Download - Audience Response Cases Donna M. Weber, MD Professor of Medicine, Department of Lymphoma/Myeloma
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Audience Response Cases
Donna M. Weber, MDProfessor of Medicine, Department of Lymphoma/Myeloma
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Case 1
• 59 yr old male
• 7/2012: Dyspnea, chest pain, pain between shoulders
• 8/2012: Cardiac work-up: Stent placement
• 9/2012: Pain continued: MRI spine: T7 compression, C5-6 and C3-4 encroachment on neural foramina
• 9/18/2012: Hospitalized for respiratory infection: Hgb 8.3 g/dL, creatinine 2.03, Ca++ 12.3 mg/dL,
albumin 1.8 g/dL, hydrated sent home
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Case 1
• Bone marrow 85% CD38, CD138, CD56, λ +, κ – PCT. Protein 12.4 g/dL, Albumin 3.0 g/dL, M-protein
5.7 g/dL: IgG λ, Bence Jones Protein 1250 mg/dayFree λ 2420 mg/L Free κ 14.6 mg/L Free κ: λ 0.01β2M 44.7 mg/L Alb 3.0g/dL: ISS stage III
• Bone survey: lytic lesions skull, ribs, T7 compression
• Hgb 10.9 g/dL, Plt 206 k/μL , WBC 7.9 k/μL, 3% plasma cells, BUN 53 creatinine 4.69, Ca++ 13.1 mg/dL, albumin 3.0 g/dL, uric acid 13.3
• Cytogenetics: t(4;14), del 13, del 1q
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Case 1 (Questions)
What would you do first?
2. Chemotherapy/Immunotherapy
3. Chemo/Immunotherapy + Dialysis
1. Dialysis
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High Cut Off Hemodialysis (HCO-HD)• 2005: 97 pts randomized to conventional therapy or conventional therapy w/ 5-7
plasma exchanges (stratified by dialysis) w/ no benefit in mortality, dialysis dependence, or GFR < 30 ml/min at 6 mos.
Clark et al: Ann Intern Med 143: 777-84, 2005
• 2010: 27 pts MM w/ HD dependence (CrCl < 15 ml/min) 19 pts had biopsy proven cast-nephropathy and received combination chemo and FLC removal by HCO-HD).
8 hrs/day x 5 days then 8 hrs q.o.d. x 12 days or more13/19 pts achieved sustained reduction FLC6 pts not achieving sustained reduction had chemo interrupted
Dialysis equally effective, difference due to FLC production ratesUninterrupted Baseline FLC: D12 FLC = 1%
Interrupted Baseline FLC: D12 FLC = 266%
14/19 became dialysis independent
Hutchison et al: Clin J Am Soc Nephrol 4: 745-54, 2009
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Case 1: Results With Therapy Initiation
Chemo held temporarily due to infection
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Case 1 (Questions)What would be the best induction therapy?
2. Lenalidomide and dexamethasone (once weekly)
3. Bortezomib and dexamethasone (day of and after B)
4. Bortezomib, melphalan and prednisone
5. Bortezomib, cyclophosphamide, dexamethasone
1. Thalidomide and dexamethasone (once weekly)
6. Bortezomib, lenalidomide, dexamethasone
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Criteria for Renal ResponseReversibility of Renal Failure
Renal ResponseSustained (lasting 2 months) improvement of creatinine clearance
Complete (CRrenal)Improvement of CrCl from < 50 ml/min to > 60 ml/min
Partial (PRrenal)Improvement of CrCl from < 15 ml/min to 30-59 ml/min
Minor (MRrenal)Improvement of CrCl from < 15 ml/min to 15-29 ml/min
OR15-29 ml/min to 30-59 ml/min
Dimopoulos et al, Clin Lymphoma Myeloma 2009:9:302-6
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Considerations for Induction Therapy Using Novel Agents in Patients with Renal Failure
Thalidomide Lenalidomide CarfilzomibConsideration Bortezomib
No Yes NoRenal metabolism No
No Possible Possible, AvoidableRenal Toxicity No
? ? ?Efficacy for Induction in Renal Failure
?
Hyperkalemia Cytopenias NoneAdditional Toxicity in Renal Patients
None
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CC I-B B-B
32 47 17
Parameter
n
29.2 26.9 20.6Med. CrCl (ml/min)
53 53 76 %CrCl < 30ml/min
% Renal Response59 79 94 > MRrenal
41 45 71 CRrenal47 51 82 > PRrenal p0.04
Roussou et al, Leukemia Research 2010:9: 1395-1397
Reversibility of Renal Failure Newly Diagnosed
1.8 1.6 0.69Med. Mos to Response p0.007
9 19.1 23.5%Renal Response w/o MM Response
CC = Combination Chemotherapy (VAD/VAD-like, Melphalan + HD Dex)I-B = IMiD-Based Thalidomide or lenalidomide + HD Dex +/- cyclophosphamide/melphalan
B-B = Bortezomib-based + HD Dex
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Lenalidomide
Lenalidomide Dose (mg)
Creatinine Clearance (m/min)
10 mg/Day> 30 - 50
5 mg/D after dialysisOn dialysis
15 mg q48 hours
< 30, NOT on dialysis
Celgene Product Information available at www. Revlimid.com/pdf/revlimid/pl.pdf
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Case 2• 36 yr old female
• 2/2010: Rt Chest wall pain during pregnancy Did not resolve after pregnancy
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• 3/2010: Rt. Rib resection: + CD38 +CD56 +Kappa Plasma cells
• 3/2010: Preoperative creatinine 0.8 mg/dL Postoperatively 5.1 mg/dL Dexamethasone 40 mg x 1 Transfer to MD Anderson Cancer Center
Case 2
• Hgb 7.5 g/dL, Plt 611 k/μL , WBC 10.2 k/μL, BUN 48 creatinine 4.1mg/dL, Ca++ 10 mg/dL, albumin 4.1 g/dL, uric acid 7.5, potassium 5.5 meq/L, phosphorus 5.5 mg/dL
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Case 2
• Bone survey: Rib lesion + Small lytic lesions bilateral femora + humeri
• Bone marrow 50% CD38, CD138, CD56, λ -, κ + PCT. Protein 7.3 g/dL, Albumin 4.3 g/dL, M-protein 0.2 g/dL, IgG K, Bence Jones Protein 4925 mg Kappa/dFree λ 10.4 mg/L Free κ 15,300 mg/L Free κ: λ 1471.5β2M 9.9 mg/L Alb 4.3g/dL: ISS stage III
• Cytogenetics: Deletion 13 and Deletion 17p13.1
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Case 2 What Would Be the Best Induction Therapy?
1. Lenalidomide and dexamethasone (once weekly)
2. Bortezomib and dexamethasone (day of and after B)
3. Bortezomib, melphalan and dexamethasone
4. Bortezomib, cyclophosphamide, dexamethasone
5. Bortezomib, lenalidomide, dexamethasone
6. Bortezomib, doxorubicin, dexamethasone (PAD)
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Case 2
Would you proceed with myeloablative therapy and stem cell transplant after successful
induction?
2. No
1. Yes
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Case 2
After successful induction therapy +/-myeloablative therapy and autologous stem cell transplant what maintenance therapy (if any)
would you use?
2. Lenalidomide
1. None
3. Bortezomib
4. Other
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Avet-Loiseau H et al. JCO 2010;28:4630-4634©2010 by American Society of Clinical Oncology
Bortezomib Induction: Impact in del 17p
Deletion 17p (n = 54) No deletion 17p (n = 453)
Bortezomib + Dex x 4 cycles
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ARM A ARM BParameter
Med. PFS (mos)12 22 (26.2) Deletion 17p
17 69 Deletion 17p8 62 Deletion 17p in >60%PC
3 yr OS (%)
Sonneveld et al, J Clin Oncol 30: 2946-55, 2012
Bortezomib Induction & Maintenance: Hovon-65/GMMG-HD4
ARM A: VAD + CyAD + HDM/AuSCT + Thal 50 mg po qD x 2yrs
ARM B: P(Bortezomib)AD + CyAD + HDM/AuSCT + Bortezomib 1.3 mg/M2 q 14d x 2yrs
Neben et al, Blood 119 (4): 940-8), 2012
80 85 No Deletion 17p
p.01(.02)
p.028
p.48p.037
12 25.7 Deletion 17p in >60%PC p.017
24 >54 Deletion 17pMed. OS (mos)
p.003
NS NS No Deletion 17p
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Cycle 1Bortezomib, Cyclophosphamide, Dexamethasone Days 1-4, 9-12, 17-20
Cycles 2-4Bortezomib, Cyclophosphamide, Dexamethasone D1,8,15,22
High-Dose Melphalan + AuSCT
Bortezomib Maintenance q2wks
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Bortezomib, lenalidomide, Dexamethasone
HD Melphalan + AuSCT
Bortezomib, lenalidomide, Dexamethasone
HyperCVAD + bortezomib
VDT-PACE
lenalidomide Thalidomide, Dexamethasone
Mandibular soft tissue mass despite improved protein
Bortezomib, Dexamethasone + XRT
Pt decided steroid + XRT only + supportive care
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Case 3• 72 yr old male
• 12/2006: Rib pain
• 2/2007: Sharp burning pain from Rt hip radiating to leg
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Case 3
• Bone marrow 30% +CD38, +CD138, -CD56, λ -, κ + PCT. Protein 7.5 g/dL, Albumin 3.0 g/dL, M-protein 2.8
g/dL: IgG λ, Bence Jones Protein 0 mg/dayFree λ 4.39 mg/L Free κ 8.27 mg/L Free κ: λ 1.884β2M 1.8 mg/L Alb 3.0g/dL: ISS stage II
• Bone survey: T12 lesion + osteoporosis
• Hgb 12 g/dL, BUN 53 creatinine 1.4mg/dL, Ca++ 9.1 mg/dL
• Radiation 20 Gy Thalidomide 200 mg daily + Dexamethasone WeeklySecond opinion at MD Anderson
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Case 3
HDM + AuSCT
Thalidomide + Dexamethasone
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• 4/2007-7/2007: Thalidomide + DexamethasoneDeveloped Grade 2 neuropathy during induction.
Case 3
• 7/2007: HDM + AuSCT: Worsening of neuropathy. VGPR: No Maintenance; neuropathy persists, but
improved to grade 2 without pain.
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Case 3What would you use for Relapse?
Thalidomide + Dexamethasone
HDM + AuSCT
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Case 3What would you use for Relapse?
2. Lenalidomide and dexamethasone (once weekly)
3. Bortezomib and dexamethasone (day of and after B)
4. Lenalidomide-based 3 drug combination
1. Thalidomide and dexamethasone (once weekly)
4. Bortezomib-based 3 drug combination
5. Carfilzomib
5. Pomalidomide + Dexamethasone
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Study PX171-004: Phase 2 Trial of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma
Cohort 120 mg/m2
Cohort 2†
20 mg/m2 cycle 1 Escalation to 27 mg/m2 in all subsequent cycles
Carfilzomib IVQD x 2 for 3 weeks (28-day cycle for up to 12 cycles
BOR-treated*(n=35)
BOR-naïve (n=59)BOR-naïve (n=59)
BOR-naïve (n=70)BOR-naïve (n=70)
Study Population (N=165)• Measurable disease• Responsive to
≥1 prior therapy• Relapsed and/or refractory MM
following 1–3 prior treatment regimens
• ECOG PS 0–2
Vij et al, Blood: 119(24):5661-70, 2012
ORR (CR+VGPR+PR)
42.4% 52.2% 47.6%
CBR (ORR+MR) 59.3% 64.2% 61.9%
Cohort 1 Cohort 2 TotalBortezomib Naive
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Cohort 120 mg/m2
Cohort 2†
20 mg/m2 cycle 1 Escalation to 27 mg/m2 in all subsequent cycles
Study PX171-004: Phase 2 Trial of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma
Duration of Clinical Benefit Resp. (med. Months)
11.5 NR
Time to Clinical Benefit Response (med. months)
1.9 0.5
Time to Response (med. months)
1.0 0.5
Duration of Remission (med. Months)
13.1 NR
Median TTP (med. Months)
8.3 NR
Vij et al, Blood: 119(24):5661-70, 2012
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History of Neuropathy at Baseline 69.8%
Treatment Emergent Peripheral Neuropathy (all but 1pt Gr I or II in both studies) 17.1%
Median QOL FACT-GOG No Change
Grade 1 or 2 Neuropathy at Study Entry 53%
Phase 2 Trials of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma
15.2%
87%
PX-171-004 Bortezomib Naive
PX-171-003-A0 Bortezomib Exposed
Vij et al, Blood: 119(24):5661-70, 2012
Jagannath et al,, Clinical lymphoma, myeloma & leukemia. 12(5):310-8, 2012
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Grade 1 Neuropathy 51%
0
0
Grade 2 Neuropathy 29%
Phase 1 Trial of Pomalidomidein Relapsed and/or Refractory Multiple Myeloma
Pomalidomide 2 mg po daily
Pomalidomide 4 mg po daily
Lacy et al, Blood 118(11): 2970-2975, 2011
Grade 3 Neuropathy
Grade 4 Neuropathy
69%
3%
0
17%
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Low Neuropathic Novel Agents
Elotuzumab
Doxorubicin/ Liposomal Doxorubicin*
Pomalidomide?
Bendamustine
Low Neuropathic Conventional Agents
Steroids
Carfilzomib* Cyclophosphamide Dexamethasone
Lenalidomide Melphalan Prednisone
Potential Low Neuropathic Complications
* Combination of carfilzomib with anthracyclines has not been reported; because of potential cardiac effects with carfilzomib this combination should be avoided based on lack of data
Use of these combinations outside a clinical trial should be limited to those with previously reported results.
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Case 3This Patient: Carfilzomib at Relapse
Thalidomide + Dexamethasone
HDM + AuSCT
Carfilzomib
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Case 4
• 57 yr old female
• 7/2012: Right Hip X-rays show lytic lesion right femur
• Cytogenetics 46XX, FISH negative for high-risk
• Hgb 9.8 g/dL, Plt 251 k/μL , WBC 6.8 k/μL, creatinine 0.7 mg/dL, Ca++ 9.1 mg/dL, albumin 3.0 M-protein 5.3 g/dL, IgA λ, Bence Jones Protein 98 mg/day, free λ 65 mg/L free κ 1.6 mg/L free κ: λ 0.01, β2M 7.2 mg/L Alb 3.0g/dL: ISS stage III
• Bone survey: lytic lesions skull, ribs, femur
• Bone marrow 17% CD38, CD138, CD56, λ +, κ – PC
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Case 4
VRD
Myeloablative therapy + AuSCTM-P
rote
in (g
/dL)
Months1 2 3 4 5 6 7
1
2
3
4
5
6
Lenalidomide 10 mg Maint.
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Case 4M
-Pro
tein
(g/d
L)
Months1 2 3 4 5 6 7
1
2
3
4
5
6 VRD
Myeloablative therapy + AuSCT
Lenalidomide 10 mg
Maint.
M-Protein 1.6g/dL BM: 56% plasma
cells Cytogenetics: t(4;14)
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Case 4: What would you use for relapse?
2. Bortezomib-based 3-drug regimen
3. Myeloablative therapy and Autologous SCT
4. Allogeneic SCT
5. Clinical Trial
1. Lenalidomide-based 3-drug regimen
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Bortezomib + High – Dose Melphalan (HDM) for Early Transplant Relapse and High-Risk Myeloma
Wong Doo et al. Leukemia & Lymnphoma 2012; online
HDM + BORTEZOMIBStem Cell Harvest: Cyclophosphamide + G-CSF
(usually collected before transplant 1)Day -2: Melphalan 200mg/M2 IV
(RI:Melphalan 140mg/M2 IV)Day -1: Bortezomib 1.3 – 1.6 mg/M2 IV)Day 0: Stem cells infused
Day 1 + Day 4: 2 pts Bortezomib 1.3 – 1.6 mg/M2 IV
Day 2: 12 pts: Bortezomib 1.3 – 1.6 mg/M2 IV
HDMStem Cell Harvest: Cyclophosphamide + G-CSF
(usually collected before transplant 1)Day -2: Melphalan 200mg/M2 IV
(RI:Melphalan 140mg/M2 IV)Day 0: Stem cells infused
N=16 PTS: Relapsed or Refractory 2nd Salvage
N=16 PTS: Historical Control Relapsed or refractory
> MR
VGPRMed. PFSMed. OSMed. OS Early relapse
81.3%
37.5%7 mos
28 mos14.5 mos
p 0.22
p 0.22
p 0.299
21 mos p 0.11
8 mos p 0.522
87.5%
12.5%7 mos
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Allogeneic Stem Cell Transplant
PFS or EFS BenefitOverall Survival
IFM: Garban et al Blood 2006
(High-Risk del 13, B2M > 3)
No No
EFS Benefit Yes
OS Benefit
Auto – RIC Allo SCT Vs.
Auto-Auto
Italian: Bruno et al Blood 2010 (No risk stratification)
No 3yr PFS Benefit
NoBMT CTN: Krishnan et al, Lancet Oncol
(High-Risk del 13, B2M > 3)
5Yr YesBjorkstrand et al J Clin Oncol, 2011 (High-Risk del 13, B2M > 3)
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Allogenic hematopoietic stem cell transplantation with reduced‐ ‐intensity conditioning in patients with refractory and recurrent
multiple myeloma
Shimoni et al, Cancer 116 (15): 3621-3630, 5 MAY 2010 DOI: 10.1002/cncr.25228
SCT from a female donor to a male
achievement of a CR. occurrence of chronic GVHD
Chemoresistance at the time of SCT
Bad Risk
Good Risk
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Myeloma Section
Robert Orlowski, MDRaymond Alexanian, MD
Jatin Shah, MDSheeba Thomas, MDMichael Wang, MD
Department of Blood and Marrow
Transplantation
Richard Champlin , MDMuzaffar Qazilbash, MD
Simrit Parmar, MDUday Popat, MDNina Shah, MD
Thank you to the nurses, research staff and most importantly, the patients!