Upload
others
View
8
Download
0
Embed Size (px)
Citation preview
New Ingredients & Recipes for Myeloma TherapyTherapy
Amrita Krishnan MD FACPAmrita Krishnan MD FACPDirector, Judy and Bernard Briskin Center for Myeloma
DISCLOSURES
Speakers Bureau: Celgene, Takeda, Janssen and Onyx
Consultant : Celgene and Janssen
INGREDIENTS For Myeloma Treatment
Continuing Evolution of MM Treatment: Selected New Classes and Targets 2016
Basic Ingredients
• Immunomodulatory agents;(th lid id l lid id(thalidomide, lenalidomide, pomalidomide)
P t i hibit• Proteasome inhibitors; (bortezomib, carfilzomib, ixazomib)
id• Steroids; (dexamethasone, prednisone)
• Alkylators; (melphalan,cytoxan, bendamustine)
New Ingredients
A ib di ( l b d b P b )• Antibodies; (elotuzumab, daratumumab, Pembro)
Restaurant Only
• Nuclear Transport Inhibitors (Selinexor)Nuclear Transport Inhibitors (Selinexor)• Bromodomain Inhibitors• Antibody Drug Conjugates• Antibody Drug Conjugates• Bispecific Antibodies• TCELL ( BCMA CD19)• TCELL ( BCMA, CD19)
Advances in Genomics of MMRevised International Staging System
(R‐ISS) for MM( )
P l b A t l J Cli O l 2015 33 2863Palumbo A et al. J Clin Oncol. 2015;33:2863.
mSMART 2.0 Variable Outcomes in MM
HighHigh IntermediateIntermediate StandardStandard20%20% 20%20% 60%60%
• FISH‒ del 17p
• FISH t(4;14)• Amplification
• Others‒ Hyperdiploiddel 17p
‒ t(14;16)‒ t(14;20)
• GEP
Amplification chromosome 1q
Hyperdiploid‒ t(11;14)‒ t(6;14)
G P‒ High‐risk signature
3 4 5 6 8 103–4 years 5–6 years 8–10 yearsMikhael JR et al. Mayo Clin Proc. 2013;88:360.
Mikhael JR et al. Mayo Clin Proc. 2013;88:360.
Cytogenetics: Biologically Defined Unique Subsetsq
Garand R et al. Leukemia. 2003;17:2032.1. Jaksic W et al. J Clin Oncol. 2005;23:7069.
2. An G et al. Leuk Res. 2013;37:1251.
Risk Stratification in MyelomaHow do we customize treatment?
• t(4;14) MM( ; )– Inferior outcomes with traditional ASCT– Results better with integration of novel agents, particularly BTZ
(consolidation or maintenance) and use of tandem transplant(consolidation or maintenance) and use of tandem transplant
• Del17p (p53 deletion) MM– Improved outcome for low‐risk del17p with aggressive multi‐
combination and prolonged therapy– New treatment approaches required (eg, immune‐based approaches,
use of epigenetic modulators)
• Hyperdiploid– Myc dependant– Super responders to IMiDsSuper responders to IMiDs
New Ingredient:Venetoclax in t(11;14) MM( ; )
Kumar S et al. Blood. 2016;128: Abstract 488. A.K. Stewart, unpublished
Stamelos et al. Journal of Molecular Signaling 2012, 7:12
BclBcl--2 Dependent2 DependentABTABT--199 sensitive199 sensitiveABT-199
BimBim
BimBim BimBim
MclMcl--11 MclMcl--11 BclBcl--xxLLBclBcl--xxLL BclBcl--22 BclBcl--22
BimBim
MclMcl--11 BclBcl--xxLL BclBcl--22
BaxBax BaxBax
Cell DeathCell Death MitochondriaImage courtesy of: Vikas Gupta, MD PhD, Emory University
Genomic Landscape in MM
W lk BA t l J Cli O l 2015 33 3911Ch MA t l N t 2011 471 467 Walker BA et al. J Clin Oncol. 2015;33:3911.Lonial S et al. Blood. 2014;124: Abstract 722.
Keats JJ et al. Blood. 2012;120:1067.
Chapman MA et al. Nature. 2011;471:467.Bolli N et al. Nat Commun. 2014;5:2997.Lohr JG et al. Cancer Cell. 2014;25:91.
Most Mutations Are Subclonal
Kortuem KM et al. Blood Cancer J. 2016;26:e397.
Myeloma‐Specific Gene Mutation Panel Tracks Clonal Changes Over Time
Kortuem KM et al. Ann Hematol. 2015;94:1205.
Mutations in the Cereblon Pathway in at Least 26% of Relapsed/Refractory Patientsp y
*gene found mutated in cohort
Kortüm KM et al. Blood. 2016;128:1226.
CoMMpass Enrollment
CoMMpass: Triplets versus Doublets
SWOG S0777: Study Design
Alliance RVD DARA RVD
2016: Combination Study of Carfilzomib, Lenalidomide, and Dexamethasone in Patients With NDMM
Combination Study of Carfilzomib, Lenalidomide, and Dexamethasone in Patients With NDMM: Efficacy
Best Response and Best Overall Response by Treatment Duration
Relapsed Myeloma:
• Mix ingredients• Think about genomics• Might be time to throw in some “exotic” agents
Phase 3 Trials in Relapsed MM
Differences Between Studies in Baseline Characteristics
1. Stewart AK et al. N Engl J Med. 2015;372:142. 2. Lonial S et al. N Engl J Med. 2015;373:621. 3. Moreau P et al. N Engl J Med. 2016;374:1621.4. Dimopoulos MA et al. Lancet Oncol. 2016;17:27.
2017 Trends in MM Rx:Restoring Immune Functiong
• Immunomodulatory drugs, other small moleculesImmunomodulatory drugs, other small molecules (eg, HDACi’s)
M l l ib di• Monoclonal antibodies
• Checkpoint inhibitors p
• Vaccines
• Cellular therapies
Monoclonal Antibodies Kill MM Through Multiple Mechanismsg p
Daratumumab: Mechanism of Action
Phase 3 Randomized Controlled Study of DVd vs Vd in Pts With Relapsed or Refractory MM: CASTOR
Phase 3 Randomized Controlled Study of DVd vs Vdin Pts With Relapsed or Refractory MM: CASTOR
Daratumumab + Lenalidomide + Dexamethasone: Overall Response Ratep
Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX
Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX
Daratumumab in High‐Risk Patients
Immune Checkpoint Inhibitors in MM
Immune Checkpoint Inhibitors for Relapsed/Refractory Multiple Myeloma
Pneumonitis
Type Trial Patient Types StudyPhase Site(s)
CART-19 for multiple myeloma Relapsed/ refractory 1 University of Pennsylvania
CAR T
Pennsylvania
Safety study of CAR-modified T cells targeting NKG2D-ligands Relapsed/ refractory 1 Dana-Farber
Cancer Institute
Study of T cells targeting B-cell National Cancer Instit teS y g g
maturation antigen (BCMA) for previously treated multiple myeloma
Relapsed/ refractory 1 InstituteUniversity of Pennsylvania
Tadalafil and lenalidomide Newly diagnosed; Sidney Kimmelmaintenance with or without activated marrow infiltrating lymphocytes (MILs)
in high-risk myeloma
Newly diagnosed; relapsed (without
prior ASCT)2
Sidney Kimmel Comprehensive Cancer Center
MILs Adoptive immunotherapy with activated marrow-infiltrating
lymphocytes and cyclophosphamide graft-versus-host disease prophylaxis in patients with relapse of hematologic
Relapsed/ refractory 1Sidney Kimmel Comprehensive Cancer Centerp p g
malignancies after allogeneic hematopoietic cell transplantation
Affinity-enhanced
Engineered autologous T cells expressing an affinity enhanced TCR Relapsed/ 1/2
City of HopeUniversity ofenhanced
T cellsexpressing an affinity-enhanced TCR specific for NY-ESO-1 and LAGE-1
prefractory 1/2 University of
Maryland
DLI CD3/CD28 activated Id-KLH primed autologous lymphocytes Post-transplant 2 University of
Pennsylvania
Myeloma CAR Therapy
• Which Target:– CD19, CD138, CD38, CD56, kappa, Lewis Y, CD44v6, CS1 (SLAMF7), BCMA
• Many questions remain about CAR design:– Optimal costimulatory domains– Optimal vector– Optimal dose and schedule– Need for chemotherapy– Perhaps “cocktails” of multiple CARs or CARs + chemotherapy will be required for best outcomes
Which Target: BCMAB cell maturation antigen (BCMA) A member of the TNF receptor
superfamily
E i i l l t i t d t Expression is largely restricted to plasma cells and mature B cells
Not detectable in any other normal
Multiple myeloma cells expressing BCMA
Not detectable in any other normal tissues
Expressed nearly universally on multiple expressing BCMA
(brown color = BCMA protein)
p y y pmyeloma cells
Anti-MM efficacy validated in initial studies1
1. Ali et al., Blood 2016 128: 1688. Cohen et al.,ASH 2016, abstract 1147
CRB‐401 Study Design
Adverse Events Generally Mild, No ≥ Grade 3 CRS* or Neurotoxicityy
No DLTs to date
Cytopenias related Cytopenias related to fludarabine/cyclophosphamide lymphodepletionlymphodepletion, as expected
No ≥ Grade 3 cytokine releasecytokine release syndrome or neurotoxicity
*CRS uniformly graded according to Lee et al., Blood 2014;124:188-
195
Best Response and Time Since bb2121 Infusion
Cytokine Release Syndrome Summary
UPENN; BCMA CAR TRIALCohort 11 - 5 x 108
CAR+ T cells
Cohort 2Cytox 1.5 g/m2
+
Cohort 3Cytox 1.5 g/m2
+ 4 week CAR+ T cells
(n=3-6)+
1 - 5 x 107
CAR+ T cells(n=3-6)
+ 1 - 5 x 108
CAR+ T cells(n=3-6)
delay between subjects
Up to n=9 Up to n=9 Up to n=9
• Primary objective– Safety
• Secondary– Feasibility– Efficacy (response rates, PFS, OS, MRD)
MA
-CA
R Pre Day 71) Flow
• Exploratory: – CART-BCMA expansion, persistence, phenotype– Impact on normal B cell and PC compartments– BCMA expression pre- and post-treatment– Cytokine/chemokine levels CD8
BC
M– Soluble BCMA, BAFF, APRIL levels– Assess for anti-CAR immune responses– Impact on tumor microenvironment 2) qPCR
Patient characteristics – Cohort 1 (n=9)Characteristic Median (range) or %
Age 57 (44 – 70)
Gender 67% male; 33% female
Isotype IgG (33%), IgA (44%), LC (22%)
Prior lines of therapy 9 (4-11)
Lenalidomide 100% (refractory: 78%)Lenalidomide 100% (refractory: 78%)
Bortezomib 100% (refr: 89%)
Pomalidomide 100% (refr: 89%)
Carfilzomib 100% (refr: 89%)
Autologous SCT 78%
Cyclophosphamide 100% (refr: 67%)
Daratumumab 44% (refr: 44%)
A ti PD1 33% ( f 33%)Anti-PD1 33% (refr: 33%)
High-risk genetics-17p or TP53 mutation
100%67%
Extramedullary dz 33%
% BM plasma cells 80 (15 – 95)
Day 0 absolute CD3 258/µL (117 – 1354)
Safety (n=9)Other Grade 3-4 Toxicities (n, %)
Hypophosphatemia 4 (44%)
Infection 4 (44%)
Thrombocytopenia 3 (33%)
Anemia 2 (22%)
Neutropenia 2 (22%)Neutropenia 2 (22%)
Hypocalcemia 2 (22%)
Hypokalemia 2 (22%)
Encephalopathy/delirium 2 (22%) 1 death on study (d+24):
candidemia, progressive Fatigue 1 (11%)
Alk phos increased 1 (11%)
AST increased 1 (11%)
Hypofibrinogenemia 1 (11%)
p gMM / evolving PCL
Hypofibrinogenemia 1 (11%)
Lymphopenia 1 (11%)
Leukopenia 1 (11%)
Hypertension 1 (11%)
Pleural effusion 1 (11%)
Hyponatremia 1 (11%)
Clinical responsespPt
BM PC%
CytogeneticsCART dose received
(% of planned)CRS grade
Time to 1st
response (days)
Best Hemeresponse
PFS (mos.)
+11
Pt 01
01 70+11‐17p ‐16q
2 x 10e8(40%)
3 (toci) 14 sCR* 12+
02 60+1q +4p‐17p
5 x 10e8(100%)
1 14 MR 2
+1q03 95
+1qt(4;14) –16q
2 x 10e8(40%)
3 (toci) 15 VGPR* 5
09 15t(11;14)‐16q
‐17p5 x 10e8(100%)
2 ‐ SD 2
10 95+1q
t(11;14)1.8 x 10e8(100%)
‐ ‐ PD 0.5
11 80+1q
t(4;14)‐17p
5 x 10e8(100%)
2 25 MR 2.5*
07 15+1q,
+11, ‐4, ‐14, ‐16
5 x 10e8(100%)
2 14 uPR** 1.5
08 80‐1p
+1q, ‐45 x 10e8(100%)
4 (toci) ‐ PD 0.5
*on IVIG
‐17p(100%)
15 90 +1q, t(11;14)5 x 10e8(100%)
2 (toci) 14 VGPR* 2+
*No MM by flow**unconfirmed; 24 hour UPEP not repeated
Conclusions CART‐BCMA manufacturing is feasible in heavily pre‐treated MM patients Significant expansion in 7/9 patients, without lymphodepleting chemo Toxicity
• Grade 3/4 CRS in 3/9, responds to toci• Severe neurotoxicity in 2/9 1 with PRES responding to steroids/cytoxan• Severe neurotoxicity in 2/9, 1 with PRES responding to steroids/cytoxan• No other off‐target or off‐tumor toxicities
Clinical activity seen (2 MR, 1 PR, 2 VGPR, 1 sCR)• 1 VGPR lasting 5 mos., 1 ongoing sCR at 12 mos., 1 ongoing VGPR at 2
mos.• Associated with CART expansion, CRS
‐ Not associated with baseline BCMA expression Loss/down regulation of BCMA may be escape mechanism Enrollment in cohorts with cyclophosphamide ongoing Enrollment in cohorts with cyclophosphamide ongoing
• May enhance expansion/persistence
Other T cell targets ; CS1Study Overview: Phase I Develop CAR T Cells for Multiple MyelomaPhase I – Develop CAR T-Cells for Multiple MyelomaCandidate Tumor Associate Antigens and Better CAR for T-Cell Therapy
0 15 22 28 49Days post T cell treatment 8
Redirected T‐Cell Immunotherapy for Multiple Myeloma
Study Overview: Phase II Select Better CAR for TreatmentPhase II – Select Better CAR for Treatment
Modified CS1 CAR T-Cells with a specific co-stimulatory signal (41BB) and linker (HL-CH3) showed significant anti-multiple myeloma activity.
EQ CD28
Days post T-cell treatment
Untreated
0 14 280 14 28CAR
EQ 41BB
L CD28
Mock
∆CH2 CD28
L 41BB∆CH2 41BB
vector for clinical trial
Bi‐Specific Antibody (bsAb) Constructs
Antibody Drug Conjugates
• Allow conjugations with potent drugsAllow conjugations with potent drugs• Different targets under study ( CD352 CD74)• Precedent in Hodgkin( Brentuximab)• Precedent in Hodgkin( Brentuximab)
Recipe for Success in Myeloma
• Excess protein production
>> Target protein degradation
• Genomic abnormalities and acquired resistance
>> Target and overcome mutations
Imm ne s ppression• Immune suppression
>> Restore anti‐MM immunityy