Audience Response Cases Donna M. Weber, MD Professor 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 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 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

Case 1 (Questions) What would you do first? Dialysis 2. Chemotherapy/Immunotherapy 3. Chemo/Immunotherapy + 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. 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: 777-84, 2005 Hutchison et al: Clin J Am Soc Nephrol 4: 745-54, 2009

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

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

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 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

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

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: 1395-1397

Lenalidomide Dose (mg) Creatinine Clearance (m/min) 10 mg/Day > 30 - 50 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

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

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

Case 2 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 Bone survey: Rib lesion + Small lytic lesions bilateral femora + humeri

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)

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

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

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;28:4630-4634

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: 2946-55, 2012 Neben et al, Blood 119 (4): 940-8), 2012

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

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

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

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

Case 3 Thalidomide + Dexamethasone HDM + AuSCT

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.

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

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

QD x 2 for 3 weeks (28-day cycle for up to 12 cycles Study PX171-004: 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):5661-70, 2012

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 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):5661-70, 2012

PX-171-003-A0 Bortezomib Exposed Phase 2 Trials of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma PX-171-004 Bortezomib Naive PX-171-003-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):5661-70, 2012 Jagannath et al,, Clinical lymphoma, myeloma & leukemia. 12(5):310-8, 2012

Phase 1 Trial of Pomalidomide in Relapsed and/or Refractory Multiple Myeloma Pomalidomide 2 mg po daily Pomalidomide 4 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): 2970-2975, 2011

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

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

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++ 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 marrow 17% CD38, CD138, CD56, λ +, κ – PC Cytogenetics 46XX, FISH negative for high-risk

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

Case 4 M-Protein (g/dL) Months 1 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 10 mg Maint.

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

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

Allogeneic Stem Cell Transplant Auto – RIC Allo SCT Vs. Auto-Auto PFS or EFS Benefit OS Benefit Overall Survival IFM: Garban et al Blood 2006 (High-Risk del 13, B2M > 3) No No Italian: Bruno et al Blood 2010 (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, 2011 (High-Risk del 13, B2M > 3) 5Yr Yes

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): 3621-3630, 5 MAY 2010 DOI: 10.1002/cncr.25228

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!