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Osteonecrosis of the Jaws in Myeloma

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Hematology/Oncology, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA; ... Statistics, Cancer Research and Biostatistics, Seattle, WA, USA. ... – PowerPoint PPT presentation

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Title: Osteonecrosis of the Jaws in Myeloma


1
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.

2
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

3
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 61115 2003
  • JOMF SURG 62527 2004

4
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

5
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?

6
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

7
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
8
Numbers of Patients Responding to Survey
Total Patients
1203
Myeloma
Breast
299
904
Osteonecrosis (ONJ)
SONJ
Suspicious findings (SONJ)
ONJ
13 23
62 54
36
116
SONJ Suspicious findings bone erosions
bone spurs exposed bone
9
Overall Likelihood of ONJ from Time of Diagnosis
904 myeloma patients
10
New Cases of ONJ Each Year Among Respondents
57 patients 12 patients
11
Frequency of Therapeutic Interventions in Myeloma
Respondents
Overall
ONJ
  • Bisphosphonates 804/904 (89) 57/62
    (92)
  • AREDIA (ONLY) 267/904 (30) 17/62
    (27)
  • ZOMETA (EVER) 515/904 (57) 40/62
    (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)

12
Increasing Incidence of ONJ Among Respondents
from Date of Diagnosis
Months from Diagnosis
13
Mean Time from Myeloma DX to Onset of ONJ or SONJ
MONTHS FROM DIAGNOSIS
ONJ
Suspicious ONJ
Bisphosphonate treatment
  • Zometa only 18 months 19 months
  • Aredia only 72 months 32 months

ONJ mean times for Aredia only and Zometa only
significantly different, p0.002.
14
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
81
91
94
68
19
9
6
Alone or switched to Zometa
15
ONJ Among Respondents vs. Duration of Aredia or
Zometa Treatment
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
16
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
17
Prednisone Does Not Increase the Likelihood of
ONJ
Months from Diagnosis
18
Thalidomide and Dexamethasone Do Not Increase the
Likelihood of ONJ
Log-rank P gt 0. 5
Thalidomide
Dexamethasone
19
The Increased Occurrence of ONJ and SONJ Since
2001
  • CORRELATES WITH
  • The impact of Aredia after 6 years
  • The impact of Zometa after 18 months
  • The highest risk (45) is in the group of
    patients switching from Aredia to Zometa

20
No Difference in Likelihood of ONJ or SONJ in
Myeloma versus Breast Cancer
Duration of bisphosphonate therapy censored at 3
years
21
Zometa Only is Associated with earlier onset of
ONJ or SONJ MM and breast combined
Duration of bisphosphonate therapy censored at 3
years
22
Frequency of Prior Dental Problems
ONJ Patients
Overall
  • 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
    lt0.0001
  • Other than Suspicious ONJ findings

23
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

24
Acknowledgements
Special thanks to Judith Peterson
Special thanks to Vanessa Bolejack
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