Genetic Factors Related with Early Onset of Osteonecrosis of the Jaw in Patients with Multiple Myeloma Under Zoledronic Acid Therapy
Authors: Melea Pelagia , Bagratuni Tina , Terpos Evangelos , Eleutherakis-Papaiakovou Evangelos , Gavriatopoulou Maria , Melakopoulos Ioannis , Kastritis Efstathios , Dimopoulos Meletios A. 
Published: October 2019

Abstract
Bisphosphonates are extensively used in the treatment of myeloma-related bone disease as they reduce pain and skeletal related events (SREs), such as pathologic fractures, need for radiation and surgery to the bone. One of the complications of prolonged therapy with bisphosphonates, especially of amino-bisphosphonates, such as zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). Recent studies have attempted to correlate specific genetic polymorphisms (SNPs) and ONJ. Such SNPs include cytochrome P4502C8 (CYP2C8; Sarasquete et al, Blood 2008) and peroxisome proliferator-activated receptor gamma (PPAR-γ; Di Martin et al, Br J Haematol 2011) that have been linked to increased risk of ONJ in two different series. The aim of this study was to investigate a possible association between SNPs in CYP2C8 and PPAR-γ and the risk of developing ONJ in a large number of MM patients who received ZA.
We screened 36 patients who developed ONJ and 104 patients who did not develop ONJ for the SNPs of interest in PPAR-γ (rs1152003) and CYP2C8 (rs193495) genes by direct sequencing of peripheral blood derived DNA. All patients were treated with similar systemic anti-myeloma therapies during the same period of time, had received only ZA as antiresorptive therapy and were followed prospectively for the development of ONJ in a single center (Department of Clinical Therapeutics, University of Athens, Greece).
The median follow up of the cohort was 72 months. The median number of ZA infusions was 27 (range: 4-107). Patients who developed ONJ had a median of 31 infusions versus 25 infusions for patients who did not develop ONJ. However, 31% of patients who developed ONJ had received less than 24 infusions of ZA. Median time to development of ONJ was 47 months (range: 7-182 months). The median relative dose intensity for ZA was 2.85 mg/month; it was 3.3 mg/month for those who developed ONJ and 2.7 mg/month for those who did not. An extraction preceded the development of ONJ in 60% of patients who developed ONJ, it was unprovoked in 20%, it was associated with trauma from dentures in another 15% and in 5% ONJ was preceded by a periodontal and/or periappical inflammation (abscess formation etc).
There was no significant difference in frequency of the presence of SNPs in the two studied genes between patients with and without ONJ. However, there is a subset of patients who develop ONJ rather early, after the infusion of relatively few doses of ZA while others develop ONJ after protracted exposure to ZA. Since the most important factor associated with the development of ONJ after ZA therapy in patients with myeloma is the total dose of ZA, we analyzed separately patients who had less than 24 versus those who had at least 24 infusions of ZA. In patients with <24 infusions of ZA, the presence of SNPs in both PPAR-γ and CYP2C8 was associated with a significantly higher probability and a shorter time to development of ONJ. More specifically, the presence of SNPs in the PPAR-γ was associated with a significantly higher risk of development of ONJ with less than 24 ZA infusions (55% versus 16%, p=0.011) and at a significantly shorter time to development of ONJ (19 versus 69 months, p<0.001). The presence of SNPs in the CYP2C8 was associated with a higher risk of developing ONJ with less than 24 ZA infusions (29% versus 7%, p=0.07) and at a shorter time (44% versus 13% at 3 years, p=0.037). Combining the genotype risk, those with high risk of SNPs in both genes had a 70% cumulative incidence of ONJ within 24 months from initiation of ZA versus 17% for those carrying one of the two SNPs and 0% for those without any high risk of SNPs (p<0.001).
In conclusion, our data indicate that SNPs in the CYP2C8 and PPAR-γ genes are associated with a risk of early development of ONJ. However, increasing cumulative dose of ZA increases substantially the risk of ONJ in all patients, independently of genotype-defined risk.

Disclosures
No relevant conflicts of interest to declare.