Granulocytic Myeloid Derived Suppressor Cells are Increased in Multiple Myeloma and can Predict outcome in Patients Treated upfront with Lenalidomide

Research Article

Ann Hematol Oncol. 2016; 3(2): 1078.

Granulocytic Myeloid Derived Suppressor Cells are Increased in Multiple Myeloma and can Predict outcome in Patients Treated upfront with Lenalidomide

Romano A*, Parrinello NL, La Cava P, Tibullo D, Giallongo C, Parisi M, Vetro C, Conticello C and Di Raimondo F

Division of Hematology, University of Catania, Italy

*Corresponding author: Alessandra Romano, Division of Hematology, University of Catania, UOC Hematology with Bone Marrow Transplantation, Ferrarotto Hospital, Via Citelli 6, 95124 Catania, Italy

Received: March 16, 2016; Accepted: May 02, 2016; Published: May 04, 2016


Background: Recent studies have indicated a role for the myeloid compartment in the biology of Multiple Myeloma (MM) and the neutrophil to lymphocyte ratio (NLR) is emerging predictors of progression free survival (PFS) and overall survival (OS) in MM. In addition, Myeloid-Derived Suppressor Cells (MDSC), a heterogeneous population of myeloid cells with peculiar immunosuppressive properties against T-cells, are increased in MM, as recently described.

Aim: We investigated MDSC and clinical variables at diagnosis (including NLR) and their impact on outcome of patients treated upfront with novel agents (Lenalidomide and bortezomib).

Methods: We evaluated by flow cytometry G-MDSC (CD11b+CD33+CD14- HLADR-) in 45 newly diagnosed MM patients treated upfront with lenalidomide (N=30) or bortezomib (N=15), compared to 50 MGUS and 30 healthy subjects matched for sex and age.

Results: G-MDSC percentage in MM whole blood was greater than healthy controls (61.2±1.6% versus 51.7±1.4%, p< 0.001) with a large overlapping with granulocytes.

G-MDSC were higher in presence of extensive bone disease (p= 0.02), in patients carrying LDH ≥2 UPN (p= 0.0025) and fibrinogen ≥40 mg/dL (p= 0.01). G-MDSC were also positively correlated with neutrophil to lymphocyte ratio (NLR) recently described as a novel biomarker in MM (r2=0.60, p< 0.0001).

G-MDSCwb was reduced after exposure to lenalidomide-based regimen (p< 0.0001) but not to bortezomib. Patients treated upfront with lenalidomide and G-MDSCwb >60% at diagnosis had shorter progression free survival (PFS) than those with less than 60% (16.8 versus 47.0 months, p= 0.04).

Conclusion: G-MDSC is increased in MM; they can predict response to lenalidomide. NLR could be surrogates for G-MDSC and this can explain the recently reported prognostic meaning.

Keywords: Multiple myeloma; G-MDSC; MGUS


Multiple myeloma (MM) is the second most frequent hematological neoplasia, characterized by the accumulation of malignant plasma cells within the marrow microenvironment leading to variable anemia, bone pain, renal impairment, hypercalcemia and infections [1,2].

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic, pre-malignant disorder characterized by monoclonal plasma cell proliferation in the bone marrow and absence of end-organ damage [3].

Virtually all cases of MM arise from MGUS through a multi-stage process of proliferation and dissemination [4-6]. MGUS plasma cells do not exhibit clear genetic and/or phenotypic markers distinguishing from MM [7-9], and it is still not possible to predict MGUS progression to MM in individual patients, with a heterogeneous average rates of progression as low as 0.26% and as high as 12% per year [5].

While in MGUS T-cells isolated from the bone marrow are able of mounting vigorous response against autologous pre-malignant cells, this phenomenon is not observed in MM [10]. On the contrary, in MM the immune function is impaired as consequence of cellular defects and represents an immunologically “permissive” microenvironment [11]. Several mechanisms may concur in the reduction of immunesurveillance in MM [12,13] and in this perspective, the presence of myeloid derived suppressor cells (MDSC) has been recently described in mouse models [14,15] and human MM [14,16,17].

MDSC are a heterogeneous population of myeloid derived cells [18] that can utilize multiple pathways to elicit tumor immune-editing, including secretion of immunosuppressive cytokines, up-regulation of reactive oxygen species, and T-cell function impairment through perturbation of the arginine metabolism [19]. In tumor-bearing mice two main MDSC populations have been distinguished based on their immunophenotype and morphology: monocytic MDSCs (mo-MDSC) identified as CD11b+CD115+Ly6-G-Ly6-Chigh, and granulocytic MDSCs (G-MDSC) with the phenotype CD11b+CD115– Ly6G+Ly6Clow, which represent up to 75% of all MDSC, while the identification and isolation of human MDSC subsets are challenging due to the heterogeneous characteristics [20,21] and for G-MDSC the overlapping immunophenotype with granulocytes circulating in peripheral blood [22-27].

MDSC are increased in MM [16] and most recent reports indicate that the G-MDSC subpopulation could play a role in the biology of disease [14,17]. However, its clinical impact has never been elucidated.

Thus, we investigated the clinical impact of G-MDSC in MGUS and in newly diagnosed MM patients undergoing treatment with novel agents.


Patients and controls

Between January 2010 and December 2012, G-MDSC was investigated in 45 newly diagnosed MM and 50 MGUS patients (Table 1). Patients were devoid of immune-mediated diseases and acute or chronic viral infections (based on routinely clinical assessment for TORCH agents and replicative status of HAV, HBV, HCV and HIV viruses) to exclude any interference on immune-regulatory mechanisms. All MM patients had measurable disease, defined as a serum-M protein level of at least 1g per deciliter, a urine-M protein level of at least 200 mg per day, or both according to International Myeloma Working Group Criteria [28]. All MGUS patients had a stable condition with at least 2 years of follow up. Thirty healthy subjects (age 35-60 years) were recruited in the study as controls.