Bone Disease in Myeloma

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Bone Disease in Myeloma

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Boston Massachusetts Saturday, July 26, 2008 Boston, Massachusetts

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Bone Disease in Myeloma

Lytic Lesions

Spikep

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Biology of Myeloma Vascular Microenvironment Lymphocytes/ Macrophages/ Hematopoietic Cytokines Hormones

Cells/ DNA/ RNA

p / / Chemicals Microbes Myeloma Cells Neuro Nor-adrenaline Bone osteoclasts/ osteoblasts/ matrix

Other organs – Liver/ lymphatic/ brain… matrix

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Micro Environment and Bone Biology S t i Systemic • 1GF1 Osteoblasts • Osteoblasts… Local • Cells • Cells • Matrix • Blood Vessels…

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Bone Lesions in Myeloma

™

80% of patients have:

Lytic lesions and/or Diffuse osteoporosis

™

Bone lesions cause:

™

Bone lesions cause:

Pain

Fractures Fractures

Pressure on nerves/spine

I i bl d l i

(6)

Diagnosis of Bone Lesions

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X-ray: full skeletal survey

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X ray: full skeletal survey

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CT scan or MRI with

gadolinium*

gadolinium*

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Bone density

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Whole body FDG/PET with CT

and SUV assessment

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Bone turnover studies, e.g.

NTX

(7)

Bone Disease Classification

Based upon Focal Lesions on X-ray

(8)

Staging With FDG-PET and CT

™ FL PET & MRI

Multiple Myeloma FDG PET:

Severe Diffuse (D) and Focal (F) Disease

™ FL on PET & MRI: Severe Diffuse (D) and Focal (F) Disease

F F F F D D D D F F F F D D D D D D FF D D MRI – STIR weighted of thoracic spine FDG PET scan of thoracic spine

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Serial PET Shows Early Response

X-ray January

JAN APRIL JUNE

MRI M-protein T1 STIR MRI November January April

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MRI-CR “lags” Behind Clinical Response

Incidence of nCR/CR and Incidence of MRI-CR

Patients with 1+ Baseline FL detectable by PET and by MRIPET Shows Earlier Evidence of Responsey y

80% 100%

60% 80%

PET & actual

MRI 40% 12-Month 0% 20% MRI-CR nCR/CR Events / N 12 / 59 33 / 59 12 Month Estimate 17% 61% P<0.001 0% 0 6 12 18 24

Months After Starting VAD

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Treatment for Bone Disease

™Treat the myeloma ™Treat the myeloma

Chemotherapy Radiation

Radiation

™Treat the bone

Bisphosphonates Bisphosphonates Calcium/Vitamin D S ti Supportive care Kyphoplasty

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Bisphosphonates

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Primary Therapy for myeloma bone

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Primary Therapy for myeloma bone

disease to reduce skeletal related

events (SREs)

events (SREs)

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Recommended as ongoing therapy

for all myeloma patients with bone

disease

(13)

Bisphosphonate Use Guidelines 2007

Mayo/ IMF Perspectives* ™Starting BP ™Duration of therapy ™Duration of therapy ™Choice of BP ™R l i ™Renal issues ™Dental evaluation

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Starting Bisphosphonates

™ Lesions on x-ray ™ Lesions on x ray

™ Positive findings on MRI and/or CT PET

MRI: > 7 lesions and/or progression/ pain MRI: > 7 lesions and/or progression/ pain PET: high SUV; CT abnormal

™ R d d b i l ti it ?

™ Reduced bone mineral activity? ™ Increased bone turnover?

(15)

Duration of Bisphosphonates

™ Not indefinite

™ Minimum 2 years

™ Can consider stopping early if > VGPR ™ Can consider stopping early if > VGPR

AND

N ti b di

No active bone disease

™ Stop* at 2 years if no active bone disease

™ Restart if new disease

(16)

Stopping versus Reduced

Dose/ Schedule

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Consider both renal/ ONJ issues

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No data on Q2 or 3 months

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Clinical trials needed

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Clinical trials needed

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Choice of Bisphosphonate

™ Consensus that “efficacy equivalent” ™ Consensus that efficacy equivalent

(S.R.E.s) for available BPs:

Pamidronate; Clodronate; Zoledronic Pamidronate; Clodronate; Zoledronic acid….

™ Concern that there is higher risk of ™ Concern that there is higher risk of

toxicities with Zometa

Jaw osteonecrosis major concern Jaw osteonecrosis major concern, but renal toxicity also greater.

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Current Bisphosphonates

™Aredia ™Aredia 90 mg over 2-4 hrs. monthly ™Zometa ™Zometa

4 mg over 15-45 minutes monthly

Questions:

I f i ti

Infusion times

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How Frequent is Osteonecrosis?

™Rare prior to 2001

™2003 Ma epo ted 36 patients

™2003 – Marx reported 36 patients [JOMF SURG 61:115 2003]

™2004 – Ruggiero, et al reported 63 patients diagnosed 2001-2003 [JOMF SURG 62:527 2004]

d ag osed 00 003 [ ]

– Durie, et al reported 75 patients from IMF survey [NEJM July 7th, 2005] : 4% for Aredia; 10% for Zometa

for Zometa

™2005 – Groups from US, Italy, Greece and elsewhere document bisphosphonate associated p p

osteonecrosis (BAO).

– M.D. Anderson† 4.5% [J. Bon Min Res 20(1) 555; 1218 2005]

G 9 9%

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How frequent is osteonecrosis?

(Continued)

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™ 2007 – Now total of 26 case reports and 13 case series (120 cases) evaluating

case series (120 cases) evaluating

bisphosphonate associated osteonecrosis

[Krieger, et al. The Annuals of Pharmacotherapy 41: 276-284 2007]

ONJ more common with Zometa – ONJ more common with Zometa – ONJ >6-7% at 2 years

– Additional risk factors under investigation, including:

including:

Diabetes mellitus

[Khamaisi, et al. J. Clin Endocrinol Metab 92: 1172-1175 2007]

Oxidative stress; bone remodeling factors Oxidative stress; bone remodeling factors…

™2008- New report from Germany: ONJ 3.5 times higher with Zometa [Boonyapakorn et al Oral Onc.

higher with Zometa [Boonyapakorn et al Oral Onc. Feb 2008]

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Time to Onset of Osteonecrosis in Myeloma 25% 36-Month Zometa vs Aredia 20% 25% Zometa Aredia Events / N 10 / 211 10 / 413 36 Month Estimate 10% 4% P = .002

15% Data censored at 36 months

5% 10% 0% 5% 0 12 24 36 0 12 24 36

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Management Recommendations for ONJ

™Before starting bisphosphonates (BP)

Dental evaluation/ treatment Dental evaluation/ treatment

™While On BP

Regular dental care/ check-upsegu a de ta ca e/ c ec ups

Avoid dental extraction/ procedures Review type/ schedule of BP with MD

d k “d h l d ”

? Reduce Frequency or take “drug holiday”

™Established ONJ

Antibiotics Antibiotics

Minor dental procedures

Rinses/ supportive measurespp Stop BP Rx to allow healing Possible hyperbaric 02

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New Approaches to Enhance Osteoblast Activity and Heal Bones

Activity and Heal Bones

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Denusomab (Amgen)

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Denusomab (Amgen)

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MIP 1

α modulation

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DKK 1 protein inhibition

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VELCADE

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VELCADE

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Cholesterol lowering statins, e.g.

g

, g

Lipitor

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Quadramet (Samarium)

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Overall Strategies

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Diagnose & monitor bone

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Diagnose & monitor bone

disease

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Take bisphosphonate therapy

with good monitoring

with good monitoring

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Exercise

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Get pain relief

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Avoid risky situations

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Figure

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References

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