Proposed Second Revision of the International Staging System for Survival in Multiple Myeloma

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As reported in the Journal of Clinical Oncology by D’Agostino et al in the European Myeloma Network, a second revision (R2-ISS) of the Revised International Staging System (R-ISS) incorporates a risk scoring system that permits delineation of four prognostic risk groups in newly diagnosed multiple myeloma.

As stated by the investigators, “Patients with newly diagnosed multiple myeloma show heterogeneous outcomes, and approximately 60% of them are at intermediate risk according to the R-ISS, the standard-of-care risk-stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+.”

Study Details

As part of the HARMONY project, the European Myeloma Network collected individual data from 10,843 patients with newly diagnosed multiple myeloma enrolled in 16 clinical trials. An additive scoring system was developed using the top features predicting progression-free and overall survival.

Key Findings

At a median follow-up of 75 months in the training set (n = 7,072), ISS stage, del(17p), lactate dehydrogenase level, t(4;14), and 1q+ had the highest impact on progression-free and overall survival. All variables were simultaneously present in 2,226 patients. Values assigned to each risk feature according to overall survival impact were:

  • ISS-III = 1.5
  • ISS-II = 1
  • del(17p) = 1
  • High lactate dehydrogenase = 1
  • 1q+ = 0.5 points.

Patients were stratified into four R2-ISS risk groups according to the total additive score: low (R2-ISS-I) = 0 points (19.2% of patients); low-intermediate (R2-ISS-II) = 0.5 to 1 point (30.8% of patients); intermediate-high (R2-ISS-III) = 1.5 to 2.5 points (41.2% of patients), and high (R2-ISS-IV) = 3 to 5 points (8.8% of patients).

For R2-ISS I, II, III, and IV groups, median overall survival was not reached, 109.2 months, 68.5 months, and 37.9 months, respectively. Comparisons between IV, III, and II vs I were all significant (at P < .0001). Overall survival at 5 years was 88%, 75%, 56%, and 37%. Median progression-free survival was 68, 45.5, 30.2, and 19.9 months (all comparisons significant at P < .0001).  

The scoring system was validated in an independent validation set (n = 3,771), including 1,214 patients with complete data to calculate R2-ISS scores. The proportions of patients in R2-ISS I, II, III, and IV groups were 11.1%, 26.5%, 51.6%, and 10.7%. Respective median overall survival durations were not reached, 88.8 months, 56.2 months, and 33.9 months (P for comparison of II vs I = .032; P < .0001 for III and IV vs I). Overall survival at 5 years was 80%, 70%, 48%, and 24%. Median progression-free survival was 39.3, 28, 19.4, and 14.9 months (P for II vs I = .061; P < .0001 for III and IV vs I).

The investigators concluded, “The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk newly diagnosed multiple myeloma. The additive nature of this score fosters its future implementation with new prognostic variables.”

Mattia D’Agostino, MD, of SSD Clinical Trial in Oncoematologia e Mieloma Multiplo, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the HARMONY project, funded by the European Innovative Medicines Initiative Joint Undertaking (IMI-JU). For full disclosures of the study authors, visit

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