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Nieuwste middelen NIELS VAN DE DONK Department of Hematology, VU University Medical Center Amsterdam DHC2016, Januari 2016 VU University Medical Center Amsterdam The Netherlands Waar komen we vandaan ? VU University Medical Center Amsterdam The Netherlands 1844 1844: First description of Multiple Myeloma by Solly; 39-year old Sarah Newbury R/ rhubarb and orange skin Solly Med Chir Trans Lond 1844 VU University Medical Center Amsterdam The Netherlands 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 NY Acad Sci 1958; Bergsagel Cancer Chemother Rep 1962 VU University Medical Center Blokhin Ann NY Acad Sci 1958; Bergsagel Cancer Chemother Rep 1962 Amsterdam The Netherlands 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 VU University Medical Center Amsterdam The Netherlands 2000+: Anti-myeloma drugs IMIDs PIs Alkylators/ Steroids Thalidomide Bortezomib anthracyclins Dexamethasone Melphalan Prednisone Lenalidomide Cyclophosphamide Doxorubicin Patient features Age Co-morbidities Performance status Myeloma features ISS Cytogenetics LDH Previous therapy Response Duration Adverse events Transplant? Waar gaan we naar toe ? VU University Medical Center Amsterdam The Netherlands Nieuwste middelen Nieuwe medicijnen die toegepast worden in huidige Myeloom studies in Nederland Monoclonale antistoffen Daratumumab Durvalumab Elotuzumab Nieuwe proteasoom remmer Ixazomib Carfilzomib Nieuwe IMID Pomalidomide Andere middelen Selinexor VU University Medical Center Amsterdam The Netherlands Dara, SAR, ELo 2014 Behring en Ehrlich: magic bullet DARATUMUMAB VU University Medical Center Amsterdam The Netherlands CD38 as a Therapeutic Target 1. 2. 3. 4. 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) Malavasi F, et al. Physiol Rev. 2008;88(3):841-886. Lin P, et al. Am J Clin Pathol. 2004;121(4):482-488. Santonocito AM, et al. Leuk Res. 2004;28(5):469-477. Deaglio S, et al. Leuk Res. 2001;25(1):1-12. VU University Medical Center Amsterdam The Netherlands 12 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 VU University Medical Center Amsterdam The Netherlands How do monoclonal antibodies work? Monoclonal antibodies Natural killer cell the bind to surface of the myeloma cell Macrophage As a results…… Adapted from: VU University Medical Center Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53 Amsterdam The Res Netherlands Tai & Anderson Bone Marrow 2011;2011:924058 Monoclonal antibodies bind to malignant cells and act through different modes of action Activation of natural Natural killer killer cells cell Antibody-dependent cellular cytotoxicity (ADCC) Macrophage Adapted from: VU University Medical Center Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53 Amsterdam The Res Netherlands Tai & Anderson Bone Marrow 2011;2011:924058 Monoclonal antibodies bind to malignant cells and act through different modes of action Activation of natural Natural killer killer cells cell Antibody-dependent cellular cytotoxicity (ADCC) Activation of macrophages Induction of phagocytosis (Antibodydependent cellmediated phagocytosis = ADCP) Macrophage Adapted from: VU University Medical Center Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53 Amsterdam The Res Netherlands Tai & Anderson Bone Marrow 2011;2011:924058 Monoclonal antibodies bind to malignant cells and act through different modes of action Activation of natural Natural killer killer cells cell Antibody-dependent cellular cytotoxicity (ADCC) Activation of macrophages Activation of the complement system Complement-dependent cytotoxicity (CDC) Induction of phagocytosis (Antibodydependent cellmediated phagocytosis = ADCP) Macrophage Adapted from: VU University Medical Center Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53 Amsterdam The Res Netherlands Tai & Anderson Bone Marrow 2011;2011:924058 Monoclonal antibodies bind to malignant cells and act through different modes of action Activation of natural Natural killer killer cells cell Antibody-dependent cellular cytotoxicity (ADCC) Activation of macrophages Activation of the complement system Complement-dependent cytotoxicity (CDC) Induction of phagocytosis (Antibodydependent cellmediated phagocytosis = ADCP) Macrophage Direct induction of apoptosis Apoptosis / growth arrest via targeting of signaling pathways Adapted from: VU University Medical Center Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53 Amsterdam The Res Netherlands Tai & Anderson Bone Marrow 2011;2011:924058 Induction of ADCP Daratumumab 3:1 Isotype control - Effector cell: mouse mø (green) - Target cell: Daudi (red) - In vitro 30 minutes VU University Medical Center Amsterdam The Netherlands 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):311-321. VU University Medical Center Amsterdam The Netherlands 20 Daratumumab: waterfall plot 16 mg/kg: ORR 35% VU University Medical Center Lokhorst NEJM 2015 Amsterdam The Netherlands Van De Donk Cancer Manag Res 2012 LENALIDOMIDE VU University Medical Center Amsterdam The Netherlands Nijhof Clinical Cancer Res 2015 DARA and Len: synergistic killing of MM cells from a LEN/Bort-double refractory MM patient VU University Medical Center Amsterdam The Netherlands VU University Medical Center Amsterdam The Netherlands MMY3006 (cassiopeia) Screening (-28 days) Stratify by: Cytogenetics, ISS, region Randomize #1 Arm A Arm B VTD 4 cycles Stage 1 VTD + Dara 4 cycles Induction Phase Stem cell mobilization, conditioning, and transplant VTD + Dara 2 cycles VTD 2 cycles Consolidation Phase Subjects with PR or better Stage 2 Randomize #2 Dara Q8Wk until PD Stratify by: dara treatment, response, MRD status Observation until PD (maximum of 2 years) Followed by observation until PD Maintenance Phase Follow-up VU University Medical Center Amsterdam The Netherlands Other monoclonal antibodies Elotuzumab Immuun checkpoint remmers VU University Medical Center Amsterdam The Netherlands VU University Medical Center Amsterdam The Netherlands VU University Medical Center Amsterdam The Netherlands Myeloom: rem op de T cel T cel MM cel VU University Medical Center Amsterdam The Netherlands PD-L1 downregulates cytotocix T-cell activity to maintain immune homeostasis MM cell PD-L1 downregulates cytotocix T-cell activity to maintain immune homeostasis MM cell PD-L1 downregulates cytotocix T-cell activity to maintain immune homeostasis MM cell Targeting the PD-1/PD-L1 Pathway PD-1 immunologic checkpoint Postow, MA, et al. J Clin Oncol. 2015 Jan 20. [Epub ahead of print] Targeting the PD-1/PD-L1 Pathway PD-1 immunologic checkpoint Postow, MA, et al. J Clin Oncol. 2015 Jan 20. [Epub ahead of print] MM001 – Durvalumab – Durvalumab + pomalidomide – Durvalumab + pomalidomide + dexamethasone Other “new” novel agents VU University Medical Center Amsterdam The Netherlands MLN9708 (ixazomib citrate) MLN9708 is an orally availbale proteasome inhibitor VU University Medical Center Amsterdam The Netherlands HOVON-126: Ixazomib-thalidomidedexamethason Randomized phase 2 study in NDMM Ixazomib until progression 9Td Ixazomib 1x/week oral Thalidomide 100 mg/day Dexamethasone 40 mg/week 9 cycles every 4 weeks Placebo until progression VU University Medical Center Amsterdam The Netherlands Carfilzomib VU University Medical Center Amsterdam The Netherlands Background Carfilzomib • Carfilzomib is a selective irreversible proteasome inhibitor1,2 – Sustained target suppression – Effective in bortezomib-refractory disease – Low frequency of polyneuropathy Tetrapeptide H N N O 1. 2. O O N H Adapted from Kuhn DJ, et al. Blood. 2007;110:3281-3290. Arastu-Kapur S, et al. Clin Cancer Res. 2011;17:2734-2743. H N O Epoxyketone O O N H O Carfilzomib versus bortezomib VU University Medical Center Amsterdam The Netherlands HOVON 129 Primary plasma cell leukemia Meest agressieve myeloom variant Tumorcellen stromen vanuit beenmerg uit naar het bloed Slechte prognose VU University Medical Center Amsterdam The Netherlands 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 KRd • Carfilzomib + lenalidomide + dexamethason EMN12: Elderly patients: ≥65 years Induction Maintenance 8 x carfilzomiblenalidomidedexamethasone Lenalidomide 10 mg daily on days 1-21 Carfilzomib once daily on days 1,2,15,16 until progression EMN12: Younger patients Induction Auto-SCT Consolidation 4 x carfilzomiblenalidomidedexamethasone High-dose melphalan (200 mg/m2) 2 x carfilzomiblenalidomidedexamethasone Stem cell harvest RIC Allo-SCT -allo-SCT in patients with a sibling or MUD donor -Conditioning: busulfan+fludarabine Maintenance carfilzomib: starting 2 months post-alloSCT for 6 months; followed by lenalidomide plus carfilzomib until progression Carthadex Newly diagnosed MM Induction and consolidation with carfilzomibthalidomide-dexamethasone (CTd) Last cohort almost full ! VU University Medical Center Amsterdam The Netherlands Anti-myeloma drugs: 2016 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) Anti-PD1/anti-PD-L1 (nivolumab/durvalumab/..) Myeloma: prognosis Antibodies: DARA /SAR/ ELO VU University Medical Center Amsterdam The Netherlands Questions ? VU University Medical Center Amsterdam The Netherlands VUmc, MM team MM group, clinical Henk Lokhorst Sonja Zweegman Niels van de Donk MM group, laboratory Tuna Mutis Anton Martens Richard Groen PhD students/technicians VU University Medical Center Amsterdam The Netherlands Problems with antibodies in MM VU University Medical Center Amsterdam The Netherlands Landsteiner In 1930 he received the Nobel Prize in Physiology or Medicine VU University Medical Center Amsterdam The Netherlands Blood group system VU University Medical Center Amsterdam The Netherlands Other blood groups Other blood groups: Kell / Kidd / duffy / …. VU University Medical Center Amsterdam The Netherlands Tranfusion with lamb=letal VU University Medical Center Amsterdam The Netherlands VU University Medical Center Amsterdam The Netherlands Blood transfusion VU University Medical Center Amsterdam The Netherlands Antibodies against RBCs Naturally occurring antibodies (anti-A, anti-B) Acquired antibodies (anti-D (Rhesus)) Pregnancy Previous transfusion Transplant VU University Medical Center Amsterdam The Netherlands VU University Medical Center Amsterdam The Netherlands VU University Medical Center Amsterdam The Netherlands Treatment Interference With The Indirect Coombs Assay Y Donor RBCs Treated Serum Containing Drug A Abs Y Y Y Y Y Y Y YY Y Y Y YY Y Y Coombs Reagent Coombs Reagent Y Y Y Y Y Y Y Y Y Y Y Coombs Reagent Y Y Y Y YY Donor RBCs Y Recipient Serum Containing Abs Y Donor RBCs Treatment Interference False Positive Y Recipient Serum No Abs Positive Result Agglutination Y Negative Result Agglutination Y 68 Y Phase 2 study : KRd upfront Induction Auto-SCT Consolidation 4x KRd High-dose melphalan (200 mg/m2) 4x KRd After 4x KRd PostAfter 8x transplant KRd After 18x KRd ≥PR 98 100 100 100 ≥VGPR 78 97 100 100 ≥nCR 14 44 91 100 sCR 10 25 70 86 Maintenance KRd with K on days 1,2,15,16 Cycle 9-18 Maintenance Lenalidomide Cycle 19+ PFS 1 year: PFS 2 yr: OS 1 yr: OS 2 yr: 98% 98% 100% 100% Zimmermann ASCO 2015 abstract 2850; Jakubowiak IMW 2015