The Second Revision of the International Staging System (R2‐ISS) was recently introduced to improve risk stratification over that provided by the extensively applied standard revised International Staging System (R‐ISS). In addition to the variables included in the R‐ISS, the R2‐ISS incorporates chromosome 1q gain/amplification and divides the patients into 4 groups with different survival outcomes, better stratifying patients within the R‐ISS intermediate‐risk. The new model was developed based on a great quantity of data from patients participating in uniform clinical trials and has not been validated in real‐world clinical practice. Therefore, we retrospectively analyzed the prognostic value of the R2‐ISS in 474 consecutive patients with multiple myeloma receiving immunomodulatory drugs or proteasome inhibitor‐based regimens as their first‐line treatment. According to the R2‐ISS, 41 (8.6%), 76 (16%), 275 (58%), and 82 (17.3%) patients were identified as R2‐ISS I, R2‐ISS II, R2‐ISS III, and R2‐ISS IV, respectively. The median progression‐free survival (PFS) was 48 (95% CI: 38–58), 35 (95% CI: 23–47), 24 (95% CI: 21–27), and 12 (95% CI: 7–17) months, and the estimated median overall survival (OS) was 110 (95% CI: 42–178), 88 (95% CI: 75–101), 50 (95% CI: 43–57), and 26 (95% CI: 19–33) months (p < 0.001) in the 4 groups, respectively. The R2‐ISS could also classify groups with distinct survival among patients with renal impairment or classified as R‐ISS II. Adjusted by age, sex, treatment approaches and transplantation status, the R2‐ISS was an independent prognostic factor associated with OS with a hazard ratio of 7.055 (95% CI: 3.626–13.726) (p < 0.001) for R2‐ISS IV versus R2‐ISS I and 2.707 (95% CI: 1.436–5.103) (p = 0.002) for R2‐ISS III versus R2‐ISS I. In conclusion, our results suggest that the R2‐ISS is a simple and robust risk stratification tool for patients with multiple myeloma treated with novel drugs and could be used in everyday clinical practice.