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 A.K. Stewart, unpublished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