COSTEM Berlin, October 11, 2013

Transcription

1 Chemotherapy for the collection of Hematopoietic Stem Cells in Multiple Myeloma: A pro/con debate COSTEM Berlin, October 11, 2013 Roberto M. Lemoli Chair of Hematology, Department of Internal Medicine (DIMI) University of Genoa, Italy

2 The views expressed in the following debate / presentation are those of the individual authors and do not necessarily reflect the views of Sanofi. Sanofi does not recommend the use of its products in any manner inconsistent with that described in the full prescribing information available in your country. Before prescribing the product always refer to the prescribing information in the summary of product characteristics available in your country.

3 Objectives of Meeting This educational session aims to help participants: Understand the place of auto SCT in multiple myeloma To address the different methods of mobilizing HSC for auto SCT in multiple myeloma Chemo-mobilization vs. mobilization with G-GSF +/- plerixafor To weigh up the pros and cons of each approach in terms of: Efficacy Side effects Patient burden Resource allocation

4 Meeting Overview Welcome and introduction Roberto M. Lemoli Italy 13:05 13:50 The Great Debate: chemotherapy vs. steady state mobilization for the collection of HSC in multiple myeloma Is the efficacy of both approaches similar? Are the side effects more severe in chemo-mobilization? Is the QOL for the patients better with steady state mobilization? Is there any difference in resource utilization between the two approaches? Hartmut Goldschmidt Germany arguing for chemotherapy Sergio Giralt USA arguing for steady state mobilization 13:50 14:00 Closing remarks Roberto M. Lemoli Italy

5 Overall survival (%) Overall survival (%) High-dose therapy in Multiple Myeloma 100 IFM MRC Transplant 75 Transplant 50 Conventional p = Conventional p = Treatment (months) Treatment (months) 1. Attal M, et al. N Engl J Med. 1996;335: Child JA, et al. N Engl J Med. 2003;348:1875.

6 Hematopoietic Stem Cell Transplants in Europe 2010 Autologous transplants (first transplants) N = 17,736 13% Multiple myeloma (PCD) 31% 44% Hodgkin's disease Non-Hodgkin's Lymphoma Other 12% Passweg JR et al. Bone Marrow Transplantation (2012), 1 18

7 Autologous SCT in Multiple Myeloma For Multiple Myeloma patients under the age of 65 treatment strategies include a maximum of 2 or 3 auto SCTs for upfront as well as for relapse treatment A major goal is therefore: To mobilize sufficient stem cells to achieve prompt and durable hematopoietic reconstitution after high dose chemotherapy

8 Failure to mobilize is detrimental to the patient and requires additional costs to manage Patients failing to mobilize require additional treatment which may include: Remobilization procedures. While some may be successful, some patients may still fail to collect targets after remobilization 1,2 Alternative procedures (allogeneic/ BMT) which are considered suboptimal relative to ASCT 2,3 Patients who are not suitable for further procedures may only receive salvage/ palliative care Successful mobilization/collection Poor mobilizers Success Failure to mobilize Remobilization Failure Failure to mobilize is costly due to the requirement for remobilizations or further treatment For example Van Agthoven 4 estimated the cost of bone marrow harvest as ~ 19,000, versus ~ 15,000 for ASCT Alternative strategies: Allogeneic transplantation Bone marrow harvest Salvage therapies 1 Pusic et al (2008) Biol Blood Marrow Transplant 14 (9): Jantunen E, Kvalheim G (2010) Eur J Haematol 85 (6): Jantunen E, Kuittinen T (2008) European journal of haematology 80 (4): Van Agthoven et al (2001) Eur J Cancer 37:

9 Impact of CD34 + cell yield in Multiple Myeloma Clear correlation between CD34 + cell dose and engraftment especially platelet engraftment 1-6 Most studies showed optimal dose 5 x 10 6 CD34 + cells/kg Most transplant centers recommended at least 2 x 10 6 CD34 + cells/kg IMWG (International Myeloma Working Group) recommended: at least 4 x 10 6 CD34 + cells/kg for transplantation and 8 10 x 10 6 CD34 + cells/kg for tandem transplantation 7 1. Tricot et al. Blood Jan 15;85(2): Weaver CH et al. Blood Nov 15;86(10): Ketterer N et al. Blood May 1;91(9): Siena E et al. J Clin Oncol Mar;18(6): Allan DS et al. Bone Marrow Transplant Jun;29(12): Klaus J et al. Eur J Haematol Jan;78(1): Giralt C et al. Leukemia Oct;23(10):

10 Probability of platelet recovery ( /L) Relationship between transplanted dose and platelet recovery (to cells/l) 1.0 Cox proportional analysis CD34 + cells ( 10 6 /kg) Siena et al. J Clin Oncol 2000;18: Time post transplant (days)

11 Important issues associated with stem cell mobilization beside CD34 + cell yield in Multiple Myeloma Mobilization of clonal myeloma cells 1-4 Collection technique 5 Higher number of lymphocytes and dendritic cells in apheresis product 6-11 Morbidity and use of financial resources Predictivity of mobilizing strategies Anti-tumor effect of chemotherapy (Cy 12, Eto, Bort) 1. Zhou P et al. Blood Jul 15;102(2): Stewart AK et al. J Clin Oncol Sep 1;19(17): Bourhis JH et al. Haematologica Aug;92(8): Fruehauf S et al. Bone Marrow Transplant Feb;45(2): Moog R. Transfus Apher Sci Jun;38(3): Porrata LF et al. Leukemia Jun;18(6): Hiwase DK et al. Biol Blood Marrow Transplant Jan;14(1): Atta EH et al. Am J Hematol Jan;84(1): Holtan SG et al. Clin Lymphoma Myeloma Jan;7(4): Gazitt Y et al. Stem Cells Dev Apr;15(2): Retting et al., Desikan KR et al. JCO 1998; 16:

12 Plerixafor Phase III Trial Study Design Study 3101 NHL patients (n=300) Study 3102 MM patients (n=300) G-CSF (10 ug/kg/day) + plerixafor (240 ug/kg) G-CSF (10 ug/kg/day) + placebo G-CSF (10 ug/kg/day) + plerixafor (240 ug/kg) G-CSF (10 ug/kg/day) + placebo Endpoint: > 5 million CD34 + cells/kg in 4 or fewer apheresis Successful and durable engraftment Endpoint: > 6 million CD34 + cells/kg in 2 or fewer apheresis

13 Study 3102 MM patients (n=300)

14 Efficacy (MM) Primary endpoint 1 Patients achieving CD34 + cells/kg in 2 days of apheresis, n (%) 1 Secondary endpoint 1 Patients achieving CD34 + cells/kg in 4 days of apheresis, n (%) 1 Patients proceeding to transplant, n (%) 2 Plerixafor + G- CSF (n = 148) Placebo + G-CSF (n = 154) p a 106 (71.6%) 53 (34.4%) < (75.7%) 79 (51.3%) < (96.0%) 136 (88.3%) a Estimate of treatment effect: p value assessed by Cochran-Mantel-Haenszel test, blocked by study centre, and Pearson chi-squared with similar results. DiPersio et al. Blood 2009;113:

15 Failure Rate (%) Failure Rates of G-CSF ± Chemotherapy Mobilization Regimens G-CSF G-CSF/Chemo NHL MM Chemo, chemotherapy; G-CSF, granulocyte colony stimulating factor; MM, multiple myeloma; NHL, non-hodgkin s lymphoma. Pusic et al. Biol Blood Marrow Transplant 2008;14:

16 Pre-emptive use of plerixafor in auto-sct Chemotherapy / G-CSF mobilization (Day 10/4) PB CD34 + count or 1 st apheresis < 1 x 10 6 CD34 + cells/kg < 10 cells/µl cells/µl > 20 cells/µl Give plerixafor in evening Measure CD34 + in PB in the morning Dynamic approach based on patient's disease characteristics, treatment history, CD34 + cell requirement A P H E R E S I S Costa LJ et al, BMT 2011; 46: adapted from: Jantunen E, Lemoli RM. Transfusion Apr;52(4): and Mohty M et al. EBMT 2013 meeting: abstract 705

17 Pre-emptive use of plerixafor after cyclophosphamide 4g/m 2 Day 0: CYCLO 4 g/m 2 Stem Cell Mobilization Protocol Mobilization Collection Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 13 Day 14 Day 15 Daily dose of G-CSF (5 μg/kg/day) Apheresis sessions (2 blood volume ± 10% apheresis) Plerixafor (240 μg/kg/day SC) - given in the evening at 10:00 PM prior to each apheresis G-CSF dose of 5 μg/kg/day at 07:00 after each plerixafor dose, about 2 hours prior to starting apheresis Day +13 is the predicted mobilization day. If CD34 count is not high enough to go on the machine, patient needs preemptive plerixafor Lemoli RM, unpublished

18 Chemotherapy vs. steady state mobilization for the collection of HSC in Multiple Myeloma Efficacy Morbidity Is the efficacy of both approaches similar? What are the differences in side effect profiles? 1) Damon L. et al. BBMT Cy (6 gr/m 2 ) or Eto (2 gr/m 2 ): 71% response (17% CR-no stringent criteria). Patients proceeding to ASCT= 81% (5% did not due to toxicity). Three weeks cytopenia. TRM= 2.5% 2) Desikan RK. Et al. JCO Cy (6 gr/m 2 ) vs G-CSF: Increased % hospitalization (100%,Cy), plt and rbc transfusion (86%,Cy), higher % FUO and documented infections. Similar efficacy (77% vs 82% pts achieved SC target). No difference for engraftment despite higher numbers of CD34 + cells in Cy group (approx 11x 10 6 /Kg vs 3 x 10 6 /Kg). Antitumor effect of Cy= 10% pts partial response.

19 Overall survival of 126 patients with multiple myeloma as a function of ALC recovery at day 15 after ASCT. Median overall survival time for patients with an ALC greater than or equal to 500 cells/μl was 33 months versus 12 months for patients with an ALC less than 500 cells/μl (P <.0001). Porrata LF et al. Blood 2001;98:

20 Multiple Myeloma cell mobilization and positive selection of CD34 + HSC for tumor cell purging

21 Clonotypic cells/ml peripheral blood* Are tumor cells mobilized after plerixafor administration? Screening G-CSF G-CSF + plerixafor * Detection by quantitative allele-specific oligonucleotide (ASO)-PCR Fruehauf et al. Bone Marrow Transplant 2010;45:

22 Chemotherapy vs. steady state mobilization for the collection of HSC in Multiple Myeloma Weighing up the evidence Chemo-mobilization Hartmut Goldschmidt Steady state mobilization Sergio Giralt

23 Chemo-mobilisation Hartmut Goldschmidt Steady state mobilisation Sergio Giralt Statement 1: The efficacy of both approaches seems to be similar

24 Berlin Stem-Cell-Mobilization in MM with Chemotherapy plus Growth Factor: YES Hartmut Goldschmidt Department of Medicine V, Heidelberg University Medical Center & National Center for Tumor Diseases (NCT) Heidelberg

25 Hartmut Goldschmidt University of Heidelberg Stem-Cell-Mobilization in MM with Chemotherapy plus Growth Factor: YES Disclosure of Conflict of Interest (List) Amgen Chugai Research support Research support

26 The views expressed in the following debate / presentation are those of the individual authors and do not necessarily reflect the views of Sanofi. Sanofi does not recommend the use of its products in any manner inconsistent with that described in the full prescribing information available in your country. Before prescribing the product always refer to the prescribing information in the summary of product characteristics available in your country. 26

27 1 Statement: The efficacy of both approaches seems to be similar No: Chemotherapy plus growth factor is more effective

28 Stem cells harvesting during Toxic chemotherapy (e.g. Cyclophosphamide 4-7 g/m²) Colony forming units as control of quality of harvested stem cells cell culture 7-14 days Pretreatment with alkylating agents (e.g. Melphalan) before stem cell mobilization Introduction of G- and GM-CSF CD 34+ as quality control and deescalation of mobchemotherapy e. g. Cyclophosphamide 7 => 4 => 2 => 1 g/m²

29 Peak values of CD34+ cells in Leukapheresis products after 7g/m² Cy followed by 300 μg G-CSF per day with negative correlation to duration of melphalan-containing treatment Goldschmidt et al: Br J Haemtology, 1997

30 MM5-Trial symptomatic MM 1st line treatment 18-70a Randomization 3 x PAd A1 + B1 3 x VCD A2 + B2 1) 1) CAD + leukapheresis HDM + TPL 2. HDM + TPL (if no ncr/cr) Standard intensification according to local protocol (GMMG standard) 2 x Lenalidomide A1 B1 A2 B2 Lenalidomide for 2 years Lenalidomide if no CR Lenalidomide for 2 years Lenalidomide if no CR 1) High Risk Patients, optional in Phase II trial Flowsheet

31 Stem cells harvesting during Chemotherapy for mobilization deescalated. CAD not more toxic than VCD Daily analysis of harvested CD 34+ cells No treatment with alkylating agents (e.g. Melphalan) before stem cell mobilization GMMG and Heidelberg experience CAD plus G-CSF in >80% of the first leukapheresis > 7.5 CD 34+ x 10 6 cells per kg BW

32 Mobilization Revisited Sergio Giralt, MD Chief Adult BMT Service Memorial Sloan Kettering Cancer Center Professor of Medicine Weill-Cornell College of Medicine

33 The views expressed in the following debate / presentation are those of the individual authors and do not necessarily reflect the views of Sanofi. Sanofi does not recommend the use of its products in any manner inconsistent with that described in the full prescribing information available in your country. Before prescribing the product always refer to the prescribing information in the summary of product characteristics available in your country.

34 Plerixafor vs. Chemo- Mobilization First Statement The efficacy of both approaches seems to be similar.

35 Ideal Mobilization Regimen Reliable High likelihood of collecting sufficient number of progenitors Predictable Able to predict day of collection with precision Low failure rate Limited toxicity Limited number of days of apheresis required Low tumor contamination Low resource utilization

36 What is a Successful Stem Cell Collection? Mobilize sufficient number of cells capable of prompt and durable hematopoietic reconstitution Minimize apheresis time 1 Optimize total CD34+ cell collection 2 Minimize toxicity 3 Achieve adequate neutrophil and platelet engraftment Neutrophil engraftment: first of 3 consecutive days where the absolute neutrophil count is > 0.5 K/µL 4-6 Platelet engraftment: first day where the platelet count is > 20 K/µL without transfusion for previous 7 days 4,5 1 Dingli D, et al. Clin Lymphoma Myeloma. 2006;6: ; 2 Sola C, et al. Hematology. 1999;4: ; 3 Desikan KR, et al. J Clin Oncol. 1998;16: ; 4 Champlin RE, et al. Blood. 2000;95: ; 5 Akkok CA, et al. Transfusion. 2008;48: ; 6 Ali MY, et al. Bone Marrow Transplant. 2002;30:

37 In Conclusion The most effective mobilization regimen will allow collection of THE LARGEST number of CD34+ cells with the LEAST toxicities and RESOURCES utilized.

38 G-CSF vs Chemotherapy + G-CSF Study Alegre A, et al. 1 Desikan KR, et al. 2 Dazzi C, et al. 3 Narayanasami U, et al. 4 Pusic I, et al. 5 Disease State(s) MM MM NHL NHL, HD NHL, MM, HD N Mobilization Regimen Median Total Collected CD34+ Cells X 10 6 /kg (Range) Median Apheresis Sessions (Range) Number of Mobilization Failures 22 G-CSF 4.85 ( ) 3 (2 6) NR 18 Cy+GM-CSF 6.8 ( ) 5 (4 12) NR 22 G-CSF 5.8 (NR) 5 23% 22 Cy+G-CSF 33.4 (NR) 7 18% 12 G-CSF 2.89 ( ) 16 total NR 12 Cy+G-CSF 6.41 ( ) 15 total NR 22 G-CSF 2.5 ( ) NR (1 3) 1 24 Cy+G-CSF 7.2 ( ) NR (1 3) G-CSF 3.36 (NR) 2 (1 5) Chemo+G-CSF 5.43 (NR) 1.5 (1 5) 12 Chemo = various chemotherapeutic agents; Cy = cyclophosphamide; HD = Hodgkin's disease; MM = multiple myeloma; NHL = non-hodgkin's lymphoma; NR = not reported. 1 Alegre A, et al. Bone Marrow Transplant. 1997;20: ; 2 Desikan KR, et al. J Clin Oncol. 1998;16: ; 3 Dazzi C, et al. Leuk Lymphoma. 2000;39: ; 4 Narayanasami U, et al. Blood. 2001;98: ; 5 Pusic I, et al. Biol Blood Marrow Transplant 2008;14:

39 NO RANDOMIZED TRIALS What about plerixafor vs. chemo-mobilization?

40 Non Randomized Comparative Trials Author Diagnosis N Regimen CD34+ yield (x 10 6 /kg) First Line Mobilization DiPersio (63) NHL 150 UP+GCSF 148 GCSF DiPersio (64) MM 148 UP+GCSF 154 GCSF Shaughnessy (132) Campen (134) NHL MM, NHL 33 CM+G 33 P+G 34 Cy+G 8 UP Adel (133) MM 98 Cy+G 35 UP NR NR NR NR Failure rates 41%/10% 80%/45% 28% 66% % 12.5% 21% 6% Preemptive Mobilization Costa (92) MM, Ly 34 PEP 6.3 3% Costa (136) MM, Ly 81 CM+G 50 PEP % 2%

41 Plerixafor vs. Chemo- Mobilization First Statement The efficacy of both approaches seems to be similar My Position Definitely YES

42 Chemo-mobilisation Hartmut Goldschmidt Steady state mobilisation Sergio Giralt Statement 2: The side effects are more severe in chemo-mobilization

43 2 Statement: The side effects are more severe in chemo-mobilization Yes: best approach is to combine tumor debulking with stem cell mobilization

44 International Myeloma Working Group Perspective Optimal target number of cells for one autograft 4-6 CD 34 + x 10e6 cells per kg BW Open question: single versus double transplantation ABSCT in relapse as one option => Number of harvested cells should be save for two or three autografts > 8-12 CD 34 + x 10 6 cells per kg BW

45 Heidelberg - GMMG Perspective Minimal target number of cells for one autograft is at least 2.0 CD 34 + x 10 6 cells per kg BW => safe hematopoietic reconstitution To have the option for double transplantation and transplantation in relapse our minimal number of harvested cells after induction treatment is least 6.0 (7.5) CD 34 + x 10 6 cells per kg BW

46 Hematopoetic reconstitution of MM patients receiving unselected PBSCT Klaus et al. Eur J of Hematol. 2006

47 Hematopoetic reconstitution of MM patients receiving selected PBSCT Klaus et al. Eur J of Hematol. 2006

48 HOVON 50/GMMG-HD3 MM Stage II or III, Age Randomization 3 x VAD CAD Mobilization & Leukapheresis 3 x AD CAD Thalidomide mg MEL PBSCT MEL PBSCT MEL PBSCT a-interferon 9 Mio. U/Week Allogeneic Tx 2Gy + Fludara HOVON 54 EBMT NMAM2000 MEL PBSCT Thalidomide 50 mg

49 Stem cell collection after CAD Cyclophosphamide 1000 mg/m 2 day 1 Adriamycin 15 mg/m 2 day 1-4 Dexamethasone 40 mg day 1-4 G-CSF 10 g day 5-12 Arm A Arm B P-value Days from CAD to leuc No of leukapheresis CD 34+ collected Failure to collect 11 (9-17) 11 (7-19) N.S 1 (1-7) 1 (1-7) N.S 9.9 (9-43) 7.9 (2-33) N.S.

50 Plerixafor vs. Chemo Second Statement: The side effects are more severe in chemo-mobilization.

51 Advantages of Chemotherapy- Based Mobilization Can be used both to treat patient and collect CD34 + cells Commonly used regimens are relatively predictable Timing of leukapheresis CD34 + cell yields More likely than cytokine alone to result in very high CD34 + cell yields

52 Disadvantages of Chemotherapy- Based Mobilization Risk of Infection Time elapsed between chemomobilization and CD34+ cell peak is unpredictable 1,3 Criteria for initiating apheresis varies 2,3,5,6 Need for hospitalization Need for transfusion support Increased costs 1 Hicks ML, et al. Transfusion. 2007;47(4): ; 2 Desikan KR, et al. J Clin Oncol. 1998;16(4): ; 3 Bargetzi MJ, et al. Bone Marrow Transplant. 2003;31(2):99-103; 4 Humpe A, et al. Transfusion. 2000; 40(11): ; 5 Venditti A, et al. Bone Marrow Transplant. 1999;24(9): ; 6 Arora M, et al. Biol Blood Marrow Transplant. 2004;10(6):

53 Advantages of Cytokine-Only Mobilization Predictable kinetics of mobilization Lower toxicity and resource utilization compared to chemotherapy based Avoid need for hospitalization and transfusions Makes staffing easier

54 the most common adverse event seen with chemo-mobilization was febrile neutropenia, which was reported in 43% of studies in which chemotherapy formed part of the mobilization strategy In studies where chemotherapy was used, the percentage of patients requiring hospital admission ranged from 20% to 48%.

55 Plerixafor is generally well tolerated and not associated with AEs typical of chemotherapy Related adverse events are typically mild or moderate and serious adverse events are rare, with a similar profile to G-CSF alone The most common AEs associated with plerixafor are GI disorders such as diarrhoea and nausea and injection site reactions Plerixafor is not associated with the febrile neutropenia DiPersio et al. Blood 2009;113:

56 Plerixafor vs. Chemo Second Statement: The side effects are more severe in chemo-mobilization My Position Definitely YES

57 Chemo-mobilisation Hartmut Goldschmidt Steady state mobilisation Sergio Giralt Statement 3: The QOL is better for patients with steady state mobilization

58 3 Statement: The QOL is better for patients with steady state mobilization No data is available - but likely to be true. Data about tumor cell mobilization are available

59 Leukapheresis products contain cells of the malignant clone => purging approaches 7% 73 LP analyzed 68 PCR-positive 5 PCR-negative PCR-positive 93% 16 of 16 PCRnegative 16 PCR-positive LP CD34- CD19-6 of 6 PCRpositive 6 of 6 PCRpositive

60 Tumor load after Mobilization: Cremer et al. Cremer et al. Exp. Hematol. 1998

61 Study Design G-CSF ( μg) versus Cyclophosphamide (4-7 g/m²) plus G-CSF (300 μg) in 8 pts Min. number of harvested cells (>2.0 CD34 x10 6 cells kg/bw) Quantitative PCR-assay for assessment of tumor load in leukapheresis products Standard CD34 assessment in PB und LP Cremer et al. Exp. Hematol. 1998

62 Analysis of the tumor load of the LP-CY (upper lanes) and the LP-S (lower lanes). Five PCRs at three dilution levels (1:1 to 1:10 and 1:3 to 1:30) are shown. Cremer et al. Exp. Hematol. 1998

63 Intraindividual comparison of the number of malignant cells per CD34+ cell in LP-CY and LP-S of the eight patients (A-H) with MM. Cremer et al. Exp. Hematol. 1998

64 Plerixafor vs. Chemo Third Statement: The QOL is better for patients with steady state mobilization.

65 Two Components to QOL Collection Few studies No comparative trials Stem Cell Transplant No studies comparing SCT QOL with chemomobilized versus plerixafor mobilized stem cells

66 Details of Mobilization / Apheresis Period Stem Cell Mobilization Protocol Screening Mobilization Collection Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Randomization Daily dose of G-CSF (10 mcg/kg/day) Apheresis session (3 Volume ± 10% apheresis) Plerixafor (240 mcg/kg/day SQ) or Placebo dosing Given in the evening at 10:00 PM prior to each pheresis Primary Endpoint: Collection of 6 million CD34+ cells/kg in 2 days Patients Eligible for Rescue: Failure to collect 0.8 x 10 6 CD34+ cells/kg after 2 days of apheresis or 2 x 10 6 CD34+ cells/kg after 4 days of apheresis DiPersio J, et al. Blood. 2007;110:137a-138a. Abstract 445.

67 MM Study 3102 Efficacy Results (ITT): CD34+ Cell Mobilization Plerixafor + G-CSF n=150 Placebo + G-CSF n=148 p value* Primary Endpoint Patients achieving 6 x 10 6 CD34+ cells/kg in 2 or less days of apheresis Secondary Endpoint Patients achieving 6 x 10 6 CD34+ cells/kg in 4 or less days of apheresis 71.6% 34.4% < % 51.3% < *Estimate of treatment effect: p value assessed by Cochran Mantel-Haenszel test blocked by study center and Pearson chi-square with similar results DiPersio J, et al. Blood. 2007;110:185a. Abstract 601.

68 Potential Symptom Burden Curve for Plerixafor Stem Cell Mobilization Protocol Screening Mobilization Collection Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 GCSF bone pain rarely fever Plerixafor GI disturbance Apheresis Fatigue fluid shifts

69 Plerixafor vs. Chemo Third Statement: The QOL is better for patients with steady state mobilization. MY POSITION No data is available-but likely to be true.

70 Chemo-mobilisation Hartmut Goldschmidt Steady state mobilisation Sergio Giralt Statement 4: Plerixafor will use less resources than chemotherapy

71 4 Statement: Plerixafor will use less resources than chemotherapy Not clear Induction chemotherapy and growth factor is low toxic and effective

72 MM5-Trial symptomatic MM 1st line treatment 18-70a Randomization 3 x PAd A1 + B1 3 x VCD A2 + B2 1) 1) CAD + leukapheresis HDM + TPL 2. HDM + TPL (if no ncr/cr) Standard intensification according to local protocol (GMMG standard) 2 x Lenalidomide A1 B1 A2 B2 Lenalidomide for 2 years Lenalidomide if no CR Lenalidomide for 2 years Lenalidomide if no CR 1) High Risk Patients, optional in Phase II trial Flowsheet

73 Daily praxis to mobilize hematopoetic stem cells at our center CAD (Cyclophosphamide based 1 g/sqm, Doxorubicin, Dexamethason) plus G-CSF in private praxis or cooperating hospitals as antimyeloma therapy G-SCF given from the center (mobilization) At day 15 (Leuko >5) evaluate the number of circulating CD 34+ cells => start harvesting > 80% of the patients more than >7.5 CD34 x10 6 cells kg/bw

74 Plerixafor vs. Chemomobilization Fourth Statement: Plerixafor will use less resources than chemotherapy

75 Use of Resources Resource Plerixafor Chemomobilization Hospitalization to administer Comments Sometimes Always Rarely given as outpatient Drug cost ++ Expensive Cyclophosphamide inexpensive Toxicity costs Low 30% admissions Depends on hospitalization costs Apheresis Costs 1-2 collections 1-2 collections Savings from predictability of plerixafor not accounted for Failure Costs May be less 1. Shaughnessy P et al. Biol Blood Marrow Transplant Sep;19(9): Li J et al. Transfusion Oct;51(10): Abdel et al. J Oncol Pharm Pract May 15.

76 Shaughnessy Li Abdel Roberts Total cost per patient: Plerixafor $20,298 Chemo $19,173 Plerixafor fewer G doses,hospitalizations, transfusions, Plerixafor and G less costly in 69% of patients Plerixafor 1.5 times less costly when all resources included Cost of successful collections G alone 62% $23000 Chemo + G 70% $20000 Plerixafor 63% $31000 Just in Time Plerixafor 76% $26000

77 Plerixafor vs Chemomobilization Fourth Statement: Plerixafor will use less resources than chemotherapy My Position Definitely YES

78 Chemo-mobilisation Hartmut Goldschmidt Steady state mobilisation Sergio Giralt Closing remarks

79 Summary Today chemotherapy plus growth factor is increasing the remission rate and less toxic Number of mobilized hematopoietic stem cells is high Time to best CD34+ mobilization is predictable Number of myeloma cells in autografts after chemotherapy plus G-CSF is relative low

80 Conclusions & Current Issues with Mobilization Few randomized trials The advent of plerixafor opens doors to a series of interesting questions Stem cell dosing Graft composition Logistics Plerixafor for all (just in USA) Plerixafor given Just in Time Plerixafor only for the failures Plerixafor failures occur Optimal strategy for them? Prospective randomized trials are needed

81 Concluding remarks Both speakers agree that chemo-mobilization results in a higher yield of HSC than cytokine alone. However, the addition of Plerixafor to G-CSF may be as effective as chemotherapy. Prof. Giralt pointed to the high percentage of patients with FN and the high rate of hospitalization after chemo-mobilization whereas Prof. Goldschmidt underlined the potential anti-tumor effect of chemo-mobilization. The use of chemo-mobilization with Cy my reduce tumor cell load in the autologous graft as compared to cytokine alone (Prof. Goldschmidt). Use of resources and pharmocoeconomics: the use of Plerixafor just in time on demand pre emptive appears to be as effective as CHT and cost-effective (Prof. Giralt).