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 mg/dL, albumin 1.8 g/dL, hydrated sent home

3. Case 1
Hgb 10.9 g/dL, Plt 206 k/μL , WBC 7.9 k/μL, 3% plasma cells, BUN 53 creatinine 4.69, Ca mg/dL, albumin 3.0 g/dL, uric acid 13.3
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
Cytogenetics: t(4;14), del 13, del 1q
Bone survey: lytic lesions skull, ribs, T7 compression

4. Case 1 (Questions) What would you do first? Dialysis
2. Chemotherapy/Immunotherapy
3. Chemo/Immunotherapy + 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.
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
Clark et al: Ann Intern Med 143: , 2005
Hutchison et al: Clin J Am Soc Nephrol 4: , 2009

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

7. What would be the best induction therapy?
Case 1 (Questions)
What would be the best induction therapy?
Thalidomide and dexamethasone (once weekly)
2. Lenalidomide and dexamethasone (once weekly)
3. Bortezomib and dexamethasone (day of and after B)
4. Bortezomib, melphalan and prednisone
5. Bortezomib, cyclophosphamide, dexamethasone
6. Bortezomib, lenalidomide, dexamethasone

8. Reversibility of Renal Failure Criteria for 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 ml/min
Minor (MRrenal)
Improvement of CrCl from < 15 ml/min to ml/min OR
15-29 ml/min to 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
Carfilzomib
Consideration
Bortezomib No
Yes
Renal metabolism
Hyperkalemia
Cytopenias
None
Additional Toxicity in Renal Patients No
Possible
Possible, Avoidable
Renal Toxicity ?
Efficacy for Induction in Renal Failure

10. Reversibility of Renal Failure Newly Diagnosed
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
Parameter CC
I-B
B-B n 32 47 17
Med. CrCl (ml/min)
29.2
26.9
20.6
%CrCl < 30ml/min 53 53 76
% Renal Response
> MRrenal 59 79 94
Bortezomib based therapy and CrCl> 30 independently predicted renal recovery and shorter time to response
> PRrenal 47 51 82
p0.04
CRrenal 41 45 71
Med. Mos to Response
1.8
1.6
0.69
p0.007
%Renal Response w/o MM Response 9
19.1
23.5
Roussou et al, Leukemia Research 2010:9:

11. Lenalidomide Dose (mg)
Creatinine Clearance (m/min)
10 mg/Day
>
15 mg q48 hours
< 30, NOT on dialysis
5 mg/D after dialysis
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. Case 2 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
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 marrow 50% CD38, CD138, CD56, λ -, κ + PC
T. Protein 7.3 g/dL, Albumin 4.3 g/dL, M-protein 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
β2M 9.9 mg/L Alb 4.3g/dL: ISS stage III
Cytogenetics: Deletion 13 and Deletion 17p13.1
Bone survey: Rib lesion + Small lytic lesions bilateral femora + humeri

15. What Would Be the Best Induction Therapy?
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?
Yes
2. No

17. Case 2
After successful induction therapy +/-myeloablative therapy and autologous stem cell transplant what maintenance therapy (if any) would you use?
None
2. Lenalidomide
3. Bortezomib
4. Other

18. Bortezomib Induction: Impact in del 17p
Bortezomib + Dex x 4 cycles
Deletion 17p (n = 54)
No deletion 17p (n = 453)
©2010 by American Society of Clinical Oncology
Avet-Loiseau H et al. JCO 2010;28:

19. 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
Parameter
ARM A
ARM B
Med. PFS (mos)
Deletion 17p 12
22 (26.2)
p.01(.02)
Deletion 17p in >60%PC 12
25.7
p.017
3 yr OS (%)
Deletion 17p 17 69
p.028
Bortezomib based therapy and CrCl> 30 independently predicted renal recovery and shorter time to response
Deletion 17p in >60%PC 8 62
p.037
No Deletion 17p 80 85
p.48
Med. OS (mos)
Deletion 17p 24
>54
p.003
No Deletion 17p NS NS
Sonneveld et al, J Clin Oncol 30: , 2012
Neben et al, Blood 119 (4): 940-8), 2012

20. Cycle 1
Bortezomib, Cyclophosphamide, Dexamethasone Days 1-4, 9-12, 17-20
Cycles 2-4
Bortezomib, Cyclophosphamide, Dexamethasone D1,8,15,22
High-Dose Melphalan + AuSCT
Bortezomib Maintenance q2wks

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

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 Hgb 12 g/dL, BUN 53 creatinine 1.4mg/dL, Ca++ 9.1 mg/dL
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
Radiation 20 Gy
Thalidomide 200 mg daily + Dexamethasone Weekly
Second opinion at MD Anderson

24. Case 3
Thalidomide + Dexamethasone
HDM + AuSCT

25. Case 3 4/2007-7/2007: Thalidomide + Dexamethasone
Developed Grade 2 neuropathy during induction.
7/2007: HDM + AuSCT: Worsening of neuropathy.
VGPR: No Maintenance; neuropathy persists, but improved to grade 2 without pain.

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

27. What would you use for Relapse?
Case 3
What would you use for Relapse?
Thalidomide and dexamethasone (once weekly)
2. Lenalidomide and dexamethasone (once weekly)
3. Bortezomib and dexamethasone (day of and after B)
4. Lenalidomide-based 3 drug combination
4. Bortezomib-based 3 drug combination
5. Carfilzomib
5. Pomalidomide + Dexamethasone

28. QD x 2 for 3 weeks (28-day cycle for up to 12 cycles
Study PX : Phase 2 Trial of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma
Carfilzomib IV
QD x 2 for 3 weeks (28-day cycle for up to 12 cycles
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
Cohort 1
20 mg/m2
BOR-treated*
(n=35)
BOR-naïve (n=59)
Cohort 2†
20 mg/m2 cycle 1
Escalation to 27 mg/m2 in all subsequent cycles
BOR-naïve (n=70)
Bortezomib Naive
Cohort 1
Cohort 2
Total
ORR (CR+VGPR+PR)
42.4%
52.2%
47.6%
CBR (ORR+MR)
59.3%
64.2%
61.9%
Vij et al, Blood: 119(24): , 2012

29. Escalation to 27 mg/m2 in all subsequent cycles
Study PX : 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
Time to Response (med. months)
1.0
0.5
Time to Clinical Benefit Response (med. months)
1.9
0.5
Duration of Remission (med. Months)
13.1 NR
Duration of Clinical Benefit Resp. (med. Months)
11.5 NR
Median TTP (med. Months)
8.3 NR
Vij et al, Blood: 119(24): , 2012

30. PX-171-003-A0 Bortezomib Exposed
Phase 2 Trials of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma
PX Bortezomib Naive
PX A0 Bortezomib Exposed
History of Neuropathy at Baseline
69.8%
Grade 1 or 2 Neuropathy at Study Entry
53%
87%
Treatment Emergent Peripheral Neuropathy (all but 1pt Gr I or II in both studies)
17.1%
15.2%
Median QOL FACT-GOG
No Change
Vij et al, Blood: 119(24): , 2012
Jagannath et al,, Clinical lymphoma, myeloma & leukemia. 12(5):310-8, 2012

32. Phase 1 Trial of Pomalidomide in Relapsed and/or Refractory Multiple Myeloma
Pomalidomide mg po daily
Pomalidomide mg po daily
Grade 1 Neuropathy
51%
69%
Grade 2 Neuropathy
29%
17%
Grade 3 Neuropathy 3%
Grade 4 Neuropathy
Lacy et al, Blood 118(11): , 2011

33. Potential Low Neuropathic Complications
Low Neuropathic Novel Agents
Low Neuropathic Conventional Agents
Steroids
Carfilzomib*
Cyclophosphamide
Dexamethasone
Lenalidomide
Melphalan
Prednisone
Elotuzumab
Bendamustine
Pomalidomide?
Doxorubicin/ Liposomal Doxorubicin*
Use of these combinations outside a clinical trial should be limited to those with previously reported results.
* 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

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

35. Case 4
57 yr old female
7/2012: Right Hip X-rays show lytic lesion right femur
Bone survey: lytic lesions skull, ribs, femur
Hgb 9.8 g/dL, Plt 251 k/μL , WBC 6.8 k/μL, creatinine 0.7 mg/dL, Ca mg/dL, albumin 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 marrow 17% CD38, CD138, CD56, λ +, κ – PC
Cytogenetics 46XX, FISH negative for high-risk

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

37. Case 4 M-Protein (g/dL) Months1 2 3 4 5 6 7
Case 4
VRD
M-Protein 1.6g/dL BM: 56% plasma cells Cytogenetics: t(4;14)
Myeloablative therapy + AuSCT
Lenalidomide mg Maint.

38. Case 4: What would you use for relapse?
Lenalidomide-based 3-drug regimen
2. Bortezomib-based 3-drug regimen
3. Myeloablative therapy and Autologous SCT
4. Allogeneic SCT
5. Clinical Trial

39. Bortezomib + High – Dose Melphalan (HDM) for Early Transplant Relapse and High-Risk Myeloma
N=16 PTS: Relapsed or Refractory 2nd Salvage
N=16 PTS: Historical Control Relapsed or refractory
HDM + BORTEZOMIB
Stem Cell Harvest: Cyclophosphamide + G-CSF (usually collected before transplant 1)
HDM
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
Day -2: Melphalan 200mg/M2 IV (RI:Melphalan 140mg/M2 IV)
Day 0: Stem cells infused
> MR
81.3%
87.5%
p 0.22
VGPR
37.5%
12.5%
p 0.22
Med. PFS
7 mos
7 mos
p 0.299
Med. OS
28 mos
21 mos
p 0.11
Med. OS Early relapse
14.5 mos
8 mos
p 0.522
Wong Doo et al. Leukemia & Lymnphoma 2012; online

40. Allogeneic Stem Cell Transplant
Auto – RIC Allo SCT Vs. Auto-Auto
PFS or EFS Benefit
OS Benefit
Overall Survival
IFM: Garban et al Blood (High-Risk del 13, B2M > 3) No No
Italian: Bruno et al Blood (No risk stratification)
EFS Benefit
Yes
BMT CTN: Krishnan et al, Lancet Oncol (High-Risk del 13, B2M > 3)
No 3yr PFS Benefit No
Bjorkstrand et al J Clin Oncol, (High-Risk del 13, B2M > 3)
5Yr Yes

41. Allogenic hematopoietic stem‐cell transplantation with reduced‐intensity conditioning in patients with refractory and recurrent multiple myeloma
Bad Risk
SCT from a female donor to a male
Chemoresistance at the time of SCT
Good Risk
occurrence of chronic GVHD
achievement of a CR.
Shimoni et al, Cancer 116 (15): , 5 MAY 2010 DOI: /cncr.25228

42. Department of Blood and Marrow Transplantation
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!