Audience Response Cases

Donna M. Weber, MDProfessor of Medicine, Department of Lymphoma/Myeloma

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

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

Case 1 (Questions)

What would you do first?

2. Chemotherapy/Immunotherapy

3. Chemo/Immunotherapy + Dialysis

1. Dialysis

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

Case 1: Results With Therapy Initiation

Chemo held temporarily due to infection

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

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

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

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

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

Case 2• 36 yr old female

• 2/2010: Rt Chest wall pain during pregnancy Did not resolve after pregnancy

• 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

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

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)

Case 2

Would you proceed with myeloablative therapy and stem cell transplant after successful

induction?

2. No

1. Yes

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

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

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

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

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

Case 3• 72 yr old male

• 12/2006: Rib pain

• 2/2007: Sharp burning pain from Rt hip radiating to leg

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

Case 3

HDM + AuSCT

Thalidomide + Dexamethasone

• 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.

Case 3What would you use for Relapse?

Thalidomide + Dexamethasone

HDM + AuSCT

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

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

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

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

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%

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.

Case 3This Patient: Carfilzomib at Relapse

Thalidomide + Dexamethasone

HDM + AuSCT

Carfilzomib

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

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.

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)

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

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

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)

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

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!