Presentation on theme: "Developments in the Treatment of Multiple Myeloma"— Presentation transcript:
1 Developments in the Treatment of Multiple Myeloma Kenneth C. Anderson, M.D.Kraft Family Professor of MedicineHarvard Medical SchoolDirector, Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute
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 MM and now part of induction, consolidation, and maintenance therapyNine FDA approvals in the last decade and median survival prolonged from 2-3 yrs to at least 5-7 yrs, with additional prolongation seen from maintenanceNew approaches needed to treat and ultimately prevent relapse
5 Chromosomes and Prognosis in Multiple MyelomaFor conventional low and high dose theapy:Nonhyperdiploid worse prognosis than hyperdiploidt(11;14), hyperdiplody -standard riskt(4;14), t(14;16),t(14;20), del(17p), del(13q14)-high riskFor novel treatmentsBortezomib, but not lenalidomide, can at least partially overcome t(4;14), del(13q14)-del(17p) p53 remains high risk
6 Combinations in the Upfront Treatment of MM Stewart AK, Richardson PG, San Miguel JF Blood 2009
7 Lenalidomide and Bortezomib/Lenalidomide-Based Consolidation Study detailsResponse dataIFMLen consolidation (2 mos)Maintenance randomization: Len vs placeboIFM 20082VRD inductionASCTVRD consolidation (2 cycles)Len maintenancen=572Pre-consolidationPost-consolidationpCR (IF–)14%20%<0.0001≥ VGPR58%67%n=31Post-inductionPost-ASCTPost-consolidationsCR13%26%38%CR10%≥ VGPR62%68%84%≥PR94%91%1Attal et al. Haematologica 2011; 96 (s1): S23; oral presentation at IMW 20112Roussel et al. ASH 2010 (Abstract 624), oral presentation
8 CALGB 100104:LEN Maintenance significantly prolonged PFS & OS vs CALGB :LEN Maintenance significantly prolonged PFS & OS vs. placeboPFSOSASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo. McCarthy PL. N Engl J Med. 2012;366:
9 Lenalidomide Maintenance Therapy Meta-Analysis Oral Abstract #407 - Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized Trials Monday, December 9, 2013: 11:30 AMThere was significant prolongation of both PFS (HR 0.49, 95% CI, 0.41–0.58, p<0.001) and OS (HR 0.77, 95% CI, 0.62–0.95, p=0.013) with LM vs. placebo/no maintenanceSingh M, et al. ASH Abstract 407.
10 Bortezomib induction and maintenance in ASCT NDMM, TE, sge 18–65 yBortezomib1.3 mg/m2i.v.Doxorubicin9 mg/m2Dexameth40 mgRandomization3 x VAD3 x PADCAD + GCSFCAD + GCSFMEL PBSCTMEL PBSCTIn GMMG 2ndMEL PBSCTAllogeneic TxIn GMMG 2ndMEL PBSCTThalidomidemaintenance 50 mg/day for 2 yearsBortezomibMaintenance1.3 mg/m2 / 2 weeks for 2 yearsSonneveld et al, ASH 201310
11 ResultsBortezomib-based treatment consistently improves PFS (median 27 m vs 36 m) and OS (median 84 m vs not reached, p=0.05) in patients with newly diagnosed MM who are transplant eligibleBortezomib significantly improves the long-term outcome of patients presenting with renal failure (p<0.001)Sonneveld et al, ASH 2013
12 Carfilzomib With Thalidomide and Dexamethasone in ASCT Intensification* (1 cycle)Induction (4 28-day cycles)Consolidation (4 28-day cycles)Carfilzomib, 20/27 mg/m2Days 1,2,8,9,15,16Carfilzomib, 27 mg/m2Days 1,2,8,9,15,16Phase II open-labeldose-escalationtrial (N=70)Thalidomide, 200 mgDays 1-28Thalidomide, 50 mgDays 1-28C, cyclophosphamide; CPR, cyclophosphamide/prednisone/lenalidomide; d, low-dose dexamethasone; M, melphalan; MPR, melphalan/prednisone/lenalidomide; NDDM, newly diagnosed multiple myeloma; P, prednisone; qod, every other day; R, lenalidomide; Rd, lenalidomide/low-dose dexamethasone.Dexamethasone, 40 mgDays 1,8,15,21Dexamethasone, 40 mgDays 1,8,15,21*High-dose melphalan 200 mg/m2 plus ASCTCarfilzomib 27 mg/m2 dose escalation: Cohort 1 treatment as above; Cohort 2 to 36 mg/m2; Cohort 3 to 45 mg/m2; Cohort 4 to 56 mg/m2.Sonneveld P, et al. ASH Abstract 688.
13 Carfilzomib/Thalidomide/ Dexamethasone: Response and AEs Patient Response, %High-risk* PatientsStandard Risk PatientsAll PatientsCR/sCR574851≥VGPR907684PR96*t(4;14) and/or del(17p) and/or 1q and/or ISS3.Grade 3/4 AEs ≥ 5% by carfilzomib dose:20/27 mg/m2=GI toxicity, 16%, skin, 12%; metabolism, 10%; myelotoxicity, 8%; fatigue, 8%; cardiovascular, 6%20/36 mg/m2=metabolism, 10%; myelotoxicity, 8%; GI toxicity, 5%Neuropathy < 5% in both cohortsSonneveld P, et al. ASH Abstract 688.
14 Substantial improvements in PFS and OS Impact of Novel Agents in the Treatment of Elderly Pts with Newly Diagnosed MMSubstantial improvements in PFS and OSMedian PFS (mos)Median OS (mos)MP1-811–2029.1–49.4MPT1-615–27.529–51.6VMP7,8,1121.7–27.468.5% (3-yr OS)*MPR-R931N/AVMP-VT/VP103474% (3-yr OS)*VMPT-VT1137.285% (3-yr OS)**Median OS not reachedN/A: not available1Palumbo et al. Blood 2008; 112:3107–31142Facon et al. Lancet 2007; 370:1209–12183Hulin et al. J Clin Oncol 2009; 27:4Waage et al. Blood 2010; 116:5Wijermans et al. J Clin Oncol 2010; 28:3160-66Beksac et al. Eur J Haematol 2011;86:16-227San Miguel et al. N Engl J Med 2008; 359(9): 906–917; Supplementary Appendix8Mateos et al. J Clin Oncol 2010; 28(13):9Palumbo et al. ASH 2010 (Abstract 622)10Mateos et al. Lancet Oncol 2010; 11(10):11Palumbo et al. ASH 2010 (Abstract 620)
15 Active Treatment + PFS Follow-up Phase PD or Unacceptable Toxicity FIRST Trial: Study DesignScreeningActive Treatment + PFS Follow-up PhaseLT Follow-UpRANDOMIZATION 1:1:1LEN + Lo-DEX ContinuouslyLENALIDOMIDE mg D1-21/28Lo-DEX mg D1,8,15 & 22/28PD or Unacceptable ToxicitySubsequent anti-MM TxPD, OS andArm AContinuous RdArm BRd18LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE mg D1-21/28Lo-DEX mg D1,8,15 & 22/28MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN mg/kg D1-4/42PREDNISONE mg/kg D1-4/42THALIDOMIDE mg D1-42/42Arm CMPTThe FIRST trial was a randomized multicentre, open-label, pivotal phase III trial with 3 comparison arms.FIRST was designed to compare the efficacy and safety of Rd, given continuously or for a fixed number of cycles, with MPT.Patients were stratified according to age (≤75 years vs. >75 years), ISS disease stage (I and II vs. III), and country.Starting doses of LEN were adjusted based on renal function (20 mg/D 10 mg/D 15 mg/every other day).Starting doses of DEX were adjusted based on age (40 mg 20 mg).Starting dose of MEL was adjusted based on age and ANC, platelet count, and renal function (0.25/0.125 mg/kg 0.20/0.10 mg/kg)Starting dose of THAL was adjusted based on patient age (200 mg 100 mg)All patients received low-dose aspirin ( mg/day) or other prophylactic anticoagulation throughout the study.The active treatment and PFS follow-up phase was followed by a long-term follow-up phase to assess OS and the impact of subsequent therapyPts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL mg/kg D1–4Stratification: age, country and ISS stageISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival1Facon T, et al. Lancet 2007;370: ; 2Hulin C, et al. JCO. 2009;27:Facon T, et al. Blood. 2013;122:abstract 2.
16 FIRST Trial: Final Progression-free Survival Median PFSRd (n=535)25.5 mosRd18 (n=541)20.7 mosMPT (n=547)21.2 mos10080604020Hazard ratioRd vs. MPT: 0.72; P =Rd vs. Rd18: 0.70; P =Rd18 vs. MPT: 1.03; P =Patients (%)42% (Rd)23% (Rd18)23% (MPT)With regard to the primary endpoint, continuous Rd significantly reduced the risk of disease progression by 28% compared with MPT (hazard ratio 0.72; P = )Continuous Rd also significantly reduced the risk of disease progression by 30% compared with giving Rd for 72 weeks (hazard ratio 0.70; P = )There was no significant difference in PFS between Rd given for 72 weeks and MPT (hazard ratio 1.03; P = ).Median PFS was 25.5 months with continuous Rd, compared with 20.7 months with Rd for 72 weeks and 21.2 months with MPTThe benefit was independent of age, gender, race, geographic region, ISS stage, renal function, beta-2-microglobulin level, albumin level, ECOG performance status, lactate dehydrogenase level, and cytogenetic risk.6121824303642485460Time (months)Rd53540031926521816810555192Rd1854139116710856307MPT547380304244170116582861mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.Facon T, et al. Blood. 2013;122:abstract 2.
17 FIRST Trial: Consistent PFS Benefit Across Subgroups Hazard ratio (HR) and 95% CIHR (95% Cl)Age > 75Age ≤ 75Gender: femaleGender: maleAsiaEuropeNorth America and PacificISS stage: I or IIISS stage: IIICrCI < 30 ml/minCrCI 30 – 50 ml/minCrCI 50 – 80 ml/minCrCI ≥ 80 ml/minECOG PS Grade 0ECOG PS Grade 1ECOG PS Grade 2LDH < 200 IU/lLDH ≥ 200 IU/lCytogenetics High-riskCytogenetics Non-high RiskITT patients0.81 ( )0.68 ( )0.73 ( )0.71 ( )0.61 ( )0.77 ( )0.64 ( )0.70 ( )0.75 ( )0.76 ( )0.66 ( )0.74 ( )0.71 ( )0.54 ( )0.81 ( )0.80 ( )0.69 ( )0.96 ( )1.23 ( )0.69 ( )0.72 ( )The PFS benefit of continuous Rd over MPT was independent of most baseline characteristics, including age, gender, race, geographic region, ISS stage, renal function, beta-2-microglobulin level, albumin level, ECOG performance status, and cytogenetic risk (please confirm High-risk cytogenetics)0.1250. 250.51248Favoring RdFavoring MPTITT, intention to treat; ITT comparison for continuous Rd vs. MPTFacon T, et al. Blood. 2013;122:abstract 2.Cytogenetics high-risk included t(4;14), t(14;16), del(17p)
18 FIRST Trial: TTP and Time to 2nd Anti-myeloma Therapy Time to ProgressionTime to 2nd AMTMedian Time to 2nd AMTRd (n=535)39.1 mosRd18 (n=541)28.5 mosMPT (n=547)26.7 mosMedian TTPRd (n=535)32.5 mosRd18 (n=541)21.9 mosMPT (n=547)23.9 mosTTP (months)Patients (%)1008060402061218243036424854Hazard ratioRd vs. MPT: 0.68; P=Rd vs. Rd18: 0.62; P≤Rd18 vs. MPT: 1.11; P=10080604020Patients (%)Hazard ratioRd vs. MPT: 0.66; P<Rd vs. Rd18: 0.74; P=Rd18 vs. MPT: 0.88; P=Similar results were seen in terms of time to progression (TTP) and time to 2nd line antimyeloma therapy (TAMT)Continuous Rd significantly prolonged TTP and TAMT compared with MPTTTP: 32.5 vs 23.9 months; hazard ratio 0.68; P =TAMT: 39.1 vs 26.7 months; hazard ratio 0.66; P <Continuous Rd also significantly prolonged TTP and TAMT compared with Rd given for 72 weeksThere was no significant difference in TTP and TAMT between Rd given for 72 weeks and MPTCurves are separating early for Time to 2nd AMT continuous Rd vs. MPTTime to 2nd AMT clearly illustrates that the choice of prior Tx matters6121824303642485460Time to 2nd AMT (months)RdRd18MPT5355415473983893793183173032632652422181671691081151055658553028197621RdRd18MPT53554154744545142237137535131933129327526623922418117714211110177614228169321Facon T, et al. Blood. 2013;122:abstract 2.
19 FIRST Trial: Conclusions Continuous Rd significantly extended PFS, with an OS benefit vs. MPTPFS:HR= 0.72 (P= )Consistent benefit across most subgroupsRd better than Rd18 (HR= 0.70, P= )3 yr PFS: 42% Rd vs. 23% Rd18 and MPTPlanned interim OS: HR= 0.78 (P= )Rd was superior to MPT across all other efficacy secondary endpointsSafety profile with continuous Rd was manageableHematological and non-hematological AEs were as expected for Rd and MPTIncidence of hematological SPM was lower with continuous Rd vs. MPTIn NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of careThis is the largest registrational phase III trial conducted in transplant ineligible patients with newly diagnosed myeloma comparing Rd (an alkylator-free doublet) vs. the triplet MPT.EfficacyThe study met its primary endpoint - PFSContinuous administration of Rd, significantly reduced the risk of progression or death by 28% vs. MPT.The PFS clinical benefit is associated with an OS advantage associated with continuous Rd vs. MPT.All other secondary endpoints were positiveSafetyRd is as good as MPT in regards to safetySimilar safety seen across the armsContinuous Rd is not associated with increased safety concernsSPM was higher with MPT vs Rd consistent with previous reports, in which it has been hypothesized that the increased SPM risk in patients treated with lenalidomide may be related to prior or concurrent melphalan use (Palumbo 2012; Attal 2012; McCarthy 2012; Dimopoulos 2012)Implications & PerspectiveRd should be a new standard of careResults with a 2-drug regimen at least comparable to that achieved with a 3-drug regimenReserve alkylating agents for later in treatmentFuture development: novel agents in combination with Rd rather than alkylating agentsFacon T, et al. Blood. 2013;122:abstract 2.
22 A total of one hundred fifty two of patients were enrolled, we performed at baseline a geriatric assessement using 3 scales: Charlson index, ADL, IADL.Bortezomib was administrated subcutaneously at 1.3 mg/sqm with the weekly schedule with prednisone 50 3 times for week or plus melphalan 2 mg 3 times for week or with ciclofosfamide 50 3 times for week. All patients underwent to the maintenance phase with bortezomib days 1 and 15 until progression disease or intoleranceLarocca et al ASH 2013
24 Taking in account that mean age of global population is increasing and comorbidities, frailty and disability are growing consequently; in our study of elderly MM patients PFS and OS appeared similar between the 2 drug and three drug combinations, in term of safety melphalan is more toxic then ciclofosfamide.Geriatric assessment permitted to find out 3 different patient categories that could help clinical decision of therapeutic strategies, in particular fit patients who could benefit from full dose therapy, unfit patients who could receive a reduced-dose therapy and frail patients for whom we should consider a further reduced strategy.Larocca et al, ASH 2013
27 Oral MLN 9708 Len Dex in Newly Diagnosed MM Induction: up to 16 x 21-day treatment cyclesMaintenance12458911121521MLN9708MLN9708MLN9708MLN9708MLN9708 maintenanceDays 1, 4, 8, 1121-day cyclesDex*Dex*Dex*Dex*Lenalidomide 25 mg, days 1–14*Dex 20/10 mg cycles 1–8 / 9–16Thromboembolism prophylaxis with aspirin 81–325 mg QD or LMWH while receiving len-dex mandatoryPhase 1: oral MLN9708 dose-escalation (dose of 3.0 and 3.7 mgs)Standard 3+3 schema, 33% dose increments, based on cycle 1 DLTsPhase 2: oral MLN9708 at the RP2D from phase 1Stem cell collection allowed after cycle 4, with ASCT deferred until after 8 cyclesMLN9708 maintenance continued at tolerated dose until progression or unacceptable toxicityRichardson et al ASH 2013
28 % decreases in M-protein Subject identifier for the study Ixazomib lenalidomide dexamethasone in newly diagnosed multiple myelomaDose level (cohort): Ph 1, 3.0 mg Ph 2, 3.0 mg–20–25%–40% decreases in M-protein–50%–60–80–90%–100Subject identifier for the study56 pts treated at the RP2D were evaluable for response (7 phase 1, 49 phase 2)61% of pts had 100% decreases in M-protein or serum free light chain from baselineRichardson et al ASH 2013
30 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.
31 MM-003 Design: POM + LoDEX vs. HiDEX POM: 4 mg/day D1-21 +LoDEX: 40 mg (≤ 75 yrs) mg (> 75 yrs) D1, 8, 15, 22RANDOMIZATION 2:1Follow-Up for OS and SPM Until 5 Years Post Enrollment(n = 153)HiDEX: 40 mg (≤ 75 yrs) mg (> 75 yrs) D1-4, 9-12, 17-2028-day cyclesPDa or Unacceptable AECompanion trial MM-003CPOM 21/28 daysPDa or Unacceptable AEThromboprophylaxis was required for those receiving POM or at high risk for DVTStratificationAge (≤ 75 vs. > 75 yrs)Number of prior Tx ( 2 vs. > 2)Disease population (primary refractory vs. relapsed/refractory vs. intolerance/failure)a Progression of disease was independently adjudicated in real time. Dimopoulos MA, et al. ASH 2013 [abstract 408].
32 PFS Based on Cytogenetic Profile POM + LoDEX significantly improved PFS vs. HiDEX regardless of the presence of del17p or t(4;14)POM + LoDEXaSubgroupHiDEXaHR (95% CI)ITT Population253/302138/1530.49 ( )del(17p)/t(4;14)71/7732/350.44 ( )Standard-Risk Cytogenetics126/14863/720.55 ( )0.250.512Favors POM + LoDEXFavors HiDEXNote: Data shown only for pts with available cytogenetics; totals will not sum. a Number of events/number of patients. Dimopoulos MA, et al. ASH 2013 [abstract 408].
33 Forest Plot of OS Based on Prior Treatment SubgroupPOM + LoDEXaHiDEXaHR (95% CI)ITT Population176/302101/1530.72 ( )≤ 3 Prior Tx41/7022/330.56 ( )> 3 Prior Tx135/23279/1200.76 ( )Prior THAL102/17364/930.75 ( )No Prior THAL74/12937/600.66 ( )LEN Ref168/28694/1410.70 ( )BORT Ref142/23879/1210.77 ( )LEN and BORT Ref135/22574/1130.77 ( )LEN as Last Prior47/8532/490.56 ( )BORT as Last Prior76/13439/660.92 ( )0.250.512a Number of events/number of pts. San Miguel JF, et al. ASH 2013 [abstract 686].Favoring POM-LoDexFavoring HiDEX
34 Proportion of Patients MM-003: PFS and OS by M-Protein Reduction Patients Assigned to POM + LoDEXM-Protein ReductionMedian PFS≥ 25 % (n = 163)7.4 mos≥ 50 % (n = 113)8.4 mos< 25% (n = 96)2.3 mosM-Protein ReductionMedian OS≥ 25 % (n = 163)17.2 mos≥ 50 % (n = 113)19.9 mos< 25% (n = 96)7.5 mos0.00.20.40.60.81.048121620240.00.20.40.60.81.0481216202824Proportion of PatientsPFS (mos)OS (mos)Median PFS was 4.0 mos and median OS was 13.1 mos overall for POM + LoDEXSan Miguel JF, et al. ASH 2013 [abstract 686].
35 Pom low dose dex and bortezomib in relapsed MM Table 4. Summary of Best Response (IMWG) in Intravenous BORT CohortsOutcomeCohort 1(n = 3)Cohort 2Cohort 3Cohort 4Cohort 5 + Exp Cohort(n = 9)aOverall response, n (%)2 (67)1 (33)3 (100)6 (67)sCR/CR1 (11)VGPR4 (44)PRSD3 (33)Median cycles received (range)5 (4-16)6 (4-18)16 (5-20)10 (4-13)11 (6-15)a 8 of 9 patients were evaluable for response; one patient discontinued study treatment in cycle 2 due to treatment-unrelated metastatic pancreatic cancer. CR, complete response; Exp, expansion; IMWG, International Myeloma Working Group; PR, partial response; SC, subcutaneous; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.Richardson et al, ASH 2013
36 Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor Novel chemical class with highly selectiveand irreversible proteasome bindingImproved antitumor activity withconsecutive day dosingNo neurotoxicity in animals23% Responses lasting 7.8 months with survival 15.4 months in relapsed and relapsed/ refractory MM w/oEpoxyketoneTetrapeptideDemo et al Cancer Res 2007; 67:6383Kirk et al, Blood 2008, 112: 2765 ; Siegel et al Blood 2012:120:2817.
37 CRd in Relapsed and Upfront MM Response to CRd therapy in RRMM 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 in ND MM (94% ORR, with 80% CR,nCR after 12 cycles in a subset of pts)Wang et al ASCO 2011; Jakubowiak et al, Blood 20123737
38 Carfilzomib Pomalidomide Low dose Dex Median of 5 prior lines of therapy; 49% of patients had high/intermediate risk cytogenetics at baselineResponse rates, PFS, and OS were preserved independent of FISH/cytogenetic risk statusWell tolerated with no unexpected toxicities≥ VGPR 27%ORR 70%CBR 83%DOR (median) monthsPFS (median) 9.7 monthsOS (median) > 18 monthsShah et al ASH 2013
39 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)XmAb5592 (HM1.24)Tai & Anderson Bone Marrow Research 2011
40 Elotuzumab Anti-CS MoAb in MM CS1 is highly and uniformly expressed on MM cellsElotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting CS1Clinical trial of Elo in MM achieved SDAnti-MM activity of Elo enhanced by lenalidomide (len) in preclinical modelsPhase I/II trials: 80-90% response to len dex elo in relapsed MM with prolonged (> month 33 PFS)Phase III trial of len dex elo versus len dex in relapsed MM for new drug approvalHsi ED et al. Clin Cancer Res. 2008;14: ; Tai YT et al. Blood. 2008;112: ; Van Rhee F et al. Mol Cancer Ther. 2009;8: ; Lonial S et al. Blood. 2009;114:432; Richardson et al Blood 2010:864 Lonial et al, ASH 201240
43 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
44 Daratumumab and lenalidomide dexamethasone in relapsed MM The best change in response paraprotein evaluated according to IMWG 2011.A: serum M-protein, B: urine-M-protein44Plesner et al ASH 201344
47 Background: Targeting KSP with ARRY-520 (Filanesib) Array BioPharma Inc.9/10/2012Background: Targeting KSP with ARRY-520 (Filanesib)Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitorKSP is a microtubule motor protein critical to the function of proliferating cellsKSP inhibition induces aberrant mitotic arrest and rapid cell deathNovel mechanism of action for MMPreferentially acts on MCL-1 dependent cells including MMNot expected to be cross-resistant with other drugsCancer cell image from ELN page EARRY-520 is a new mechanism for the treatment of multiple myeloma. ARRY-520 is a highly selective allosteric inhibitor of KSP. The KSP protein is not found in differentiated cells, so there's no expectation of neuropathy with this particular mechanism. And because it is a novel mechanism, we believe there would be less or no cross resistance to other mechanisms in this area.We've done significant work in trying to link why KSP is active in multiple myeloma. It appears to be highly active because of the role of Mcl-1 in myeloma specifically, and the dependence of Mcl-1 levels on KSP activity.We've also demonstrated preclinically that ARRY-520 has synergistic efficacy with both lenalidomide and bortezomib, both standards of care in this disease.Lonial et al ASH 2013
48 Low AAG is Associated with Higher ORR Lonial et al ASH 2013Low AAG is Associated with Higher ORRFilanesib Single-agent Filanesib + DexAll Pts1AAG-HighAAG-LowAll Pts2n32621551536ORR (≥ PR)5 (16%)0 (0%)5 (24%)8 (15%)7 (19%)CBR (≥ MR)7 (22%)7 (33%)11 (20%)10 (28%)Duration of Response (months)8.6-5.1Time to Next Treatment (months)22.214.171.124.42.0OS (months)19.04.523.310.52.910.8 1 5 patients did not have a baseline AAG measurement2 4 patients did not have a baseline AAG measurement, including 1 responder
49 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:
50 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 tolerability.Time-to-progression hazard ratio reduction of 21% (P=0.02)Dimopoulos et al Lancet Oncol2013; 14:5050
51 Ricolinostat (HDAC 6 inhibitor) alone and in combination with bortezomib in relapsed refractory MM Monotherapy6/15 patients had stable disease (SD) as their best response.Combination with bortezomib and dexamethasone20/22 were evaluable for response assessment in six combination cohortsOverall response rate (≥PR): 25% in heavily pretreated patients5 patients withdrew after one cycle and 3 had progressive disease after 2 cyclesClinical benefit rate (≥SD): 60%6/10 patients refractory to bortezomib had ≥SD (1 VGPR, 1 MR, 4 SD)Responding patients have been on study 2 to 16 cyclesAll 3 patients treated 240 mg QD cohort had MR or betterVGPR2PR3MR1SD5Should we add the PDs? Did the 5 who withdrew after 1 cycle have PD??Do we need to say seperately about 240mgs??Have kept the table but would probably take outMonotherapy response data from Final CSR. Combination response data pulled fromlive database Nov 8, 20131 One patient had a 26% decrease in M Protein after Cycle 2 and withdrew after twosubsequent cycles with SD
52 Ricolinostat (HDAC 6 inhibitor) lenalidomide dexamethasone in relapsed refractory MM M protein % changeCR1VGPR3PR17MR2SD11/16 pts (69%) had PR or better16/16 pts (100%) had clinical benefit (including MR and SD)Yee, et al, Poster #3190, ASH 2013
53 PKB115125 Akt Inhibitor: Dose Limiting Toxicities Afur / Bor / Dexdose (mg)nDLTComment4None-61/6LFT elevation G2Erythema Multiforme G32/6Rash G3Rash G3 / Diarrhea G3 /Thrombocytopenia G3NAMTD / RP2D:Afuresertib mg PO dailyBortezomib mg/m2 IV/SC on days: 1,4,8,11Dexamethasone 40 mg PO on days: 1,4,8,11All DLTs were reversibleVoorhees et al ASH 2013
54 Maximum % change in M-protein or FLC from baseline Voorhees et al ASH 2013
55 Treatment of Multiple Myeloma: Conclusions In newly diagnosed transplant candidates, three drug regimens incorporating immunomodulatory drugs and proteasome inhibitors before and after transplant can prolong PFS and OS.Lenalidomide dex until progression is standard of care for non transplant patients with newly diagnosed myeloma.Lenalidomide maintenance until progression prolongs PFS and OS, with an increased risk of secondary cancers in patients who have received MP or high dose therapy and ASCT.
56 Treatment of Multiple Myeloma: Conclusions Pomalidomide low dose dex is active in relapsed refractory MM, (including 17p deletion)Bortezomib or Carfilzomib and pomalidomide low dose dex increases response and is tolerated in relapsed refractory MMNovel agents including oral proteasome inhibitor ixazomib, monoclonal antibodies SAR and daratumumab, immunotoxin indatuximab, KSP inhibitor filanesib, Akt inhibitor afuresertib, and HDAC6 inhibitor ricolinostat demonstrate promising activity in relapsed refractory MMIncorporation of novel therapies at all stages of disease is further improving patient outcome in MM