Bone Scans in Myeloma Can Underestimate Bone Involvement

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(No Transcript)
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Overview

• Identify the diagnostic criteria for multiple
  myeloma
• Compare first second line therapies, using data
  from clinical trials
• Describe adjunctive supportive therapies

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Multiple Myeloma

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

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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
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Presenting Features

• Bone disease hypercalcemia
• Recurrent infections
• Anemia and fatigue
• Renal failure due to multiple causes
• Neuropathy
• Asymptomatic in a minority of the patients

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Signs Symptoms in 1027 Newly Diagnosed Myeloma
Patients
Kyle RA. Mayo Clin Proc 20037821-33
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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
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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

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Incidence of Chromosomal Abnormalities in MM

• n 1064 patients
• Chromosomal changes observed in 90 of patients

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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
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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

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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

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Serum Protein Electrophoresis
Monoclonal Protein in Myeloma
Normal
Kyle RA and Rajkumar SV. Cecil Textbook of
Medicine, 22nd Edition, 2004
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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
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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

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Malignant Plasma Cells in Marrow
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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.
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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.
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Bone Scans in Myeloma Can Underestimate Bone
Involvement
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Bone Cell Stimulation in Malignancy
Osteoclasts
Osteoblasts
Multiple myeloma
Osteolytic solid tumors including breast cancer
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• Initial Approach to Treatment

Clearly not a transplant candidate
Potential transplant candidate
Can include melphalan- based combinations
Non-alkylator based induction
Stem cell harvest
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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.
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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
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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
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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
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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
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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
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IFM 2005-01 Bortezomib/Dex vs VAD as Induction
Treatment in MM
N482Untreated 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
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Bortezomib/Dex vs VAD Response
Response to Induction
Response Post ASCT
Harousseau JL, et al. Ash 2007, abstract 450
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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
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Bortezomib-Thalidomide-Dex
vs. Thal-Dex
Response to Induction
Response Post ASCT
Cavo et al. Blood 2007 110(11)abstract 73
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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
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Lenalidomide/Bortezomib/Dex Response

• Best response n 42 evaluable pts
• CR/nCR 29
• VGPR 52
• PR 98

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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

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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
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Melphalan Prednisone

• Response rate 40
• Duration of response 18 month
• Overall survival 24-36 months
• Cycle is repeated every 4-6 weeks

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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.
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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.
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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
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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
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Salvage Therapy

• Thalidomide-Dexamethasone
• Lenalidomide-Dexamethasone
• Bortezomib /- Dexamethasone
• Pegylated-Liposomal Doxorubicin (PLD)- based
  regimens

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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

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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)

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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.
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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
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Grade 3-4 Toxicity Results MM-009 Trial
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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

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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

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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

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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
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Adverse Events APEX Trial
Plt 0.001
Richardson et al. N Engl J Med 20053522487-98
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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
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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

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Treatment of Bone Disease

• Bisphosphonates
• Surgical procedures
• Vertebroplasty
• Balloon Kyphoplasty
• Radiotherapy
• Treatment of myeloma

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ASCO Guidelines for TreatingBone 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.
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Pamidronate in Multiple Myeloma
21-month data. Berenson JR et al. J Clin Oncol.
199816593-602.
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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

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Renal Toxicity Pamidronate Zoledronic Acid
Adapted with permission from Berenson JR.
Oncologist. 20051052-62.
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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

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Anemia Treatment Goals

• Treat the underlying malignancy
• Decrease fatigue
• Decrease need for PRBC transfusions
• Treat the patient, not the number

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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

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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

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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

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