Presentation on theme: "Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute"— Presentation transcript:
1 Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute New Paradigms, New Treatments in Relapsed/Refractory Disease: An UpdateKenneth C. Anderson, M.D.Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer InstituteHarvard Medical School
2 Conflict of Interest: Kenneth C. Anderson, M.D. Consultancy: Celgene, Onyx, Sanofi Aventis, and GileadScientific Founder: Acetylon, Oncopep
3 Integration of Novel Therapy Into Myeloma Management Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib, PomalidamideTarget MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivoEffective in relapsed/refractory, relapsed, induction, consolidation, and maintenance therapyEight FDA approvals and median survival prolonged from 3-4 to 6-7 years, with additional prolongation from maintenanceNew approaches needed to treat and ultimately prevent relapse
4 There is a well defined and recognized unmet need in multiple myeloma treatment FrontlineTreatmentRelapsedRelapsed or IntolerantExpectedsurvival (m)20-50Sensitivity totherapySensitiveTreatment limitations/comorbiditiesPeripheral neuropathy (~15% at diagnosis)14-16Less Sensitive/Resistant>80% incidence of peripheral neuropathy Compromised marrow reserveCytopenia6-10ResistantIntolerant to orineligible for available therapyElderly population ( risk for heart, lung, renal, liver dysfunction, diabetes)Adapted from: Durie BGM. Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition.Jagannath S. Clin Lymphoma Myeloma. 2008;8 Suppl 4:S149-S156.For Planning Purpose Only Not Reviewed by Legal or Regulatory
6 Overview of Phase III Trials with Len and Bortezomib in Relapsed/Refractory MM RegimenTrialORR, %CR or nCR, %≥ VGPR, %DOR, MosTTP or PFS, MosMedian OS, MosLen + dexMM-0096124NE161135MM-010602517BortezomibAPEX438630VdoxMMY-30014413271091. Weber DM, et al. N Engl J Med. 2007;357: Dimopoulos M, et al. N Engl J Med. 2007;357: Richardson PG, et al. Blood. 2007;110: Orlowski RZ, et al. J Clin Oncol. 2007;25: Weber D, et al. Blood. 2007;110:Abstract 412.6
8 SC vs IV Bortezomib for Relapsed/Refractory Myeloma Moreau et al, ASH 2010 abstr 312EQUIVALENT EFFICACYPeripheral NeuropathyBortezomib IV (N=74)Bortezomib SC(N=148)P- value*Any PN event, %53380.04Grade 2, %41240.01Grade 3, %1660.03Risk factors for PN, %Grade 1 PN at baseline2823Diabetes at baseline1113Exposure to prior neurotoxic agents8586*P-values are based on 2-sided Fisher’s exact test
9 Bortezomib, Lenalidomide and Dex Therapy Lenalidomide induces caspase 8 mediated apoptosis of MM cells in BM in vitro and in vivo; Dex (caspase 9) enhances responseSynergistic MM cell toxicity of lenalidomide (caspase 8) with Bortezomib (caspase 9>8) in vitro and in vivo (dual apoptotic signaling)Phase I-II trials show that majority (58%) of patients refractory to either agent alone respond to the combinationPhase I-II trials show 100% response with 74% CR/VGPR and 52% CR/nCR when used as initial therapy, including molecular responses.Richardson et al. JCO 2009; 27:Richardson et al. Blood 2010; 116:9
10 Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor Novel chemical class with highly selectiveand irreversible proteasome bindingImproved antitumor activity withconsecutive day dosingNo neurotoxicity in animalsDurable responses in relapsed and relapsed/ refractory MM w/o neuropathyCarfilzomib lenalidomide Dex versus lenalidomide Dex phase III trial for new drug approvalEpoxyketoneTetrapeptideDemo et al. Cancer Res 2007; 67:6383Kirk et al., Blood 2008, 112: Siegal et al. Blood 2012:120:2817.
11 Category (XX)4/15/2017Benefit of Carfilzomib in Relapsed/Refractory MM: Meaningful ORR, DOR and OSResponse CategoryTotal N = 266, n (%)1 (0.4)VGPR13 (4.9)PR47 (17.7)MRCRSD81 (30.5)PD69 (25.9)Not evaluable21 (7.9)ORR = 22.9%(95% CI: 18.0, 28.5)CBR = 35.7% (95% CI: 30.0, 41.8)Duration of responseMedian DOR = 7.8 months (95% CI: 5.6, 9.2)Overall SurvivalMedian OS = 15.4 months (95% CI: 12.5, 19.0)DRAFT
12 Jakubowiak A. et al., Blood, 2012; 120: 1801-8. CRd in Relapsed and Upfront MM Wang et al ASCO 2011; Jakubowiak et al ASH 2011Response to CRd therapy was high, with an ORR of 78%41% VGPR or betterCRd well-tolerated with durable responsesASPIRE phase 3 open-label, international, multicenter trial comparing CRd to Rd in R/R MM fully enrolled.Remarkable extent and frequency of response to CRd upfront (100% ORR, 80% CR,nCR after 12 cycles)Jakubowiak A. et al., Blood, 2012; 120:1212
13 Carfilzomib in Relapsed/Refractory MM StudyPhBTZ statusnMedian prior tx linesCFZ doseMode ofadminORRPX A11IIRelapsed andrefractory266520/27 mg/m22-10 min IV infusion24%PXI/IIRelapsed and/or204.520/56 mg/m230-min IV infusion60%Siegel et al. Blood. 2012;120(14):Papadopoulos KP, et al. Blood. 2011;118(21):Abstract and poster 2930.
14 Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory MM CFZ dose of 20/56 mg/m2 administered as a 30-minute IV infusion resulted in high response rates in our BTZ treated/refractory population.Response rates were comparable to those seen in PXCFZ dose of 20/56 mg/m2 was associated with more frequent cardiac and pulmonary toxicities, particularly HTN and pulmonary edema/CHF.Possible contribution from “supportive” measures?CFZ dose of 20/56 mg/m2 continues to be explored in ongoing Phase II/III studies.Lendvai et al, ASH 2012 Abstr 947
15 Pomalidomide in Myeloma CMM cellsIL-6TNFIL-1BABone Marrow Stromal CellsICAM-1Bone Marrow VesselsNFATIL-2IFN PKCIL-2NK CellsNK-T CellsVEGFbFGFPI3KCD28CD8+ T CellsDendriticCellsDEMitsiades et al. Blood 99: 4525, 2002Lentzsch et al Cancer Res 62: 2300, 2002LeBlanc R et al. Blood 103: 1787, 2004Hayashi T et al. Brit J Hematol 128: 192, 2005Hideshima et al. Blood 96: 2943, 2000Davies et al. Blood 98: 210, 2001Gupta et al. Leukemia 15: 1950, 2001
16 Pomalidomide With Low-Dose Dexamethasone Relapsed and Refractory Multiple Myeloma POM was effective in heavily pretreated patients who had already received LEN and bortezomib and who progressed on their last line of therapyThe combination of POM with LoDEX improves the ORR due to synergy between immunomodulatory agents and glucocorticoidsPOM + LoDEX, 34%; POM alone, 15%Response was durable with POM regardless of the addition of LoDEXPOM + LoDEX, 8.3 months ; POM alone, 8.8 monthsPOM is generally well tolerated, with low rates of discontinuations due to AEsAge had no impact on ORR, DoR, or safetyJagannath S, et al. ASH 2012 abstract 450.
17 Pom/Dex is well tolerated Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Myeloma (345 patients)Pom/Dex has high response rates even in heavily pretreated relapsed myelomaPom/Dex is well toleratedToxicity and efficacy are similar between the 2mg and 4mg dose levelsThe strongest predictors of response include the number and type of prior regimens.The strongest predictors of TTP and survival include the number and type of prior regimens, LDH, and B2M.Lacy et al. ASH 2013 Abstr 201.
18 A Phase III Clinical Trial of Pomalidomide with Low-dose Dex vs A Phase III Clinical Trial of Pomalidomide with Low-dose Dex vs. High-dose Dex in Relapsed/Refractory MMPOM + LoDEX significantly improved PFS and OSMedian PFS: 3.6 vs 1.8 monthsHR = 0.45; P < .001Median OS: not reached vs 7.8 monthsHR = 0.53; P < .001Equal benefit in pts refractory to both LEN and BORTPOM + LoDEX was generally well toleratedPOM + LoDEX should be considered as a new treatment option for these ptsDimopoulos et al. ASH 2013 LBA6
19 MM-005: A Phase 1 Trial of Pomalidomide, Bortezomib, and Low-dose Dexamethasone in Relapsed or Relapsed/Refractory MMPOM + BORT + LoDEX (PVD) well toleratedcohort 5 as the MTD/MPDPOM 4 mg; BORT 1.3 mg/m2; DEX 10/20 mgResponses in RR MM across all cohortsORR: 73%, VGPR: 27%, SD: 27%Responses were rapid; majority are ongoingEfficacy even with adverse cytogeneticsPhase III Trial Pom Bort Dex vs Bort Dex for full approvalRichardson et al. ASH 2013 Abstr 727.
20 Carfilzomib Pomalidomide Dexamethasone (Car-Pom-d) in Relapsed/Refractory MM MTD was Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg, and dexamethasone 40 mgThere are limited G 3 and 4 non hematologic toxicities; the regimen was tolerated well with no unexpected toxicityThe combination of Car-Pom–d is highly active in this heavily pretreated, refractory patient populationThe combination has encouraging preserved response rate and survival independent of FISH/cytogenetic risk status≥ VGPR 13%≥ ORR 50%≥ CBR 67%PFS (median) 7.4 monthsOS 1 yearShah et al. ASH 2012 Abstr 74.
21 Current and Future Directions Development of immune therapiesDevelopment of novel agents targeting the MM cell in the BM microenvironment3. Development of rationally-based combination therapies4. Utilization of genomics for improved classification and personalized therapyMyeloma will be a chronic illness, with sustained CR in a significant fraction of patients.
22 MAb-Based Therapeutic Targeting of Myeloma Antibody-dependentCellular cytotoxicity (ADCC)Apoptosis/growth arrestvia targetingsignaling pathwaysComplement-dependentCytotoxicity (CDC)Effector cells:MMFcRMMC1qMMCDCADCCDaratumumab (CD38)huN901-DM1 (CD56)nBT062-maytansinoid(CD138)1339 (IL-6)BHQ880 (DKK1)RAP-011 (activin A)Daratumumab (CD38)Lucatumumab or Dacetuzumab (CD40)Elotuzumab (CS1)Daratumumab (CD38)XmAb 5592 (HM1.24)Tai & Anderson Bone Marrow Research 2011
23 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 MM82% for all pts (91% in pts who had received only 1 prior therapy)92% for pts treated with elotuzumab 10 mg/kgMedian PFS was 33 mos for patients receiving elotuzumab mg/kgThe combination was generally well toleratedMost 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 201323
24 PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN RELAPSED/REFRACTORY MM Favorable safety profile as monotherapyIn 15 of 32 (47%) showed benefit4 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 dexamethasonePlesner et al. ASH 2012 Abstr 73.
25 Phase I Trial of Vaccination with DC/MM Fusions in Relapsed Refractory MM Well tolerated, no autoimmunityInduced tumor reactive lymphocytes in a majority of patientsInduced humoral responses to novel antigens (SEREX analysis)Disease stabilization in 70% of patientsDC/MM fusions induce anti-MM immunity in vitro and inhibit MM cell growth in vivo in xenograft modelsVasir et al. Brit J Hematol 2005; 129:Rosenblatt et al. Blood 2011; 117:
26 Background: MM/DC Vaccination following Autologous PBSCT for Myeloma Rosenblatt et al., CCR 2013
27 PD-L1 Plays an Important Role in Dampening the Anti-tumor Immune Response cancer cellPD-L1lymphocyteIFNg-mediated up-regulation of tumor PD-L1PD-L1/PD-1-mediated Inhibition of tumor cell killingreceptorPresence of intratumoral T-cells may lead to adaptive immune resistancePriming andActivation of T cellsPD-L1 expression in the tumor microenvironment can inhibit anti-tumor T cell activity:PD-L1 expression by tumor infiltrating immune cellsPD-L1 expression by cancer cellsImmune cell modulation of T cellsStromal PD-L1 modulation of T cellsPD-L2 mediated inhibition of TH-2 T cellsChen DS, Irving BA, Hodi FS. Clin Cancer Res. 2012;18:6580.
28 Combination Immunotherapy Posttransplant Anti PD-1 Ab administration in the early post-autologous transplant period is well toleratedAnti-PD1 results in the expansion of tumor reactive lymphocytes in the post-transplant period that persist at 6 monthsThis provides a promising platform for combination with a tumor vaccineWe have inititated enrollment into cohort 2, in which patients receive an autologous DC/myeloma fusion vaccine 1 week prior to each dose of Anti-PD-1AbAvigan et al.
29 Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy b5, 5i1, 1i2, 2iATPases/Cdc48PotentialTherapeutic Targets26S PROTEASOMEATPADPUB enzymes E1, E2 andE3-UB-LigasesUbPoly-ubiquitinated proteins(proteasome substrates)Freefor re-cyclingSix ProteaseactivitiesDegraded proteinImmunoproteasomeProteasome: Present and Future TherapiesDeubiquitylatingEnzymes (DUBs)Bortezomib,Carfilzomib,CEP-18770ONYX-0912MLN 2238NPI-0052: 5, 1, 25PR-924P5091 target USP-729
30 P5091 Specifically Target USP-7 and does not Alter Proteasome Activity USP-7 KnockoutProteasome Activity AssayP5091 (µM)Velcade (nM)Chauhan et al. Cancer Cell 2012;22:
31 P5091 Overcomes Bortezomib-Resistance in MM Cells Chauhan et al. Cancer Cell 2012; 22:
32 MLN2238/9708 Decreases Cell Viability in MM Cells and Overcomes Bortezomib-Resistance 24h48hChauhan et al.,Clin Cancer Res,2011; 17:
33 Weekly MLN9708 in Relapsed/Refractory Multiple Myeloma: Phase I Study Single-agent oral MLN9708 MTD mg/m2 on a weekly (days 1, 8, and 15 every 28 days) scheduleOral MLN9708 generally well toleratedhematologic and gastrointestinal events generally manageable, low rate of discontinuationsInfrequent PN, only 1 grade 3 PNPharmacokinetic profile supports weekly oral dosingRelapsed and/or refractory MM patients (median 4 prior lines of therapy)ORR (≥PR) of 18%, plus 2% MR and 30% SD, including relapse post BortezomibKumar ASCO 2013
34 MLN9708 in Relapsed and/or Refractory MM: Expansion Cohorts of a Phase 1 Dose-Escalation study 46 pts evaluable for response21 in dose-escalation cohorts30 in expansion cohorts (including 6 from dose-escalation cohorts)6 pts have achieved ≥PR1 CR, confirmed by bone marrow (PI-naïve expansion cohort)5 PRs (1 each at 1.2 and 2.23 mg/m2 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 months28 pts have achieved SD14 in dose-escalation cohorts9, 5, and 2 in RRMM, bortezomib-relapsed, and PI-naïve expansion cohortsDurable, with disease stabilization for up to 12.9 monthsRichardson et al. ASH 2011
35 In Vitro Anti-MM Activity of Oral Chymotryptic Inhibitor ONX 0912 (Opromazib)Myeloma Cell LinesPatient Tumor CellsPhase I clinical trials ongoingChauhan et al. Blood. 2010;116:490614
36 Marizomib: A Non-Peptide Proteasome Inhibitor Induces Rapid, Broad and Prolonged Inhibition Marizomib (NPI-0052)HNOC3lExhibits high levels of proteasome inhibition without toxicities associated with bortezomibActive in bortezomib and IMiD resistant myeloma preclinicallyChauhan et al., Cancer Cell 2005; 8:
37 Responses to Marizomib +/- Dexamethasone in Evaluable Pts at Full Dose [ >0.4 mg/m2 ]* Twice Weekly (n=21**)All PtsEBMT≥ SD11/2055%MR + PR3/2015%Uniform Criteria12/2157%PR + VGPR4/2119%Pts Refractory to BortezomibEBMT≥ SD8/1267%MR + PR2/1217%Uniform CriteriaPR + VGPRMedian Duration of Response (all Pts) = 133 days (~ 5 mos)Pts Exposed to BortezomibEBMT≥ SD11/1958%MR + PR3/1916%Uniform CriteriaPR + VGPRPts Refractory to LenalidomideEBMT≥ SD8/1362%MR + PR3/1323%Uniform Criteria9/1464%PR + VGPR4/1429%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.*As of05 Dec 11Richardson et al. ASH 2011
38 Functional Sequelae of Btk Inhibition by PCI-32765 in the MM BM milieu Stem CellMMPCI32765TRAP5bSDF-1IL-8Activin AAPRILMIP-1MIP-1TGF1RANTESBAFFPCI32765Colony formationBtk activation by IL-6, SDF-1TumormicroenvironmentAdhesionMigrationHomingIL-6SDF-1MIP-1MIP-1M-CSFMCP-1MIP-1, MIP-1, IL-8, TGF1RANTES, BAFF, TRAF2, CXCR4, LAT, PLC2, MYD88, NFATc1BoneresorptionPCI-32765M-CSF, IL-6, MCP-1RANKM-CSFfmsStromal cellsOsteoclast precursorsOsteoclastTai et al. Blood2012; 120:
39 BET Bromodomain Inhibition Suppresses c-myc Expression and Function and Triggers Anti-MM Activity Delmore JE., Issa GC, et al. Cell 2011; 146:904.
40 Additional Targeted Therapies in Development KSP inhibitors (Array 520)AKT inhibitor (GSK agent)Nuclear transport inhibitors (KPT)CDK inhibitors
41 Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Development of Rationally-based Combination Therapies (HDAC and Proteasome Inhibitors)ProteinUbprotein aggregates(toxic)UbUbUbUb26S proteasomeHDAC6Bortezomib, Carfilzomib, NPI0052,MLN9708, ONX 0912UbPanibinostat,Vorinostat, ACY1215HDAC6dyneinUbLysosomeAggresomeHDAC6UbUbdyneinMicrotubuleAutophagyHideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:
42 PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4) VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat or Placebo with Bortezomib in Relapsed MMThe combination of vorinostat + bortezomib is active in patients with relapsed and refractory MMSignificant improvement in response rateORR 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 alonePFS hazard ratio reduction of 23% (P=0.01); months (6.9–8.4)versus 6.83 months (5.7–7.7)Diarrhea, fatigue, and thrombocytopenia limited tolerabilityDimopoulos et al. ASH 2011, Lancet Oncology, in press4242
43 Bench to Bedside Translation of HDAC 6 Selective Inhibitor ACY 1215 Orally bioavailable, highly potent, selectiveinhibitor of HDAC 6 synthesized in fall 2009Synergistic MM cytotoxicity with Bortezomibin vitro and in vivoFavorable PK/PD, toxicity profilePhase 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:
44 Mutations in Myeloma 19 Patients Each With Newly Diagnosed and Relapsed MM Protein homeostasis: 42% including FAM46C, RPL10, RPS6KA1, EIF3B, XBP1, LRRK2NF-kB signaling: 10 point mutations, 4 additional structural re-arrangements affecting codingConfers bortezomib sensitivityHistone methylating enzymes: WHSC1, UTX, MLLBRAF: 4% activating : Single patient MM responseAndrulis et al Cancer Discovery 2013; 3:PSMB5 b5 proteasome subunit mutation confers proteasome inhibitor resistance in laboratory, not identified in clinicLichter et al Blood 2012: 120:Chapman et al. Nature 2011; 471:
45 (Munshi et al, ASH 2011 Abstract 276) Whole Genome Sequencing Identifies Acquisition of New Changes in MM: 71 Patient Study(Munshi et al, ASH 2011 Abstract 276)New mutations in late sampleEarly mutationnot in late sampleEarly TumorLate TumorEarly TumorLate TumorEARLYLATE
46 Relapsed Refractory Myeloma Lenalidomide dexamethasone, bortezomib, and pegylated doxorubicin are approved regimens for relapsed MM.Pomalidomide/dex and carfilzomib are newly FDA approved options.There are many promising protocols of novel immune and targeted agents which show promise, alone and in combination.4. Genomic analyses are both defining the basis for evolution underlying relapse and identifying new targets.
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