Factors That Determine Overall Survival among Patients (Pts) with Multiple Myeloma (MM) Treated with Zoledronic Acid (ZOL): Lack of Skeletal-Related Events (SREs) and Occurrence of Osteonecrosis of the Jaw (ONJ) Predict Improved Survival.
Authors: Berenson James R. , Yellin Ori , Crowley John , Duvivier Herbert , Nassir Youram , Swift Regina A. 
Published: October 2019

Abstract
New treatment options have greatly improved the overall survival for MM pts. Although many baseline prognostic factors have been identified among pts with MM in the past, few studies have evaluated prognostic factors during the past five years when these new treatment options became available. Included in the newer regimens for myeloma pts is the use of monthly infusions of ZOL to reduce skeletal complications for MM pts. During this time of changes in the therapy for MM pts, complications associated with administration of bisphosphonates have been reported among MM pts. The outcome for patients with these complications has not been well-defined. The goal of this study was to identify baseline and on-treatment prognostic factors for determining overall survival of MM pts treated with ZOL. The inclusion criteria for this study included a diagnosis of MM and having received at least one dose of ZOL in our clinic. One hundred consecutive pts were analyzed in this retrospective study. The median survival of this group was 117 months. Risk factors for an earlier death included occurrence of a SRE (hazard ratio [HR] = 3.06), increased serum creatinine (HR = 3.35), elevated serum calcium (HR = 2.60), and ISS Stage II or III at diagnosis (HR = 2.04). Notably, diabetes was found to be a significant risk factor for SREs but not overall survival (P = 0.022). Ten pts developed ONJ, of whom nine are alive and one died in remission (non-MM-related). The 2-year incidence of ONJ was approximately 5%. There was a trend toward increased risk of ONJ for diabetes, smoking, and alcohol use. When evaluating the course of ONJ, only one pt showed progression, while six improved or resolved, and three remained stable. All but one pt with ONJ remain on monthly ZOL therapy. In regards to the disease status of the nine pts surviving with ONJ, five are in complete remission, two with ongoing partial responses, and two have stable disease. The skeletal morbidity rate (SMR) was only 0.16 SRE/year among all 100 pts analyzed. Notably, pts with ONJ had a lower SMR (0.07 SRE/year) than the 90 pts treated with ZOL who did not develop ONJ (0.18 SRE/year). Importantly, overall survival was superior among pts with ONJ versus pts without ONJ in this study when analyzed both by a landmark analysis and in a time-dependent fashion. Thus, development of new SREs, elevated serum creatinine, increased serum calcium and ISS Stage II or III at diagnosis predicted for an earlier death. With active monitoring for ONJ and early input from dental experts, ONJ has been mild to moderate in severity, had minimal impact on overall quality of life, and improved or healed in the majority of pts. In this study, absence of SREs (time-dependent) and occurrence of ONJ were associated with an improved overall survival (P ≤ .01 for each). These results suggest that with proper management, ONJ is a manageable, infrequent complication of ZOL that may be associated with a reduced SRE risk and improved overall survival. This study also suggests the avoidance of SREs is associated with an increased life expectancy; and, thus, reduction in these events through ongoing bisphosphonate therapy is important in the overall management of MM pts.