Bone Disease in Myeloma
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Boston Massachusetts Saturday, July 26, 2008 Boston, Massachusetts
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
Micro Environment and Bone Biology S t i Systemic • 1GF1 Osteoblasts • Osteoblasts… Local • Cells • Cells • Matrix • Blood Vessels…
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
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
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
Bisphosphonates
Primary Therapy for myeloma bone
Primary Therapy for myeloma bone
disease to reduce skeletal related
events (SREs)
events (SREs)
Recommended as ongoing therapy
for all myeloma patients with bone
disease
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
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?
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
Stopping versus Reduced
Dose/ Schedule
Consider both renal/ ONJ issues
No data on Q2 or 3 months
Clinical trials needed
Clinical trials needed
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.
Current Bisphosphonates
Aredia Aredia 90 mg over 2-4 hrs. monthly Zometa Zometa4 mg over 15-45 minutes monthly
Questions:
I f i ti
Infusion times
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%
How frequent is osteonecrosis?
(Continued)
( )
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]
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
New Approaches to Enhance Osteoblast Activity and Heal Bones
Activity and Heal Bones
