Bone Disease in Myeloma. St. Petersburg, Russia September 16, 2009

Bone Disease in Myeloma

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St. Petersburg, Russiag, September 16, 2009

B i G M D i M D

Bone Disease in Myeloma

Lytic Lesions

Spikep

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

Bone Disease and Response to Treatmenteat e t

Bone damage is one aspect of myeloma Bone damage is one aspect of myeloma Whether or not the myeloma cells are

sensitive to treatment is something sensitive to treatment is something different

DNA changes (SNPs: polymorphisms)

DNA changes (SNPs: polymorphisms)

linked to severe bone disease are NOT linked to high risk by GEP (G17)*

linked to high risk by GEP (G17)*

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

Diagnosis of Bone Lesions



X-ray: full skeletal survey



X ray: full skeletal survey



CT scan or MRI with

gadolinium*

gadolinium*



Bone density



Whole body FDG/PET with CT

and SUV assessment



Bone turnover studies, e.g.

NTX

Bone Disease Classification

Based upon Focal Lesions on X-ray

Staging With FDG-PET and CT

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

Serial PET Shows Early Response

X-ray January

JAN APRIL JUNE

MRI M-protein T1 STIR MRI November January April

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

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

Radiotherapy



May be useful in specific situations

Pain control

Spinal cord compression Spinal cord compression

Prevent or treat pathologic fractures

d

l

Vertebroplasty

Balloon Kyphoplasty

Insert Balloon Inflate Balloon Fill Compacted Then Remove Space with Cement

Bisphosphonates



Primary Therapy

for myeloma



Primary Therapy

for myeloma

bone disease to reduce skeletal

related events (SREs)

related events (SREs)



Recommended

as ongoing

therapy for all myeloma patients

with bone disease

Starting Bisphosphonates

 Lesions on x-ray are main indication

 Lesions on x ray are main indication

 Positive findings on MRI and/or CT PET

also show bone lesions also show bone lesions

MRI: > 7 lesions and/or progression/ pain PET: high SUV plus bone destruction on CT PET: high SUV plus bone destruction on CT

 Reduced bone mineral density and/or

i d i NTX

increased urinary NTX

Bisphosphonate Guidelines

Mayo/ IMF/ASCO Perspectives*

Starting BP Duration of therapy Duration of therapy Choice of BP R l i Renal issues Dental evaluation

Duration of Bisphosphonates

 Not indefinite

 Maximum 2 years

 Can consider stopping early if > VGPR  Can consider stopping early if > VGPR

AND

N ti b di

No active bone disease

 Stop or reduce frequency at 2 years if

no active bone disease

Choice of Bisphosphonate

 Consensus that “efficacy equivalent” for  Consensus that efficacy equivalent for

available drugs:

Aredia (Pamidronate)( )

Zometa (Zoledronic Acid)

 Concern that there is higher risk of toxicities

with Zometa

Jaw osteonecrosis and renal toxicity both potential issues

issues.

BUT toxicities preventable with proper awareness … BUT toxicities preventable with proper awareness

Current Bisphosphonates

4 mg over 15-45 minutes monthly Questions:

I f i ti

Infusion times

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

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

Impact of Preventive Strategies

Dimopolous et al 2008 (Am J Oncology) Dimopolous et al 2008 (Am J Oncology)

Group A Group A

2 year hazard of ONJ (with Zometa) 16%

Group B (after implementation)

New Approaches to Target Osteoclast and/or Osteoblast and/or Osteoblast



Denusomab (Amgen)



Denusomab (Amgen)



MIP 1

 modulation



DKK 1 protein inhibition



VELCADE



VELCADE



Cholesterol lowering statins, e.g.

g

, g

Lipitor



Quadramet (Samarium)

Overall Strategies



Diagnose & monitor bone



Diagnose & monitor bone

disease



Use bisphosphonate therapy

with good monitoring

with good monitoring



Recommend exercise, pain

reduction and avoidance of

risky situations