Circulating Adiponectin and Markers of Endothelial and Cardiovascular Dysfunction Correlate with Disease Burden in Newly Diagnosed Patients with Multiple Myeloma; Increase of Adiponectin after Bortezomib- and IMiD-Based Regimens
Authors: Terpos Evangelos , Papassotiriou Ioannis , Kastritis Efstathios , Papassotiriou Gerasimos-Petros , Christoulas Dimitrios , Kanellias Nikolaos , Komitopoulou Anna , Eleutherakis-Papaiakovou Evangelos , Panagiotidis Ioannis , Gavriatopoulou Maria , Mantzou Emilia , Dimopoulos Meletios A. 
Published: October 2019

Abstract
Adiponectin is a multimeric protein of the white adipose tissue which has anti-inflammatory, anti-atherogenic, and possibly anti-neoplastic properties. Low levels of adiponectin are associated with endothelial dysfunction in several disorders, while low levels of circulating adiponectin have been recently associated with increased risk for multiple myeloma (MM) in overweight individuals. Furthermore, decreased host-derived adiponectin promotes myeloma tumor growth and osteolysis in myeloma animal models. There is no information in the literature for adiponectin levels in MM patients. The aim of this study was to evaluate circulating adiponectin in MM patients who responded to first line anti-myeloma therapy and explore possible correlations with disease features, including bone disease, endothelial dysfunction which is present in several plasma cell dyscrasias (Waldenstrom's macroglobulinemia and AL amyloidosis), angiogenesis and inflammation.
We studied 76 newly-diagnosed MM patients (46M/30F, median age 70.5 years) before the administration of any kind of therapy and after best response to front-line therapy. Forty-five patients received bortezomib-based regimens, while 31 patients were treated with IMiD based regimens (16 with lenalidomide-based therapies). Evidence of bone involvement was documented using plain radiographs. Adiponectin was measured in the serum of all patients and of 24 healthy individuals of similar age, gender and body index along with a series of biochemical markers of: i) endothelial (vWF:antigen and GDF-15) and cardiovascular dysfunction (hs-troponin and NTproBNP); ii) angiogenesis (placental-growth factor, PlGF and its receptor sFlt-1); iii) renal impairment (cystatin-C and NGAL); iv) bone disease (CTX and P1NP); and v) inflammation (hs-CRP and IL-6).
Adiponectin levels were elevated in MM patients at diagnosis compared to healthy individuals (mean±SD: 16.2±2.6 mg/L vs. 11.8±0.8 mg/L; p=0.03). The circulating vWF concentrations were markedly elevated in patients compared to controls (mean±SD: 215±16.3 IU/dl vs. 85.3±5.1; p<0.001). Similarly, all markers of cardiovascular dysfunction were elevated in MM patients compared to controls (GDF-15: 3893±970 pg/ml vs 665±50.9 pg/ml, p<0.001; hs-troponin 22.3±3.3 ng/l vs. 6.9±0.7 ng/l, p<0.001 and NTproBNP 623±153 pg/ml vs 44.2±7.2 pg/ml, p<0.001). Both cystatin-C and NGAL, sFlt-1 as well as hs-CRP, IL-6 and CTX were also elevated in MM patients (p<0.01 for all comparisons).
Adiponectin negatively correlated with M-protein (r=-0.408, p=0.01), serum calcium (r=-0.391, p=0.015) and GDF-15 (r=-0.40, p=0.01) and positively with NGAL (p=0.395, p=0.014) and CTX (p=0.385, p=0.018). VWF:antigen strongly correlated with beta2-microglobulin (r=0.524, p=0.001) and all factors of renal impairment: urea (r=0.416, p=0.009), creatinine (r=0.431, p=0.007), cystatin-C (r=0.400, p=0.012), NGAL (r=0.400, p=0.013) and eGFR (based on CKD-EPI; r=-0.416, p=0.009). Both adiponectin and vWF correlated with bone marrow plasma cell infiltration (r=-0.376, p=0.031 and r=0.354, p=0.043, respectively). Notably, all markers of endothelial and cardiovascular dysfunction increased with the increase of ISS stage: p-ANOVA for hs-troponin, NTproBNP and GDF-15 <0.001 and for vWF 0.03.
The studied population included 16 (21%) patients who achieved a CR, 19 (25%) with vgPR and 41 with PR. Response to anti-myeloma therapy resulted in a dramatic increase of adiponectin (from 16.2±2.6 mg/l to 24.2±4.2 mg/l, p<0.01). Interestingly response to IMiD-based therapies was followed by a higher increase in circulating adiponectin (from 18±1.7 mg/L to 27±2.7 mg/L; p<0.001). vWF was reduced in responders and this reduction was higher in patients who received bortezomib-based regimens (from 240±86 IU/dl to 165±78 IU/dl; p=0.018). There were no alterations in responding patients regarding GDF-15, hs-troponin and NTproBNP after treatment.
We conclude that adiponectin and markers of endothelial and cardiovascular dysfunction are elevated in newly-diagnosed patients with MM. Adiponectin and vWF correlates with bone marrow plasma cell infiltration, while all markers of endothelial and cardiovascular dysfunction correlated with ISS stage. Response to therapy increased circulating adiponectin. These results support a role of adiponectin in disease biology as suggested by experiments in murine myeloma models.

Disclosures
Terpos: Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Kastritis:Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.