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

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Presentation on theme: "Audience Response Cases Donna M. Weber, MD Professor of Medicine, Department of Lymphoma/Myeloma."— Presentation transcript:

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 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 β 2 M 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 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: , : 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: , 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 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 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 ThalidomideLenalidomideCarfilzomibConsiderationBortezomib NoYesNo Renal metabolism No Possible Possible, Avoidable Renal ToxicityNo ??? Efficacy for Induction in Renal Failure ?HyperkalemiaCytopeniasNone Additional Toxicity in Renal Patients None

10 CCI-BB-B Parameter n Med. CrCl (ml/min) %CrCl < 30ml/min % Renal Response > MRrenal CRrenal > PRrenal p0.04 Roussou et al, Leukemia Research 2010:9: Reversibility of Renal Failure Newly Diagnosed Med. Mos to Response p %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 > 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 β 2 M 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: ©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 AARM BParameter Med. PFS (mos) 1222 (26.2) Deletion 17p 1769 Deletion 17p 862 Deletion 17p in >60%PC 3 yr OS (%) Sonneveld et al, J Clin Oncol 30: , 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/M 2 q 14d x 2yrs Neben et al, Blood 119 (4): 940-8), No Deletion 17p p.01(.02) p.028 p.48 p Deletion 17p in >60%PC p >54 Deletion 17p Med. OS (mos) p.003 NS No Deletion 17p

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

21 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

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 β 2 M 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 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 PX : Phase 2 Trial of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma Cohort 1 20 mg/m 2 Cohort 1 20 mg/m 2 Cohort 2 † 20 mg/m 2 cycle 1 Escalation to 27 mg/m 2 in all subsequent cycles Cohort 2 † 20 mg/m 2 cycle 1 Escalation to 27 mg/m 2 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-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 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): , 2012 ORR (CR+VGPR+PR) 42.4%52.2%47.6% CBR (ORR+MR)59.3%64.2%61.9% Cohort 1 Cohort 2 Total Bortezomib Naive

29 Cohort 1 20 mg/m 2 Cohort 1 20 mg/m 2 Cohort 2 † 20 mg/m 2 cycle 1 Escalation to 27 mg/m 2 in all subsequent cycles Cohort 2 † 20 mg/m 2 cycle 1 Escalation to 27 mg/m 2 in all subsequent cycles Study PX : Phase 2 Trial of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma Duration of Clinical Benefit Resp. (med. Months) 11.5NR Time to Clinical Benefit Response (med. months) Time to Response (med. months) Duration of Remission (med. Months) 13.1NR Median TTP (med. Months) 8.3NR Vij et al, Blood: 119(24): , 2012

30 History of Neuropathy at Baseline69.8% Treatment Emergent Peripheral Neuropathy (all but 1pt Gr I or II in both studies) 17.1% Median QOL FACT-GOGNo Change Grade 1 or 2 Neuropathy at Study Entry53% Phase 2 Trials of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma 15.2% 87% PX Bortezomib Naive PX A0 Bortezomib Exposed Vij et al, Blood: 119(24): , 2012 Jagannath et al,, Clinical lymphoma, myeloma & leukemia. 12(5):310-8, 2012

31

32 Grade 1 Neuropathy51% 0 0 Grade 2 Neuropathy29% 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): , 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*CyclophosphamideDexamethasone LenalidomideMelphalanPrednisone 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 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, β 2 M 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 Lenalidomide 10 mg Maint.

37 Case 4 M-Protein (g/dL) Months 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/M 2 IV (RI:Melphalan 140mg/M 2 IV) Day -1: Bortezomib 1.3 – 1.6 mg/M 2 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/M 2 IV (RI:Melphalan 140mg/M 2 IV) Day 0: Stem cells infused N=16 PTS: Relapsed or Refractory 2 nd 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 mos p mos p % 12.5% 7 mos

40 Allogeneic Stem Cell Transplant PFS or EFS Benefit Overall Survival IFM: Garban et al Blood 2006 (High-Risk del 13, B 2 M > 3) No EFS BenefitYes 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, B 2 M > 3) 5Yr YesBjorkstrand et al J Clin Oncol, 2011 (High-Risk del 13, B 2 M > 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): , 5 MAY 2010 DOI: /cncr 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!


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