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R2-ISS: an Improved and Simple Prognostic Staging System Allows Better Stratification of Patients with Intermediate-Risk Newly Diagnosed Multiple Myeloma

Second revision stems on the work of the European Myeloma Network within the European Union–funded HARMONY project
01 Jun 2022
Multiple Myeloma

Within the HARMONY project, the European Myeloma Network collected data from 10,843 patients with newly diagnosed multiple myeloma to propose a second revision (R2-ISS) of the Revised International Staging System (R-ISS). The impact on overall survival (OS) of widely available prognostic tools, such as ISS, serum lactate dehydrogenase (LDH) levels, deletion (17p), translocation (4;14), and 1q gain/amplification (1q+), was used to define R2-ISS. Four risk groups predicting different OS and progression-free survival (PFS) rates were identified. Compared with the R-ISS, the R2-ISS is an improved and simple prognostic staging system that includes the independent poor prognostic factors 1q gain (3 copies of 1q) or amplification (at least 4 copies of 1q) resulting in better stratification of especially the large group of patients with intermediate-risk newly diagnosed multiple myeloma according to Dr. Mattia D’Agostino of the Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino in Torino, Italy and colleagues who published this new prognostic algorithm on 23 May 2022 in the Journal of Clinical Oncology

The authors wrote in the background that the R-ISS was introduced in 2015 with aim to develop a robust prognostic system on the basis of widely available biomarkers. It is now considered a standard risk stratification model for patients with newly diagnosed multiple myeloma. The R-ISS takes into account ISS which integrates β2-microglobulin levels and serum albumin to reflect tumour mass and renal function, high-risk chromosomal abnormalities detected by FISH, del(17p), t(4;14)(p16;q32) or t(14;16)(q32;q23)], and serum LDH levels. The R-ISS identifies 3 groups with main limitation that 62% of patients were classified into the intermediate-risk category, possibly including patients with different risk levels of progression/death.

Recently, 1q gain (three copies of 1q) or amplification (at least four copies of 1q), which were not included in the R-ISS, proved to be independent poor prognostic factors in newly diagnosed multiple myeloma. Moreover, in the R-ISS, high-risk chromosomal abnormalities were considered as present, if at least one among del(17p), t(4;14), or t(14;16) was detected, whereas emerging data showed that having more than one high-risk chromosomal abnormalities predicted poorer outcomes. 

Within the HARMONY project, the European Myeloma Network collected individual patient data from a large cohort of young and elderly patients with newly diagnosed multiple myeloma who were enrolled in 16 clinical studies to improve risk stratification and propose a revision of the current R-ISS. The prognostic value of each single baseline risk feature was analyzed in an additive fashion, including 1q gain/amplification in the risk calculation. An additive scoring system based on top features predicting PFS and OS was developed and validated.

In the training set of 7,072 patients, at a median follow-up of 75 months, ISS, del(17p), LDH, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients.

A value was assigned to each risk feature according to their OS impact. Patients were stratified into 4 risk groups according to the total additive score: low in case of 0 points (19.2%, low-intermediate in case of 0.5-1 points (30.8%), intermediate-high in case of 1.5-2.5 points (41.2%), and high in case of 3-5 points (8.8%).

Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months.

The score was validated in an independent validation set of 3,771 patients of whom 1,214 had complete data to calculate R2-ISS maintaining its prognostic value.

The authors concluded that comparing with the R-ISS, the R2-ISS adds 1q+ to the score, and its calculation takes into account the prognostic significance of the coexistence of several chromosomal abnormalities. Furthermore, compared with the R-ISS, the R2-ISS showed an improved discriminating capability, especially in the large group of patients with intermediate-risk newly diagnosed multiple myeloma. The R2-ISS score includes simple and widely used prognostic markers, and the additive nature of its calculation easily allows the future inclusion of new prognostic variables.


D’Agostino M, Cairns DA, Lahuerta JJ, et al. Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma: A European Myeloma Network (EMN) Report Within the HARMONY Project. JCO; Published online 23 May 2022. DOI: 10.1200/JCO.21.02614

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