Bone Marrow DKK-1 Levels in Smoldering Multiple Myeloma Patients: A New Independent Risk Factor for Progression

The presence of bone disease is the hallmark to differentiate patients with active multiple myeloma (MM) from those with smoldering MM (SMM). The diagnostic criteria for active MM have been recently updated; including patients previously defined high-risk SMM among those with active MM in the presence of biomarkers of malignity. Actually SMM patients can be stratified for the risk of progression to active MM based on several factors but new parameters to identify patients with a high risk of progression need to be defined. Particularly there are not any molecular factors able to differentiate the new high-risk SMM patients. Recently, we analyzed bone marrow (BM) levels of several cytokines and chemokines involved in the MM-induced alterations of the bone remodeling finding that BM levels of Activin A, C-C motif chemokine ligand 20 (CCL20), Dickkopf 1 (DKK-1) and osteoprotegerin (OPG) were significantly different among patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), SMM and MM (Dalla Palma B et al. Leukemia 2016). Thus, in this study we focused on those soluble factors in order to evaluate their possible role as new markers of risk progression in SMM patients.

We analyzed a total cohort of 87 patients with SMM as defined by the International Myeloma Working Group updated diagnostic criteria for MM and related disorders (serum monoclonal protein (IgG or IgA) ≥ 3 g/dL, or urinary monoclonal protein ≥500 mg/24 h and/or clonal BM plasma cells 10%-60%, and absence of myeloma defining events or amyloidosis) admitted to our Myeloma Unit between 2007 and 2015 and who underwent to BM aspirate. The median age of the patients was 65 years (range 38-92); 50 were males and 37 were females; light chain was kappa in 68% of patients and lambda in 32%, whereas heavy chain was IgG in 76%, IgA in 23% and IgD in 1%. Standard risk factors evaluated were size of serum M protein (≥ 3 g/dL in 14% of patients), percentage of BM plasma cells and immunoparesis (present in 66% of patients). Free Light Chain (FLC) ratio was not available in all patients. DKK-1, Activin A, CCL20, and OPG BM plasma levels were measured by ELISA assay. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher's exact test. P value of <0.05 was considered significant. The influence of BM cytokine and chemokine levels on the progression to active MM in SMM patients was examined by Kaplan-Meier and Cox regression analysis.

With a median follow-up time of 42 months, 21 patients progressed to active MM; median time to progression was 16 months. BM Activin A, CCL20 and OPG median levels were not significantly different between progressed and not SMM patients (median levels: Activin A 401.97 pg/mL vs 402.93 pg/ml, p=0.70; CCL20 68.68 pg/mL vs 62.08 pg/mL, p=0.80; OPG 101.94 pg/mL vs 118.74 pg/mL, p=0.86). Conversely SMM patients progressed to active MM showed significantly higher DKK-1 BM levels as compared to patients who had not progressed (median levels: 1777.50 pg/mL vs 782.77 pg/mL, p=0.007). The progression-free survival was significantly worse in patients with BM DKK-1 above the median (DKK-1 median level: 971 pg/mL; p=0.021 by log rank test). In multivariate analysis, adjusted for standard risk factors such as the size of serum M protein, the percentage of BM plasma cells, the presence of the immunoparesis, we found that BM DKK-1 levels remained an independent prognostic factor for progression to active MM (p=0.001).

In conclusion, our study indicates that BM median levels of DKK-1 are able to identify the SMM patients with higher risk of progression to active MM, and may represent a new independent risk factor for progression in SMM patients.