The Second Revision of the International Staging System (R2-ISS) has been validated as a prognostic tool for patients with relapsed or refractory multiple myeloma (RRMM) treated with modern therapies, including anti-CD38 monoclonal antibodies. This independent validation, using pooled data from the ICARIA-MM and IKEMA phase 3 trials, demonstrates the R2-ISS's ability to stratify patients into distinct risk groups with significantly different progression-free survival (PFS) and overall survival (OS) outcomes.
Improved Risk Stratification with R2-ISS
The R2-ISS incorporates five prognostic risk factors to categorize patients into four stages. The study showed that re-allocation of patients into R2-ISS stages was able to demonstrate 4 subgroups that showed a progressive decline in median PFS with increasing disease stage (stage I, 38.8 months; stage II, 21.2 months; stage III, 12.2 months; stage IV, 7.0 months). These PFS differences reached statistical significance for stages III and IV, when each was compared with stage I. The R2-ISS improves upon the original R-ISS by better differentiating the large intermediate-risk group, splitting it into R2-ISS stages II and III, leading to a more even distribution of patients across the four stages.
Impact of Isatuximab-Based Therapy
The analysis confirmed the benefit of isatuximab-based triplet therapy (Isa-Pd or Isa-Kd) over doublet therapy (Pd or Kd) across all R2-ISS stages. This finding reinforces the role of isatuximab in combination regimens for RRMM, regardless of the specific doublet backbone used. In patients with early relapse, a clear benefit of isatuximab-based triplet therapy over doublet therapy was observed (aHR 0.624 [95% CI 0.459–0.848]).
Clinical Implications and Future Directions
The study supports the use of R2-ISS for stratifying patients in clinical trials involving RRMM and highlights its potential to refine risk assessment as novel therapies, such as monoclonal antibody-based quadruplet therapies and CAR-T cell therapies, become more prevalent. While the study acknowledges limitations such as the retrospective nature of 1q21+ characterization in ICARIA-MM and missing cytogenetic data, it emphasizes the importance of comprehensive laboratory and cytogenetic testing at diagnosis. The findings suggest that the R2-ISS can help translate clinical trial results to real-world practice by providing a more accurate prognostic assessment in the context of evolving treatment landscapes.
