Osteonecrosis of the Jaws in Myeloma Time Dependent Correlation with AREDIA and ZOMETA Use BRIAN G.M. DURIE, M.D., Michael Katz, Jason McCoy, MS and John Crowley, PhD Hematology/Oncology, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA; Web Support/Data Analysis, International Myeloma Foundation, Los Angeles, CA, USA; and Statistics, Cancer Research and Biostatistics, Seattle, WA, USA.
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 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/ 2005 Myeloma specialty groups report 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 • What 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 there 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 email 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 Myeloma Rx VELCADE ZOMETA Bortezomib (Velcade) Thalidomide Bisphosphonates Stem cell transplantation High-dose chemotherapy Vincristine, doxorubicin, dexamethasone Radiation Melphalan + Prednisone THAL THAL AREDIA AREDIA CLOD. CLOD. ALLO ALLO ALLO SCT SCT SCT HDC HDC HDC VAD VAD VAD STEROIDS STEROIDS STEROIDS STEROIDS RAD RAD RAD RAD MP MP MP MP 1950-1960s 1970-1980s 1990s 2000s
Numbers of Patients Responding to Survey Total Patients 1203 Myeloma Breast 904 299 Osteonecrosis (ONJ) SONJ Suspicious findings* (SONJ) ONJ 13 23 62 54 36 116 * SONJ: Suspicious findings: bone erosions; bone spurs; exposed bone
Overall Likelihood of ONJ 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 Overall ONJ • Bisphosphonates804/904 (89%) 57/62 (92%) • AREDIA (ONLY) 267/904 (30%) 17/62 (27%) • ZOMETA (EVER) 515/904 (57%) 40/62 (65%) • Steroids738/904 (81%) 55/62 (89%) • PREDNISONE 210/904 (23%) 24/62 (39%) • DEXAMETHASONE 525/904 (58%) 64/62 (55%) • Thalidomide496/904 (55%) 37/62 (59%) • Radiation to head/ neck 61/904 (7%) 3/62 (5%) • Stem Cell Transplant 426/904 (47%) 26/62 (42%)
Increasing Incidence of ONJ Among Respondents from Date of Diagnosis Months from Diagnosis
Mean Time from Myeloma DX to Onset of ONJ or SONJ MONTHS FROM DIAGNOSIS Bisphosphonate treatment ONJ Suspicious ONJ Zometa only 18 months* 19 months Aredia only72 months*32 months *ONJ: mean times for Aredia only and Zometa only significantly different, p=0.002.
Pattern of bisphosphonates in patients with ONJ or SONJ Myeloma Breast 103 27 Myeloma Breast Overall ONJ SONJ Overall ONJ SONJ 904 57 46 299 11 16 Zometa* Aredia Alone 47% 70% 68% 81% 91% 94% 19% 9 % 6 % * Alone or switched to Zometa
ONJ Among Respondents vs. Duration of Aredia or Zometa Treatment 100% 80% 60% 40% 20% 0% 0 24 48 72 96 120 144 Events / N Z only 10 / 211 Log-rank P=.01 A only 14 / 231 A and Z 14 / 182 Months from start of Aredia or Zometa
Duration of Aredia and/or Zometa use censored at 3 years 25% 36-Month Events / N Estimate P = .002 Z only 10 / 211 10% A +/- Z 10 / 413 4% 20% 15% 10% 5% 0% 0 12 24 36 Months from start of Aredia or Zometa
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 WITH • The impact of Aredia after6 years • The impact of Zometa after18 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 onset of ONJ or SONJ: MM and breast combined Duration of bisphosphonate therapy censored at 3 years
Frequency of Prior Dental Problems* ONJ Patients Overall • Total Population 396/1203(33%) 59/75 (79%) • Myeloma294/904 (32%) 50/62 (81%) • Breast Cancer 102/299 (34%) 9/13 (69%) Two sided P-value for dental problems and osteonecrosis: in Breast: 0.0129 in Myeloma: <0.0001 * Other than Suspicious ONJ findings
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 higher 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