Multiple Myeloma Therapies What lies in the future? Parameswaran Hari MD, MS Chief, Hematology Oncology Medical College of Wisconsin

Transcription

1 Multiple Myeloma Therapies What lies in the future? Parameswaran Hari MD, MS Chief, Hematology Oncology Medical College of Wisconsin

2 Conflict of Interest Am a consultant or advisor and grant recipient from virtually every company that works in the Myeloma field

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4 Framework for Newly Diagnosed MM Patient Treatment Plan Eligibility for Transplant: Co-morbidities PS Age Transplant Candidate Not Transplant Candidate Induction Therapy Induction therapy Stem Cell Harvest ASCT (early vs delayed) Maintenance or extended therapy phase Consolidation and/or Maintenance

5 MAINTENANCE AFTER TRANSPLANT: A MUST! CALGB IFM REF:

6 TRANSPLANT STUDIES IN MM (NOVEL ERA) Study Author Year N ISS III High risk cytogenetics Follow-up (months) Induction Conditioning SDT regimen Maintenance (HDT +SDT) GIMEMA RV- MM PI-209 Palumbo % 28.8% 51.2 Rd Mel 200 x 2 MPR TRANSPLANT for MM Continues to remain standard LEN (till progression) vs. None RV-MM-EMN- 441 Gay F % 21.8% 52 Rd MEL 200 x 2 CRD LEN + P vs. LEN (till progression) IFM/DFCI 2009 Attal M % 12.8% 44 RVD MEL 200 RVD x 8 LEN x 1 year EMN02/HO95 Cavo M % 25% 26 CyBorD MEL 200 x 1 or 2 VMP x 4 LEN till progression

7 MINIMAL RESIDUAL DISEASE AND TRANSPLANT ARMS MRD negativity (%) HDT (EARLY) 79% SDT (DELAYED) 65% Attal et al. NEJM 2017

8 Minimal Residual Disease: New Definitions for CR S.S. Patient Newly diagnosed 1 x Disease burden CR Stringent CR 1 x x 10 4 Molecular/flow CR Sequencing CR True Cure? 0.0

9 FDA Approved MRD testing

10 VACCINE POST TRANSPLANT(CTN 1401)

11 TREATMENT MILESTONES IN MULTIPLE MYELOMA Kenneth C. Anderson Clin Cancer Res 2016;22:

12 Prehistory Myeloma Multiple myeloma has probably been present as a human disease for centuries. There is evidence that multiple myeloma might date back to the time of the ancient Egyptians. Four cases of possible multiple myeloma were found in Native American skeletons from 200 to 900AD. Xray and skull 25 yrold female Indian with lytic lesions. Estimated to be from 200 to 900 AD. Anticancer Res.1999; Vol;19(5B): Bull NY Acad Med. 1974; Vol 50. p

13 Clinical Trials. MAKING MYELOMA History

14 New Drugs Are they Chemotherapy?

15 CD38 ANTIBODIES

16 TRANSPLANT INELGIBILBE- WHAT IS NEW?

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19 RANDOMIZE CAN WE MOVE DARATUMUMAB UPFRONT? INDUCTION TRANSPLANT CONSOLIDATION MAINTENANCE Dara-VRD x4 STEM CELL TRANSPLANT Dara-VRD X 2 Dara +LEN MMY2004 RANDOMZIED PHASE II TRIAL VRD x4 STEM CELL TRANSPLANT VRD X2 LEN

20 1:1 Randomization (N = 706) ALCYONE STUDY DESIGN VMP 9 cycles (n = 356) Key eligibility criteria: Transplant- ineligible NDMM ECOG 0-2 Creatinine clearance 40 ml/min No peripheral neuropathy grade 2 Bortezomib: 1.3 mg/m 2 SC Cycle 1: twice weekly Cycles 2-9: once weekly Melphalan: 9 mg/m 2 PO on Days 1-4 Prednisone: 60 mg/m 2 PO on Days 1-4 D-VMP 9 cycles (n = 350) Daratumumab: 16 mg/kg IV Cycle 1: once weekly Cycles 2-9: every 3 weeks D Cycles mg/kg IV Follow-up for PD and survival Primary endpoint: PFS Secondary endpoints: ORR VGPR rate CR rate MRD (NGS; 10 5 ) OS Safety Same VMP schedule + Every 4 weeks: until PD Stratification factors ISS (I vs II vs III) Region (EU vs other) Age (<75 vs 75 years) Cycles 1-9: 6-week cycles Cycles 10+: 4-week cycles Statistical analyses 360 PFS events: 85% power for 8-month PFS improvement a Interim analysis: ~216 PFS events ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; EU, European Union; SC, subcutaneously; PO, orally; D, daratumumab; IV, intravenously; PD, progressive disease; PFS, progression-free survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease; NGS, next-generation sequencing; OS, overall survival. a 8-month PFS improvement over 21-month median PFS of VMP.

21 % surviving without progression Median (range) follow-up: 16.5 ( ) months EFFICACY:PFS month PFS a 87% 18-month PFS a 80 72% 60 76% D-VMP Median: not reached No. at risk VMP D-VMP HR, 0.50 (95% CI, ; P <0.0001) Months 50% reduction in the risk of progression or death in patients receiving D-VMP % VMP Median: 18.1 months 0 0 HR, hazard ratio; CI, confidence interval. a Kaplan-Meier estimate. 21

22 QUIZ Walgreens Enema Syringe

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24 Relapsed, Refractory Disease: New Agents

25 CURREN TREAMENTS OPTIONS-- for relapse DARATUMAB-REVLIMID-DEXAMETHASONE DARATUMUMAB-VELCADE-DEXAMETHASONE DARATUMUMAB-POMALIDOMIDE-DEXAMETHASONE CARFILZOMOB-REVLIMID-DEXAMETAHSONE ELOTUZUMAB-REVLIMID-DEXAMETHASONE IXAZOMIB-REVLIMID-DEXAMETAHSONE

26 Phases of Clinical Trials Phase I studies primarily concerned with assessing the drug's safety. How much can be safely given? Phase II test for efficacy. How well does the drug work in this disease? Phase III How well does the new drug compare against standard treatment? Prevention Trials Diagnostic Trials Screening Trials Quality of Life Trials

27 Don t wait for other people Jump in

28 Not all trials succeed..

29 MAN O - GRAM

30 SELINEXOR Exportin 1 (XPO1) is the nuclear exporter for the majority of tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and eif4e-bound oncoprotein mrnas Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression

31 SELINEXOR: EFFICACY Category N ORR (%) CBR (%) VGPR (%) PR (%) MR (%) Overall (21%) 26 (33%) 4 (5%) 12 (15%) 10 (13%) Quad Refractory Penta Refractory 6 Doses / Month 8 Doses / Month (21%) 14 (29%) 2 (4%) 8 (17%) 4 (8%) 30 6 (20%) 12 (40%) 2 (7%) 4 (13%) 6 (20%) (20%) 15 (29%) 3 (6%) 7 (14%) 5 (10%) 27 6 (22%) 11 (41%) 1 (4%) 5 (19%) 5 (19%) Vogl DT, et al. Blood. 2016;128:491.

32 VENETOCLAX Venetoclax induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those positive for the translocation t(11;14), which correlates with higher ratios of BCL2 to MCL1 and BCL2 to BCL2L1 (BCL-X L ) mrna 1,2 1. Touzeau C, et al. Leukemia. 2014;28(1): Punnoose E, et al. Mol Cancer Ther. 2016;15(5):

33 P e rc e n ta g e o f P a tie n ts % N o t P r o g r e s s e d VENETOCLAX: EFFICACY 5 0 s C R C R V G P R P R T im e to P r o g r e s s io n 4 0 O R R 4 0 % 4% A ll P a tie n ts t(1 1 ;1 4 ) n o n -t(1 1 ;1 4 ) % O R R 2 1 % 3% 1 3 % % % 6% A ll P a t ie n t s N = % t( 1 1 ; 1 4 ) n = 3 0 O R R 6 % 3% 3% n o n - t ( 1 1 ; 1 4 ) n = M o n th s s in c e firs t d o s e N o. a t ris k N o. a t ris k N o. a t ris k Kumar S, et al. Blood. 2016;128:488.

34 BCMA expressed on normal and malignant plasma cells Promotes MM cell survival BCMA THE NEW TARGET BCMA-targeted therapies, including CAR T cells, show pre-clinical and early clinical activity in myeloma Penn/Novartis CART-BCMA cells Autologous T cell product Human anti-bcma scfv CD3ζ /41BB stimulatory domains Lentiviral vector CD3/CD28 bead-stimulated manufacturing Tai et al, Blood 2014; Carpenter et al, Clin Can Res 2013; Tai et al, Blood 2016; Ali et al, Blood 2016; Cohen et al, ASH 2016, #1147; Lin et al, EHA 2017; Fan et al ASCO 2017, #LBA3001; Singh R et al. submitted 2017

35 Pagel, J JAMA Oncol 2017

36 Ali SA, et al. Blood. 2016;128: BCMA CAR-T

37 37 TUMOR RESPONSE 800 x x x x 10 6 * *12 *21 *18 *16 *13 *10 7 * * *6 5 *3 *2 1 PD PD PD PD Patient 12 died of cardiopulmonary arrest Patient 4 died of MDS following discontinuation PD U PD Weeks on Study U PD U 17/18 (94%) ORR, 10/18 (56%) CR at active doses 9/10 evaluable patients MRD negative Durable ongoing responses over 1 year Responses continue to improve as late as month 15 (VGPR to CR) Median PFS not reached in active dose cohorts 4 patients progressed Median follow up 40 weeks CR/sCR VGPR PR Stable Disease PD Deceased U Unconfirmed response * MRD- MRD+ High Tumor Burden (>50% Bone Marrow Involvement)

38 38 Preferred Term SELECT TREATMENT EMERGENT TOXICITIES Dose Escalation Patients (N = 21) 1 Overall n (%) Grade 3 or higher n (%) Cytokine release syndrome 15 (71) 2 (10) Neurotoxicity 2 5 (24) 0 Neutropenia 18 (86) 18 (86) Thrombocytopenia 11 (52) 9 (43) Anemia 14 (67) 12 (57) 1 Data cut-off of October 2, Neurotoxicity includes the preferred terms: depressed level of consciousness, confusional state, bradyphrenia, somnolence No dose-limiting toxicities (DLTs) observed in dose escalation Cytopenias mostly related to Cy/Flu lymphodepletion Recovery to Grade < 3 cytopenias by Month 2 following infusion: ANC 1000/mm 3 70% of patients PLT 75/mm 3 75% of patients 5 deaths 3 due to disease progression at dose 2 in patients treated at active doses in CR at the time of death (cardiac arrest, MDS following discontinuation) 14 patients experienced 1 or more SAEs CRS* Grade 1-2 that required hospitalization per protocol (N=4) Pyrexia (N=2) *CRS uniformly graded according to Lee et al., Blood 2014;124:

39 COMPARISON OF BCMA TARGETED CAR-T CELLS Anti-BCMA CAR (1) Bb2121 (2) LCAR-B38M (3) CART-BCMA (4) Group/Company NCI Bluebird/Celgene/NCI Nanjing Legend Biotech Novartis/UPenn Binder/co-stimulatory signaling Murine/CD3 & CD28 Murine/CD3 & 41-BB Murine/CD3 & 41-BB Fully human/cd3 & 41-BB Transfection Gamma-retroviral Lentiviral Lentiviral Lentiviral Trial ID NCT NCT NCT NCT BCMA expression required? Yes Yes Yes No Median prior lines of therapy Reported Efficacy CR (relapsed), 7 PRs in 16 patients 10 CRs, 6 VGPRs, 1 PR in 18 patients 15 CRs and 13 PRs in 35 patients 2 CRs, 3 VGPRs, 6 PRs in 24 patients Safety Data Substantial but reversible 1 death, cardiopulmonary arrest (unrelated) Transient CRS 1 death progressive disease/candidemia 1. Ali S et al, Blood Berdeja J et al, ASH Wanghong Zao et al, ASCO Cohen A, et al. ASH 2017

40 x TARGETING BCMA: GSK GSK is a humanized - afucosylated IgG1 anti-bcma antibody conjugated to a microtubule disrupting agent MMAF via a stable, protease resistant maleimidocaproyl linker BCMA AD C BCMA Lysosome BCMA Malignant Plasma Cell BCMA Fc Receptor GSK ADC C Effecto r Cell Fc region of the Antibody Linker Target specific Enhanced ADCC Stable in circulation Cell death Drug MMAF (non cell permeable, highly potent auristatin 1. ADC mechanism 2. ADCC mechanism 3. Immunogenic cell death 4. BCMA receptor signalling inhibition Tai YT, et al. Blood. 2014;123(20):

41 DREAMM-1 RESPONSE ORR = 60% (21/35; 95% CI: 42.1%, 76.1%) 1 scr, 2 CR, 15 VGPR, 3 PR * Trudel et al. ASH 2017

42 RESPONSE contd.. Part 2 (N=35) Prior daratumumab (N=14) Refractory to both IMiD and PI (N=31) Refractory to IMiD, PI and prior daratumumab (N=12) scr % CR % VGPR % PR % NE % ORR* % (n = 21) (n = 6) (n = 18) (n = 5)

43 Progression-free Survival and duration of response Number of subjects 35 Progressed or died 15 (43%) Censored, f/u ended 3 (9%) Censored, f/u ongoing 17 (49%) Progression-free survival (months) Q1 (95% CI) 2.3 (0.7, 6.8) Median (95% CI) 7.9 (3.1, -) Q3 (95% CI) N/A Number of subjects 21 Progressed or died 4 (19%) Censored, f/u ended 0 Censored, f/u ongoing 17 (81%) Duration of response (months) Q1 (95% CI) 6.7 (1.6, -) Median (95% CI) N/A (6.7, -) Q3 (95% CI) N/A 43

44 mab-based Therapeutic Targeting of Tumor Antibody-dependent cellular cytotoxicity (ADCC) Complementdependent cytotoxicity (CDC) Apoptosis/growth arrest via targeting signaling pathways Antibody-delivery of toxic payload (ADC) Bispecific Monoclonal Antibodies Elotuzumab (SLAMF7) Daratumumab, Isatuximab, MOR202, TAK079 (CD38) Lucatumumab or dacetuzumab (CD40) Daratumumab, Isatuximab, MOR202, TAK-079 (CD38) Siltuximab (IL-6) BHQ880 (DKK1) RAP-011 (activin A) Daratumumab/ Isatuximab (CD38) Brentuximab (CD30) hun901-dm1 (CD56) nbt062-maytansinoid (CD138) GSK (BCMA) SGN (CD48A) BCMA SLAMF7 CD123 CD38 Adapted from Tai YT, Anderson KC. Bone Marrow Res. 2011;2011:

45 Bispecific Monoclonal Antibodies (BiTE, Duobodies, etc.) 2 BCMA BiTe 1 CD38 BiTe at MCW BCMA CD38 SLAMF7 Frankel SR et.al 2013 Current Opinion in Chemical Biology

46 Anti CD 74 Ab Drug Conjugate OPEN AT MCW Embry, M et al. Blood :4420

47 Antibody-coupled T cell receptor (ACTR) in Myeloma ACTR SEA-BCMA OPEN AT MCW Kudo K et. al Cancer Res 2014 Jan; 74(1):93-103, Cheema et al Cancer Res 2017

48 BCMA APRIL TACI AXIS

49 April Antibody in MM OPEN AT MCW Tai et al, Blood 2016

50 Neri P et al. CCR 2016 IMMUNE APPROACHES SUMMARY

51 Beyond Single Hypothesis Testing: Master Protocols Functional high-risk patients Profiling for alterations (NCT ) No detectable actionable alterations RAF/RAS mutations IDH activating mutations CCND1 activating alteration PI3K/AKT activating alterations FGFR3 activating alterations t(11;14) Backbone regimen + immune checkpoint inhibitor Backbone regimen MAPKi MAPKi + backbone regimen IDHi IDHi + backbone regimen CDKi CDKi + backbone regimen AKTi AKTi + backbone regimen FGFRi FGFRi + backbone regime BCLi BCLi + backbone regimen

52 Multiple Myeloma Precision Medicine Trials

53 RISK ASSESSMENT TOOLS

54 Sources of Information and what to do with them?

55 CONCLUSIONS Significant progress made in myeloma treatment armamentarium Disease relapse inevitable --- BUT Great potential with newer therapies (immune and non-immune approaches) Goal deep and lasting remissions; potential cure

56 NEW AGENT TRIALS AT MEDICAL COLLEGE OF WISCONSIN Vaccine (MM-DC fusion) PROMISS Oprozomib Anti cd 74 Anti-April Aduro BCMA BITE short acting / long acting Tak 079 anti CD38 GSK Car-T: 4 trials (UNM, JUNO, bb21, and Jansen)

57 AND CLINICAL TRIALS

58 QUESTIONS?

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