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
Mattia D'Agostino 1 , David A Cairns 2 , Juan José Lahuerta 3 , Ruth Wester 4 , Uta Bertsch 5 , Anders Waage 6 , Elena Zamagni 7 8 , María-Victoria Mateos 9 , Daniele Dall'Olio 10 , Niels W C J van de Donk 11 , Graham Jackson 12 , Serena Rocchi 7 8 , Hans Salwender 13 , Joan Bladé Creixenti 14 , Bronno van der Holt 15 , Gastone Castellani 8 , Francesca Bonello 1 , Andrea Capra 1 , Elias K Mai 5 , Jan Dürig 16 , Francesca Gay 1 , Sonja Zweegman 11 , Michele Cavo 7 8 , Martin F Kaiser 17 , Hartmut Goldschmidt 5 , Jesús María Hernández Rivas 18 , Alessandra Larocca 1 , Gordon Cook 2 , Jesús F San-Miguel 19 , Mario Boccadoro 1 , Pieter Sonneveld 4
Purpose: Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (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+.
Patients and methods: The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated.
Results: In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, 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 (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). 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, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value.
Conclusion: The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables.
CITATION J Clin Oncol. 2022 Oct 10;40(29):3406-3418. doi: 10.1200/JCO.21.02614. Epub 2022 May 23.