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Multicenter Study
. 2020 Oct 16;10(10):102.
doi: 10.1038/s41408-020-00366-3.

International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)

María-Victoria Mateos  1 , Shaji Kumar  2 , Meletios A Dimopoulos  3 , Verónica González-Calle  1 , Efstathios Kastritis  3 , Roman Hajek  4 , Carlos Fernández De Larrea  5 , Gareth J Morgan  6 , Giampaolo Merlini  7 , Hartmut Goldschmidt  8 , Catarina Geraldes  9 , Alessandro Gozzetti  10 , Charalampia Kyriakou  11 , Laurent Garderet  12 , Markus Hansson  13 , Elena Zamagni  14 , Dorotea Fantl  15 , Xavier Leleu  16 , Byung-Su Kim  17 , Graça Esteves  18 , Heinz Ludwig  19 , Saad Usmani  20 , Chang-Ki Min  21 , Ming Qi  22 , Jon Ukropec  22 , Brendan M Weiss  22 , S Vincent Rajkumar  23 , Brian G M Durie  24 , Jesús San-Miguel  25
Affiliations
Multicenter Study

International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)

María-Victoria Mateos et al. Blood Cancer J. .

Abstract

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2-3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.

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Conflict of interest statement

M.-V.M. reports grants from Janssen, Celgene, Amgen, Takeda, Abbvie, GSK, Adaptive, EDO Mundipharma, Pharmamar, Roche, Seattle Genetics, outside the submitted work; S.K. reports research funding for clinical trials to the institution: Celgene, Takeda, Janssen, BMS, KITE, Merck, AbbVie, Medimmune, Novartis, Roche-Genentech, Amgen, Tenebio, Carsgen; and Consulting/Advisory Board participation: (with no personal payments) Celgene, Takeda, Janssen, AbbVie, Genentech, Amgen, Molecular Partners and (with personal payment) Oncopeptides, Gene Centrix, Cellectar. M.A.D. reports personal fees from Amgen, Celgene, Takeda, Janssen, and BMS, outside the submitted work. V.G.-C. reports grants from Janssen, personal fees from Advisory Board of Prothena, non-financial support from Janssen and Celgene, outside the submitted work; E.K. reports grants and personal fees from Amgen, personal fees and non-financial support from Genesis Pharma, grants, personal fees, and non-financial support from Janssen, personal fees from Takeda and Pfizer, during the conduct of the study; R.H. has nothing to disclose. C.F.d.L. reports grants, personal fees, and non-financial support from Janssen, Celgene, Takeda, and Amgen, outside the submitted work; G.J.M.: Advisory Boards from Celgene, BMS, Sanofi, Karyopharm, Janssen, Roche, and Genentech. G.M. has nothing to disclose. H.G. reports grants, personal fees and other fees from Celgene, Janssen, BMS, and Sanofi, grants and other from Chugai, grants from John Hopkins University and Dietmar Hopp Stiftung, other fees from Amgen, Molecular Partners, MSD, Mundipharma, and Art Tempi, personal fees and other fees from Takeda and Novartis, non-financial support and other fees from Adaptive Biotechnology, outside the submitted work. C.G. has nothing to disclose. A.G. reports grants and personal fees from Janssen, personal fees from Celgene, Amgen, and Takeda, outside the submitted work; C.K. has nothing to disclose. L.G. has nothing to disclose. M.H. has nothing to disclose. E.Z.: Advisory Board for Sanofi, BMS, Janssen, and Takeda. D.F. reports personal fees from Amgen, Janssen, Varifarma, Tecnofarma, Takeda, Sanofi, Glaxo, and Bristol Myers, outside the submitted work; X.L. has nothing to disclose. B.-S.K. reports grants from National Research Foundation of Korea (NRF), during the conduct of the study; G.E. has nothing to disclose. H.L. reports grants from Amgen, Takeda, personal fees from Amgen, Takeda, Janssen, BMS, Celgene, Seattle Genetics, and Sanofi, outside the submitted work; S.U. reports grants and personal fees from Amgen, Celgene, Sanofi, Seattle Genetics, Janssen, Takeda, SkylineDX, and Merck, personal fees from Abbvie and MundiPharma, grants from BMS and Pharmacyclics, outside the submitted work; C.-K.M. has nothing to disclose. M.Q.: employment from Janssen Research and Development; stock or other ownership from Janssen Research and Development. J.U.: employment from Janssen; stock or other ownership from Janssen. B.M.W. is an employee of Janssen Research & Development. S.V.R. has nothing to disclose. B.G.M.D.: Advisory Board for Amgen, Janssen, Celgene/BMS, and Takeda. J.S.-M. reports other fees from Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, GSK, AbbVie, and Karyopharm, outside the submitted work.

Figures

Fig. 1
Fig. 1. Probability of progression over time in the full study cohort (n = 1996).
The median time to progression for the entire cohort was 6.4 years (95% CI 6.0–7.2); the 2-, 5-, and 10-year risk of progression were 22, 42, and 64%, respectively.
Fig. 2
Fig. 2. Risk of progression at 2 years based on presence or absence of risk factors in patients with smoldering multiple myeloma.
a Probability of progression at 2 years in the three different subgroups of patients according to the model 2/20/20. Patients with no risk factors (low-risk group) had a risk of progression at 2 years of 6%, those with one factor (intermediate-risk group) had a risk of progression of 18% at 2 years, and those with ≥2 factors (high-risk group) had a 44% progression risk at 2 years. b Probability of progression at 2 years according to the model 2/20/20 with separation of high-risk group based on presence of 2 or 3 risk factors. Of the 396 patients included in the high-risk group, 92 presented with the three risk factors and had a slightly higher risk of progression to MM.
Fig. 3
Fig. 3. Probability of progression at 2 years in the four different subgroups of patients according to the model 2/20/20 plus cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q/monosomy 13).
This model defined four groups of SMM patients: low risk with none of the factors had a progression risk at 2 years of 6%, low–intermediate with one factor present had a progression risk at 2 years of 23%, intermediate risk with the presence of 2 factors had a risk of progression at 2 years of 37%, and the high risk with ≥3 of the factors had a progression risk at 2 years of 63%.
Fig. 4
Fig. 4. Risk of progression according to the risk score.
Risk score was developed using the entire range of the values for BMPC, serum FLC, and serum M-spike as well as cytogenetic abnormality. Patients with total risk score between 0 and 4 had a 2-year progression risk of 3.8%, patients with a total score between 5 and 8 had a risk of 26%, those with a score between 9 and 12 had a risk of progression of 51%, and those with a score >12 had a risk of progression of 73%.
See this image and copyright information in PMC

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