Update in Multiple Myeloma

Transcription

1 Update in Multiple Myeloma NIELS VAN DE DONK Department of Hematology, Amsterdam September 2015

2 Outline Multipel myeloom Nieuwe medicijnen die toegepast worden in HOVON Myeloom studies Daratumumab Ixazomib carfilzomib

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9 Biology Myeloma-defining events CRAB criteria Van De Donk Haematologica 2014

10 Definitions Myeloma-defining events CRAB criteria Biomarkers of malignancy 60% MM cells FLC ratio 100 > 1 focal lesion on MRI Van De Donk Haematologica 2014

11 Van de Donk Leukemia 2005 BM Microenvironment

12 THERAPIE

13 : First description of Multiple Myeloma by Solly; 39-year old Sarah Newbury R/ rhubarb and orange skin Solly Med Chir Trans Lond 1844

14 Melphalan 1958: Blokhin, 3 out of 6 patients respond to melphalan 1962: Daniel Bergsagel starts phase 2 studies in MD Anderson Houston, TX Third drug tested was melphalan Response in 8/24 patients Blokhin Ann N Acad Sci 1958; Bergsagel Cancer Chemother Rep 1962 Blokhin Ann N Acad Sci 1958; Bergsagel Cancer Chemother Rep 1962

15 Melphalan en Prednisone 1969: Alexanian starts phase 3 study with melphalan-prednisone (MP) versus melphalan. Survival benefit of 6 months for MP Melphalan-prednisone as standard of care for next 40 years Alexanian JAMA 1969 Alexanian JAMA 1969

16 Anti-myeloma drugs IMIDs PIs Alkylators/ Steroids Thalidomide Bortezomib anthracyclins Dexamethasone Lenalidomide Carfilzomib Melphalan Prednisone Pomalidomide Ixazomib Cyclophosphamide Oprozomib Doxorubicin Patient features Age Co-morbidities Performance status Myeloma features ISS Cytogenetics LDH Previous therapy Response Duration Adverse events Transplant?

17 Dara, SAR, ELo 2014 Behring en Ehrlich: magic bullet

18 Anti-myeloma drugs: 2015 IMIDs PIs Alkylators/ Steroids Thalidomide Bortezomib anthracyclins Dexamethasone Lenalidomide Carfilzomib Melphalan Prednisone Pomalidomide Ixazomib Cyclophosphamide Oprozomib Doxorubicin Patient features Age Co-morbidities Performance status Myeloma features ISS Cytogenetics LDH Previous therapy Response Duration Adverse events Transplant? MoAbs Anti-CD38 (daratumumab, SAR, MOR) Anti-CS1 (elotuzumumab)

19 mabs in MM Van de Donk Leukemia 2012

20 DARATUMUMAB

21 CD38 as a Therapeutic Target High expression on myeloma cells combined with its role in cell signaling suggest CD38 as a potential therapeutic antibody target for treatment of multiple myeloma (MM) 1. Malavasi F, et al. Physiol Rev. 2008;88(3): Lin P, et al. Am J Clin Pathol. 2004;121(4): Santonocito AM, et al. Leuk Res. 2004;28(5): Deaglio S, et al. Leuk Res. 2001;25(1):

22 Generation of daratumumab Human Ig transgenic mice were immunized with recombinant CD38 protein and CD38-transfected NIH 3T3 cells Generation of hybridomas (fusion of mice spleen/lymph node cells with SP2/0 MM cells) Testing of 42 anti-cd38 mabs in CDC assays only one mab was capable to induce CDC this antibody was selected for further testing=daratumumab

23 Daratumumab binds to unique epitope (two beta strand-containing amino acids and of CD38

24 How do monoclonal antibodies work? Natural killer cell Monoclonal antibodies bind to the surface of the myeloma cell Macrophage As a results Adapted from: Golay & Introna M. Arch VU Biochem University Biophys Medical 2012 Center ;526(2): Tai & Anderson Amsterdam Bone Marrow The Res Netherlands 2011;2011:924058

25 Monoclonal antibodies bind to malignant cells and act through different modes of action Activation of natural killer cells Antibody-dependent cellular cytotoxicity (ADCC) Natural killer cell Macrophage Adapted from: Golay & Introna M. Arch VU Biochem University Biophys Medical 2012 Center ;526(2): Tai & Anderson Amsterdam Bone Marrow The Res Netherlands 2011;2011:924058

26 Monoclonal antibodies bind to malignant cells and act through different modes of action Activation of natural killer cells Antibody-dependent cellular cytotoxicity (ADCC) Natural killer cell Activation of macrophages Induction of phagocytosis (Antibodydependent cellmediated phagocytosis = ADCP) Macrophage Adapted from: Golay & Introna M. Arch VU Biochem University Biophys Medical 2012 Center ;526(2): Tai & Anderson Amsterdam Bone Marrow The Res Netherlands 2011;2011:924058

27 Monoclonal antibodies bind to malignant cells and act through different modes of action Activation of natural killer cells Antibody-dependent cellular cytotoxicity (ADCC) Activation of macrophages Induction of phagocytosis (Antibodydependent cellmediated phagocytosis = ADCP) Macrophage Natural killer cell Activation of the complement system Complement-dependent cytotoxicity (CDC) Adapted from: Golay & Introna M. Arch VU Biochem University Biophys Medical 2012 Center ;526(2): Tai & Anderson Amsterdam Bone Marrow The Res Netherlands 2011;2011:924058

28 Monoclonal antibodies bind to malignant cells and act through different modes of action Activation of natural killer cells Antibody-dependent cellular cytotoxicity (ADCC) Activation of macrophages Induction of phagocytosis (Antibodydependent cellmediated phagocytosis = ADCP) Macrophage Natural killer cell Activation of the complement system Complement-dependent cytotoxicity (CDC) Direct induction of apoptosis Apoptosis / growth arrest via targeting of signaling pathways Adapted from: Golay & Introna M. Arch VU Biochem University Biophys Medical 2012 Center ;526(2): Tai & Anderson Amsterdam Bone Marrow The Res Netherlands 2011;2011:924058

29 Daratumumab 3:1 Induction of ADCP Isotype control - Effector cell: mouse mø (green) - Target cell: Daudi (red) - In vitro 30 minutes

30 Macrophage-mediated Phagocytosis of CD38+ Tumor Cells in the Presence of Daratumumab 0 sec 300 sec 400 sec 500 sec 600 sec 700 sec 800 sec Time-lapse imaging microscopy, bright field images of mouse macrophages (arrow) that sequentially engulfed 5 individual Daudi cells (numbers) over a period of 800 seconds Overdijk MB, et al. MAbs. 2015;7(2):

31 Determinants of efficacy

32 Daratumumab: waterfall plot 16 mg/kg: ORR 35%

33 Van De Donk Cancer Manag Res 2012 LENALIDOMIDE

34 Nijhof Clinical Cancer Res 2015 DARA and Len: synergistic killing of MM cells from a LEN/Bort-double refractory MM patient

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36 MM3006 (cassiopeia) Screening (-28 days) Arm A Randomize #1 Arm B Stratify by: Cytogenetics, ISS, region VTD + Dara 4 cycles VTD 4 cycles Induction Phase Stage 1 Stem cell mobilization, conditioning, and transplant VTD + Dara 2 cycles VTD 2 cycles Consolidation Phase Subjects with PR or better Randomize #2 Stratify by: dara treatment, response, MRD status Stage 2 Dara Q8Wk until PD (maximum of 2 years) Followed by observation until PD Observation until PD Maintenance Phase Follow-up

37 Problems with antibodies in MM

38 Landsteiner In 1930 he received the Nobel Prize in Physiology or Medicine

39 Blood group system

40 Other blood groups Other blood groups: Kell / Kidd / duffy /.

41 Tranfusion with lamb=letal

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43 Blood transfusion

44 Antibodies against RBCs Naturally occurring antibodies (anti-a, anti-b) Acquired antibodies (anti-d (Rhesus)) Pregnancy Previous transfusion Transplant

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47 Treatment Interference With The Indirect Coombs Assay Negative Result Agglutination Positive Result Agglutination Treatment Interference False Positive Recipient Serum No Abs Donor RBCs Recipient Serum Containing Abs Donor RBCs Treated Serum Containing Drug A Abs Donor RBCs Coombs Reagent Coombs Reagent Coombs Reagent 47

48 Other new novel agents

49 MLN9708 (ixazomib citrate) MLN9708 is an orally availbale proteasome inhibitior

50 HOVON-126: Ixazomib-thalidomidedexamethason Randomized phase 2 study in NDMM 9Td Ixazomib until progression Ixazomib 1x/week oral Thalidomide 100 mg/day Dexamethasone 40 mg/week 9 cycles every 4 weeks Placebo until progression

51 HOVON 129 Primary plasma cell leukemia

52 Survival improvement in ppcl vs MM Multiple myeloma (Mayo) Primary PCL (SEER analysis) Early mortality due to aggressive presentation with severe complications Gonsalves Blood 2014; Kumar Leukemia 2014

53 CRd Carfilzomib + lenalidomide + dexamethasone (CRd) Relapsed/refractory setting Effective in relapsed/refractory myeloma patients 1 ASPIRE: phase 3 trial of lenalidomide + dexa ± carfilzomib ASH 2014: 1-3 lijnen; PFS 26.3 vs 17.1 months; trend for OS Frontline setting Rapid induction of high-quality responses and a favorable toxicity profile (myelosuppression limited, low rate of PNP) 2 High-rate of MRD-negative disease 3 1 Niesvizky CCR 2013; 2 Jakubowiak Blood 2012; 3 Korde ASH 2013 CRd Carfilzomib mg/m2 IV Day 1, 2, 8, 9, 15, 16 (20 mg/m2 on days 1 and 2 of cycle only) Lenalidomide 25 mg Days 1-21 Dexamethasone 40 mg once weekly days 1, 8, 15, and 22

54 Induction ppcl years (younger patients) 4x carfilzomiblenalidomidedexamethasone ppcl patients ppcl 66 years (elderly patients) 8x carfilzomiblenalidomidedexamethasone - EMN12/HOVON129 PCL Cyclophosphamide 2000 mg/m 2 + G-CSF Stem Cell Harvest High-dose melphalan (200 mg/m 2 ) Auto-SCT - no donor - ineligible for allo-sct - patient s wish High-dose melphalan (200 mg/m 2 ) Auto-SCT CRd is (currently) probably the most effective (induction) therapy for MM - Consolidation 2x carfilzomiblenalidomidedexamethasone RIC Allo-SCT (Allo-SCT in patients with a sibling or MUD donor. Conditioning: busulfanfludarabine) Maintenance carfilzomib: starting 2 months post-allo-sct for 6 months followed by lenalidomide plus carfilzomib until progression 4x carfilzomiblenalidomidedexamethasone carfilzomiblenalidomide 28 days cycle until progression Off protocol treatment

55 Carthadex Newly diagnosed MM Induction and consolidation with carfilzomibthalidomide-dexamethasone (CTd) Last cohort almost full!

56 Myeloma: prognosis Antibodies: DARA /SAR/ ELO

57 Questions?

58 VUmc, MM team MM group, clinical MM group, laboratory Henk Lokhorst Tuna Mutis Sonja Zweegman Anton Martens Niels van de Donk Richard Groen PhD students/technicians