with S-phase ≥2%, 53% (68/129) experienced progression-free survival (PFS) under 18 months with upfront therapy. Elevated S-phase was associated with a 2.5-fold higher risk of progression within 18 months [OR 2.55 (95% CI: 1.7-3.7), p <
0.001]. Patients with elevated S-phase but no IMS-high risk had a median OS of 5.7 years (95% CI: 4.7-9.2), similar to the IMS-high risk cohort without elevated S-phase (5.4 years, 95% CI: 4-NR). Those with both elevated S-phase and IMS-high risk had significantly worse OS (3.1 years, 95% CI: 1.6-NR, p = 0.043). These findings suggest that S-phase ≥2% is a powerful, independent prognostic marker for NDMM.