Increased levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Inter-Cellular Adhesion Molecule-1 (ICAM-1) Correlate with Advanced Disease Features and Poor Survival in Newly Diagnosed Patients with Multiple Myeloma. Reduction Post-Bortezomib- and Lenalidomide-Based Regimens.
Authors: Migkou Magdalini , Terpos Evangelos , Christoulas Dimitrios , Gavriatopoulou Maria , Boutsikas Georgios , Gkotzamanidou Maria , Iakovaki Marina , Kastritis Efstathios , Papatheodorou Athanasios , Dimopoulos Meletios A. 
Published: October 2019

Abstract
Abstract 1824
Poster Board I-850
Interactions between myeloma (MM) cells and bone marrow stromal cells (BMSCs) are strongly implicated in the biology of MM. The aim of this study was to evaluate the serum levels of adhesion molecules, such as VCAM-1 (CD106), ICAM-1 (CD54), P-, L- and E-selectin in patients with MM and explore possible correlations with clinical and laboratory data. The study population included 87 newly diagnosed patients (42M/45F; median age 68 years): 59 with symptomatic MM, 21 with asymptomatic MM (AMM) and 7 with MGUS, as well as 21 MM patients at first relapse (11M/10F, median age 69 years) who received the combination of bortezomib/dexamethasone (VD) and 20 MM patients at first relapse (11M/9F, median age 68.5 years) who were treated with the combination of lenalidomide plus low-dose dexamethasone (Rd). The aforementioned adhesion molecules were measured in the serum of newly-diagnosed patients before the administration of any kind of therapy, in relapsed patients on Day 1 of cycle 1 and on the last day of cycle 4 and in 43 healthy controls using ELISA method (R&D Systems, Minneapolis, MN, USA). Patients with newly-diagnosed or relapsed MM had increased levels of all studied molecules compared to controls (p<0.01), while in MGUS only serum VCAM-1 and ICAM-1 levels were elevated compared to controls (p<0.01). Newly-diagnosed patients with symptomatic MM had increased levels of VCAM-1 (mean±SD: 1168.5±810.4 ng/ml) and ICAM-1 (371.0±162.7 ng/mL) when compared to AMM patients (642.6±340.9 ng/ml, p<0.0001; and 274.4±65.5 ng/ml, p=0.002, for VCAM-1 and ICAM-1, respectively) and to MGUS patients (629.8±228.5 ng/ml, p=0.012; and 247.9±53.9, p=0.009, for VCAM-1 and ICAM-1, respectively). Furthermore, newly-diagnosed symptomatic MM had increased levels of E-selectin (43.2±20.0 ng/ml) compared to AMM (33.6±16.6 ng/ml, p=0.047). VCAM-1 was lower in patients with ISS-1 (768.2±225.1 ng/ml) compared to patients with ISS-2 (1121.7±991.2 ng/ml) and ISS-3 (1456.8±785.7 ng/ml; ANOVA p=0.04), while P-selectin was higher in ISS-1 (172.7±76.6 ng/ml) compared to ISS-2 (118.7±75.5 ng/ml) and ISS-3 MM (108.3±76.4; ANOVA p=0.042). For all newly-diagnosed patients, there was a strong correlation between VCAM-1 and ICAM-1 (r=0.598, p<0.0001). Serum VCAM-1 showed strong positive correlations with β2-microglobulin (r=0.564, p<0.0001), urea (r=0.384, p=0.001) and creatinine (r=0.376, p=0.001) and negative correlation with Hb (r=-0.346, p=0.002). Similarly, ICAM-1 positively correlated with β2-microglobulin (r=0.340, p=0.003), creatinine (r=0.290, p=0.01) and urea (r=0.254, p=0.025), and negatively correlated with Hb (r=-0.237, p=0.037). Serum P-selectin positively correlated with platelet counts (r=0.555, p<0.0001), Hb (r=0.416, p<0.0001) and albumin (r=0.270, p=0.017), but negatively correlated with β2-microglobulin (r=-0.383; p=0.001) and creatinine (r=-0.294, p=0.009). For L-selectin there was a positive correlation with albumin (r=0.370; p=0.001). The median follow-up of patients with newly-diagnosed symptomatic MM was 22 months (range: 4-54 months) and the median OS was 42 months. Increased levels of VCAM-1, ICAM-1 and L-selectin predicted for inferior survival. In particular, patients with VCAM-1 >1358.5 ng/ml had a median OS of 20 months in comparison to 42 months of all others (p=0.006), while patients with elevated ICAM-1 (>400.6 ng/ml) had a median OS of 13 months compared to 42 months of all others (p<0.0001) and patients with L-selectin >928.2 ng/ml had a median OS of 23 months compared to 42 months of all others (p=0.024). MM patients at first relapse had increased levels of VCAM-1 and ICAM-1 even compared to newly-diagnosed symptomatic MM patients (p<0.01). Both BD and Rd administration reduced dramatically serum VCAM-1 and ICAM-1 after 4 cycles of therapy (p<0.01 for all comparisons) but had no effect on the levels of selectins. The reduction of VCAM-1 and ICAM-1 was more pronounced in responders than in non-responders (p=0.032). In conclusion, patients with newly diagnosed MM have increased serum levels of VCAM-1 and ICAM-1 that correlate with advanced disease features and poor survival suggesting an important role in the biology of the disease. Selectins seem also to participate in MM pathogenesis. The administration of novel agents such as bortezomib and lenalidomide resulted in the reduction of VCAM-1 and ICAM-1 and supports a direct effect on the adhesion of MM cells to BMSCs.

Disclosures
No relevant conflicts of interest to declare.