ORIGINAL ARTICLE Preserved levels of uninvolved immunoglobulins are independently associated with favorable outcome in patients with symptomatic multiple myeloma E Kastritis 1 , F Zagouri 1 , A Symeonidis 2 , M Roussou 1 , A Sioni 3 , A Pouli 3 , S Delimpasi 4 , E Katodritou 5 , E Michalis 6 , M Michael 7 , E Hatzimichael 8 , A Vassou 8 , P Repousis 9 , A Christophoridou 10 , Z Kartasis 11 , E Stefanoudaki 12 , C Megalakaki 9 , S Giannouli 13 , M-C Kyrtsonis 14 , K Konstantopoulos 15 , M Spyroupoulou-Vlachou 16 , E Terpos 1 and MA Dimopoulos 1 for the Greek Myeloma Study Group Suppression of uninvolved immunoglobulins is common in multiple myeloma (MM) but the prognostic significance of this phenomenon has not been assessed. We evaluated the prognostic significance of the preservation of uninvolved immunoglobulins in 1755 consecutive, unselected, patients with newly diagnosed, symptomatic MM with pre-therapy immunoglobulin levels measured by nephelometry. Suppression of at least one uninvolved immunoglobulin was observed in 87% of patients and was more common in patients with immunoglobulin A myeloma, those aged over 65 years, in patients with advanced-International Staging System (ISS) stage, extensive-bone marrow infiltration, anemia, low platelet counts, high levels of serum M-monoclonal protein or renal dysfunction. Patients with preserved immunoglobulins had a better survival than patients with suppressed immunoglobulins (median survival 55 vs 41.5 months, Po0.001). In multivariate analysis, preservation of uninvolved immunoglobulins was independently associated with better survival (hazard ratio: 0.781, 95% confidence interval: 0.618–0.987, P ¼ 0.039); irrespective of the treatment. In a subset of 500 patients, which were strictly followed for disease progression, preservation of uninvolved immunoglobulins was associated with a significantly longer progression-free survival (60 vs 25 months, Po0.001), independently of other common prognostic factors. In conclusion, preservation of uninvolved immunoglobulins in newly diagnosed patients with symptomatic MM was independently associated with long term disease control and improved survival. Leukemia (2014) 28, 2075–2079; doi:10.1038/leu.2014.110 INTRODUCTION Multiple myeloma (MM) is a relatively common hematological malignancy characterized by a monoclonal proliferation of malig- nant plasma cells and suppression of the nonmalignant plasma cell population. 1 The majority of MM patients have high levels of monoclonal immunoglobulin in the serum and/or urine and suppressed levels of the uninvolved immunoglobulins. 2–4 This suppression of the uninvolved immunoglobulins is considered a common finding in patients with symptomatic MM reported in 85–91% of newly diagnosed patients. 2,3,5–7 In patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) or Asymptomatic Multiple Myeloma (AMM), immunoglobulin suppression has been associated with a higher risk of progression to symptomatic MM. 8–12 However, there are very limited data on the prognostic significance of uninvolved-immunoglobulin suppression in patients with symptomatic MM and the association with other features of the disease. 2,5 Recently, a novel immunoassay that measures serum concentrations of the immunoglobulin (Ig) heavy chain/light chain subsets IgGk, IgGl, IgAk and IgAl, and also identifies suppression of the uninvolved (polyclonal) Ig of the same isotype as the tumor, has shown prognostic significance for progression-free survival (PFS) in a selected population of patients, 13 indicating that the suppression of the uninvolved immunoglobulins in patients with symptomatic MM may be of prognostic value. However, this method is not widely available yet while quantification of immunoglobulins with nephelometry is extensively used and has been a validated method of assessment of immunoglobulin levels. 14 To assess the prognostic significance and the association of the suppression of uninvolved immunoglobulins, measured with nephelometry, with the other features of the disease, we analyzed the outcomes of a large unselected population of patients with newly diagnosed symptomatic MM. MATERIALS AND METHODS Between January 1990 and December 2012, 1755 consecutive patients with symptomatic myeloma were prospectively included in the database 1 Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece; 2 Hematology Division, Department of Internal Medicine, University of Patras Medical School, Patras, Greece; 3 Department of Hematology, St Savvas Oncology Hospital, Athens, Greece; 4 Department of Hematology and Bone Marrow Transplantation Unit, Evangelismos Hospital, Athens, Greece; 5 Department of Hematology, Theagenio Cancer Hospital, Thessaloniki, Greece; 6 Department of Hematology, ‘Georgios Gennimatas’ General Hospital, Athens, Greece; 7 Department of Hematology, Nicosia General Hospital, Nicosia, Cyprus; 8 Department of Hematology, University Hospital of Ioannina, Ioannina, Greece; 9 Department of Hematology, Metaxa Cancer Hospital, Piraeus, Greece; 10 Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece; 11 Department of Hematology, General Hospital of Chalkida, Chalkida, Greece; 12 Department of Hematology, Amalia Fleming General Hospital, Athens, Greece; 13 Second Department of Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece; 14 Hematology Section and Laboratory, First Department of Propaedeutic Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 15 First Department of Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece and 16 Immunology Labaratory, ‘Alexandra’ Hospital, Athens, Greece. Correspondence: Professor MA Dimopoulos, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, 80 Vas. Sofias Avenue, Athens 11528, Greece. E-mail: mdimop@med.uoa.gr Received 6 January 2014; revised 9 February 2014; accepted 14 February 2014; accepted article preview online 18 March 2014; advance online publication, 11 April 2014 Leukemia (2014) 28, 2075–2079 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu