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 Lymphocytes/ Macrophages/ Hormones Hematopoietic Cells/ DNA/ RNA Chemicals Myeloma Cells Microbes Microenvironment Neuro Nor-adrenaline Bone osteoclasts/ osteoblasts/ matrix Other organs Liver/ lymphatic/ brain
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
Diagnosis of Bone Lesions X-ray: full skeletal survey CT scan or MRI Whole body CT/PET Bone density Bone turnover studies, e.g. NTX
Bone Disease Classification Based upon Focal Lesions on X-ray and/or MRI
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
Serial PET Shows Early Response X-ray January JAN APRIL JUNE M-protein MRI November T1 STIR January April
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 33 / 59 P<0.001 12-Month Estimate 17% 61% 0% 0 6 12 18 24 Months After Starting VAD * Walker, et al. 2005 ASH
Treatment for Bone Disease Treat the myeloma Chemotherapy Radiation Treat the bone Bisphosphonates Calcium/Vitamin D Supportive care Kyphoplasty
Radiotherapy May be useful in specific situations ti Pain control Spinal cord compression Prevent or treat pathologic fractures However, radiation damages normal marrow
Source: Fourney et al. J Neurosurg (Spine 1) 2003;98:21 30. Vertebroplasty
Balloon Kyphoplasty: A Minimally Invasive Fracture Reduction Procedure KyphX Introducer Tool Kit: Allows precise, minimally invasive access to the vertebral body. Provides working channel KyphX IBT inflation: Reduces the fracture. Compacts the bone. May elevate endplates KyphX IBT Removal: Leaves a defined cavity and trabecular dam that can be filled with an approved bone void filler of the physician ss choice
Balloon Kyphoplasty p y Case Study Patient: 61 YO Female Diagnosis: Multiple Myeloma Fracture Reduced: T11, L2, 1 ½ yrs old Courtesy of Kent Grewe, M.D., Portland, OR
Lieberman and Reinhardt Study Myeloma Patient Outcomes: Pain Improvement Visual Analog Scale Mean Self-Rated Pain (0 to 10 0) 7 6 5 4 3 2 1 0 6.18 pre-op p<0.0001 2.84 post-op op 0 = no pain Source: Lieberman and Reinhardt. Clinical Orthopaedics and Related Research. 2003;415(S):176-186.
Bisphosphonates Primary Therapy for myeloma bone disease to reduce skeletal related events (SREs) Recommended as ongoing therapy for all myeloma patients with bone disease
Bisphosphonate Use Guidelines Starting BP Duration of therapy Choice of BP Renal l issues Dental evaluation See both Mayo and IMWG Guidelines See both Mayo and IMWG Guidelines Mayo Clinic Proceedings, 82(4);516-522. April 2007
Starting Bisphosphonates Lesions on x-ray? Yes or No? Positive findings on MRI and/or CT PET? MRI: > 7 lesions and/or progression/ pain PET: high SUV; CT abnormal Reduced d bone mineral density? Urinary NTX increased?
Duration of Bisphosphonates Not indefinite Minimum 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
Stopping versus Reduced Dose/ Schedule Consider both renal/ ONJ issues No data on Q2 or 3 months Clinical trials needed
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
Current Bisphosphonates Aredia 90 mg over 2-4 hrs. monthly Zometa 4 mg over 15-45 minutes monthly Questions: Infusion times Long term duration/ schedule
Osteonecrosis of Jaw on Panorex
20% Time to Onset of Osteonecrosis in Myeloma Zometa vs Aredia 25% 36-Month Events / N Estimate Zometa 10 / 211 10% P =.002 Aredia 10 / 413 4% 15% Data censored at 36 months 10% 5% 0% 0 12 24 36 Months from start of Aredia or Zometa
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
New Approaches to Enhance Osteoblast Activity and Heal Bones Denosumab (Amgen) MIP 1 modulation DKK 1 protein inhibition VELCADE Cholesterol lowering statins, e.g. Lipitor Quadramet (Samarium)
Mechanism of Action for Denosumab
Overall Strategies Diagnose & monitor bone disease Take bisphosphonate therapy with good monitoring Exercise Get pain relief Avoid risky situations