Preserved Levels Of Uninvolved Immunoglobulins Are Associated With Better Overall Survival In Patients With Multiple Myeloma Independently Of Disease Burden: A Role For The Immune System?
Authors: Dimopoulos Meletios A. , Symeonidis Argiris S. , Zagouri Flora , Sioni Anastasia , Pouli Anastasia , Delimpasi Sosana , Katodritou Eirini , Michalis Eurydiki , Michael Michalis , Hatzimichael Eleftheria , Vassou Amalia , Repousis Panagiotis , Christoforidou Anna , Kartasis Zafiris , Stefanoudaki Ekaterini , Megalakaki Catherine , Giannouli Stavroula , Kyrtsonis Marie-Christine , Konstantopoulos Kostas , Terpos Evangelos , Kastritis Efstathios 
Published: October 2019

Abstract
Suppression of uninvolved immunoglobulins is a common finding in MM patients. The prognostic importance of this finding has not been extensively studied in patients with MM and current data come from older series which included limited number of patients. Recent publications indicated that a novel immunoassay, which measures serum concentrations of the Ig heavy chain/light chain subsets IgGκ, IgGλ, IgAκ and IgAλ and which also identifies suppression of the uninvolved (polyclonal) Ig of the same isotype as the tumor was of prognostic significance for progression free survival in a selected population of patients. However, this is not a widely available method yet. Thus, we studied the prognostic significance of suppression of uninvolved immunoglobulins in a large unselected population of patients with newly diagnosed, symptomatic, MM.
Suppression of the immunoglobulins was defined as at least one of the uninvolved immunoglobulins below lower limit of normal (for IgG was <700 mg/dl, for IgA <70 mg/dl and for IgM <40 mg/dl). The analysis included 1702 consecutive patients with IgG, IgA or light chain myeloma, who were treated within the Greek Myeloma Study Group and who had available pre-therapy immunoglobulin levels measured by nephelometry. Median age was 67 years (range 20-96 years). Uninvolved immunoglobulin suppression was observed in 87% of the patients and was slightly more common in patients with IgA myeloma (91.6% vs. 88.6% for light chains myeloma and 84.3% for IgG myeloma, p=0.001). Also, it was more common in patients >65 years (89% vs. 84.5% for patients ≤65 years, p=0.008). Anemia (hemoglobin <10 gr/dl in 47% vs. 27.5%, p<0.001), low platelet counts (<130x109/l, 13% vs. 5%, p<0.001) and renal dysfunction (eGFR <60 ml/min/1.73m2in 16% vs. 10%, p<0.001) were more common in patients with suppressed immunoglobulins. Uninvolved immunoglobulins were more frequently suppressed in patients with advanced ISS stage (78% vs. 88% vs. 94% of patients with ISS-1, -2 and -3 disease respectively, p<0.001) and with extensive BM infiltration (78% vs. 93% of patients with >40% of plasma cell infiltration, p<0.001). Levels of serum M-monoclonal protein were higher in patients with suppressed immunoglobulins (median 3.4 vs. 2 g/dl, p<0.001).
Preserved immunoglobulins were associated with better overall survival: patients with preserved uninvolved immunoglobulins had a median survival of 55 months vs. 41.5 months for patients with suppressed immunoglobulins (p=0.001). Because immunoglobulin suppression was associated with other features of advanced tumor load, we performed a multivariate analysis in order to adjust for the impact of other well defined prognostic factors. Importantly, in the multivariate analysis, the suppression of at least one of the uninvolved immunoglobulins was independently associated with survival (HR: 0.781, 95% CI 0.618-0.987, p=0.039). Other factors which were independently associated with inferior survival in multivariate analysis included age >65 years (p<0.001), eGFR <60 ml/min/1.73m2 (p=0.001), performance status >1 (p<0.001), treatment without novel agents (p<0.001), hemoglobin <10 g/dl (p=0.033), platelet counts <130x109/l (p<0.001), advanced ISS stage (p<0.001) and LDH >300 IU/L (p=0.05). The prognostic significance of the suppression of uninvolved immunoglobulins remained important across groups who received primary therapy with either conventional chemotherapy regimens (3-year OS 62% vs. 51%, p=0.002) or novel agent -based (IMiD or bortezomib-based) regimens (3-year OS 79% vs. 65%, p=0.036). There was no significant association of immunoparesis with increased risk of early death.
In conclusion, our data from a large number of consecutive unselected patients indicate that preservation of all uninvolved immunoglobulins is seen in 13% of patients with symptomatic MM and is associated with longer survival. Preserved immunoglobulins were an independent favorable prognostic factor even in patients treated with novel agents. Our findings also point to the role of normal plasma cell compartment in myeloma and the need for further investigation of the role of the immune system.

Disclosures:
No relevant conflicts of interest to declare.