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.

Cedars Sinai Outpatient Cancer Center Los Angeles CA USA

Clinica Universidad de Navarra CIMA CIBERONC IDISNA Pamplona Spain

Department of Clinical Hematology Centro Hospitalar e Universitário de Coimbra Coimbra Portugal

Department of Experimental Diagnostic and Specialty Medicine DIMES University of Bologna Bologna Italy

Department of Haematology London North West Healthcare London UK

Department of Hemato Oncology Hallym University Dongtan Sacred Heart Hospital Hwasung South Korea

Department of Hematology Amyloidosis and Myeloma Unit Hospital Clínic IDIBAPS University of Barcelona Barcelona Spain

Department of Hematology and Medical Oncology Atrium Health Levine Cancer Institute Charlotte NC USA

Department of Hematology Hopital de La Milétrie CHU Poitiers France

Department of Hematology Hospital de Santa Maria Lisboa Portugal

Department of Hematology Hospital Italiano de Buenos Aires Buenos Aires Argentina

Department of Hematology Sahlgrenska University Hospital Goteborg and Skane University Hospital Lund Sweden

Department of HematoOncology University Hospital Ostrava and Faculty of Medicine Ostrava University Ostrava Czech Republic

Department of Internal Medicine 5 University Medical Hospital and National Center of Tumor Diseases Heidelberg Germany

Department of Medicine Center for Oncology Hematology and Palliative Care Wilhelminenspital Vienna Austria

Department of Medicine Surgery and Neurosciences University of Siena Siena Italy

Department of Molecular Medicine Amyloidosis Research and Treatment Center Foundation 'Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo' University of Pavia Pavia Italy

Division of Hematology Mayo Clinic Rochester MN USA

Hematology and Medical Oncology Department of Clinical Therapeutics National and Kapodistrian University of Athens School of Medicine Athens Greece

Hematology Department of Internal Medicine Seoul St Mary's Hospital The Catholic University of Korea Seoul South Korea

Janssen Pharmaceuticals Horsham PA USA

Perlmutter Cancer Center NY Langone Health New York NY USA

Service d'Hématologie Hôpital Pitié Salpêtrière Paris France

Servicio de Hematologia Hospital Universitario de Salamanca Centro de Investigación del Cáncer Instituto de Biología Molecular y Cellular del Cáncer Salamanca Spain

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