Bone Marrow DKK-1 Levels Identify Patients With Smoldering Myeloma With Higher Risk of Progression to Active Multiple Myeloma

Smoldering multiple myeloma (SMM) patients can be stratified for the risk of progression to active MM based on several factors, however new parameters to identify patients with a high risk of progression need to be defined. 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. In this study we focused on the potetial role of these soluble factors in the progression of SMM patients. We analyzed a total cohort of 87 patients with SMM as defined by the International Myeloma Working Group updated diagnostic criteria admitted to our Myeloma Unit between 2007 and 2015. The median age of the patients was 65 years (range 38-92). Standard risk factors evaluated were size of serum M protein, percentage of BM plasma cells (BMPCs) and immunoparesis. Free Light Chain (FLC) ratio and FISH analysis,was available in about 30% of the patients. DKK-1, Activin A, CCL20, and OPG BM plasma levels were measured by ELISA assay. With a median follow-up time of 42 months, 21 patients progressed to active MM; median time to progression was 16 months. We firstly analyzed the main clinical features at diagnosis, finding that the percentage of BMPCs, serum M protein > 3 g/dL and immunoparesis were statistically significant correlated with progression to active MM (p<0,0001, p=0.023 and p=0.0016 respectively). BM Activin A, CCL20 and OPG median levels were not significantly different between progressed and not SMM patients, 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). BM DKK-1 levels and BMPCs were not statistically significant correlated (p=0.25 by Spearman's correlation); Consistently BM DKK-1 median levels were not significantly higher in patients with more than 20% BMPCs as compared to those with minus 20% of BMPCs. 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). Finally, we found that time to progression (TTP) to active MM 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). Our study indicates that BM median levels of DKK-1 identify the SMM patients with higher risk of progression to active MM, and represent a new independent risk factor for progression in SMM patients.