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Bone Scans in Myeloma Can Underestimate Bone Involvement

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Bone Scans in Myeloma Can Underestimate Bone Involvement Bone Cell Stimulation in Malignancy Multiple myeloma Osteolytic solid tumors including breast cancer ... – PowerPoint PPT presentation

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Title: Bone Scans in Myeloma Can Underestimate Bone Involvement


1
(No Transcript)
2
Overview
  • Identify the diagnostic criteria for multiple
    myeloma
  • Compare first second line therapies, using data
    from clinical trials
  • Describe adjunctive supportive therapies

3
Multiple Myeloma
  • Plasma cell malignancy
  • Second most common hematologic malignancy
  • Characterized by monoclonal immunoglobulin
  • MGUS
  • Smoldering MM
  • Amyloidosis

4
MM Epidemiology
  • 19,900 new cases per yr, 50,000 total cases, 2
    cancer deaths in U.S.
  • Higher incidence in African Americans, Pacific
    Islanders
  • Median age 71 yrs
  • Exposure to radiation, petroleum products,
    pesticides Agent Orange

Greenlee RT. CA Cancer J Clin 20015115.
Bergsagel DE. Blood 1999941174
5
Presenting Features
  • Bone disease hypercalcemia
  • Recurrent infections
  • Anemia and fatigue
  • Renal failure due to multiple causes
  • Neuropathy
  • Asymptomatic in a minority of the patients

6
Signs Symptoms in 1027 Newly Diagnosed Myeloma
Patients
Kyle RA. Mayo Clin Proc 20037821-33
7
Criteria for Diagnosis
  • Active MM
  • ?10 PC
  • M spike
  • AND
  • MGUS
  • lt3 g M spike
  • lt10 PC
  • AND
  • Smoldering MM
  • ?3 g M spike
  • OR ?10 PC

Anemia, bone lesions, high calcium or abnormal
kidney function
No anemia, bone lesions normal calcium and
kidney function
Kyle RA. N Engl J Med 2002 346 564
8
Myeloma Prognostic Factors
  • Serum ?2 microglobulin
  • Cytogenetics - del13 or 13q-, t(414), 17p-,
    hypodiploid
  • C-reactive protein
  • LDH
  • Plasmablastic morphology
  • Peripheral blood plasma cells
  • Gene expression profile

9
Incidence of Chromosomal Abnormalities in MM
  • n 1064 patients
  • Chromosomal changes observed in 90 of patients

10
International Staging System (ISS) for
Symptomatic Myeloma
ß2m lt 3.5 mg/L and albumin lt 3.5 g/dL or ß2m
3.5 - lt 5.5 mg/L, any albumin
Greipp et al. J Clin Oncol 2005 23 3412-20
11
Initial Diagnostic Evaluation
  • Hx and physical examination
  • Blood work-up
  • CBC with diff and platelet counts
  • BUN, Creatinine
  • Calcium, albumin
  • Serum protein electrophoresis (SPEP) and
    immunofixation
  • Quantitative immunoglobulins
  • Serum free lyte chains
  • ?2-microglobulin

12
Initial Diagnostic Evaluation
  • Urine
  • Bence Jones quantitation
  • 24-hr protein electrophoresis (UPEP) and
    immunofixation
  • Other
  • Skeletal survey
  • Unilateral bone marrow aspirate and biopsy for
    histology, cytogenetics and FISH

13
Serum Protein Electrophoresis
Monoclonal Protein in Myeloma
Normal
Kyle RA and Rajkumar SV. Cecil Textbook of
Medicine, 22nd Edition, 2004
14
Immunofixation to Determine Type of Monoclonal
Protein
IgG kappa M protein
Lambda Light Chains
Kyle RA and Rajkumar SV. Cecil Textbook of
Medicine, 22nd Edition, 2004
15
Distribution of Monoclonal Proteins
  • M protein found in serum or urine or both at time
    of diagnosis 97
  • Serum M spike by protein electrophoresis 80
  • Abnormal serum immunofixation 93
  • Abnormal urine immunofixation 75
  • Non-secretory myeloma 3

16
Malignant Plasma Cells in Marrow
17
Bone Involvement in Different Tumor Types
1. National Cancer Institute. Available at
http//seer.cancer.gov/csr/1973-1999/prevalence.pd
f. Accessed 1/27/2005. 2. Coleman RE.
Oncologist. 20049(suppl 4)14-27. 3. Kyle RA et
al. Mayo Clin Proc. 200378 21-33. 4. Smith W
et al. Semin Oncol. 200431(suppl 4)11-15. 5.
Lipton A. J Support Oncol. 20042205-213. 6. Tu
S-M, Lin S-H. Cancer Treat Res. 200411823-46.
7. Palumbo A et al. Blood. 20041043052-3057.
18
Bone Imaging in MM
  • Skeletal radiography is the primary diagnostic
    test to detect destructive bony lesions in
    multiple myeloma
  • MRI is useful in assessing whether spinal
    compression fractures are due to a focal mass or
    from osteopenia due to increased osteolysis
  • PET scans can be used to detect soft tissue or
    bone metastases

Angtuaco EJ et al. Radiology. 200423111-23.
19
Bone Scans in Myeloma Can Underestimate Bone
Involvement
20
Bone Cell Stimulation in Malignancy
Osteoclasts
Osteoblasts
Multiple myeloma
Osteolytic solid tumors including breast cancer
21
  • Initial Approach to Treatment

Clearly not a transplant candidate
Potential transplant candidate
Can include melphalan- based combinations
Non-alkylator based induction
Stem cell harvest
22
Thalidomide in Myeloma
  • 63 response when combined with Dex versus 41 to
    Dex as initial therapy (FDA approved May 2006)
  • Does not compromise subsequent PBSC mobilization
    and collection


Barlogie et al. Blood 200198 492.
Anagnostopoulos et al. Brit J Hematol
2003121768. Rajkumar et al. J Clin Oncol 2006
24431-6. Palumbo et al. Blood 104(Suppl) 63a,
2004.
23
SWOG S0232 Dex vs Lenalidomide/Dex in
Newly-diagnosed MM
RANDOMI ZAT ION
Dex 40 mg/d po, days 1-4, 9-12, 17-20
Lenalidomide 25 mg/day po, days 121 Dex 40 mg/d
po, days 1-4, 9-12, 17-20
Zonder et al Abstract LBA8025
24
Lenalidomide/Dex (LD) vs Dex (D) Interim
Analysis of Response, PFS OS
LD (n61 evaluable for response) D (n72
evaluable for response)
Response,
P0.001
Zonder JA et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
25
EA403 Lenalidomide with High vs. Low-dose Dex in
Newly-diagnosed MM
RANDOMI ZAT ION
High-dose dex
Lenalidomide 25 mg/day po, days 1-21 Dex 40 mg/d
po, days 1-4, 9-12, 17-20
Low-dose dex
Lenalidomide 25 mg/day po, days 1-21 Dex 40 mg/d
po, once weekly
Rajkumar et al. Abstract 74. ASH Annual Meeting
December 8-11, 2007, Atlanta, GA
26
Lenalidomide with High vs. Low-dose Dex in
Newly-diagnosed MM Serious AEs ( 3)
LLenalidomide DStandard-dose dexamethasone
dLow-dose dexamethasone Fishers exact
Rajkumar SV et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
27
Lenalidomide with High vs. Low-dose Dex Overall
Survival
Rev/low dose dex
Rev/high dose dex
Probability
Time in months
Rajkumar et al. Blood 2007110(11) abstract 74
28
IFM 2005-01 Bortezomib/Dex vs VAD as Induction
Treatment in MM
N482 Untreated MM age 65 yr
VAD 4
Bort/Dex 4
Induction
Melphalan 200 mg/m2 ASCT
Melphalan 200 mg/m2 ASCT
Transplant 1
Second ASCT or RIC allo if ltVGPR
Harousseau J-L et al. Presented at 49th ASH
Annual Meeting December 811, 2007 Atlanta, GA
29
Bortezomib/Dex vs VAD Response
Response to Induction
Response Post ASCT
Harousseau JL, et al. Ash 2007, abstract 450
30
Bortezomib-Thalidomide-Dex vs. Thal-Dex in Newly
Diagnosed MM
Bortezomib 1.3mg/m2 D 1, 4, 8,
11 Thalidomide 200mg/day Dex 40mg/d PO
D 1-2, 4-5, 8-9, 11-12 (n129)
Newly diagnosed MM (n256)
PBSC harvest ASCT x 2 with MEL-200
Thalidomide 200mg/day Dex 40mg/day PO D 1-4,
8-12 (n127)
Patients randomized to LMWH (40mg/day), ASA
(100mg/day) or warfarin (1.25mg/day)
Cavo et al. Blood 2007 110(11)abstract 73
31
Bortezomib-Thalidomide-Dex
vs. Thal-Dex
Response to Induction
Response Post ASCT
Cavo et al. Blood 2007 110(11)abstract 73
32
Lenalidomide/Bortezomib/Dex for Patients with
Newly Diagnosed MM
Decks, 40 mg/day D 1, 2, 4, 5, 8, 9, 11 and 12
20 mg, cycles 58 Amended to 20mg/10mg cycles
1-4/5-8 based on safety data
Richardson et al. Blood 2007 110(11)abstract
187
33
Lenalidomide/Bortezomib/Dex Response
  • Best response n 42 evaluable pts
  • CR/nCR 29
  • VGPR 52
  • PR 98

34
Initial Therapy Considerations
  • Ensure patient does not have smoldering
    (asymptomatic) MM
  • Approach to therapy is based on whether a pt is a
    transplant candidate
  • Consider clinical trials if available
  • Improving complete response rates is a key goal
    of current trials

35
Therapy Options NonTransplant Candidate
  • Melphalan Prednisone (MP)
  • Melphalan Prednisone Thalidomide (MPT)
  • Dexamethasone (Dex)
  • Thalidomide Dexamethasone (Thal/Dex)
  • Lenolidomide Dexamethasone (Rev/Dex)
  • Bortezomib /- Dexamethasone (Vel/Dex)

NCCN Practice Guideline-v.2.2008
36
Melphalan Prednisone
  • Response rate 40
  • Duration of response 18 month
  • Overall survival 24-36 months
  • Cycle is repeated every 4-6 weeks

37
MP vs. MPT Randomized Studies
  • Study Age (yrs) Regimen
  • Palumbo et al gt 65 MP vs MPT
  • Facon et al gt 65 MP vs MPT vs Mel100x2
  • Hulin et al gt 75 MP vs MPT

Palumbo et al. Lancet 2006 367825-41. Palumbo
et al. Blood 2008 May 27. Facon et al. Lancet
20073701209-18. Hulin et al. Blood 200711083
Abstract 75.
38
Summary of MP-Thalidomide Trials
Palumbo et al. Lancet 2006 367825-41. Palumbo
et al. Blood 2008 May 27. Facon et al. Lancet
20073701209-18. Hulin et al. Blood 200711083
Abstract 75.
39
VMP vs MP in Previously Untreated MM Patients
(VISTA)
R A N D O M I Z E
MP
9 x 6-week cycles (54 weeks) in both arms
VMP
  • 65 yrs or lt65 yrs and not transplant-eligible
    KPS 60
  • Primary Endpoint TTP
  • Secondary Endpoints CR, ORR, TRR, DOR, PFS, TNT,
    OS, QoL

San Miguel, et al. Blood. 200711078a, abstract
76
40
VMP vs MP Response to Treatment
ORRobjective response rates CRcomplete
response, immunofixation-negative
measured in serum and/or urine by central
laboratory
San Miguel, et al. Blood. 200711078a, abstract
76. Bladé et al. Br J Haematol 19981021115
41
Salvage Therapy
  • Thalidomide-Dexamethasone
  • Lenalidomide-Dexamethasone
  • Bortezomib /- Dexamethasone
  • Pegylated-Liposomal Doxorubicin (PLD)- based
    regimens

42
Thalidomide in Relapse MM
  • PR in 30 relapsed and/or refractory MM
  • 47 response when combined with Dex
  • No advantage of any dose gt200 mg/day
  • Toxicities sedation, constipation, peripheral
    neuropathies and VTE

43
Lenalidomide (Revlimid)
  • More potent immunomodulator than thalidomide
  • SE myelosuppression
  • Only available through RevAssist Distribution
    Program
  • Monitor CBCs weekly for first 8 wks
  • Increase risk of VTE (DVT and PE)

44
2 Phase Trials Lenalidomide/Dex in Relapsed or
Refractory MM
  • North American study MM-009
  • European study MM-010
  • Dose 25mg days 1-21
  • Dex 40mg days 1-4, 9-12, 17-20 x 4 courses
  • Primary endpoint TTP
  • Secondary endpoints OS, RR, safety, first SRE, PS

Dimopoulos et al. N Engl J Med 2007 3572123-32.
Weber et al. N Engl J Med 2007 3572133-42.
45
Response Dex vs. Len-Dex
80
(gt50)
PR
61.2
60
59
CR (gt20)
Response Rate ()
plt0.001
40
34.7
22.8
24
20
44
18.7
20.6
26.5
15
4.1
3.4
0
Len/dex
Len/dex
Dex
Dex
009
010
009
010
Weber D. ASCO 2005 Dimopoulos Blood
2005106abstract 6
46
Grade 3-4 Toxicity Results MM-009 Trial
47
VTE Prevention with Immunomodulating Agents
  • As single agents minimal risk prophylaxis may
    be considered
  • Concomitant chemotherapy especially dex,
    anthracyclines ESAs, increase risk as much as
    58
  • Low-dose warfarin not protective
  • ASA adequate in lower risk patients receiving
    dex an immunomodulator
  • LMWH (enoxaparin 40mg QD), full dose warfarin,
    are recommended for patients at high risk for VTE

48
Bortezomib (Velcade)
  • Reversible inhibitor of chymotrypsin-like
    activity of 26-S proteasome
  • Prevents proteolysis of ubiquitinated proteins
    can lead to apoptosis of tumor cells
  • Dosing 1.3 mg/m2 IV bolus d 1, 4, 8, 11 (21-d
    treatment cycle) for a maximum of 8 cycles
  • FDA approved for MM that has relapsed after 1
    prior standard therapies

49
Bortezomib vs. HDD in Relapse MM Apex Trial
  • International trial, 93 sites
  • Pts had to receive 1-3 prior therapies
  • Dex-refractory excluded
  • Induction therapy
  • 1.3mg/m2 IV days day 1, 4, 8, 11 x eight 3-wk
    cycles vs Dex 40mg PO 1-4, 9-12, 17-20 x four
    5-wk cycles
  • Maintenance therapy
  • 1.3mg/m2 IV days 1, 8, 15, 22 x three 5-wk cycles
    vs Dex 40mg PO day 1-4 x five 5-wk cycles

50
Results APEX Trial
TTP Times to Progression CR (IF-) Complete
response, immunofixation negative PR (combined
complete and partial response rates)
Richardson et al. N Engl J Med 20053522487-98
51
Adverse Events APEX Trial
Plt 0.001
Richardson et al. N Engl J Med 20053522487-98
52
Pegylated Liposomal Doxorubicin Bortezomib
  • Combination
  • Significant increase in TTP
  • 45 risk reduction of recurrence
  • No significant change in ORR
  • Increase in grade III-IV toxicities seen in
    combination group (64 vs. 80) mostly due to
    myelosuppression
  • High PLD discontinuation rate secondary to AE
    (36)

Orlowski et al. J Clin Oncol. 2007
253892-3901
53
Treatment Options-Relapsed Patient
  • Since no therapy is curative, all options need to
    be tried sequentially
  • No good data on optimum sequence or regimen
  • All patients should be encouraged to participate
    in ongoing clinical trials
  • Cumulative toxicities from prior therapies may
    influence decision

54
Treatment of Bone Disease
  • Bisphosphonates
  • Surgical procedures
  • Vertebroplasty
  • Balloon Kyphoplasty
  • Radiotherapy
  • Treatment of myeloma

55
ASCO Guidelines for Treating Bone Loss in
Multiple Myeloma
MM patients with lytic disease or osteopenia on
plain radiographs or imaging studies
Intravenous pamidronate 90 mg deliver over at
least 2 hrs or zoledronic acid 4 mg over 15
minutes every 3 to 4 weeks.
Continue therapy for 2 yrs consider stopping in
patients w/ responsive or stable disease further
use at physicians discretion
Kyle RA et al. J Clin Oncol. 2007252464-72.
56
Pamidronate in Multiple Myeloma
21-month data. Berenson JR et al. J Clin Oncol.
199816593-602.
57
Issues with BP Therapy
  • Renal toxicity
  • Osteonecrosis of the jaw
  • Decreases skeletal events by 50 patients still
    progress but at a slower rate
  • No clear anti-tumor activity

58
Renal Toxicity Pamidronate Zoledronic Acid
Adapted with permission from Berenson JR.
Oncologist. 20051052-62.
59
Osteonecrosis of the Jaw
  • Features of Suspected ONJ
  • Exposed bone in maxillofacial area associated
    with dental surgery or occurs spontaneously, with
    no evidence of healing
  • Working Diagnosis of ONJ
  • No evidence of healing after 8 weeks of
    appropriate dental care
  • No evidence of metastatic disease in the jaw or
    osteoradionecrosis

60
Anemia Treatment Goals
  • Treat the underlying malignancy
  • Decrease fatigue
  • Decrease need for PRBC transfusions
  • Treat the patient, not the number

61
2007 ASCO Practice Guidelines for ESA
  • General
  • Review peripheral smear consider iron, folate,
    and B12 deficiency as potential causes for
    anemia, assess for occult blood loss.
  • Comparative effectiveness
  • Agents are considered equivalent in terms of
    safety and efficacy
  • No reason to believe that a patient who fails to
    respond to one ESA will have a response to a
    different ESA

62
Myeloma Features Unique to VA Patient Population
  • Agent Orange and radiation exposure
  • Minority population
  • Older patients
  • Co-morbidities
  • Larger number unable to undergo transplantation
  • Social issues nursing home and rehab facilities

63
Myeloma Initiative at VA (MIVA)
  • Investigator-driven effort for multi-VA clinical
    research
  • Patients get access to the most advanced therapy
  • Provides proof of efficacy of therapy
  • Allows VA to participate in new drug development
  • Patient education program
  • Tablet PCs
  • Provider education program

64
VANTS Call
  • July 15, 2008, 2 pm ET
  • August 26, 2008, 2 pm ET
  • 1-800-767-1750
  • Access code 86360
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