Vascular Cell Adhesion Molecule-1 Is An Independent Prognostic Factor For Newly-Diagnosed Patients With Multiple Myeloma; Reductions Post VD and Rd In Myeloma Patients At First Relapse

The adherence of myeloma cells to the bone marrow stromal cells plays a key role in the biology of the disease as it supports the growth of myeloma cells in the marrow microenvironment. The aim of our study was to evaluate the levels of circulating adhesion molecules in myeloma patients, to explore possible correlations with disease characteristics, including survival, and to examine their alterations post-therapy with novel agents. We measured circulating levels of vascular cell adhesion molecule-1 (VCAM-1; CD106), intercellular adhesion molecule-1 (ICAM-1; CD54), P-, L- and E-selectin using an ELISA methodology (R&D Systems, Minneapolis, MN, USA) in 232 consecutive myeloma patients: 145 with newly diagnosed symptomatic MM (NDMM) who were treated with novel agent based therapies and 87 with relapsed myeloma (RMM) at first relapse. Of the later, 47 received lenalidomide with low-dose dexamethasone (Rd) and 40 patients received bortezomib with dexamethasone (VD). Serum was collected just before initiation of therapy for NDMM patients, or before initiation of the first Rd or VD cycle (on day 1) for RMM patients and after the completion of the 4^thcycle of Rd or VD (on day 28 or 21, respectively).

Patients with NDMM had increased circulating levels of VCAM-1 and ICAM-1 compared to controls (n=17, p<0.001 for all comparisons), while the levels of selectins did not differ between MM patients and controls. VCAM-1 was lower in patients with ISS-1 [590 ng/ml (range: 312-869 ng/ml)] compared to patients with ISS-2 [639ng/ml (226-4163ng/ml)] and ISS-3 [1189 ng/ml (288-2997ng/ml), ANOVA p=0.002). For NDMM patients, there was a positive correlation between VCAM-1 and ICAM-1 (r=0.466, p<0.001) and a negative correlation between VCAM-1 and P-selectin (r=-0.216, p<0.001). Serum VCAM-1 showed also strong correlation with β2-microglobulin (r=0.560, p<0.001) and serum creatinine (r=0.436, p<0.001) but had not correlation with the extent of marrow infiltration by plasma cells.

The median follow-up of symptomatic patients with NDMM was 31 months and the median overall survival (OS) was 53 months (CI 95% 46-59 months). The median progression-free survival (PFS) for all patients was 23 months; patients who had VCAM-1 values >median had a median PFS of 19 months vs. 32 months of the others (p<0.0001). Importantly, VCAM-1 was an independent prognostic factor for PFS in the multivariate analysis (VCAM-1 >median was associated with a HR: 2.17, CI 95%: 1.18-4, p=0.012). Increased levels of VCAM-1 (>median) were also associated with inferior survival. In particular, patients with high VCAM-1 had a median OS of 45 months vs. 75 months for those with levels <median (p=0.001). As continuous variable, increasing levels of VCAM-1 correlated with shorter OS (p=0.003). Other adverse prognostic factors for OS in the univariate analysis included: advanced ISS stage (p=0.026), LDH ≥300 U/L (p<0.001) and platelet counts (<150x10⁹/l, p<0.001). In the multivariate analysis, VCAM-1 >median (HR: 2.46, CI 95%: 1.06-5.68, p=0.034) had an independent prognostic value for inferior survival.

MM patients at first relapse had increased levels of ICAM-1 and L-selectin even compared to newly-diagnosed symptomatic MM patients (p=0.001 and p=0.017, respectively) and increased levels of VCAM-1 compared to controls (p<0.01 for all comparisons). Both VD and Rd reduced dramatically serum VCAM-1 after 4 cycles of therapy (p<0.001 and p=0.008 respectively), but only VD reduced serum ICAM-1 (p=0.001). The reduction of VCAM-1 was more pronounced after Rd than after VD (median % reduction: 38% vs. 17%; p=0.002). Therapy with Rd increased P-selectin and decreased L- and E-selectin (p≤0.01 for all comparisons), while VD had no effect on selectins. All changes were independent of response to therapy.

Our study provides evidence about the role of microenvironment in the outcome of myeloma patients. In particular, VCAM-1 had an independent prognostic value for both PFS and OS in patients with newly-diagnosed symptomatic disease who were treated with novel agent-based therapies. Interestingly, in patients at first relapse, both Rd and VD produced a dramatic reduction of VCAM-1, irrespective of response to treatment indicating an effect of these drugs on the microenvironment, while Rd altered also the levels of all studied selectins suggesting an effect of Rd on the vascular niche and the endothelium.