# Presentation: 666923

## Osteonecrosis of the Jaws in Myeloma

- 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.

***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 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

**Increase in Treatment Options Over Time**

**1950-1960s**

**1970-1980s**

**1990s**

**2000s**

**Bortezomib (Velcade)**
**Thalidomide**
**Bisphosphonates**
**Stem cell transplantation**
**High-dose chemotherapy**
**Vincristine, doxorubicin, dexamethasone**
**Radiation**
**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**

**STEROIDS**

**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 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%)
- 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 ONJ**

**Bisphosphonate treatment**

**MONTHS FROM DIAGNOSIS**

****ONJ: mean times for Aredia only and Zometa only significantly different, p=0.002.******   ***

## Pattern of bisphosphonates in patients with ONJ or SONJ

**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 Treatment

- 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**

## Duration of Aredia and/or Zometa use censored at 3 years

- 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 ****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 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

## No Difference in Likelihood of ONJ or SONJ in Myeloma versus Breast Cancer

**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*

- 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

**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 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