osteonecrosis of the jaws in myeloma brian g.m. durie, m.d., michael katz, jason mccoy, ms and john...
DESCRIPTION
How Frequent Is Osteonecrosis? Rare prior to Marx* reported 36 patients Ruggiero** et al reported 63 patients diagnosed / 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: ** JOMF SURG 62:TRANSCRIPT
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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 Research and Biostatistics, Seattle, WA, USA.
Time Dependent Correlation with AREDIA and ZOMETA Use
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Osteonecrosis of the Jaws – What Is It?
Exposed bone in the maxilla or mandibleDue to disruption of the resorption-remodeling cycle of bone and inhibition of endothelial cell proliferationPoor healing and secondary infection can lead to loss of teeth and segments of jaw bones.
Pictures courtesy Dr. Sal Ruggiero
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How Frequent Is Osteonecrosis?
Rare prior to 20012003 - Marx* reported 36 patients2004 - Ruggiero** et al reported 63 patients diagnosed 2001-20032004/ 2005Myeloma 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
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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
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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?
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OUR STUDY
Anonymous WEB Based Survey: Summer 2004Included 1203 Myeloma(904) and Breast Cancer (299) patientsRecruited 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
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Increase in Treatment Options Over Time
1950-1960s1970-1980s1990s 2000s
Bortezomib (Velcade)ThalidomideBisphosphonates
Stem cell transplantationHigh-dose chemotherapy
Vincristine, doxorubicin, dexamethasone
RadiationMelphalan + Prednisone
ALLOCLOD.
THAL
ALLOCLOD.
VELCADE
SCTHDCVAD
SCTHDCVAD
MPRAD
STEROIDS
SCTHDCVAD
ALLO
MPRAD
STEROIDS
RADSTEROID
S
MP MPRAD
STEROIDS
Myeloma Rx
AREDIA
ZOMETATHAL
AREDIA
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Numbers of Patients Responding to Survey
Total Patients 1203
299904
Osteonecrosis (ONJ)
Suspicious findings* (SONJ)
ONJ SONJ 13 23
62 5436
116 * SONJ: Suspicious findings: bone erosions; bone spurs; exposed bone
Myeloma Breast
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Overall Likelihood of ONJ from Time of Diagnosis
0%
10%
20%
30%
40%
50%
0 24 48 72 96 120 144 168Months from diagnosis
904 myeloma patients
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New Cases of ONJ Each Year Among Respondents
57 patients 12 patients
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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%)ZOMETA (EVER) 515/904 (57%) 40/62 40/62
(65%)(65%)
Steroids 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
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Increasing Incidence of ONJ Among Respondents from Date of Diagnosis
Months from Diagnosis
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Mean Time from Myeloma DX to Onset of ONJ or SONJ
Zometa only 18 months* 19 months
Aredia only 72 months* 32 months
ONJ Suspicious ONJBisphosphonate treatment
MONTHS FROM DIAGNOSIS
*ONJ: mean times for Aredia only and Zometa only significantly different, p=0.002.
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47%
Pattern of bisphosphonates in patients with ONJ or SONJ
Zometa*
Aredia Alone
Myeloma Breast103 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
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ONJ Among Respondents vs. Duration of Aredia or Zometa Treatment
0%
20%
40%
60%
80%
100%
0 24 48 72 96 120 144
Log-rank P=.01
Months from start of Aredia or Zometa
Events / NZ only 10 / 211
A only 14 / 231 A and Z 14 / 182
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0%
5%
10%
15%
20%
25%
0 12 24 36
Months from start of Aredia or Zometa
Z onlyA +/- Z
Events / N10 / 21110 / 413
36-MonthEstimate
10%4%
P = .002
Duration of Aredia and/or Zometa use censored at 3 years
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Prednisone Does Not Increase the Likelihood of ONJ
Months from Diagnosis
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Thalidomide and Dexamethasone Do Not Increase the Likelihood of ONJ
0%
10%
20%
30%
40%
50%
0 24 48 72 96 120 144 168Months from diagnosis
Myeloma, Thalidomide useMyeloma, No Thalidomide
Events / N33 / 48521 / 397
60-MonthEstimate
8%5%
Log-rank P > 0. 5
Thalidomide Dexamethasone
0%
10%
20%
30%
40%
50%
0 24 48 72 96 120 144 168Months from diagnosis
Myeloma, Dex useMyeloma, No Dex
Events / N29 / 51525 / 367
60-MonthEstimate
6%7%
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The Increased Occurrence of ONJ and SONJ Since 2001
CORRELATES WITH
The impact of Aredia after 6 yearsThe impact of Zometa after 18 months
* The highest risk (45%) is in the group of patients switching from Aredia to Zometa
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No Difference in Likelihood of ONJ or SONJ in Myeloma versus Breast Cancer
Duration of bisphosphonate therapy censored at 3 years
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Zometa Only is Associated with earlier onset of ONJ or SONJ:
MM and breast combinedDuration of bisphosphonate therapy censored at 3 years
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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 osteonecrosis:in Breast: 0.0129 in Myeloma: <0.0001
* Other than Suspicious ONJ findings
OverallONJ
Patients
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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 ArediaNone of the other therapies analyzed were associated with a time dependent increased risk of ONJPatients 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
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Acknowledgements
Special thanks to Judith Peterson
Special thanks to Vanessa Bolejack