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

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

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

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 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

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

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

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

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%)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

Increasing Incidence of ONJ Among Respondents from Date of Diagnosis

Months from Diagnosis

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.

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

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

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

Prednisone Does Not Increase the Likelihood of ONJ

Months from Diagnosis

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%

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

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 combinedDuration 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 osteonecrosis:in Breast: 0.0129 in Myeloma: <0.0001

* Other than Suspicious ONJ findings

OverallONJ

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 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

Acknowledgements

Special thanks to Judith Peterson

Special thanks to Vanessa Bolejack