title: Clinical course of light-chain smouldering multiple myeloma (idiopathic Bence Jones proteinuria): a retrospective cohort study.
abstract: BACKGROUND
  Bence Jones proteinuria is a disorder that is defined by the excretion of monoclonal light-chain protein. About 15-20% of patients with multiple myeloma secrete monoclonal light chains only, without expression of the normal immunoglobulin heavy chain, which constitutes light-chain multiple myeloma. The definition, prevalence, and progression of these premalignant phases of light-chain multiple myeloma have not been fully characterised. We aimed to identify a subset of patients with idiopathic Bence Jones proteinuria who had a high risk of progression to light-chain multiple myeloma analogous to that seen in patients with smouldering multiple myeloma.
  
  
  METHODS
  In this retrospective cohort study, we studied all patients seen at the Mayo Clinic (Rochester, MN, USA) within 30 days of diagnosis of idiopathic Bence Jones proteinuria between Jan 1, 1960, and June 30, 2004. Inclusion criteria were monoclonal light chain in the urine (≥0·2 g/24 h), absence of intact monoclonal immunoglobulin (M protein) in the serum, and no evidence of multiple myeloma, light-chain amyloidosis, or other related plasma-cell proliferative disorders. The primary endpoint was progression to symptomatic multiple myeloma or light-chain amyloidosis. We examined the cumulative probability of progression and the association of potential risk factors on progression rates to identify patients with a high risk of progression to multiple myeloma or light-chain amyloidosis.
  
  
  RESULTS
  We identified 101 patients with idiopathic Bence Jones proteinuria. During 901 total person-years of follow-up, 27 (27%) patients developed multiple myeloma and seven (7%) developed light-chain amyloidosis. The major risk factors for progression were amount of urinary excretion of M protein per 24 h, proportion of bone marrow plasma cells, presence of a markedly abnormal free-light-chain ratio (<0·01 or >100), and reduction of all three uninvolved immunoglobulins. Based on the risk of progression, monoclonal light-chain excretion of 0·5 g/24 h or greater or at least 10% bone marrow plasma cells, or both, in the absence of end-organ damage was used to define light-chain smouldering multiple myeloma. The cumulative probability of progression to active multiple myeloma or light-chain amyloidosis in patients with light-chain smouldering multiple myeloma was 27·8% (95% CI 14·2-39·2) at 5 years, 44·6% (27·9-57·4) at 10 years, and 56·5% (36·3-70·2) at 15 years.
  
  
  CONCLUSIONS
  Light-chain smouldering multiple myeloma as defined in this study is associated with a high risk of progression to symptomatic light-chain multiple myeloma, and this subset of patients needs careful observation and could benefit from clinical trials of early intervention.
  
  
  BACKGROUND
  Jabbs Foundation (Birmingham, UK), US National Cancer Institute, and Henry J Predolin Foundation (Madison, WI, USA).
authors.affiliation: Division of Hematology (Prof R A Kyle MD, Prof A Dispenzieri MD, Prof S Kumar MD, Prof S V Rajkumar MD), Division of Biostatistics (D R Larson MS, Prof T M Therneau PhD, J T Benson BA), and Division of Epidemiology (Prof L J Melton 3rd MD), Mayo Clinic, Rochester, MN, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kyle
authors.affiliation: Division of Hematology (Prof R A Kyle MD, Prof A Dispenzieri MD, Prof S Kumar MD, Prof S V Rajkumar MD), Division of Biostatistics (D R Larson MS, Prof T M Therneau PhD, J T Benson BA), and Division of Epidemiology (Prof L J Melton 3rd MD), Mayo Clinic, Rochester, MN, USA.
authors.forename: Dirk R
authors.initials: DR
authors.lastname: Larson
authors.affiliation: Division of Hematology (Prof R A Kyle MD, Prof A Dispenzieri MD, Prof S Kumar MD, Prof S V Rajkumar MD), Division of Biostatistics (D R Larson MS, Prof T M Therneau PhD, J T Benson BA), and Division of Epidemiology (Prof L J Melton 3rd MD), Mayo Clinic, Rochester, MN, USA.
authors.forename: Terry M
authors.initials: TM
authors.lastname: Therneau
authors.affiliation: Division of Hematology (Prof R A Kyle MD, Prof A Dispenzieri MD, Prof S Kumar MD, Prof S V Rajkumar MD), Division of Biostatistics (D R Larson MS, Prof T M Therneau PhD, J T Benson BA), and Division of Epidemiology (Prof L J Melton 3rd MD), Mayo Clinic, Rochester, MN, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Dispenzieri
authors.affiliation: Division of Hematology (Prof R A Kyle MD, Prof A Dispenzieri MD, Prof S Kumar MD, Prof S V Rajkumar MD), Division of Biostatistics (D R Larson MS, Prof T M Therneau PhD, J T Benson BA), and Division of Epidemiology (Prof L J Melton 3rd MD), Mayo Clinic, Rochester, MN, USA.
authors.forename: L Joseph
authors.initials: LJ
authors.lastname: Melton
authors.affiliation: Division of Hematology (Prof R A Kyle MD, Prof A Dispenzieri MD, Prof S Kumar MD, Prof S V Rajkumar MD), Division of Biostatistics (D R Larson MS, Prof T M Therneau PhD, J T Benson BA), and Division of Epidemiology (Prof L J Melton 3rd MD), Mayo Clinic, Rochester, MN, USA.
authors.forename: Joanne T
authors.initials: JT
authors.lastname: Benson
authors.affiliation: Division of Hematology (Prof R A Kyle MD, Prof A Dispenzieri MD, Prof S Kumar MD, Prof S V Rajkumar MD), Division of Biostatistics (D R Larson MS, Prof T M Therneau PhD, J T Benson BA), and Division of Epidemiology (Prof L J Melton 3rd MD), Mayo Clinic, Rochester, MN, USA.
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Hematology (Prof R A Kyle MD, Prof A Dispenzieri MD, Prof S Kumar MD, Prof S V Rajkumar MD), Division of Biostatistics (D R Larson MS, Prof T M Therneau PhD, J T Benson BA), and Division of Epidemiology (Prof L J Melton 3rd MD), Mayo Clinic, Rochester, MN, USA.
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Rajkumar