Monitoring therapy and mitigating side effects

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1 Monitoring therapy and mitigating g side effects Noopur Raje, MD Director, Center for Multiple Myeloma MGH Cancer Center Associate Professor of Medicine Harvard Medical School Issues with BP Therapy Renal Toxicity Osteonecrosis of the jaw Stress Fractures Decreases skeletal events by 50%; patients still progress but at a slower rate 1

2 Renal Profile of Pamidronate and Zoledronic Acid in Patients With Metastatic Breast Cancer or Multiple Myeloma 100 tients without increase e (%) Pat Zoledronic acid 4 mg Pamidronate 90 mg Time after start of study drug (days)* Berenson JR. Oncologist. 2005;10: Zoledronic Acid Renal Safety Zoledronic acid renal safety is comparable to pamidronate 1,2 Grades 3 and 4 abnormalities in serum creatinine* Zol Acid *Grade 3 3x upper limit of normal; grade 4 6x upper limit of normal. 1.Data on file. Novartis Pharmaceuticals Corporation. 2. Zoledronic acid Prescribing Information. 2

3 Guidelines for Renal Patients Calculate baseline creatinine clearance (CrCl) to determine a patient-specific starting dose Zol Acid Zoledronic Acid is not recommended Zoledronic acid* Prescribing Information. Guidelines for Renal Patients Guidelines for patients with elevated creatinine Calculate baseline creatinine clearance (CrCl) to determine a patientspecific starting dose Before each zoledronic acid dose, serum creatinine should be measured Withhold zoledronic acid temporarily if patient has Increase of 0.5 mg/dl in serum creatinine (SCr) for patients with normal SCr Increase of 1.0 mg/dl in SCr for patients with abnormal SCr Resume zoledronic acid at the starting dose when SCr returns to within 10% of baseline value Zoledronic acid Prescribing Information. 3

4 ZMAX Trial Berenson JR. J Supp Oncolet al. 2010; in press. Osteonecrosis of the Jaw Clinical Features of Suspected ONJ Exposed bone in maxillofacial area that occurs in association with dental surgery or occurs spontaneously, with no evidence of healing* Working Diagnosis of ONJ No evidence of healing after 8 weeks of appropriate evaluation and dental care No evidence of metastatic disease in the jaw or osteoradionecrosis Koshla et al. J Bone Miner Res. 2007;22:

5 ONJ: Clinical Features Patient #2: h/o dental extraction p/w roughness and irritation h/o dex 4 mths, CTX, EDAP 3/3 mths, PBSCT and Pamidronate 61 mths and zoledronic acid 20 mths Raje et al. Clin Can Res. 2008;14(8): Raje et al. Clin Can Res 2008 Risk Factors Linked to ONJ Invasive Dental Procedure- surgery or extraction Longer time from diagnosis (median 4.2 years for patients with ONJ) Age Many of the patients t had osteomyelitis and positive cultures for actinomycetes or mixed flora Badros et al. J Clin Oncol. 2006;24(6):

6 Biochemical and GEP studies suggest inhibition of bone formation PROTEIN KINASE C FAMILY ONJ MM Normals Raje et al. Clin Can Res 2008 Management of ONJ Current management of ONJ is empirical. At present, a conservative approach is recommended. This includes antibiotics, oral rinses, pain control, and limited debridement Cases refractory to conservative management may benefit from investigational therapies Koshla et al. J Bone Miner Res Oct;22(10):

7 ASCO Clinical Practice Guidelines: Update Bisphosphonates Indicated for MM pts w/ lytic bone disease osteopenia Useful as an adjunct for pts w/ bone pain The bisphosphonates recommended are either Zoledronic acid: 4 mg over 15 mins, IV q 3-4 wks Palmidronate: 90 mg over > 2 hrs, IV q 3-4 wks Monitoring w/ serum creatinine (both BPs) and/or urine albumin (for palmidronate only) PAM preferred in setting of renal dysfunction Re-evaluate after 2 years and consider stopping if stable disease Kyle R et al. J Clin Oncol. 2007;2(17)5: High Dose Zoledronic Acid increases Trabecular Bone Pozzi et al, Clin Can Res

8 High Dose Zoledronic Acid Decreases Bone Formation Zoledronic Acid decreased osteoblast numbers associated with increased tendency to fracture Pozzi et al, Clin Can Res 2009 Denosumab vs. Zoledronate Phase 3 trial in 1,776 patients with solid tumors (not breast or prostate) or myeloma. Primary endpoint median time to first SRE Delay in time to first SRE or subsequent SRE was not statistically different SAEs were similar ONJ infrequent and similar (10 vs 11 patients) Henry D et al. EJC Supplements. 2009;7(3):12. Abstract 20LBA. 8

9 Stress Fractures Patient #2: p/w roughness and irritation, h/o dex 4 mths, CTX, EDAP 3/3 mths, PBSCT and Pamidronate 61 mths and Zoledronic acid 20 mths, h/o dental extraction Site: subtrochanteric or proxymal diaphyseal fracture of the femur + other rare locations Radiology: defined as a simple transverse or oblique ( 30 ) fracture with beaking of the cortex and diffuse cortical thickening of the proximal femoral shaft; pattern called simple with thick cortex and is sometimes associated to controlateral cortical thickening. - May be associated with a controlateral stress reaction, of the other femur Grasko, J Oral Maxillofacial Surg 2009 Prognostic variables for SRE and Death Terpos E et al.leukemia 2010;24:

10 Prognostic variables for SRE and Death Terpos E et al.leukemia 2010;24: OBJECTIVES: Urine NTx to tailor Therapy To evaluate the NTX levelsl monthly for 6 months in MM patients off IV bisphosphonate treatment after a single dose of zoledronic acid. T d t i h th NTX l l b To determine whether NTX levels can be used as a surrogate to tailor Zoledronic acid therapy 10

11 Study Design 30 MM patients in CR and or PR with h/o 8-12 months of IV bisphosphonate therapy 6 m end of study with BM aspirate and biopsy and Skeletal Survey Baseline NTX followed by monthly x 6 Serum Markers followed by monthly x 6 BM aspirate and core Skeletal Survey Zoledronic acid single dose ClinicalTrials.gov Identifier: NCT Raje et al. J Clin Oncol 2010 ASCO Ab Results NTx levels (n=28patients) NTx Level NTx Values Months ClinicalTrials.gov Identifier: NCT Raje et al. J Clin Oncol 2010 ASCO Ab 11

12 Phase IV ZMARK Trail Multiple Myeloma BP treated: Up to 6-24mo N = 120 NTX < 50nM-q12w NTX >50nM-q4wk n = 120 NTX directed q4 or 12 wk 0 24 months NTX < 50nM-Obs NTX >50nM-Rx Obs or NTX directed 36 months * Primary efficacy endpoint: Time to first SRE ClinicalTrials.gov Identifier: NCT Raje et al. Blood, ASH 2010, Ab Interim Analysis (n=60) 58 patients started q 12 weeks Rx 12 patients were switched to q 4 weeks either due to NTx increase or relapse Only 2 SREs noted in the q 12 week schedule Raje et al.blood, ASH 2010, Ab 12

13 Take Home Generally well tolerated No difference in renal toxicity between ZA and PAM ONJ and Stress Fractures reflection of potency of anti-resoptive activity Novel biomarker directed therapy will allow tailoring Novel biomarker directed therapy will allow tailoring therapy 13