Prognostic Value of the Parameters of Myeloma Bone Disease Signaling in Patients with Newly Diagnosed Multiple Myeloma Treated with Proteasome Inhibitors
Authors: Minarik Jiri , Hermanova Zuzana , Hrbek Jan , Petrova Pavla , Flodr Patrik , Krhovska Petra , Pika Tomas , Bacovsky Jaroslav , Herman Miroslav , Scudla Vlastimil 
Published: October 2019

Abstract
Aims: The aim of our study was to assess the prognostic potential of parameters reflecting myeloma bone disease (MBD) assessed at the time of multiple myeloma (MM) diagnosis with respect to the extent of the disease, treatment approach and response to treatment.
Patients and methods: We assessed prospectively a cohort of 52 patients with newly diagnosed multiple myeloma indicated for treatment initiation. The median age was 68 years (40-88) with M/F ratio 1:1,3. All patients were treated initially using proteasome inhibitor (PI) based regimen - either bortezomib based (N=48) or carfilzomib based (N=4). 15 patients (29%) underwent autologous stem cell transplant (ASCT). 3 patients only continued with lenalidomide based maintenance.
We evaluated parameters reflecting the extent of the disease and bone involvement, presence of extramedullary masses, and activation of MBD signaling pathways with respect to treatment response and progression free survival (PFS). For the assessment of the extent of bone involvement we used whole-body techniques, either low-dose computed tomography scan (LD-CT) or magnetic resonance imaging (WB-MRI) or both. Following parameters reflecting MBD signaling were assessed from peripheral blood: hepatocyte growth factor (HGF, Human HGF Quantine ELISA), macrophage inflammatory factor alpha (MIP-1 α,Human CCL3/MIP-1a Quantikine ELISA), Syndecan-1 (Human Syndecan-1 (CD138) ELISA), osteoprotegerin (OPG, Human Osteoprotegerin ELISA), Activin A (Human Activin A Quantikine ELISA), Dickkopf-related protein-1 (DKK1, Human DKK-1 Quantikine ELISA), Annexin A2 (Human Annexin A2 ELISA kit), nuclear factor-kappa B (NF-κB, Human Nuclear factor-kappa B),Sclerostin (Sclerostin ELISA kit, Biomedica), matrix metalloproteinase 9 (MMP9, BlueGene Biotech ELISA kit).
For statistical estimation we used Kaplan-Meier analysis, Chi-square test, with log rank test (Mantel-Cox) at p < 0,05. To construct the PFS curves for each serum parameter we used median levels as cut-off for even distribution.
Results: PFS of the whole cohort was 21months. Overall survival did not reach median (M) yet, with 36-month survival of 79,6%. Despite low patient count there were significant differences between patients reaching complete remission (CR), very good partial remission (VGPR) and partial remission (PR) with PFS medians 36 vs 23 vs 17 months (p = 0,039, RR 3,189). The curves reflecting relationship of PFS and Durie-Salmon staging system showed better course with lower stages, still, the limited number of patients with stage I (N=3) precluded valid statistical estimation. Similarly, we could trace differences between ISS stages (M not reached vs 20 vs 17 months), the difference was, however, not statistically significant.
Out of the whole cohort, 16 patients were found to have an extramedullary myeloma. Interestingly, there was no significant difference in PFS based on the presence of extramedullary disease. Similarly, we did not find significant difference with respect to skeletal involvement based on LD-CT or WB-MRI.
From the selected parameters of MBD signaling, we found significant correlation to PFS in the case of HGF and MIP-1α. Patients with HGF≤ 3048pg/mL had significantly better PFS than patients with HGF>3048pg/mL (M 36 vs 17 months, p = 0,001, RR 3,835), and patients with MIP-1α≤25,5pg/mL had sigificantly better PFS than patients with MIP-1α>25,5pg/mL (29 vs 17 months, p = 0,025, RR 2,361).
With regard to treatment apporach, patients undergoing ASCT had significantly better PFS than patients with standard treatment only (M not reached vs 17months, p = 0,0005).
Conclusions: We found statistically significant prognostic value of HGF and MIP-1α in patients with newly diagnosed MM treated using PI based induction treatment. Despite limited number of patients, our cohort confirmed the significance of the depth of treatment response and ASCT on PFS. Interestingly, patients with extramedullary disease treated with PI based regimen did not have adverse PFS with respect to patients without the presence of extramedullary massess.
With support of the grant IGA_LF_2016_001.

Disclosures
No relevant conflicts of interest to declare.