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

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1 Bone Disease in Myeloma St. Petersburg, Russia September 16, 2009 Bi Brian G.M. GMDurie, M.D. MD

2 Bone Disease in Myeloma Lytic Lesions Spike Bone Marrow Plasma Cells Collapse of Vertebrae

3 Biology of Myeloma Vascular Cytokines Lymphocytes/ Macrophages/ Hormones Hematopoietic Cells/ DNA/ RNA Chemicals Myeloma Cells Microbes Microenvironment Neuro Nor-adrenaline Bone osteoclasts/ osteoblasts/ matrix Other organs Liver/ lymphatic/ brain

Myeloma Cells Microbes Microenvironment Neuro Nor-adrenaline

4 Bone Disease and Response to Treatment e t Bone damage is one aspect of myeloma Whether or not the myeloma cells are sensitive to treatment is something different DNA changes (SNPs: polymorphisms) linked to severe bone disease are NOT linked to high risk by GEP (G17)* *Durie et al, Leukemia 2009

something different DNA changes (SNPs: polymorphisms) linked to severe

5 Bone Lesions in Myeloma 80% of patients have: Lytic lesions and/or Diffuse osteoporosis Bone lesions cause: Pain Fractures Pressure on nerves/spine Increase in blood calcium

6 Diagnosis of Bone Lesions X-ray: full skeletal survey CT scan or MRI with gadolinium* Bone density Whole body FDG/PET with CT and SUV assessment Bone turnover studies, e.g. NTX * Caution required with gadolinium

Whole body FDG/PET with CT and SUV assessment Bone

7 Bone Disease Classification Based upon Focal Lesions on X-ray and/or MRI

8 Staging With FDG-PET and CT FL on PET & MRI: Multiple Myeloma FDG PET: Severe Diffuse (D) and Focal (F) Disease F F D D F D D D D F FDG PET scan of thoracic spine MRI STIR weighted of thoracic spine

9 Serial PET Shows Early Response X-ray January JAN APRIL JUNE M-protein MRI November T1 STIR January April

10 MRI-CR lags Behind Clinical Response 100% Incidence of ncr/cr and Incidence of MRI-CR Patients with PET 1+ Shows Baseline Earlier FL detectable Evidence by of PET Response and by MRI 80% 60% PET & actual MRI 40% 20% MRI-CR ncr/cr Events / N 12 / / 59 P< Month Estimate 17% 61% 0% Months After Starting VAD * Walker, et al ASH

by MRI 80% 60% PET & actual MRI 40% 20% MRI-CR ncr/cr Events / N 12 / 59 33 / 59 P<0.

11 Treatment for Bone Disease Treat the myeloma Chemotherapy Radiation Treat the bone Bisphosphonates Calcium/Vitamin D Supportive care Kyphoplasty

12 Radiotherapy May be useful in specific situations Pain control Spinal cord compression Prevent or treat pathologic fractures However, destroys normal marrow

$pathologic fractures However, destroys$

13 Source: Fourney et al. J Neurosurg (Spine 1) 2003;98: Vertebroplasty

14 Balloon Kyphoplasty Insert Balloon Inflate Balloon Fill Compacted Then Remove Space with Cement

15 Bisphosphonates Primary Therapy for myeloma bone disease to reduce skeletal related events (SREs) Recommended as ongoing therapy for all myeloma patients with bone disease

16 Starting Bisphosphonates Lesions on x-ray are main indication Positive findings on MRI and/or CT PET also show bone lesions MRI: > 7 lesions and/or progression/ pain PET: high SUV plus bone destruction on CT Reduced bone mineral density and/or increased urinary NTX Both support possibility of bone disease

progression/ pain PET: high SUV plus bone destruction on CT Reduced bone

17 Bisphosphonate Guidelines Mayo/ IMF/ASCO Perspectives* Starting BP Duration of therapy Choice of BP Renal l issues Dental evaluation *SEE: Mayo Clinic Proceedings, 82(4); April 2007

18 Duration of Bisphosphonates Not indefinite Maximum 2 years Can consider stopping early if > VGPR AND No active bone disease Stop or reduce frequency at 2 years if no active bone disease Restart if new disease

No active bone disease Stop or reduce frequency at

19 Choice of Bisphosphonate 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. BUT toxicities preventable with proper awareness

is higher risk of toxicities with Zometa Jaw osteonecrosis and renal

20 Current Bisphosphonates Aredia 90 mg over 2-4 hrs. monthly Zometa 4 mg over minutes monthly Questions: Infusion times Long term duration/ schedule

21 Osteonecrosis of Jaw on Panorex

22 20% Time to Onset of Osteonecrosis in Myeloma Zometa vs Aredia 25% 36-Month Events / N Estimate Zometa 10 / % P =.002 Aredia 10 / 413 4% 15% Data censored at 36 months 10% 5% 0% Months from start of Aredia or Zometa

23 Management Recommendations for ONJ Before starting bisphosphonates (BP) Dental evaluation/ treatment While On BP Regular dental care/ check-ups Avoid dental extraction/ procedures Review type/ schedule of BP with MD? Reduce Frequency or take drug holiday ld Established ONJ Antibiotics Minor dental procedures Rinses/ supportive measures Stop BP Rx to allow healing Possible hyperbaric 0 2

24 Impact of Preventive Strategies Dimopolous et al 2008 (Am J Oncology) Group A 2 year hazard of ONJ (with Zometa) 16% Group B (after implementation) 2 year hazard 5%

25 New Approaches to Target Osteoclast and/or Osteoblast Denusomab (Amgen) MIP 1 modulation DKK 1 protein inhibition VELCADE Cholesterol lowering statins, e.g. Lipitor Quadramet (Samarium)

26 Mechanism of Action for Denosumab

27 Overall Strategies Diagnose & monitor bone disease Use bisphosphonate therapy with good monitoring Recommend exercise, pain reduction and avoidance of risky situations

Bone Disease in Myeloma

Bone Disease in Myeloma Washington, DC August 8, 2009 Brian G.M. Durie, M.D. Bone Disease in Myeloma Lytic Lesions Spike Bone Marrow Plasma Cells Collapse of Vertebrae Biology of Myeloma Vascular Cytokines