1、Osteonecrosis of the Jaws in Myeloma,BRIAN G.M. DURIE, M.D., Michael Katz, Jason McCoy, MS and John Crowley, PhDHematology/Oncology, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA; Web Support/Data Analysis, International Myeloma Foundation, Los Angeles, CA, USA; and Statistics, Cancer
2、Research and Biostatistics, Seattle, WA, USA.,Time Dependent Correlation with AREDIA and ZOMETA Use,Osteonecrosis of the Jaws What Is It?,Exposed bone in the maxilla or mandible Due to disruption of the resorption-remodeling cycle of bone and inhibition of endothelial cell proliferation Poor healing
3、 and secondary infection can lead to loss of teeth and segments of jaw bones.Pictures courtesy Dr. Sal Ruggiero,How Frequent Is Osteonecrosis?,Rare prior to 2001 2003 - Marx* reported 36 patients 2004 - Ruggiero* et al reported 63 patients diagnosed 2001-2003 2004/ 2005Myeloma specialty groups repor
4、t an increased frequency; 2-5% of patients at IMF seminars in Dallas/ San Diego/ LA/ Portland/ Tucson indicate osteonecrosis diagnosis* JOMF SURG 61:115 2003 * JOMF SURG 62:527 2004,Questions About Osteonecrosis,Was the diagnosis missed prior to 2001? Probably Not It is an obvious dental problem Wha
5、t caused the increased frequency of ONJ? Not Clear Marx and Ruggerio et al proposed an association with bisphosphonate use,Important Current Questions/ Issues,Is the likelihood of ONJ linked to use of Aredia and/or Zometa?To what extent do other therapies or disease processes have an impact?Are ther
6、e identifiable risk factors?What is the magnitude/severity of the problem?Are myeloma patients particularly at risk for osteonecrosis (ONJ) e.g. versus breast cancer?,OUR STUDY,Anonymous WEB Based Survey: Summer 2004 Included 1203 Myeloma(904) and Breast Cancer (299) patients Recruited using IMF ema
7、il lists/web site plus “ACOR” myeloma and breast Listservs (email), Nexcura (email) and Y-Me National Breast Cancer Organization (web site) Evaluates dates for diagnosis, treatments and complications including dental findings,Increase in Treatment Options Over Time,1950-1960s,1970-1980s,1990s,2000s,
8、Bortezomib (Velcade) Thalidomide BisphosphonatesStem cell transplantation High-dose chemotherapyVincristine, doxorubicin, dexamethasoneRadiation Melphalan + Prednisone,ALLO,CLOD.,THAL,ALLO,CLOD.,VELCADE,SCT,HDC,VAD,SCT,HDC,VAD,MP,RAD,STEROIDS,SCT,HDC,VAD,ALLO,MP,RAD,STEROIDS,RAD,STEROIDS,MP,MP,RAD,S
9、TEROIDS,Myeloma Rx,AREDIA,ZOMETA,THAL,AREDIA,Numbers of Patients Responding to Survey,Total Patients,1203,299,904,Osteonecrosis (ONJ),Suspicious findings* (SONJ),ONJ,SONJ,13 23,62 54,36,116,* SONJ: Suspicious findings: bone erosions; bone spurs; exposed bone,Myeloma,Breast,Overall Likelihood of ONJ
10、from Time of Diagnosis,904 myeloma patients,New Cases of ONJ Each Year Among Respondents,57 patients 12 patients,Frequency of Therapeutic Interventions in Myeloma Respondents,Bisphosphonates 804/904 (89%) 57/62 (92%)AREDIA (ONLY) 267/904 (30%) 17/62 (27%) ZOMETA (EVER) 515/904 (57%) 40/62 (65%)Stero
11、ids 738/904 (81%) 55/62 (89%)PREDNISONE 210/904 (23%) 24/62 (39%) DEXAMETHASONE 525/904 (58%) 64/62 (55%) Thalidomide 496/904 (55%) 37/62 (59%) Radiation to head/ neck 61/904 (7%) 3/62 (5%) Stem Cell Transplant 426/904 (47%) 26/62 (42%),Overall,ONJ,Increasing Incidence of ONJ Among Respondents from
12、Date of Diagnosis,Months from Diagnosis,Mean Time from Myeloma DX to Onset of ONJ or SONJ,Zometa only 18 months* 19 monthsAredia only 72 months* 32 months,ONJ,Suspicious ONJ,Bisphosphonate treatment,MONTHS FROM DIAGNOSIS,*ONJ: mean times for Aredia only and Zometa only significantly different, p=0.0
13、02.,47%,Pattern of bisphosphonates in patients with ONJ or SONJ,Zometa*Aredia Alone,Myeloma,Breast,103,27,904 57 46 299 11 16,Overall ONJ SONJ Overall ONJ SONJ,* Alone or switched to Zometa,Myeloma,81%,91%,94%,19%,9 %,6 %,70%,68%,Breast,ONJ Among Respondents vs. Duration of Aredia or Zometa Treatmen
14、t,Log-rank P=.01,Months from start of Aredia or Zometa,Events / N,Z only 10 / 211,A only 14 / 231,A and Z 14 / 182,0%,5%,10%,15%,20%,25%,0,12,24,36,Months from start of Aredia or Zometa,Z only,A +/- Z,Events / N,10 / 211,10 / 413,36-Month,Estimate,10%,4%,P = .002,Duration of Aredia and/or Zometa use
15、 censored at 3 years,Prednisone Does Not Increase the Likelihood of ONJ,Months from Diagnosis,Thalidomide and Dexamethasone Do Not Increase the Likelihood of ONJ,Log-rank P 0. 5,Thalidomide,Dexamethasone,The Increased Occurrence of ONJ and SONJ Since 2001,CORRELATES WITHThe impact of Aredia after 6
16、years The impact of Zometa after 18 months* The highest risk (45%) is in the group of patients switching from Aredia to Zometa,No Difference in Likelihood of ONJ or SONJ in Myeloma versus Breast Cancer,Duration of bisphosphonate therapy censored at 3 years,Zometa Only is Associated with earlier onse
17、t of ONJ or SONJ: MM and breast combined,Duration of bisphosphonate therapy censored at 3 years,Frequency of Prior Dental Problems*,Total Population 396/1203(33%) 59/75 (79%) Myeloma 294/904 (32%) 50/62 (81%) Breast Cancer 102/299 (34%) 9/13 (69%)Two sided P-value for dental problems and osteonecros
18、is:in Breast: 0.0129 in Myeloma: 0.0001* Other than Suspicious ONJ findings,Overall,ONJ Patients,Conclusions,Amongst the respondents to this survey Duration of bisphosphonate use in myeloma and breast cancer is associated with increased risk of Osteonecrosis (ONJ) 36 month estimates of ONJ are highe
19、r for Zometa versus Aredia None of the other therapies analyzed were associated with a time dependent increased risk of ONJ Patients with prior dental problems have a higher risk of ONJ It is likely that precautions related to dental care and bisphosphonates use may reduce the likelihood of ONJ,Acknowledgements,Special thanks to Judith Peterson,Special thanks to Vanessa Bolejack,
