1. Audience Response Cases
Donna M. Weber, MD
Professor of Medicine, Department of Lymphoma/Myeloma

2. 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

3. Case 1
• Bone marrow 85% CD38, CD138, CD56, λ +, κ – PC
T. Protein 12.4 g/dL, Albumin 3.0 g/dL, M-protein 5.7
g/dL: IgG λ, Bence Jones Protein 1250 mg/day
Free λ 2420 mg/L Free κ 14.6 mg/L Free κ: λ 0.01
β2M 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

4. Case 1 (Questions)
What would you do first?
2. Chemotherapy/Immunotherapy
3. Chemo/Immunotherapy + Dialysis
1. Dialysis

5. 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 more
13/19 pts achieved sustained reduction FLC
6 pts not achieving sustained reduction had chemo interrupted
Dialysis equally effective, difference due to FLC production rates
Uninterrupted 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

6. Case 1: Results With Therapy Initiation
Chemo held
temporarily due to
infection

7. 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

8. Criteria for Renal Response
Reversibility of Renal Failure
Renal Response
Sustained (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
OR
15-29 ml/min to 30-59 ml/min
Dimopoulos et al, Clin Lymphoma Myeloma 2009:9:302-6

9. Considerations for Induction Therapy Using
Novel Agents in Patients with Renal Failure
Thalidomide Lenalidomide CarfilzomibConsideration Bortezomib
No Yes No
Renal
metabolism
No
No Possible
Possible, Avo
idable
Renal Toxicity No
? ? ?
Efficacy for
Induction in
Renal Failure
?
Hyperkalemia Cytopenias None
Additional
Toxicity in
Renal Patients
None

10. 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 Response
59 79 94> MRrenal
41 45 71CRrenal
47 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

11. Lenalidomide
Lenalidomide
Dose (mg)
Creatinine Clearance
(m/min)
10 mg/Day> 30 - 50
5 mg/D
after dialysis
On dialysis
15 mg q48
hours
< 30, NOT on dialysis
Celgene Product Information available at www. Revlimid.com/pdf/revlimid/pl.pdf

12. Case 2
• 36 yr old female
• 2/2010: Rt Chest wall pain during pregnancy
Did not resolve after pregnancy

13. • 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

14. Case 2
• Bone survey: Rib lesion + Small lytic lesions bilateral
femora + humeri
• Bone marrow 50% CD38, CD138, CD56, λ -, κ + PC
T. Protein 7.3 g/dL, Albumin 4.3 g/dL, M-protein
0.2 g/dL, IgG K, Bence Jones Protein 4925 mg Kappa/d
Free λ 10.4 mg/L Free κ 15,300 mg/L Free κ: λ 1471.5
β2M 9.9 mg/L Alb 4.3g/dL: ISS stage III
• Cytogenetics: Deletion 13 and Deletion 17p13.1

15. 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)

16. Case 2
Would you proceed with myeloablative therapy
and stem cell transplant after successful
induction?
2. No
1. Yes

17. 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

18. 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

19. ARM A ARM BParameter
Med. PFS (mos)
12 22 (26.2)Deletion 17p
17 69Deletion 17p
8 62Deletion 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 85No Deletion 17p
p.01(.02)
p.028
p.48
p.037
12 25.7Deletion 17p in >60%PC p.017
24 >54Deletion 17p
Med. OS (mos)
p.003
NS NSNo Deletion 17p

20. Cycle 1
Bortezomib, Cyclopho
sphamide, Dexametha
sone Days 1-4, 9-
12, 17-20
Cycles 2-4
Bortezomib, Cyclophospha
mide, Dexamethasone
D1,8,15,22
High-Dose Melphalan
+ AuSCT
Bortezomib Maintenance q2wks

21. Bortezomib, lenalidom
ide, Dexamethasone
HD Melphalan +
AuSCT
Bortezomib, lenalidom
ide, Dexamethasone
HyperCVAD + bortezomib
VDT-PACE
lenalidomide
Thalidomide, Dexamet
hasone
Mandibular
soft tissue
mass despite
improved
protein
Bortezomib, Dexamet
hasone + XRT
Pt decided
steroid +
XRT only +
supportive
care

22. Case 3
• 72 yr old male
• 12/2006: Rib pain
• 2/2007: Sharp burning pain from Rt hip radiating to leg

23. Case 3
• Bone marrow 30% +CD38, +CD138, -CD56, λ -, κ + PC
T. Protein 7.5 g/dL, Albumin 3.0 g/dL, M-protein 2.8
g/dL: IgG λ, Bence Jones Protein 0 mg/day
Free λ 4.39 mg/L Free κ 8.27 mg/L Free κ: λ 1.884
β2M 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 Weekly
Second opinion at MD Anderson

24. Case 3
HDM +
AuSCT
Thalidomide +
Dexamethasone

25. • 4/2007-7/2007: Thalidomide + Dexamethasone
Developed 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.

26. Case 3
What would you use for Relapse?
Thalidomide +
Dexamethasone
HDM +
AuSCT

27. Case 3
What 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

28. Study PX171-004: Phase 2 Trial of Single-agent Carfilzomib
in Relapsed and/or Refractory Multiple Myeloma
Cohort 1
20 mg/m2
Cohort 2†
20 mg/m2 cycle 1
Escalation to 27 mg/m2
in all subsequent cycles
Carfilzomib IV
QD x 2 for 3 weeks (28-day cycle for up to 12 cycles
BOR-treated*
(n=35)
BOR-naïve (n=59)
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

29. Cohort 1
20 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

30. 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

32. Grade 1 Neuropathy 51%
0
0
Grade 2 Neuropathy 29%
Phase 1 Trial of Pomalidomide
in 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%

33. 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.

34. Case 3
This Patient: Carfilzomib at Relapse
Thalidomide +
Dexamethasone
HDM +
AuSCT
Carfilzomib

35. 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

36. Case 4
VRD
Myeloablative therapy + AuSCT
M-Protein(g/dL)
Months
1 2 3 4 5 6 7
1
2
3
4
5
6
Lenalidomide 10 mg Maint.

37. Case 4M-Protein(g/dL)
Months
1 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)

38. 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

39. Bortezomib + High – Dose Melphalan (HDM) for Early
Transplant Relapse and High-Risk Myeloma
Wong Doo et al. Leukemia & Lymnphoma 2012; online
HDM + BORTEZOMIB
Stem 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
HDM
Stem 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
VGPR
Med. PFS
Med. OS
Med. OS
Early relapse
81.3%
37.5%
7 mos
28 mos
14.5 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

40. Allogeneic Stem Cell
TransplantPFS or EFS Benefit
Overall 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)

41. 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

42. Myeloma Section
Robert Orlowski, MD
Raymond Alexanian, MD
Jatin Shah, MD
Sheeba Thomas, MD
Michael Wang, MD
Department of Blood
and Marrow
Transplantation
Richard Champlin , MD
Muzaffar Qazilbash, MD
Simrit Parmar, MD
Uday Popat, MD
Nina Shah, MD
Thank you to the nurses, research staff and most
importantly, the patients!