SERUM LEVELS OF DICKKOPF-1 PREDICT PROGRESSION FREE SURVIVAL IN MULTIPLE MYELOMA PATIENTS TREATED WITH AUTOLOGOUS STEM CELL TRANSPLANTAT BUT ITS PROGNOSTIC VALUE IS OVERCOME BY THE USE OF NOVEL DRUGS

ABSSUB-3658

Background: Dickkopf-1 glycoprotein (DKK-1)  is one of the key regulators of bone homeostasis. It is highly expressed in multiple myeloma and its overexpression leads to the development of myeloma bone disease by the inhibition of Wnt signalling pathway, thus inhibiting osteoblasts and activating osteoclasts.

Aims: The aim of our study was to compare the relationship of serum levels of DKK-1 to other parameters of bone marrow microenvironment, and to assess the potential prognostic value of DKK-1 in patients treated with or without the support of autologous stem cell transplantation, and in patients treated with thalidomide and bortezomib based regimens.

Methods: We assessed 128 patients with newly diagnosed symptomatic multiple myeloma at our department during 2008-2013. Serum levels of DKK-1 were measured at the time of diagnosis before therapy, and correlated to serum levels of thymidine kinase (TK), osteocalcin (OC), bone fraction of alkaline phosphatase (bALP), parathormone (PTH), C-terminal telopeptide type I collagen (ICTP), procollagen I intact N-terminal (PINP), insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), interleukin-6 receptor (IL-6R), syndecan-1 (SYN), vascular endothelial growth factor (VEGF), osteoprotegerin (OPG), endostatin (END), macrophage inhibitory protein 1α and 1β (MIP-1α, MIP-1β), and angiogenin (ANG). Also, we evaluated progression free survival and overall survival with regard to DKK-1 levels and therapeutic approach used.

Results: Spearman correlation analysis revealed weak positive relationship between serum levels of DKK-1 and TK (r = 0,274; p = 0,045); there was no other significant correlation in comparison of all other selected parameters, i.e. DKK-1 and OC, bALP, PTH, ICTP, PINP, IGF-1, HGF, IL-6R, SYN, VEGF, OPG, END, MIP-1α, MIP-1β and ANG.

In the whole cohort of patients, DKK-1 was not found a suitable predictor of progression, the area under curve (AUC) = 0,540 (<0,75). The Cox regression analysis revealed that DKK-1 is not a suitable prognostic factor of PFS and OS for the whole cohort of patients, RR = 0,96 (95%CI: 0,57-1,62; p = 0,876). In the subgroup of patients treated using autologous stem cell transplantation (ASCT, n = 30), ROC analysis found DKK-1 as a convenient progression predictor with AUC = 0,861 (>0,75). The optimal cut-off level was 9399ng/l (91% sensitivity, 74% specificity). Cox regression analysis followed by Kaplan-Meier analysis confirmed significant shorter PFS in patients with DKK-1 <9399ng/l than in patients with DKK-1 ≥9399ng/l (2,6 vs 4,2 years, p = 0,008). Due to short follow up we were not able to assess OS as the patients did not reach median OS yet. There was no significant difference in either OS or PFS in patients treated with thalidomide based regimens (n= 62) or bortezomib based regimens (n = 49).

Summary/Conclusion: Our data suggest that serum levels of DKK-1 are independent prognostic factor in MM patients treated with autologous stem cell transplantation. Patients with low DKK-1 had shorter PFS than patients with high serum levels of DKK-1. The use of novel biological drugs, however, overcomes its prognostic significance, suggesting a distinct interference of these drugs with bone marrow microenvironment.

Supported by the grant IGA MZ CR NT 14393, NT14400, NT12451-5 and NT12215-4.

Keywords: None

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