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Experimental Agents for Relapsed/Refractory Myeloma - Current Trials in Context Kenneth C. Anderson, M.D. Jerome Lipper Multiple Myeloma Center Dana-Farber.

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Presentation on theme: "Experimental Agents for Relapsed/Refractory Myeloma - Current Trials in Context Kenneth C. Anderson, M.D. Jerome Lipper Multiple Myeloma Center Dana-Farber."— Presentation transcript:

1 Experimental Agents for Relapsed/Refractory Myeloma - Current Trials in Context Kenneth C. Anderson, M.D. Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Harvard Medical School

2 Conflict of Interest: Kenneth C. Anderson, M.D. Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead Scientific Founder: Acetylon, Oncopep

3 Integration of Novel Therapy Into Myeloma Management Bortezomib, Lenalidomide, Thalidomide, Pegylated Liposomal Doxorubicin, Carfilzomib, Pomalidamide Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo Effective in relapsed/refractory, relapsed, induction, consolidation, and maintenance therapy Eight FDA approvals and median survival prolonged from 3-4 to 6-7 years, with additional prolongation from maintenance New approaches needed to treat and ultimately prevent relapse

4 VCAM-1 Fibronectin ICAM-1 LFA-1 MUC-1 VLA-4 Cytokines IL-6, VEGF IGF-1, SDF-1  BAFF, APRIL BSF-3 TNF  TGF  VEGF NF-  B BMSC adhesion molecules NF-  B Smad, ERK JAK/STAT3 MEK/ERK PI3-K GSK-3  FKHR Caspase-9 NF-  B mTOR Bad PKC Bcl-xL Mcl-1 MEK/ERK p27 Kip1 NF-  B Bcl-xL IAP Cyclin-D MM Survival Anti-apoptosis Cell cycle Survival Anti-apoptosis Cell cycle proliferation Survival Anti-apoptosis Akt migration Proliferation Anti-apoptosis cytokines Raf FGFR3 Adhesion Targeting Growth, Survival, and Drug Resistance of MM in BM Microenvironment Hideshima T and Anderson KC. Nat Rev Cancer 2007, SC CD40 CS1 BAFF-R Cell surface targets VEGFR

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6 Overview of Phase III Trials with Len and Bortezomib in Relapsed/Refractory MM 1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. 3. Richardson PG, et al. Blood. 2007;110:3557-3560. 4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-3901. 5. Weber D, et al. Blood. 2007;110:Abstract 412. RegimenTrialORR, % CR or nCR, % ≥ VGPR, % DOR, Mos TTP or PFS, Mos Median OS, Mos Len + dexMM-009 [1] 6124NE16 11 35 [5] Len + dexMM-010 [2] 6025NE1711 BortezomibAPEX [3] 4316NE8630 Vdox MMY- 3001 [4] 441327109NE

7 Palumbo et al. ASH 2010 abstr 620

8 SC vs. IV Bortezomib for Relapsed/Refractory Myeloma EQUIVALENT EFFICACY Peripheral Neuropathy Bortezomib IV (N=74) Bortezomib SC (N=148) P- value* Any PN event, %53380.04 Grade  2, % 41240.01 Grade  3, % 1660.03 Risk factors for PN, % Grade 1 PN at baseline2823 Diabetes at baseline1113 Exposure to prior neurotoxic agents8586 *P-values are based on 2-sided Fisher’s exact test Moreau et al. ASH 2010 abstr 312

9 When to Consider Retreatment Differences between biochemical relapse and symptomatic relapse need to be considered Patients with asymptomatic rise in M-protein can be observed to determine the rate of rise and nature of the relapse –Caveat: patients with known aggressive or high-risk disease should be considered for salvage even in the setting of biochemical relapse CRAB criteria are still listed as the indication to treat in the relapsed setting –C: Calcium elevation (> 11.5 mg/L or ULN) R: Renal dysfunction (serum creatinine > 2 mg/dL) A: Anemia (Hb < 10 g/dL or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis)

10 Considerations in Patients With Relapsed/Refractory Myeloma Previous therapy Response to previous therapy Patient characteristics and other prognostic factors –Older than 65 yrs of age –Increased β 2 -M, decreased serum albumin, low platelet count –Cytogenetic abnormalities: del(13q), t(4;14) –Renal dysfunction Up to 50% of patients with MM have renal dysfunction Between 20% and 30% of patients have concomitant renal failure –Extensive bone disease; extramedullary MM Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874. Facon T, et al. Blood. 2001;97:1566-1571. Barlogie B, et al. Blood. 2004;103:20-32. Fonseca R, et al. Cancer Res. 2004;64:1546-1558. Kyle RA. Stem Cells. 1995;13(suppl 2):56-63. Bladé J, et al. Arch Intern Med. 1998;158:1889-1893.

11 1.Development of immune therapies 2.Development of new oral proteasome inhibitors 3. Development of rationally based combination therapies 4. Identification of novel targets Current and Future Directions

12 Antibody-dependent Cellular cytotoxicity (ADCC) ADCC Effector cells: MM FcR Complement-dependent Cytotoxicity (CDC) CDC MM C1q Apoptosis/growth arrest via targeting signaling pathways MM  Lucatumumab or Dacetuzumab (CD40)  Elotuzumab (CS1)  Daratumumab (CD38)  XmAb5592 (HM1.24)  huN901-DM1 (CD56)  nBT062-maytansinoid (CD138)  1339 (IL-6)  BHQ880 (DKK1)  RAP-011 (activin A)  Daratumumab (CD38) MAb-Based Therapeutic Targeting of Myeloma Tai & Anderson Bone Marrow Research 2011

13 Phase II: Elotuzumab + Len + Low-Dose Dex in Rel/Ref MM (Study 1703) Len/dex: lenalidomide plus low dose dexamethasone † Progression defined by IMWG Criteria. Phase 2: Pts (n=73) with relapsed and/or refractory MM with 1-3 prior therapies were randomized to elotuzumab 10 or 20 mg/kg IV combined with –Lenalidomide 25 mg PO –Low-dose dexamethasone 40 mg PO Endpoints –Primary: ORR (≥PR per IMWG Criteria) –Key secondary endpoints: PFS and safety Phase 2 N=73 Phase 2 N=73 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE Elotuzumab 10 mg/kg IV + Len/dex n=36 Elotuzumab 10 mg/kg IV + Len/dex n=36 Elotuzumab 20 mg/kg IV + Len/dex n=37 Elotuzumab 20 mg/kg IV + Len/dex n=37 Phase 1* N=28 Phase 1* N=28 PROGRESSIONPROGRESSION PROGRESSIONPROGRESSION † *Lonial et al. J Clin Oncol. 2012 Richardson et al. ASH 2012

14 Efficacy: Maximum Percent Reduction in Serum M Protein* 10 mg/kg Elotuzumab (n=36)20 mg/kg Elotuzumab (n=29) † -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 Percentage Change from Baseline -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 Percentage Change from Baseline *Maximum percentage decrease from baseline to 60 d after permanent discontinuation of elotuzumab or start of new line of MM therapy. † Eight pts without measurable disease (baseline and all on-study serum M-protein levels <0.5 g/dL) were not included. Richardson et al. ASH 2012

15 ASH 2012: Progression Free Survival At a median follow-up of 20.8 mos, median PFS has not been reached in the 10 mg/kg arm –Preliminary median PFS of 26.9 mos was reported in the abstract; after 2.7 mos of additional follow-up, no new PD or death reported. These pts had an increased PFS duration, and in the updated analysis, median PFS was not yet reached Median Time to Progression/Death: 10 mg/kg (n=36): not yet reached 20 mg/kg (n=37): 18.6 mos (95% CI 12.9-29.7) 0 10 20 30 40 50 60 70 80 90 100 03 6 91215 18 2124273033 Mos Proportion of Progression Free Patients (%) 36323029232018 13930 Number at Risk: 3729262321171513 1030 10 mg/kg 20 mg/kg Richardson et al. ASH 2012

16 Phase 2 Elotuzumab + Lenalidomide Low- Dose Dex in Relapsed/Refractory MM Elotuzumab plus lenalidomide and low-dose dexamethasone has a high ORR in relapsed and relapsed/refractory MM –82% for all pts (91% in pts who had received only 1 prior therapy) –92% for pts treated with elotuzumab 10 mg/kg Median PFS was 33 mos for patients receiving elotuzumab 10 mg/kg The combination was generally well tolerated –Most common Grade 3/4 treatment-emergent AEs were neutropenia (16%), thrombocytopenia (16%), and lymphopenia (16%) –Premedication regimen decreased incidence and mitigated severity of infusion reactions* Richardson et al. ASH 2012, Lonial et al. ASCO 2013

17 Daratumumab A human CD38 mAb with broad-spectrum killing activity Lokhorst et al. EHA 2012 18 of 29 patients in phase I benefit (5PR,4MR,9SD)

18 Daratumumab Response Maximal Change in Paraprotein A A AA A A A A A A AA A A AA A A A A B B B B C A C C C C CC 2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg < 1 mg/kg A: serum M-component B: urine M-component C: FLC

19 Phase I/Ii Study of Daratumumab Cd38 Monoclonal Antibody in Relapsed/Refractory Mm Favorable safety profile as monotherapy In 15 of 32 (47%) showed benefit –4 patients achieving PR (13%) –6 patients achieving MR (19%) –5 patients achieving SD (16%) At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%) To be combined with lenalidomide & dexamethasone Plesner et al. ASH 2012 Abstr 73

20 Phase I Trial of Vaccination with DC/MM Fusions in Relapsed Refractory MM Well tolerated, no autoimmunity Induced tumor reactive lymphocytes in a majority of patients Induced humoral responses to novel antigens (SEREX analysis) Disease stabilization in 70% of patients Rosenblatt et al. Blood 2011; 117:393-402. DC/MM fusions induce anti- MM immunity in vitro and inhibit MM cell growth in vivo in xenograft models DC/MM fusions induce anti- MM immunity in vitro and inhibit MM cell growth in vivo in xenograft models Vasir et al. Brit J Hematol 2005; 129: 687-700 Vasir et al. Brit J Hematol 2005; 129: 687-700

21 20S 19S    5,  5i  1,  1i  2,  2i ATPases/ Cdc48 Potential Therapeutic Targets 26S PROTEASOME ATPADP UB enzymes E1, E2 and E3-UB-Ligases Ub Poly-ubiquitinated proteins (proteasome substrates) Free for re-cycling Six Protease activities Degraded protein Ub Immunoproteasome Proteasome: Present and Future Therapies Deubiquitylating Enzymes (DUBs)) Bortezomib, Carfilzomib, CEP-18770 ONX-0912 MLN 2238 NPI-0052:  5,  1,  2 55 PR-924 P5091 target USP-7

22 MLN2238/9708 Decreases Cell Viability in MM Cells and Overcomes Bortezomib Resistance 24h48h Chauhan et al. Clin Cancer Res, 2011; 17: 5311-21.

23 MLN9708 (Ixazomib) in Relapsed/Refractory MM Relapsed and refractory Refractory to most recent therapy (PD while on or within 60 days of last therapy) Relapsed and refractory Refractory to most recent therapy (PD while on or within 60 days of last therapy) Expansion cohorts Dose- escalation cohorts Dose-escalation: 3+3 schema, based on cycle 1 DLTs (modified Fibonacci dose sequence) 0.24→0.48→0.8→1.2→1.68→2.23→2.97→3.95 mg/m 2 Dose-escalation: 3+3 schema, based on cycle 1 DLTs (modified Fibonacci dose sequence) 0.24→0.48→0.8→1.2→1.68→2.23→2.97→3.95 mg/m 2 Bortezomib- relapsed Relapsed after previous bortezomib therapy but not refractory Bortezomib- relapsed Relapsed after previous bortezomib therapy but not refractory Proteasome inhibitor-naïve Relapsed after ≥1 therapy including an IMiD compound, no proteasome inhibitor Proteasome inhibitor-naïve Relapsed after ≥1 therapy including an IMiD compound, no proteasome inhibitor Prior carfilzomib Received prior carfilzomib and with relapsed or refractory disease Prior carfilzomib Received prior carfilzomib and with relapsed or refractory disease MTD established Oral single-agent MLN9708 administered on days 1, 8, and 15 of a 28-day cycle, for up to 12 cycles* Kumar et al. ASCO 2013

24 Weekly MLN9708 in Relapsed/Refractory Multiple Myeloma: Phase I Study Single-agent oral MLN9708 MTD 2.97 mg/m 2 on a weekly (days 1, 8, and 15 every 28 days) schedule Oral MLN9708 generally well tolerated –hematologic and gastrointestinal events generally manageable, low rate of discontinuations –Infrequent PN, only 1 grade 3 PN Pharmacokinetic profile supports weekly oral dosing Relapsed and/or refractory MM patients (median 4 prior lines of therapy) –ORR (≥PR) of 18%, plus 2% MR and 30% SD, including relapse post Bortezomib Kumar et al. ASCO 2013

25 MLN9708 in Relapsed and/or Refractory MM: Expansion Cohorts of a Phase 1 Dose-Escalation Study Richardson et al. ASH 2011 46 pts evaluable for response –21 in dose-escalation cohorts –30 in expansion cohorts (including 6 from dose-escalation cohorts) 6 pts have achieved ≥PR –1 CR, confirmed by bone marrow (PI-naïve expansion cohort) –5 PRs (1 each at 1.2 and 2.23 mg/m 2 in dose-escalation cohorts; 1 in RRMM and 2 in bortezomib-relapsed expansion cohorts) 1 pt achieved MR (bortezomib-relapsed expansion cohort; 40% M-protein reduction) All 7 pts remain in response, with duration of disease control of up to 15.9 months 28 pts have achieved SD –14 in dose-escalation cohorts –9, 5, and 2 in RRMM, bortezomib-relapsed, and PI-naïve expansion cohorts –Durable, with disease stabilization for up to 12.9 months

26 Phase 1/2 Study of MLN9708 Lenalidomide and Dex in Patients with Previously Untreated MM Oral weekly MLN9708, lenalidomide, and dexamethasone is well tolerated –incidence of PN has been limited At median drug exposure of 6 months, 92% PR or better, including ≥VGPR 55% and CR 23% –Responses increased with number of cycles and deepened over time –88% of patients achieving CR who were evaluable for MRD status were confirmed as MRD-negative A phase 3 trial of MLN9708 plus lenalidomide–dexamethasone versus placebo plus lenalidomide–dexamethasone in patients with relapsed and/or refractory MM is currently enrolling (NCT01564537) for new drug approval Kumar et al. ASH 2012 Abstr 332

27 Phase I clinical trials ongoing In Vitro Anti-MM Activity of Oral Chymotryptic Inhibitor ONX 0912 (Oprozomib) Myeloma Cell LinesPatient Tumor Cells Chauhan et al. Blood. 2010;116:490614.

28 Marizomib: A Non-Peptide Proteasome Inhibitor Induces Rapid, Broad and Prolonged Inhibition Chauhan et al. Cancer Cell 2005; 8: 407-19. Exhibits high levels of proteasome inhibition without toxicities associated with bortezomib Active in bortezomib and immunomodulator- resistant myeloma preclinically Marizomib (NPI-0052) H N O O O CH 3 OH Cl H H H

29 Responses to Marizomib +/- Dexamethasone in Evaluable Pts at Full Dose [ >0.4 mg/m 2 ]* Twice Weekly (n=21**) Richardson et al. ASH 2011 All Pts EBMT ≥ SD 11/2055% MR + PR 3/2015% Uniform Criteria ≥ SD 12/2157% PR + VGPR 4/2119% Pts Exposed to Bortezomib EBMT ≥ SD 11/1958% MR + PR 3/1916% Uniform Criteria ≥ SD 11/1958% PR + VGPR 3/1916% *As of 05 Dec 11 Response criteria defined with baseline SPEP ≥ 0.5 g/dL or UPEP ≥ 200 mg/24h with at least 2 assessments after treatment Day 1 for EBMT ; also by free lite for UC**. Refractory defined as having PD during or within 60 days of last regimen. Pts Refractory to Bortezomib EBMT ≥ SD 8/1267% MR + PR 2/1217% Uniform Criteria ≥ SD 8/1267% PR + VGPR 2/1217% Pts Refractory to Lenalidomide EBMT ≥ SD 8/1362% MR + PR 3/1323% Uniform Criteria ≥ SD 9/1464% PR + VGPR 4/1429% Median Duration of Response (all Pts) = 133 days (~ 5 mos)

30 Additional Targeted Therapies in Development KSP inhibitors (ARRY-520) AKT inhibitor (GSK2110183) Nuclear transport inhibitors (KPT) CDK inhibitors BTK inhibitors Bromodomain inhibitors

31 Protein protein aggregates (toxic) Ub 26S proteasome Ub Aggresome Panobinostat, Vorinostat, ACY1215 dynein Ub dynein Microtubule Autophagy Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912 Ub Lysosome HDAC6 Ub Development of Rationally based Combination Therapies (HDAC and Proteasome Inhibitors) Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:3441-9.

32 VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat or Placebo with Bortezomib in Relapsed MM The combination of vorinostat + bortezomib is active in patients with relapsed and refractory MM – Significant improvement in response rate – ORR 54% vs. 41% (P<0.0001); CBR 71% vs 53% (P<0.0001) PFS and TTP were prolonged in the combination arm compared with bortezomib alone PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4) versus 6.83 months (5.7–7.7) Diarrhea, fatigue, and thrombocytopenia limited tolerability. Dimopoulos et al. ASH 2011, Lancet Oncology, in press

33 Bench to Bedside Translation of HDAC 6 Selective Inhibitor ACY1215 Orally bioavailable, highly potent, selective inhibitor of HDAC 6 synthesized in fall 2009 Synergistic MM cytotoxicity with bortezomib in vitro and in vivo Favorable PK/PD, toxicity profile Phase Ia/Ib/II clinical trials of ACY1215, alone and with bortezomib and with lenalidomide/dexamethasone, ongoing; trials with pomalidomide and carfilzomib this year. Santo et al. Blood 2012;119:2579-89

34 Mutations in Myeloma 19 Patients Each With Newly Diagnosed and Relapsed MM Chapman et al. Nature 2011; 471: 467-72. Protein homeostasis: 42% including FAM46C, RPL10, RPS6KA1, EIF3B, XBP1, LRRK2 NF-kB signaling: 10 point mutations, 4 additional structural re- arrangements affecting coding Confers bortezomib sensitivity Histone methylating enzymes: WHSC1, UTX, MLL BRAF: 4% activating : Single patient MM response Andrulis et al Cancer Discovery 2013; 3: 862-9. PSMB5 b5 proteasome subunit mutation confers proteasome inhibitor resistance in laboratory, not identified in clinic Lichter et al. Blood 2012: 120: 4513-16.

35 1.Development of immune therapies 2.Development of new oral proteasome inhibitors 3. Development of rationally based combination therapies 4. Identification of novel targets Current and Future Directions

36 United Nations Against Myeloma: Bench to Bedside Research Team Kenneth Anderson Nikhil Munshi Paul Richardson Robert Schlossman Irene Ghobrial Steven Treon Jacob Laubach Deborah Doss Kathleen Colson Mary McKenney Kim Noonan Tina Flaherty Kathleen Finn Muriel Gannon Stacey Chuma Janet Kunsman Diane Warren Carolyn Revta Andrea Freeman Alexis Fields Andrea Kolligian John Feather Farzana Masood Nora Loughney Heather Goddard Tiffany Poon Nicole Stavitzski Ranjit Banwait Shawna Corman Heather Goddard Meghan Marie Leahy Caitlin O’Gallagher Christina Tripsas Karin Anderson Shannon Viera Katherine Redman Amber Walsh Samir Amin Wanling Xie Parantu Shah Holly Bartel Lisa Popitz Jeffrey Sorrell Teru Hideshima Constantine Mitsiades Dharminder Chauhan Noopur Raje Yu-Tzu Tai Ruben Carrasco James Bradner Gullu Gorgun Jooeun Bae Francesca Cottini Michele Cea Antonia Cagnetta Teresa Calimeri Edie Weller Ajita Singh Ze Tian Diana Cirstea Yiguo Hu Naoya Mimura Jiro Minami Sun-Yung Kong Weihua Song Douglas McMillin Catriona Hayes Steffen Klippel Jana Jakubikova Panisinee Lawasut Niels van de Donk Eugen Dhimolea Jake Delmore Hannah Jacobs Masood Shammas Mariateresa Fulciniti Jianhong Lin Jagannath Pal Samantha Pozzi Loredana Santo Claire Fabre Anuj Mahindra Rao Prabhala Jake Delmore Puru Nanjappa Michael Sellito Avani Vaishnav USA UK India Italy Japan Canada Germany China Greece Taiwan Australia Ireland Israel Turkey Austria


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