Post on 23-Feb-2016
description
Experimental Agents for Relapsed/Refractory Myeloma - Current Trials in Context
Kenneth C. Anderson, M.D.
Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute
Harvard Medical School
Conflict of Interest: Kenneth C. Anderson, M.D.
Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead
Scientific Founder: Acetylon, Oncopep
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
VCAM-1Fibronectin
ICAM-1LFA-1
MUC-1
VLA-4
CytokinesIL-6, VEGFIGF-1, SDF-1BAFF, APRILBSF-3
TNFTGFVEGF
NF-B
NF-BBMSC
adhesion molecules
NF-B
Smad, ERK
JAK/STAT3
MEK/ERK
PI3-K
GSK-3FKHRCaspase-9NF-BmTORBad
PKC
Bcl-xLMcl-1
MEK/ERKp27Kip1
NF-BBcl-xLIAPCyclin-D
MM
SurvivalAnti-apoptosisCell cycle
SurvivalAnti-apoptosisCell cycle
proliferation
SurvivalAnti-apoptosis
Akt
migration
ProliferationAnti-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 surfacetargets
VEGFR
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.
Regimen Trial ORR, %
CR or nCR, %
≥ VGPR, %
DOR, Mos
TTP or PFS, Mos
Median OS, Mos
Len + dex MM-009[1] 61 24 NE 16 1135[5]
Len + dex MM-010[2] 60 25 NE 17 11
Bortezomib APEX[3] 43 16 NE 8 6 30
Vdox MMY-3001[4] 44 13 27 10 9 NE
Efficacy and Toxicity by Bortezomibschedule
46.8 mg/m267.6 mg/m267.6Total planned dose
4%16%NAPN discontinuation
35%32%NAPFS @ 3 years
2%14%13%Grade 3-4
NA
44%
30%
VMP*(VISTA)
40 mg/m2
21%
23%
VMP once weekly N=190
Sensory PN
43%Any grade
41 mg/m2Total delivered dose
27%CR
VMP twice weekly N=63
**MateosMateos et al. J et al. J ClinClin OncolOncol 2010; 2010; PN: peripheral neuropathyPalumbo et al. ASH 2010 abstr 620
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, % 53 38 0.04 Grade 2, % 41 24 0.01 Grade 3, % 16 6 0.03Risk factors for PN, % Grade 1 PN at baseline 28 23 Diabetes at baseline 11 13 Exposure to prior neurotoxic agents 85 86
*P-values are based on 2-sided Fisher’s exact test
Moreau et al. ASH 2010 abstr 312
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)
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 β2-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.
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
Antibody-dependentCellular cytotoxicity
(ADCC)
ADCC
Effector cells:
MM
FcR
Complement-dependentCytotoxicity (CDC)
CDC
MM
C1q
C1q
Apoptosis/growth arrest
via targetingsignaling 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)
Daratumumab (CD38)
MAb-Based Therapeutic Targeting of Myeloma
Tai & Anderson Bone Marrow Research 2011
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 2N=73
RANDOMIZE
Elotuzumab 10 mg/kg IV+ Len/dex
n=36
Elotuzumab 20 mg/kg IV + Len/dex
n=37
Phase 1*N=28
PROGRESSION†
*Lonial et al. J Clin Oncol. 2012Richardson et al. ASH 2012
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
0102030405060
Perc
enta
ge C
hang
e fr
om B
asel
ine
-100-90-80-70-60-50-40-30-20-10
0102030405060
Perc
enta
ge C
hang
e fr
om B
asel
ine
*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
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 reached20 mg/kg (n=37): 18.6 mos (95% CI 12.9-29.7)
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33Mos
Prop
ortio
n of
Pr
ogre
ssio
n Fr
ee P
atie
nts
(%)
36 32 30 29 23 20 18 18 13 9 3 0Number at Risk:
37 29 26 23 21 17 15 13 13 10 3 0
10 mg/kg
20 mg/kg
Richardson et al. ASH 2012
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
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)
9 2
5
1 20
19 10 12 3116 29 8 13
4 2615 3 7 11
1714
3327
21 6 3018 34
23
32
22 28-100
-50
0
50
100
Rel
etiv
e ch
ange
in p
arap
rote
ine
from
bas
elin
e (%
)
Patient number
Daratumumab ResponseMaximal Change in Paraprotein
A AA A AA AAA
AAA AA AA AA AAB
BB B
CA
C C CCC C
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
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
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
• Vasir et al. Brit J Hematol 2005; 129: 687-700
20S20S
19S
19S
5, 5i1, 1i2, 2i
ATPases/Cdc48
PotentialTherapeutic Targets
26S PROTEASOME
ATP ADP
UB enzymes E1, E2 andE3-UB-Ligases
UbUb
Ub
Poly-ubiquitinated proteins (proteasome substrates)
Free for re-cycling
Six Proteaseactivities
Degraded proteinUb
Immunoproteasome
Proteasome: Present and Future Therapies
DeubiquitylatingEnzymes (DUBs))
Bortezomib, Carfilzomib, CEP-18770ONX-0912MLN 2238
NPI-0052: 5, 1, 2
5
PR-924P5091 target USP-7
MLN2238/9708 Decreases Cell Viability in MM Cells and Overcomes Bortezomib Resistance
24h 48h
Chauhan et al. Clin Cancer Res, 2011; 17: 5311-21.
MLN9708 (Ixazomib) in Relapsed/Refractory MM
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/m2
Bortezomib-relapsed
Relapsed after previous bortezomib
therapy but not refractory
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
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
Weekly MLN9708 in Relapsed/Refractory Multiple Myeloma: Phase I Study
• Single-agent oral MLN9708 MTD 2.97 mg/m2 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
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/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 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
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
• Phase I clinical trials ongoing
In Vitro Anti-MM Activity of Oral Chymotryptic Inhibitor ONX 0912 (Oprozomib)
Myeloma Cell Lines Patient Tumor Cells
Chauhan et al. Blood. 2010;116:490614.
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)
HN
O
O
O
CH3
OH
Cl
H
H
H
Responses to Marizomib +/- Dexamethasone in Evaluable Pts at Full Dose [ >0.4 mg/m2 ]* Twice Weekly (n=21**)
Richardson et al. ASH 2011All Pts
EBMT ≥ SD 11/20 55%MR + PR 3/20 15%
Uniform Criteria ≥ SD 12/21 57%PR + VGPR 4/21 19%
Pts Exposed to Bortezomib EBMT ≥ SD 11/19 58%MR + PR 3/19 16%
Uniform Criteria ≥ SD 11/19 58%PR + VGPR 3/19 16%
*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 BortezomibEBMT ≥ SD 8/12 67%MR + PR 2/12 17%
Uniform Criteria ≥ SD 8/12 67%PR + VGPR 2/12 17%
Pts Refractory to LenalidomideEBMT ≥ SD 8/13 62%MR + PR 3/13 23%
Uniform Criteria ≥ SD 9/14 64%PR + VGPR 4/14 29%
Median Duration of Response (all Pts) = 133 days (~ 5 mos)
Additional Targeted Therapies in Development
• KSP inhibitors (ARRY-520)• AKT inhibitor (GSK2110183)• Nuclear transport inhibitors (KPT)• CDK inhibitors • BTK inhibitors• Bromodomain inhibitors
Protein
protein aggregates(toxic)
UbUb
UbUb
26S proteasome
UbUb
Ub UbUb
Aggresome
Panobinostat,Vorinostat, ACY1215
dynein
UbUb
dynein
MicrotubuleAutophagy
Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912
Ub UbUb
Lysosome
HDAC6
HDAC6
HDAC6
Ub
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.
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
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
Mutations in Myeloma19 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 codingConfers 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.
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
United Nations Against Myeloma: Bench to Bedside Research Team
Kenneth AndersonNikhil MunshiPaul RichardsonRobert SchlossmanIrene GhobrialSteven TreonJacob LaubachDeborah DossKathleen ColsonMary McKenneyKim NoonanTina FlahertyKathleen Finn Muriel GannonStacey ChumaJanet KunsmanDiane WarrenCarolyn RevtaAndrea FreemanAlexis FieldsAndrea KolligianJohn FeatherFarzana MasoodNora LoughneyHeather GoddardTiffany PoonNicole StavitzskiRanjit BanwaitShawna CormanHeather GoddardMeghan Marie LeahyCaitlin O’GallagherChristina TripsasKarin AndersonShannon VieraKatherine RedmanAmber WalshSamir AminWanling XieParantu ShahHolly BartelLisa PopitzJeffrey Sorrell
Teru HideshimaConstantine MitsiadesDharminder ChauhanNoopur RajeYu-Tzu TaiRuben CarrascoJames BradnerGullu GorgunJooeun BaeFrancesca CottiniMichele CeaAntonia CagnettaTeresa CalimeriEdie WellerAjita SinghZe TianDiana CirsteaYiguo HuNaoya MimuraJiro MinamiSun-Yung KongWeihua SongDouglas McMillinCatriona HayesSteffen KlippelJana JakubikovaPanisinee LawasutNiels van de DonkEugen DhimoleaJake DelmoreHannah JacobsMasood ShammasMariateresa FulcinitiJianhong LinJagannath PalSamantha PozziLoredana SantoClaire FabreAnuj MahindraRao PrabhalaJake DelmorePuru NanjappaMichael SellitoAvani Vaishnav
USA
UK
India
Italy
Japan
Canada
Germany
China
Greece
Taiwan
Australia
IrelandIsrael
Turkey
Austria