• Elias Eythorsson, Saemundur Rognvaldsson, Sigrun Thorsteinsdottir, Einarsson LongThorirT0000-0003-2377-7886Faculty of Medicine, University of Iceland, Reykjavík, Iceland, and Skåne University Hospital, Lund, Sweden (T.E.L.)., Elin Ruth Reed, Gudrun Asta Sigurdardottir, Brynjar Vidarsson, Pall Torfi Onundarson, Bjarni A Agnarsson, Margret Sigurdardottir, Isleifur Olafsson, Ingunn Thorsteinsdottir, Signy Vala Sveinsdottir, Fridbjorn Sigurdsson, Asdis Rosa Thordardottir, Runolfur Palsson, Olafur Skuli Indridason, Asbjorn Jonsson, Gauti Kjartan Gislason, Andri Olafsson, Jon Sigurdsson, Hlif Steingrimsdottir, Malin Hultcrantz, DurieBrian G MBGM0000-0002-9883-3769Cedars-Sinai Samuel Oschin Cancer Center, Los Angeles, California (B.G.M.D.)., Stephen Harding, Ola Landgren, Thor Aspelund, Thorvardur Jon Love, and Sigurdur Yngvi Kristinsson.
• Landspítali-The National University Hospital of Iceland and Faculty of Medicine, University of Iceland, Reykjavík, Iceland (E.E., S.R., P.T.O., B.A.A., R.P., O.S.I., S.Y.K.).
• Ann. Intern. Med. 2024 Apr 1; 177 (4): 449457449-457.

BackgroundMonoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management.ObjectiveTo develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model.DesigniStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597).SettingIcelandic population of adults aged 40 years or older.Patients1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample.MeasurementsMonoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater.ResultsThe c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds.LimitationThe prediction model will require external validation.ConclusionThis accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology.Primary Funding SourceInternational Myeloma Foundation and the European Research Council.

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