Rate Of Skeletal-related Events Research Articles

Excellent long-term pain response and local control following postoperative radiotherapy in patients with multiple myeloma.

Multiple myeloma is associated with osteolytic bone lesions, often requiring surgery of the spine and postoperative radiotherapy (RT). Although common, data for clinical and informed decision-making are sparse. In this monocentric retrospective study, we aim to report the outcome of patients who underwent spinal surgery and postoperative RT due to multiple myeloma. Atotal of 54patients with multiple myeloma who underwent prior spinal surgery and postoperative RT at our institution between 2009 and 2020 were analyzed. Spinal instability neoplastic score (SINS) and Bilsky score, posttherapeutic adverse events, clinical data, and outcomes were collected and analyzed. The primary endpoint of this study was overall survival (OS), secondary endpoints were progression-free survival (PFS), pain response, local control, and skeletal-related events (SRE). The 3‑ and 5‑year overall survival (OS) was 74.9% (95% confidence interval [CI]: 63.5-88.4%) and 58% (95% CI: 44.5-75.6%), respectively. Median survival was not reached and 75% survival was 34.3months (95% CI: 28.7-95.4 months). Median follow-up was 63months (95% CI: 49-94months). The number of patients with good to adequate performance status (Karnofsky performance score [KPS] ≥ 70) significantly increased after surgery (p < 0.01). We observed no grade3/4 toxicity and only 13 (24%) grade1/2 adverse events. Two patients (4%) experienced SRE. Overall, 92% of patients reported reduced pain after radiotherapy, with 66% reporting complete pain response. There was no difference in pain response between patients with different Bilsky scores. Bisphosphonate therapy and lower Bilsky score at the start of RT were associated with improved OS in univariate analysis (all p < 0.05). Multivariate Cox regression confirmed aBilsky score of2 or3 as an independent negative prognostic factor (HR 3.89; 95CI 1.4-10.7; p < 0.01). We observed no in-field recurrences. In this study, we were able to show that the current standard of RT after spinal surgery of osteolytic lesions is safe. In addition, we observed avery low rate of SRE (4%) and no in-field recurrences, demonstrating the local efficacy of RT in multiple myeloma patients. Higher Bilsky scores were associated with worse OS in multivariate analysis, but had no effect on pain response.

Bone Metastases in Patients with Pancreatic NETs: Prevalence and Prognosis.

The clinical relevance of bone metastases (BM) in advanced pancreatic neuroendocrine tumors (PanNETs) is poorly described. We analyzed 314 consecutive PanNET patients treated at the European Neuroendocrine Tumour Society (ENETS) Center Essen between 2009 and 2021 in terms of the occurrence and clinical and prognostic impact of BM using hybrid imaging with 68Ga-DOTATOC PET/CT. According to UICC staging, 171/314 (54.5%) patients had stage IV PanNETs. BM was diagnosed in 62/171 (36.3%) patients. Initially, 35% of BMs were visible by pathological tracer uptake only. Skeletal-related events (SREs) were detected in 11 of the 62 patients (17.7%). Patients with antiresorptive therapy had a significantly lower rate of SRE (2/36, 5.6%) than individuals without bone-specific therapy (9/26, 34.6%) (odds ratio 9.0, p=0.0054, Fisher's exact test). The median overall survival (OS) was 82 months (53.6-110.4, 95% CI) in the stage IV PanNET cohort. The median OS was significantly lower for patients with BM (63 months; 49.9-76.0, 95% CI) than for patients with distant metastases other than BM (116 months; 87.6-144.3, 95% CI) (p=0.016, log-rank test). BM occurs in more than one-third of advanced PanNETs and is associated with an unfavorable prognosis. One in five patients experiences a persistent quality-of-life-lowering SRE. Antiresorptive therapy is associated with a more favorable risk of SREs and should be offered to all patients with BM in PanNETs.

Impact of Bone Modifying Agent Initiation Time, Frequency, and Duration on Skeletal-Related Events in Patients with Multiple Myeloma

Background: Skeletal related events (SREs) including pathologic fractures, surgery or radiation to bone, and spinal cord compression contribute to diminished quality of life in patients with multiple myeloma. Bone modifying agents (BMA) such as denosumab or the bisphosphonates zoledronic acid and pamidronate, are used to inhibit osteoclast activity to prevent SREs. The Bone Working Group of the International Myeloma Working Group suggests monthly administration of zoledronic acid for 12 months in newly diagnosed myeloma patients. This is followed by an option to discontinue or decrease administration frequency to every 3, 6, or 12 months if a very good partial response or better is achieved. The ideal start time of BMA from diagnosis and the duration of administration has not been adequately established to optimize reduction of SREs. Methods: This was a retrospective, single-center study that included newly diagnosed myeloma patients treated at the Mayo Clinic between 9/1/2018 and 9/1/2020 who had received at least one dose of a BMA. The primary objective was to evaluate the impact of BMA dosing frequency and duration on SREs. Secondary objectives included time to BMA initiation, time to relapse or progressions following BMA start, and safety. Data was summarized using frequencies and percentages for categorical data, and medians and interquartile ranges (IQR) for continuous data. A spline plot and cut-point analysis were used to assess the association of time from multiple myeloma diagnosis to BMA initiation with skeletal related outcomes. Rates of SREs were estimated using the Aalen-Johansen method, where death was treated as a competing risk. Associations of factors with SREs were assessed using Cox proportional hazards regressions, and these associations were summarized using hazard ratios (HR) and corresponding 95% confidence intervals (CI). Variables that could change throughout follow-up including BMA frequency, cumulative BMA dose, and duration of BMA were treated as time-dependent covariates in the Cox proportional hazards models, where the information for these variables was updated each time an additional dose of BMA was given. All analyses were performed using SAS version 9.4 software (SAS Institute, Inc.; Cary, NC) and R version 4.2.2 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). Results: Sixty-seven patients were included with a median age of 65 years old. The most frequently used BMA was zoledronic acid (88.1%), followed by pamidronate (7.5%), and denosumab (4.5%). Fifty-five patients (82.1%) had bone disease at baseline. Within 2 years of starting BMA, SREs occurred in 42.2% of patients with baseline bone disease and 8.3% of patients without (p=0.054). Median time to BMA initiation after diagnosis was 45 days (IQR 14-105) in patients with baseline bone disease and 87 (IQR 32-496) in patients without. Among the 26 patients with a SRE, median time from start of BMA to SRE was 170 days (IQR 32-496). No significant association was found between time to initiation and development of a SRE (Figure 1). BMA dosing frequencies of every 3 months and 6 months had a HR for SREs of 1.67 and 0.47, respectively compared to every 1 month, (P-values &amp;gt;0.25). After excluding patients without baseline bone disease, compared to every 1 month dosing, dosing every 3 months and every 6 months increased the risk of SRE, although the differences were not statistically significant (3 months: HR=1.92, 95% CI 0.76-4.88, p=0.17; and 6 months: HR=1.26, 95% CI 0.14-10.94, p=0.84). Patients without bone disease at baseline remained on BMAs for a median of 1.8 years while patients with bone disease received BMAs for a median of 2 years. There was no statistically significant difference found with varying duration or cumulative dose and SRE development (Table 1). Relapse or progression occurred in 32.1% of patients within 2 years of starting BMA, while death occurred in 7.5% of patients. Osteonecrosis of the jaw occurred in 1 patient with bone disease at baseline who received zoledronic acid every 3 months for a duration of 596 days. Conclusions: No significant association between time of BMA initiation, dosing frequency, or duration on development of SREs were observed. This suggests delaying the start time of BMAs to allow for dental clearance and initial treatment would not increase risk of SREs. Prospective trials are needed to confirm these findings.

Randomized phase II study of zoledronate dosing every four versus eight weeks in patients with bone metastasis from lung cancer (Hanshin Cancer Group0312)

BackgroundZoledronic acid (ZA) reduces the incidence of skeletal-related events (SREs) in patients with bone metastases from solid tumors. However, the optimal dosing interval of ZA for patients with lung cancer is uncertain. MethodsWe conducted a randomized, open-label, feasibility phase 2 trial at eight Japanese hospitals. Patients with bone metastases from lung cancer were randomly assigned to receive either 4 mg of ZA every four weeks (4wk-ZA) or every eight weeks (8wk-ZA). The primary endpoint was the time to the first SRE and the rate and types of SREs after one year. SREs were defined as pathologic bone fracture, bone radiation therapy or surgery, and spinal cord compression. Secondary endpoints were the SRE incidence at six months, pain assessment, changes in analgesic consumption, serum N-telopeptide, toxicity, and overall survival. ResultsBetween November 2012 and October 2018, 109 patients were randomly assigned to the 4wk-ZA group (54 patients) and the 8wk-ZA group (55 patients). The number of patients who received chemotherapy or molecular-targeted agents was 30 and 23 and 18 and 16 in the 4wk-ZA and 8wk-ZA groups, respectively. The median time to the first SRE could not be calculated because of a low SRE. The time to the first SRE of all patients did not differ between the groups (P = 0.715, HR = 1.18, 95% CI = 0.48, 2.9). The SRE rate of all patients after 12 months was 17.6% (95% CI = 8.4, 30.9%) in the 4wk-ZA and 23.3% (95% CI = 11.8, 38.6%) in the 8wk-ZA group, without significant differences between the groups. There was no difference in any secondary endpoint between groups, and these endpoints did not differ among treatment modalities. ConclusionsAn eight-week ZA interval does not increase the SRE risk for patients with bone metastasis from lung cancer and could be considered clinically.

Abstract P4-07-06: Implementation of A Bone Modifying Agent Pathway at UChicago Medicine for Metastatic Breast Cancer Patients

Abstract Background: In 2019, a quality improvement (QI) research project was conducted at UChicago Medicine (UCM) to evaluate bone modifying agent (BMA) use for skeletal-related event (SRE) prevention in patients with metastatic breast cancer and metastatic castration-resistant prostate cancer. Denosumab was the preferred BMA agent at UCM in this setting. Compared to zoledronic acid (ZA), denosumab was associated with higher drug cost and lower adherence rate mainly due to the difficulty of maintaining the 4-weekly frequency. Studies have shown that ZA can be de-escalated from 4-weekly to 12-weekly for SRE prevention. There is still no convincing evidence to show that this de-escalated schedule can be applied to denosumab. One study evaluated the noninferiority of 12-weekly compared with 4-weekly denosumab suggested that the health-related quality of life was non-inferior (Clemons et al., 2021). However, the study was not powered to evaluate the statistical difference in SRE rates. Based on the results of the 2019 QI project, a BMA pathway was generated at UCM in September 2020 with the purpose of guiding physician prescribing patterns, improving adherence rate, and reducing drug costs. This pathway recommended using ZA as the preferred agent for SRE prevention instead of denosumab. Methods: This was a retrospective study that included 198 patients who had metastatic breast cancer and received at least one dose of ZA or denosumab from UCM outpatient oncology clinic for SRE prevention. All included patients must have bone metastases. 107 patients from the pre-implementation study period (July 1st, 2018 to June 30th, 2019) and 91 patients from the post-implementation study period (November 10th, 2020 to November 10th, 2021) were included. Patients were divided into four groups based on study time (pre- or post-implementation period) and BMA agent (ZA and denosumab). The primary outcome was BMA therapy adherence rate, which was defined by those who received greater than or equal to 80% of appropriately scheduled doses. Secondary outcomes included the percentage of patients on ZA or denosumab, SREs, BMA-associated adverse effects, and BMA cost. Descriptive statistics were used SREs and BMA-associated adverse effects. Results: The percentage of patients on ZA significantly increased from 12% to 64% after BMA pathway implementation (P&amp;lt; 0.0001). Denosumab use decreased from 88% to 36% (P&amp;lt; 0.0001). The overall BMA adherence rate including both ZA and denosumab patients during the post-implementation period was 68%, which was not significantly different compared to the overall adherence rate of 74% during the pre-implementation period (P=0.5461). The adherence rates in denosumab groups (63% in pre and 30% in post) were lower than in ZA groups (100% in pre and 90% in post). The most common reason for the lower adherence rates in denosumab groups was scheduling convenience. During the study period, there were 2, 0, 3, and 3 patients who had SREs in the above four groups respectively. The predominant adverse events among all groups were hypocalcemia and hypophosphatemia. The cost analysis showed using ZA as the primary BMA agent saved 1.1 million dollars of drug costs during the post-implementation study period at UCM. Conclusion: Implementing a BMA pathway encouraged the providers to choose ZA as the preferred agent for SRE prevention in metastatic breast cancer patients with bone metastasis, which dramatically reduced drug costs. The overall BMA adherence rate was not significantly improved with the implementation. The difficulty of maintaining a 4-weekly denosumab frequency continued to exist. Citation Format: Kun Lin, Jordan Baur, Sandeep Parsad, Heng Yang. Implementation of A Bone Modifying Agent Pathway at UChicago Medicine for Metastatic Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-06.

Skeletal-Related Events After Surgery With or Without Radiotherapy for Bone Metastases to Weight-Bearing Bones.

Introduction In patients with metastatic disease involving weight-bearing bones, postoperative radiotherapy (PORT) is commonly administered following surgical stabilization of an impending or confirmed pathologic fracture to reduce the risk of a seeded local recurrence. The goalwas to re-evaluate the beneficial effect of PORT in a modern cohort of patientsand determine any potential clinical predictors of skeletal-related events (SREs) which were defined as a pathologic fracture or the necessity for radiation or surgery to the affected bone. Methods Consecutive patients undergoing surgical stabilization of metastatic disease to weight-bearing bones of the extremities between 2012 and 2019 were reviewed. Patient, disease, and treatment factors were abstracted. The cumulative incidenceof SREs was determined using competing risks methodology; overall survival (OS) was estimated using the Kaplan-Meier method. Results A total of 82 patients were identified, 74% of whom had undergone intramedullary nail fixation and 26% internal fixation or replacement. The femur was the most commonly involved bone (94%).A majority (78%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1-2. Bone-strengthening agents were given to 38% and PORT to 54%. The median PORT dose was 30 Gy in 10 fractions and the median percent coverage of surgical hardware was 100% (range, 25-100). SREs occurred in 10 of 82 patients. There were no differences between no RT and RT groups for the two-year cumulative incidence of SREs (8.2% vs 11.5%, p=0.59) or two-year cumulative incidence of local failure (10.8% vs4.6%, p=0.53). The only identified predictors of SREs were the use of bone-strengthening agents (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.05-1.06, p=0.06) and malnutrition (HR 3.69, 95% CI 0.91-14.93, p=0.07). For patients treated with PORT, a biologically effective dose or percent coverage of surgical hardware was not associated with SREs. Conclusion In this series, the addition of PORT following surgery for metastatic disease involving weight-bearing bones does not significantly affect the rate of SREs. The use of bone-strengthening agents appears protective, and malnourished patients appear particularly at high risk for future SRE.

The effects of bone targeted therapy in patients with greater than two years survival with metastatic breast cancer and bone metastasis.

e13076 Background: Administration of bone targeted therapy such as zoledronic acid (ZA) or of denosumab (D) decrease the risk of skeletal related events (SRE) such as radiation to the bone, pathological bone fractures, and spinal cord compression in patients with a diagnosis of metastatic breast cancer (MBC) and bone metastasis. As these patients continue to live longer it is unknown what are the impacts from long-term administration of ZA or D among those who live longer than 2 years. Methods: This was a retrospective analysis of patients with MBC and bone metastasis who lived for more than 2 years since diagnosis and received treatment at MD Anderson Cancer Center for MBC in addition to ZA and/or D between 2015 and 2021. Patient demographics, date of diagnosis, tumor characteristics, bone targeted agent treatment plans and SRE were extracted from the institutional database and electronic health records. We defined 3 patterns of receipt of bone targeted therapy: Pattern A: ZA every 3-4 weeks; Pattern B: D every 4-6 weeks; Pattern C; D every 4-6 weeks for a period followed by every 3 months. The association between these patterns and SRE was assessed using Fisher’s exact test. Results: We included 178 patients: Pattern A with 49 patients, Pattern B with 85 patients, and Pattern C with 44 patients. The proportion of patients who suffered a SRE in Patterns A, B, and C were 22.4% (11/49), 20% (17/85), and 21.4% (10/44). There was no statistical difference in the proportion of SRE between these three groups (p = 0.92). Conclusions: We did not observe a difference in the rate of SRE between the three different patterns of bone targeted therapy administration in patients with MBC and bone metastasis. Other treatment patterns will be considered in future analysis.[Table: see text]

Spine-specific skeletal related events and mortality in non-small cell lung cancer patients: a single-institution analysis.

The population prevalence of non-small cell lung cancer (NSCLC) continues to increase; however, data are limited regarding the incidence rate of skeletal related events (SREs) (i.e., surgery to the spinal column, radiation to the spinal column, radiofrequency ablation, kyphoplasty/vertebroplasty, spinal cord compression, or pathological vertebral body fractures) and their impact on overall mortality. In this study, the authors sought to estimate the incidence rates of SREs in NSCLC patients and to quantify their impact on overall mortality. This was a single-institution retrospective study of patients diagnosed with NSCLC between 2002 and 2014. The incidence rates for bone metastasis and subsequent SREs (per 1000 person-years) by time since lung cancer diagnosis were calculated and analyses were stratified separately for each histological type. Incidence rates for mortality at 1, 2, and 3 years from diagnosis stratified by the presence of SREs were also calculated. Kaplan-Meier survival curves were constructed to describe crude survival ratios in patients with spine metastasis and SREs and those with spine metastasis but without SREs. These curves were used to estimate the 1- and 2-year survival rates for each cohort. We identified 320 patients with incident NSCLC (median follow-up 9.5 months). The mean ± SD age was 60.65 ± 11.26 years; 94.48% of patients were smokers and 60.12% had a family history of cancer. The majority of first-time SREs were pathological vertebral body compression fractures (77.00%), followed by radiation (35%), surgery (14%), and spinal cord compression (13.04%). Mortality rates were highest in NSCLC patients with spine metastasis who had at least 1 SRE. Stratifying by histological subtype, the incidence rate of mortality in patients with SRE was highest in the large cell cohort, 7.42 per 1000 person-years (95% CI 3.09-17.84 per 1000 person-years); followed by the squamous cell cohort, 2.49 per 1000 person-years (95% CI 1.87-3.32 per 1000 person-years); and lowest in the adenocarcinoma cohort, 1.68 per 1000 person-years (95% CI 1.46-1.94 per 1000 person-years). Surgery for decompression of neural structures and stabilization of the spinal column was required in 6% of patients. SREs in NSCLC patients with bone metastasis are associated with an increased incidence rate of mortality.

Predictors of Skeletal Related Events in Patients Treated With Surgical Stabilization for Bone Metastases With or Without Radiotherapy

<h3>Purpose/Objective(s)</h3> In patients with metastatic disease involving weight-bearing bones, postoperative radiation (PORT) is commonly administered following surgical stabilization of an impending or confirmed pathologic fracture to reduce the risk of a seeded local recurrence. The goal of this analysis was to re-evaluate the beneficial effect of PORT in a modern cohort of patients, and to determine any clinical predictors of skeletal related events (SRE). <h3>Materials/Methods</h3> Consecutive patients undergoing surgical stabilization of metastatic disease to weight-bearing bones of the extremities between 2012-2019 were reviewed. Patient, disease, and treatment factors were abstracted. Freedom from skeletal related event (SRE, defined as pathologic fracture, necessity for (re)irradiation, or surgery of the involved bone) and overall survival (OS) were estimated using the Kaplan-Meier method. Predictors of SRE were evaluated using backwards stepwise Cox proportional hazards models. <h3>Results</h3> A total of 82 patients were identified, 74% of whom had undergone intramedullary nail fixation and 26% internal fixation or replacement. 73% of surgeries were prophylactic and 27% were for pathologic fracture. The femur was the most commonly involved bone (94%) followed by the humerus (5%), and tibia (1%). Disease histology was breast (26%), lung (24%), prostate (10%), or other (40%). A majority (78%) had ECOG performance status of 1-2. Bone-strengthening agents were given to 38% and postoperative RT to 54%. Median PORT dose was 30 Gy in median 10 fractions and median percent coverage of surgical hardware was 100% (range, 25-100). SRE occurred in 10 of 82 patients. Overall, 1-year freedom from SRE was 90.4%, and notably was 89.8% vs 91% for those who did or did not receive PORT, respectively. The only identified predictors of SRE were the use of bone strengthening agents (HR 0.22, 95% CI 0.05-1.06, <i>P</i> = 0.06) and malnutrition (HR 3.69, 95% CI 0.91-14.93, <i>P</i> = 0.07). For patients treated with PORT, biologically effective dose or percent coverage of the surgical hardware was not associated with SRE. Median OS was 11.3 months (95% CI: 8.0-24.6). <h3>Conclusion</h3> In this series, the addition of PORT following surgical stabilization of metastatic disease involving weight-bearing bones does not significantly affect rate of SRE, which remained approximately 10% at 1 year. The use of bone strengthening agents appeared to be protective, and malnourished patients were at particularly high-risk for future SRE.

Multiple Myeloma Patients and Risk of Skeletal Related Events - Real-World Evidence in US Oncology Clinics

Introduction: SEER estimates that 30,280 new cases of multiple myeloma (MM) will be diagnosed in the US in 2017. Osteolytic disease is a hallmark feature of myeloma at diagnosis. Skeletal related events (SRE) including pathological fractures, spinal cord compressions, radiation and surgery to bone are frequent complications for myeloma patients. However, there have been few reports of the incidence of and risk of developing an SRE in the myeloma population, particularly relative to concomitant anti-myeloma therapy.Methods: A database of oncology electronic health records (EHR) contained in Amgen's Oncology Services Comprehensive Electronic Records (OSCER) database, generated by Flatiron Health (New York, NY, April 30, 2016) were linked to administrative claims data from the Truven Marketscan database. Patients identified were individuals 18 years or older diagnosed with MM (ICD-9: 203.00; ICD-10: C90.00), had at least 1 clinic visit within 1 month of diagnosis, and at least 1 year of follow-up after MM diagnosis. The study period was from January 1, 2011 to December 31, 2016. The baseline period for co-morbidities was 12 months prior to multiple myeloma diagnosis date. Patient diagnosis, treatment dates and administrations were ascertained from the EHR. SREs were ascertained from diagnosis codes in insurance claims. Primary outcomes of interest were occurrence of and time to SRE. Multiple SRE that occurred within a 21-day span were considered as a single SRE and ordered based on the following hierarchy: 1.) spinal cord compression, 2.) pathological fracture, 3.) surgery to bone, then 4.) radiation to bone. SRE occurring within 60 days of MM diagnosis were considered as baseline SRE. Results are also stratified by line of anti-myeloma therapy.Results: A total of 343 patients were included in this study. Approximately 55% of patients were age >65, 54% male, and 70% white race. About one-third of patients had an eGFR below 60 at MM diagnosis, 69% presented with anemia, and 35% had a baseline history of SRE (includes SREs recorded within two months after diagnosis). During a median follow-up of 25.7 months after diagnosis, 34% of patients (n=117) experienced an SRE and the median time to SRE was 228 days. Among patients that experienced a SRE, 68% occurred within the first year (n=79). Among patients with a baseline history of SRE (n=119), 61% experienced a SRE during follow-up at a median of 149 days compared to 20% of patients without SRE history (n=45) at a median of 365 days. The incidence rate of SRE for these patients with a baseline history was 103/100 person-years (PY) (n=58) versus 16/100PY compared to no baseline history (n=21) one year following MM diagnosis. The incidence rate of SRE in each of line therapy within three months of the initiation of each line increased with each subsequent line (line 1: 81/100PY, line 2: 118/100PY, line 3: 150/100PY).Conclusions: Most patients experience their first SRE soon after MM diagnosis or at the beginning of each relapse. Patients with a baseline SRE had a higher risk of future SRE. Recently relapsed patients had a higher rate of SRE compared to patients who have been on therapy for an extended period, and the incidence rate was progressively higher among patients receiving later lines of therapy. Additionally, among patients experiencing SRE, multiple SRE can occur, highlighting the importance of continued surveillance and proper management of myeloma associated bone disease. The overall SRE rate was lower than expected likely due to selection bias or recording bias in the administrative claims database. [Display omitted] DisclosuresBhatta:Amgen: Employment. Fonseca:Jansen: Consultancy; Merck: Consultancy; Mayo Clinic & Dr Fonseca: Patents & Royalties: Prognostication of myeloma via FISH, ~$2000/year; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy, Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Pharmacyclics: Consultancy; AMGEN: Consultancy. Hernandez:Amgen Inc.: Employment, Equity Ownership. Kim:Amgen, Inc.: Employment, Equity Ownership.

Rate of skeletal-related events (SREs) for abiraterone acetate (AA) versus enzalutamide (ENZ) in prostate cancer: A population-based study using the SEER-Medicare database.

e17038 Background: Skeletal-related events are common in men with prostate cancer, and are associated with significant morbidity and mortality. AA and ENZ are novel androgen signaling inhibitors used in the treatment of metastatic prostate castration-resistant prostate cancer (mCRPC). As directly comparative efficacy data do not exist between AA and ENZ, the differing toxicity profiles inform treatment selection. It is unknown whether SRE rates differ in a real-world population between AA, which is given with corticosteroids, and ENZ, which is associated with imbalance and falls. Methods: The national SEER-Medicare linked database was used to identify men with prostate cancer who received AA or ENZ between 2011-2015; approval during this period was solely for mCRPC. Inclusion criteria included Medicare Part A+B coverage 1 year before and after first receipt of AA/ENZ, without any HMO enrollment. Baseline demographic and comorbidity data were gathered. Diagnosis and procedure claims codes were used to identify SREs, defined as pathologic fracture, surgery to bone, radiation to bone, or spinal cord compression. The time to SRE was defined as time from first receipt of AA/ENZ to the first SRE of any type. A multivariable competing risk regression analysis including death as a competing risk was performed. Results: 5,856 men with prostate cancer who first received AA (N = 4,207) or ENZ (N = 1,649) were identified. The median age at initiation of AA/ENZ was 70 years (range 65-101); 78% were White, 12% Black, 4% Hispanic, 3% Asian, and 4% Other. The median follow-up was 14 months. The overall SRE rate was 13.1% after AA/ENZ start: 574 (13.6%) AA and 194 (11.8%) ENZ, with a cumulative incidence of 11.9% at 2 years. Median overall survival was 16 months (14.4 months for AA and 18.3 months for ENZ). Age, stage at diagnosis, race/ethnicity, baseline comorbidities, and prior history of SRE were balanced between AA vs ENZ, aside from baseline osteoarthritis or rheumatoid arthritis (48.0% AA vs 53.2% ENZ, P &lt; 0.001) and baseline Alzheimer’s dementia (9.2% AA vs 11.1% ENZ, P = 0.03). After controlling for these potential risk factors, receipt of AA versus ENZ was not associated with time to SRE (relative risk ratio [RR] = 0.90, 95% CI 0.77-1.06, P = 0.22). Osteoporosis (RR 1.22, 95% CI 1.01-1.49, P = 0.04), osteoarthritis or rheumatoid arthritis (RR 1.23, 95% CI 1.06-1.43, P &lt; 0.01), and prior history of SRE (RR 1.31, 95% CI 1.07-1.59, P &lt; 0.01) were statistically significant risk factors for SRE. Conclusions: In this real-world population of men with prostate cancer, there was no difference in time to SRE between AA and ENZ. Clinical decision-making on whether to prescribe AA or ENZ should be informed by other potential toxicities as well as cross-resistance with sequencing of these therapies. Analysis of impact of bone protective agent use is underway.

Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study.

Simple SummaryCarfilzomib with dexamethasone is an important therapeutic option for patients with relapsed/refractory multiple myeloma. We sought to evaluate the effect of this regimen on the bone-related outcomes, which are associated with both quality of life and survival. Among 25 patients, less than one third experienced a new skeletal-related event during treatment, even in the absence of any bone-targeted agent. Interestingly, there was a significant decrease in serum biomarkers of bone resorption, which was at least partially due to the sRANKL/OPG ratio reduction. Furthermore, Kd produced an increase in markers of bone formation. Importantly, these changes were independent of myeloma response to treatment. Therefore, the combination of carfilzomib and dexamethasone improves bone metabolism and bone health in patients with advanced multiple myeloma.Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.

Safety and efficacy of bone-modifying agents among multiple myeloma patients: A retrospective cohort study.

To determine the incidence of skeletal-related events among multiple myeloma patients who received chemotherapy without a bone-modifying agent (zoledronic acid and denosumab) versus those who received chemotherapy with a bone-modifying agent. The secondary objective was to determine the incidence of skeletal-related events in patients without any prior history of skeletal-related events and who were treated with zoledronic acid every four weeks versus those who received zoledronic acid at an extended interval of every twelve weeks. Additional secondary objectives included the incidence of nephrotoxicity, hypocalcemia and osteonecrosis of the jaw in all patients. This institutional review board-approved, retrospective cohort study included patients 18 to 89 years old with a diagnosis of multiple myeloma, who were being treated with chemotherapy between July 1, 2016 and October 31, 2019. Safety and efficacy were assessed through analysis of pertinent data collected: patient demographics, baseline skeletal-related events, development of new skeletal-related events, number and type of bone-modifying agent doses administered, and drug-related toxicities such as nephrotoxicity, hypocalcemia, and osteonecrosis of the jaw. A total of 73 patients were included. New skeletal-related events occurred in 12 patients (27%) in the chemotherapy without a bone-modifying agent group and in 5 patients (17%) in the chemotherapy with a bone-modifying agent group (OR = 0.56, 95% CI [0.172-1.8]; P = 0.32). The incidence of skeletal-related events was similar among patients receiving zoledronic acid every four weeks versus every twelve weeks in patients without a prior skeletal-related event (N = 0 vs. N = 2 respectively; P = 0.47). There were no statistically significant differences observed in each of the three secondary safety endpoints: incidence of hypocalcemia, nephrotoxicity and osteonecrosis of the jaw. Multiple myeloma patients receiving chemotherapy without a bone-modifying agent had higher rates of skeletal-related events compared to those being treated with chemotherapy and a bonemodifying agent. Our results highlight the benefit of utilizing bonemodifying agents for the prevention of skeletal-related events in all multiple myeloma patients being treated with chemotherapy.

Safety and Feasibility of Outpatient Rehabilitation in Patients With Secondary Bone Cancer: A Preliminary Study

Background: Because of fear of skeletal complications, physicians often avoid referring patients with secondary bone cancer (SBC) to physical rehabilitation. However, there is little evidence on the risk of skeletal-related events (SREs) and pathological fracture (PF) during rehabilitation therapies. Objective: To determine the risk of PF following physical rehabilitation in people with SBC. Design: Single-group, single-centered interventional clinical trial. Setting: University-based outpatient rehabilitation clinic. Patients: Forty-eight patients with confirmed diagnosis of SBC were enrolled. Interventions: Participants were prescribed a multidisciplinary rehabilitation program. Participants and rehabilitation therapists were trained to detect and report symptoms that would indicate PF. Radiographs were used to confirm the presence of PF. Measurements: The primary outcomes were safety and feasibility of an outpatient rehabilitation program for patients with SBC. Safety was measured by the rate of SREs. Feasibility was measured by the ability to successfully complete the program. Secondary outcome measures included Short Form Health Survey (SF-36) and numeric rating scale (NRS) scores to assess pain intensity. Results: One PF was detected, which occurred outside of rehabilitation therapy. Two other SREs occurred, resulting in a total event rate of 11.8 for every 10 000 hours of exposure. There was a significant improvement in NRS (95% CI, 1.41-3.08, P &lt; .001) and SF-36 measures (95% CI, 80.35-158.11, P &lt; .001). Limitations: Twenty participants (42%) did not complete the rehabilitation program due to clinical complications or death. Conclusions: Rehabilitation interventions may not increase the risk of SREs or PF in patients with SBC. Further research is indicated to verify these findings.

Pharmacologic management of metastatic bone disease.

Bone is a common site of metastases, particularly in advanced breast and prostate cancer. Skeletal related events associated with bone metastases include pathologic fracture, need for surgery/radiation to bone and cord compression. These events cause significant morbidity and mortality. Bisphosphonates as well as denosumab act on the bone microenvironment and reduce the rate of skeletal related events by approximately 25%-40%. Hence, these therapies are an important adjunctive therapy in cancer care. Despite the established efficacy and recommendations for their use in many international guidelines, these bone modifying agents are underutilized. This review examines the currently available guidelines on bone modifying agents in metastatic bone disease and summarizes their efficacy, risk and comparative benefits.

Retrospective Analysis of the Relationship between Time to Anti-Resorptive Therapy and Incidence of Skeletal Related Events in Patients with Multiple Myeloma

Background Multiple Myeloma (MM) is a plasma cell neoplasm causing a proliferation of monoclonal immunoglobulins that causes end organ damage in the form of hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. Specifically, patients with MM are at risk for developing significant bone disease eventually leading to development of skeletal related events (SRE) (pathological fractures, spinal cord compression, and/or need for radiotherapy or surgery to bone). It is well established that the use of anti-resorptive agents (i.e. Bisphosphonates, Denosumab) lead to fewer bony lesions, less severe bone disease, and fewer SREs. However, while anti-resorptive therapy is recommended for all MM patients undergoing treatment, it is common for initiation of anti-resorptive therapy to be delayed due to the need for dental clearance, clinician preference, or relative contraindications to the medications. Current studies show that this therapy is overall underutilized, likely for similar reasons. However, the effect on SRE with regards to time to initiation of anti-resorptive agent has not been well studied. Herein, we conducted a retrospective analysis to determine if time to anti-resorptive agent has an effect on incidence of SREs. Methods: We performed a retrospective cohort study using our Electronic Health Record system to identify and analyze data of patients with newly diagnosed Multiple Myeloma from July 1st, 2016 until June 30th, 2019 to determine whether time to anti-resorptive therapy affects the incidence of SRE. Patients previously treated with bisphosphonates, and patients not treated with anti-resorptive therapy were excluded. The study's primary endpoint was probability of developing SRE based on time to anti-resorptive therapy. The relationship between incidence of SREs and time to anti-resorptive therapy, sex, age, ISS stage at diagnosis, Area Deprivation Index (ADI), and prior SRE present at diagnosis was analyzed by multivariable Cox proportional hazards model. The cutoff point of anti-resorptive therapy delay was based on the recursive partitioning of univariable Cox model. Results: Three hundred and seventy-five patients with newly diagnosed multiple myeloma patients were identified. In total, 237 patients were included in the final analysis. Demographic information is detailed in the table provided. Of these, 208 patients (88%) used bisphosphonates and 29 (12%) used a RANK ligand inhibitor as their anti-resorptive agent. The median time to therapy was 55 days (IQR 135 days). One hundred twenty four (55%) patients had an SRE present at diagnosis. Forty-one (15.2%) patients developed a new SRE after initiation of anti-resorptive therapy. The model showed that patients who had a delay to anti-resorptive therapy of 31 days or greater had a higher risk of developing SRE after diagnosis (HR 2.49, 95% CI 0.95-6.55, p=0.064). In addition, when comparing ISS II to ISS I, patients with ISS II disease had a higher risk of developing SRE (HR 2.78, 95% CI 1.02-7.57, p=0.045). Conclusions: Patients with longer delays to anti-resorptive therapy had higher risk of developing SRE after diagnosis, however the difference was not statistically significant. One explanation for this may be that starting anti-resorptive therapy at any time point may be more important than time it takes to start therapy in the setting of effective anti-myeloma treatment. However, the rate of SRE in this study was lower than initially predicted based on previous studies, and therefore, our sample size may have been too small to detect a significant outcome related to time to initiation of anti-resorptive agents. Ongoing efforts to increase the sample size through multi-institutional initiatives are underway. Disclosures Binder: Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy.

Safety and Efficacy of Long-Term Zoledronic Acid in Advanced Breast Cancer with Bone Metastasis in South China.

Background This retrospective study aimed to characterize the long-term (>24 months) safety profile of zoledronic acid (ZA). We aimed to investigate whether long-term ZA treatment had greater benefits than short-term treatment in patients from southern China with advanced breast cancer (ABC) with bone metastasis. Patients and Methods. A total of 566 metastatic breast cancer cases were included and divided into two groups according to the duration of ZA treatment. The included patients had at least one lytic bone lesion and had no skeletal-related events (SREs) prior to ZA therapy. The primary endpoint was to analyze the safety and long-term adverse effects, which covered osteonecrosis of jaws (ONJ), renal impairment, and hearing impairment. The second objective was to determine the efficacy of long-term ZA treatment by the incidence of SREs. Results Fifteen patients were diagnosed with ONJ (2.7%): nine in the short-term group (3.1%) and six in the long-term group (2.2%, P = 0.606). Five cases (0.9%) had renal function impairment: two in the short-term group (0.7%) and four in the long-term group (1.1%, P = 0.676). One patient (0.2%) in the long-term group had hearing impairment after 23 months of ZA treatment (0.4%, P = 0.482). In total, 103 cases in the short-term group (35.2%) and 138 cases in long-term group (50.5%) developed SREs (P < 0.001). The mean annual SRE rate was 0.3 in the short-term group (range, 0–3.1) versus 0.2 in the long-term group (0–1.0, P = 0.269). Subgroup analysis suggested that cases with non-load-bearing bone involvement and those who received systematic anticancer therapy without chemotherapy might benefit from long-term ZA treatment. Cox regression analysis indicated poor performance status, and nonvisceral organ involvement predicted high risk for SRE. Conclusions The extension of ZA treatment did not increase the long-term adverse events and reduced the annual incidence of SREs beyond 24 months. Although longer treatment of ZA over 24 months appeared to be safe, further prospective investigation is required.

MM-039: Natural History of Skeletal-Related Events Among 620 Patients with Multiple Myeloma Who Received First- and Second-Line Therapy with Novel Agents: A Single-Center Analysis

Context: Skeletal-related events (SREs) that include pathological fractures, spinal cord compression (SCC) and need for radiotherapy or surgery to the bone are frequent complications of multiple myeloma (MM). Objective: To evaluate the SRE rate in MM patients who received frontline and second-line therapy with proteasome inhibitors (PIs) or immunomodulatory drug (IMiD)-based therapies. Design: Prospectively maintained database. Setting: A referral center in Athens, Greece. Patients: MM patients who received frontline therapy in the Department of Clinical Therapeutics, University of Athens, Greece, between 20072017. Interventions: Patients had a whole-body skeletal survey using either conventional radiography (WBXR) or low-dose CT (WBLDCT) at diagnosis and whenever clinically indicated. Main outcome measures: SRE incidence. Results: 620 consecutive patients with symptomatic MM (316M/304F, median age: 65 years) were studied. The median follow-up was 54 months. SREs were observed in 271 (44%) patients at diagnosis: 213 (34%) presented with pathological fractures, while 34 (5.5%) needed bone surgery, 45 (7.2%) radiotherapy, and 31 (5%) patients presented with SCC. SRE incidence was higher in patients with osteolytic lesions (76.4% vs. 12.4%, P Conclusions: SREs remain a significant complication in MM.

Efficacy and toxicity of extending bone modifying agents beyond two years for bone metastases in breast or castrate-resistant prostate cancer patients: A systematic review.

e24083 Background: Randomized clinical trials evaluated bone modifying agents (BMAs) such as bisphosphonates and denosumab for bone metastases for 1-2 years in duration even though BMA therapy is commonly administered for much longer. A systematic review on the risk-benefit of continuing BMAs for longer than 2 years in breast cancer or castrate-resistant prostate cancer was conducted. Methods: Medline, Embase and Cochrane Register of Controlled Trials were searched (1970 - February 2019) for randomized studies, observational studies, and case series reporting on BMA efficacy and toxicity beyond 2 years. Efficacy was assessed by skeletal-related event (SRE) rates and quality of life metrics. Toxicity was assessed by rates of osteonecrosis of the jaw (ONJ), renal impairment, hypocalcemia, and atypical femoral fractures (AFF). Results: Of 2107 citations, 64 studies were identified. A total of 3 prospective and 9 retrospective studies were eligible. Data beyond 2 years was limited to subgroup analyses in all studies. Three studies [zoledronate (ZOL) (n = 481), pamidronate (PAM) (n = 87), PAM-ZOL (n = 43) ibandronate (n = 30)] reported on SRE-related endpoints. Only one study reported SRE rates based on duration of BMA exposure and showed reduced SRE rates from 27.6% (0-24 months) to 15.5% ( &gt; 24 months) over time. None reported on quality of life. All 12 studies [denosumab (n = 948), ZOL (n = 1036), PAM (n = 163), PAM-ZOL (n = 522), ibandronate (n = 118)] reported on at least one toxicity outcome. Data from 7 bisphosphonate studies (n = 1077) and 1 denosumab study (n = 948) reported on ONJ incidence. In 3 studies (n = 67, n = 221, n = 948), ONJ incidence ranged from 1-4% in the first 2 years and from 3.8-18% beyond 2 years. In another study (n = 252), the cumulative hazard of ONJ was 0% (1% ZOL), 3% (7% ZOL), 7% (21% ZOL) and 11% (21% ZOL) at 12, 24, 36, and 48 months, respectively (p = 0.005); 4 remaining studies reported 1 (n = 181), 3 (n = 57), 7 (n = 99) and 2 (n = 200) cases of ONJ, all after 24 months. Incidence of clinically significant hypocalcemia ranged from 1-2%. Incidence of severe renal function decline was ≤ 3%. AFF occurred in two subjects in one of two studies after 37 and 79 months of BMA exposure. Conclusions: Although the evidence informing the use of BMA is heterogeneous and based on retrospective analysis, BMA exposure beyond 2 years is associated with reduced SRE risk and increased ONJ incidence. Prospective randomized studies addressing the use of BMA for more than 2 years is needed with greater emphasis on quality of life.

Trends of skeletal related events in patients with breast cancer metastasized to bone.

1098 Background: Up to three-quarters of women with advanced breast cancer develop bone metastases, predisposing to Skeletal Related Events (SRE), which are associated with a significant health care burden, poor prognosis, loss of functional independence and a decrease in quality of life. We performed a retrospective analysis on predictors of SRE in this population. We also evaluated temporal trends of outcomes and resource utilization in those with SRE. Methods: Adult breast cancer patients with metastases to bone, admitted from January 2012 to September 2015 were identified from the Nationwide Inpatient Sample database. Based on previous studies, SRE was defined by using ICD-9 codes for pathologic fracture, spinal cord compression, necessity for radiation to bone or surgery to bone. Multivariable analysis of predictors of SRE in patients with breast cancer metastatic to bone, as well as mortality in the SRE group were performed. Temporal trends of resource utilization across the years were evaluated. Results: A total of 143,455 patients with breast cancer with metastases to bone were identified, of which 17.2% had SRE. Patients with SRE had a mean age of 66 years and were predominantly white (70.2%). After adjusting for confounders, African Americans and Hispanics were less likely than Whites to develop SRE. On multivariable analysis, only comorbidity burden (in the form of high Charlson comorbidity index) predicted inpatient mortality. Rates of SRE in breast cancer patients with bone metastases did not change over the years (17.2% to 17.1%). Inpatient mortality of patients with SRE remained stable (3.76% to 3.79%). There was a statistically significant increase in surgical intervention (43.4% to 47.7%, p&lt;0.01) and decrease in radiation to bone (25.7% to 19.7%, p&lt;0.001) over time. Length of hospital stay and total hospital charges, after adjusting for inflation, remained largely unchanged. Conclusions: Incidence of SRE, inpatient outcomes and health care costs remained stagnant in those with metastatic breast cancer between 2012 and 2015, despite the advent of novel bone-targeted agents. There has been an increased trend towards surgical intervention and less utilization of local radiation over time. [Table: see text]