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6/18/2018
1
Future Directions in Myeloma Post ASCO:
Clinical Trials
Krina Patel MD MSc
Assistant Professor
Department of Lymphoma/Myeloma
University of Texas MD Anderson Cancer Center
Optimizing Dosing Schedule
Once-weekly Versus Twice-weekly Carfilzomib Dosing in Patients with Relapsed and Refractory Multiple Myeloma: Results of the Randomized Phase 3 Study A.R.R.O.W.
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting
6/18/2018
2
A.R.R.O.W. Study Rationale
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting
A.R.R.O.W. Study Design
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting
Primary Endpoint: PFS<br />
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting
6/18/2018
3
Overall Response Rates
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting
Adverse Events Summary<br />
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting
Adverse Events of Interest
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting
6/18/2018
4
Overall Survival (OS)
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting
Conclusions
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting
Maintenance Revlimid
Does dose matter?
6/18/2018
5
Maintenance Therapy with 25 versus 5 mg Lenalidomide after Prolonged Lenalidomide Consolidation Therapy <br />in Newly-Diagnosed, Transplant-Eligible Patients with Multiple
Myeloma
Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting
Study Design
Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting
Dosage
Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting
6/18/2018
6
Response
Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting
EFS and OS
Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting
Safety
Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting
6/18/2018
7
Conclusions
Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting
Targeted therapy
Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients W ith Relapsed/Refractory Multiple Myeloma
Presented By Luciano Costa at 2018 ASCO Annual Meeting
6/18/2018
8
Study Overview
Presented By Luciano Costa at 2018 ASCO Annual Meeting
Dosing
Presented By Luciano Costa at 2018 ASCO Annual Meeting
Enrollment and Patient Disposition
Presented By Luciano Costa at 2018 ASCO Annual Meeting
6/18/2018
9
Summary of Safety (N=42)
Presented By Luciano Costa at 2018 ASCO Annual Meeting
Objective Responses in All Patients and Those Refractory to PIs and IMiDs
Presented By Luciano Costa at 2018 ASCO Annual Meeting
Conclusions
Presented By Luciano Costa at 2018 ASCO Annual Meeting
6/18/2018
10
New combinations with “old”drugs
abstract 8001
Presented By Paul Richardson at 2018 ASCO Annual Meeting
Phase 3 OPTIMISMM Study Design
Presented By Paul Richardson at 2018 ASCO Annual Meeting
6/18/2018
11
Patient Disposition (ITT)
Presented By Paul Richardson at 2018 ASCO Annual Meeting
Progression-Free Survival (ITT)
Presented By Paul Richardson at 2018 ASCO Annual Meeting
Response
Presented By Paul Richardson at 2018 ASCO Annual Meeting
6/18/2018
12
Conclusions and future directions
Presented By Paul Richardson at 2018 ASCO Annual Meeting
Improving Monoclonal Antibodies
A phase II study of elotuzumab in combination with pomalidomide, bortezomib and dexamethasone (Elo–PVD) in relapsed and r efractory myeloma (abstract 8012)<br />
Presented By Rachid Baz at 2018 ASCO Annual Meeting
6/18/2018
13
Elo-PVD Results
Presented By Rachid Baz at 2018 ASCO Annual Meeting
Subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma (RRMM): Part 2 update of the open label, multicenter, dose escalation Phase Ib study ( PAVO)
(abstract 8013)
Presented By Rachid Baz at 2018 ASCO Annual Meeting
Dara IV or SC?
Presented By Rachid Baz at 2018 ASCO Annual Meeting
6/18/2018
14
Phase 1b Study of Isatuximab and Carfilzomib for the Treatment of Relapsed and/or Refractory Multiple Myeloma (abstract 8014)
Presented By Rachid Baz at 2018 ASCO Annual Meeting
KD with Isa or Dara?
Presented By Rachid Baz at 2018 ASCO Annual Meeting
Conclusions
•Available myeloma treatments are increasing at a
rate higher than ever before.
•Trials are aimed at continuing to improve efficacy
as well as quality of life.
•Optimal combinations of the varying categories
of treatments and sequence of these
combinations needs continued evaluation.
6/18/2018
15
Thank you!
Slides from ASCO meeting library
kpatel1@mdanderson.org
6/18/2018
1
Smoldering Myeloma
Irene Ghobrial, MD
Associate Professor of Medicine
Harvard Medical School
Dana Farber Cancer Institute
Boston, MA
Ductal Carcinoma in Situ
MGUS
Multiple Myeloma
Metastatic breast cancer
Treat as early
as possible
CURE
Watch and
wait until end
organ damage
NO CURE
Is it time to treat patients with Smoldering MM
Kyle R. N Engl J Med 2007; 356:2582-90; Greipp RR, et al. J Clin Oncol 2005;23:3412–3420
Which patient population to consider for SMM?
100
80
60
40
20
0
27% will convert in 15 years
Roughly 2% per year
51% will convert in first 5 yrs
~ 10% per yr
0510 15 20 25
Probability of Progression (%)
51
66
73 78
410 16 21
MGUS
Smoldering MM
Yrs Since Diagnosis
27% more will convert in remaining 15 yrs
~ 2% per yr
6/18/2018
2
Rajkumar et al. Lancet Oncology 2014; 15: e538-48
What is the definition of MM or SMM?
Identification of high-risk SMM50% of progression risk at 2y
•Mayo Clinic: ≥10% clonal plasma cell bone marrow infiltration, and ≥30g/L of serum M-protein, and
serum-free light ratio >0.125 or <8
•Spanish: ≥95% of aberrant plasma cells measured by flow plus >25% decrease in one or both uninvolved
immunoglobulins
•Heidelberg: Tumor mass defined by Mayo risk model plus t(4;14)/del17p/gains of 1q/
•Japanese: Beta 2-microglobulin ≥ 2.5 mg/L plus M-protein increment rate > 1 mg/dL/day
•SWOG: serum M-protein ≥2 g/dL plus involved free light chain >25 and GEP >-0.26 (71% of risk progression at 2 yrs)
•PENN: ≥ 40% clonal PCBM infiltration plus sFLC ratio ≥ 50 plus Albumin 3.5 mg/dL (81% of risk at 2 yrs
•Czech & Heidelberg: immunoparesis plus serum M-protein ≥ 2.3 g/dL plus involved/uninvolved sFLC > 30
(81% of risk at 2 yrs)
•Barcelona: evolving pattern plus serum M-protein ≥ 3 g/dL plus immunoparesis (80% of risk at 2 yrs)
What is high risk SMM?
Dispenzieri A. Blood 2008; 111:785-9
Mayo Clinic model: serum immunoglobulin
free-light chain (FLC) ratio (n:273)
PCsBM Infiltration ≥ 10%
Serum M protein ≥ 3 g/dL
Serum FLC ratio <1/8 or >8
6/18/2018
3
Evolution pattern of the M-spike:
evolving vs nonevolving (n:207)
Fernández Larrea C et al. ASH 2014
Evolving SMM (52 (25%)):
at least 10% increase within the first 6 months from diagnosis when
M-Protein was ≥30 g/L or progressive increase in M-Protein in each of the annual consecutive measurements during a period of 3 years
in patients with an initial MP < 30 g/L
Non-evolving (75%):
Stable serum M-protein until progression occurs
Evolving SMM
• Risk progression at 2 years: 45%
• Risk progression at 5 years: 78%
• IgA isotype:
(41,2% frente a 23,8%, p=0,02)
Median TTP 3 years
Mediana TTP 19,4 years
p< 0,001
Each model appears to identify patients at high risk, with some but not complete overlap
Bone
marrow
clonal
plasma
cells
≥10%
and
any
one
or
more
of
the
following:
•Serum
M
protein
≥3.0gm/dL
•IgA
SMM
•Immunoparesis
with
reduction
of
two
uninvolved
immunoglobulin
isotypes
•Serum
involved/uninvolved
free
light
chain
ratio
≥8
(but
less
than
100)
•Progressive
increase
in
M
protein
level
(Evolving
type
of
SMM)
†
•Bone
marrow
clonal
plasma
cells
50-60%
•Abnormal
plasma
cell
immunophenotype
(≥95%
of
bone
marrow
plasma
cells
are
clonal)
and
reduction
of
one
or
more
uninvolved
immunoglobulin
isotypes
•t
(4;14)
or
del
17p
or
1q
gain
•Increased
circulating
plasma
cells
•MRI
with
diffuse
abnormalities
or
1
focal
lesion
(≥5mm)
•PET-CT
with
one
focal
lesion
(≥5mm)
with
increased
uptake
without
underlying
osteolytic
bone
destruction
•Monoclonal
light
chain
excretion
of
500mg/24
hours
or
higher
Which patient population to consider for high risk SMM?
Rajkumar et al, Blood 2015
Should we consider therapeutic interventions in SMM
Manier, Salem, et al. Nat Rev Clin Oncol, 2016
6/18/2018
4
Whole-exome and targeted sequencing of SMM BM samples
Non-pr ogressors -
26
Progressors - 37
A.
B.
C.
D.
Bustoros et al, Unpublished data
Should we use single agents or combination
therapy to treat high-risk SMM
Genomic profile of high risk SMM indicates that it is similar to overt MM
Treatment goals for high-risk
smouldering myeloma
Landgren et al, Clin Cancer Research 2011
Early Therapeutic Intervention
Mateos MV, et al. NEJM 2013
Mateos MV, et al. Lancet Oncology 2016
6/18/2018
5
As of 08/14/2015 11 patients were enrolled on Arm B (Elotuzumab
and Revlimid). As of 1/15/16, the protocol was amended to
continue enrollment to Arm A (Elotuzumab, Revlimid, and
Dexamethasone) and halt enrollment to Arm B . To date, 40 patients
have been enrolled on Arm A.
2
Months
Elotuzumab Days 1, 8,
15, 22
Revlimid Days 1-21
6
Months
Elotuzumab Days 1, 15
Revlimid Days 1-21
16
Months
Elotuzumab Day 1
Revlimid Days 1-21
End of
Treatment
Event
Monitoring
(Up to 3 years)
2
Months
Elotuzumab Days 1, 8,
15, 22
Revlimid Days 1-21
Decadron Days 1, 8,
15, 22
6
Months
Elotuzumab Days 1, 15
Revlimid Days 1-21
Decadron Days 1, 8, 15
16
Months
Elotuzumab Day 1
Revlimid Days 1-21
End of
Treatment
Event
Monitoring
(Up to 3 years)
Arm
B
Stem Cell Mobilization and Collection
Arm
A
Stem Cell Mobilization and Collection
Phase II trial of Elotuzumab/Len/Dex in high risk SMM
Ghobrial I, et al. ASH 2016. Abstract 976
GEM-CESAR: Study Design
• Multicenter, open-label, phase II trial
Induction
6 x 28-day
cycles
*High-risk was defined according to the Mayo and/or Spanish models
- Patients with any one or more of the biomarkers predicting imminent risk of progression to MM were
allowed to be included but…
- New imaging assessments were mandatory at screening and if bone disease was detected by CT or
PET-CT, patients were excluded
High-risk*
Smouldering
MM patients
N=90
Carfilzomib i.v.
20/36 mg/m
2
Days 1, 2, 8, 9, 15,
16
Lenalidomide
25 mg
Days 1–21
Dexamethasone
40 mg
Days 1, 8, 15 & 22
Carfilzomib i.v.
20/36 mg/m
2
Days 1, 2, 8, 9, 15,
16
Lenalidomide
25 mg
Days 1–21
Dexamethasone
40 mg
Days 1, 8, 15 & 22
High-dose
Melphalan
[200 mg/m
2
]
Followedby
ASCT
High-dose
Melphalan
[200 mg/m
2
]
Followedby
ASCT
Carfilzomib i.v.
20/36 mg/m
2
Days 1, 2, 8, 9, 15,
16
Lenalidomide
25 mg
Days 1–21
Dexamethasone
40 mg
Days 1, 8, 15 & 22
Carfilzomib i.v.
20/36 mg/m
2
Days 1, 2, 8, 9, 15,
16
Lenalidomide
25 mg
Days 1–21
Dexamethasone
40 mg
Days 1, 8, 15 & 22
Consolidation
2 x 28-day
cycles
Lenalidomide
10 mg
Days 1–21
Dexamethaso
ne
20 mg
Days 1, 8, 15
& 22
Lenalidomide
10 mg
Days 1–21
Dexamethaso
ne
20 mg
Days 1, 8, 15
& 22
Maintenance
24 x 28-day
cycles
Mateos MV, et al. ASH 2017, abstract 402
Current Studies in High-Risk Smoldering MM
• Lenalidomide or observation (phase III)
1
•Ixazomib + lenalidomide + dexamethasone (phase II)
2
• Isatuximab (phase II)
3
• Daratumumab single agent at different doses (Centaurus trial)
4
•Dara ph II for high-risk MGUS and low-risk smoldering
5
•Randomized Ph III AQUILA (sc)
6
1. ClinicalTrials.gov. NCT01169337.
2. ClinicalTrials.gov. NCT02916771.
3. ClinicalTrials.gov. NCT02960555.
4. Hofmeister CC, et al. Blood 2017 130:510
5. ClinicalTrials.gov. NCT03236428.
6. ClinicalTrials.gov. NCT03301220.
Recruitment status: Recruiting
Start date: November 2017
Estimated completion date: December 2025
6/18/2018
6
Center for Prevention of Progression of Blood Cancers
PCROWD
Biology
Screening
Therapeutic
Retrospective
Studies
www.dana-farber.org/cpop
pcrowd.dana-farber.org/
Predicting progression of developing Myeloma in a
High-Risk screened population
(PROMISE)
6/18/2018
7
Gad Getz, V iktor Adelsteinsson, Ken Anderson, Rob Soiffer, Nikhil Mun shi, Paul R ichardson, Ben Ebert.
Other collaborators: David Scadden, Shaji Kumar, Ola Landgren, Antonio Palumbo, Herve Ave L’ oiseau, Xavier Leleu,, Leif Bergsagel, Marta
Chesi, Bruno Paiva, Jesus San Miguel, Richard Hynes, George D aley, Jon Licht, Gad Getz, David Root. Viktor Adalsteinsson
Aldo Roccaro, Salomon Manier, Jihye Park, Antonio Sacco, Yujia Shi, Yuji Mishima, Oksana Zavidij, Marzia C apelletti, Dai sy Huynh, Karma
Salem, Yawara Kawano, S ioban Glavey , Jiantao Shi, Michele Moschetta, Adriana Perilla-Glen, Patrick Henrick, Kim Noonan, Kaitlen
Reyes,, Joe Cappuccio, A aron Caola.
http://ghobriall ab.danafa rberdev.org/
6/18/2018
1
Future Role of CAR T Therapies
in Multiple Myeloma
Nina Shah
University of California San Francisco
B cell maturation antigen (BCMA)
•Consistently expressed on plasma cells/MM cells1
•Possibly protects MM cells in BM niche2
•BMCA expression increases with disease progression3
•Limited expression on normal, non-hematopoietic cells1
1. Carpenter et al, Clinical Cancer Research, 2013
2. Novak et al, Blood 2004
3. Sanchez, 2012
6/18/2018
2
Summary of ongoing BCMA CAR-T Trials for
MM
Name Anti-BCMA CAR Bb2121 LCAR-B38M CART-BCMA
Group NCI
Bluebird/Celgene
Nanjng/Legend
Biotech Novartis/Penn
Binder/co-
stimulatory
signal
Murine/CD3
ζ
, CD28
Murine/CD3ζ, 4-
1BB
Murine/CD3
ζ, 4
-
1BB
Fully
human/CD3ζ, 4-
1BB
Transfection
γ-retroviral Lentiviral Lentiviral Lentiviral
BCMA
expression
required? Yes Yes Yes No
ABSTRACT 8007
bb2121 Anti-BCMA CAR T Cell Therapy in Patients
With Relapsed/Refractory Multiple Myeloma:
Updated Results From a Multicenter Phase I Study
Noopur Raje, MD,1Jesus Berdeja, MD,2Yi Lin, MD, PhD,3Nikhil Munshi, MD,4David Siegel, MD, PhD,5Michaela Liedtke, MD,6Sundar Jagannath, MD,7
Deepu Madduri, MD,7Jacalyn Rosenblatt, MD,8Marcela Maus, MD, PhD,1Ashley Turka,9Lyh Ping Lam, PharmD,9Richard A. Morgan, PhD,9
M. Travis Quigley,9Monica Massaro, MPH,9Kristen Hege, MD,10 Fabio Petrocca, MD,9and James N. Kochenderfer, MD11
1Massachusetts General Hospital Cancer Center, Bos ton, MA; 2Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; 3Mayo Clinic, Rochester, MN;
4Dana-Farber Cancer Institute, Boston, MA; 5Hackensack University Medical Center, Hackensack, NJ; 6Stanford Univers ity Medical Center, Palo Alto, CA; 7Mount Sinai
Medical Center, New York, NY; 8Beth Israel Deac oness Medical Center, Boston, MA; 9bluebird bio, Inc, Cambridge , MA; 10Celgene Corporation, San Francisco, CA;
11Experimental Transplantation and Immunology Branch, National Cancer Institute/National Institutes of Health, Bethesda, MD
CRB-401 PHASE 1 STUDY DESIGN
≥50% BCMA expression
<50% BCMA expression (n=10)
≥50% BCMA expression (n=12)
Dose range: 150–450 ×106CAR+ cells
<50% BCMA expression (n=10)
≥50% BCMA expression (n=12)
Dose range: 150–450 ×106CAR+ cells
Dose Escalation (N=21) Dose Expansion (N=22)
Flu 30 m/m2
Cy 300 mg/m2
Manufacturing success rate of 100%
150 ×106
150 ×106450 ×106
450 ×106800 ×106
800 ×106
50 ×106
50 ×106
6/18/2018
3
Escalation (N=21) Expansion (N=22)
Exposed Refractory Exposed Refractory
Prior
therapies, n (%)
Bortezomib 21 (100) 14 (67) 22 (100) 16 (73)
Carfilzomib 19 (91) 12 (57) 21 (96) 14 (64)
Lenalidomide 21 (100) 19 (91) 22 (100) 18 (82)
Pomalidomide 19 (91) 15 (71) 22 (100) 21 (96)
Daratumumab 15 (71) 10 (48) 22 (100) 19 (86)
Exposed/Refractory, n (%)
Bort/Len 21 (100) 14 (67) 22 (100) 14 (64)
Bort/Len/Car/Pom/Dara 15 (71) 6 (29) 21 (96) 7 (32)
Escalation
(N=21)
Expansion
(N=22)
Median (
min, max) prior regimens 7 (3, 14) 8 (3, 23)
Prior autologous SCT, n (%)
21 (100) 19 (86)
00 3 (14)
1 15 (71) 14 (64)
>1 6 (29) 5 (23)
TREATMENT HISTORY
Data cutoff: March 29, 2018. SCT, stem cell transplant.
ADVERSE EVENTS OF SPECIAL INTEREST
TEAE, n (%)
Overall Grade ≥3
Cytokine
release syndromea27 (63) 2 (5)
Neurotoxicity
b14 (33) 1 (2)
Neutropenia
35 (81) 34 (79)
Thrombocytopenia
26 (61) 22 (51)
Anemia
24 (56) 19 (44)
Infection
c
Overall
First Month
26 (61)
10 (23)
9 (21)
2 (5)
CAR T Treatment-Emergent Adverse Events
All Infused Patients (N=43)
Data cutoff: March 29 , 2018. NE, not estimable. aCRS uniformly graded per Lee DW, et al. Blood. 2014;124(2):188-195. bEvents occurr ing in first 28 d and including dizziness, bradyphrenia, somnolence, confusional state, nystagnmus,
insomnia, memory impairment, depressed level of consciousness, neurotoxicity, lethargy, tremor and hallucination. cI ncludes the SOC Infections and Infestations. Events observed in >10% include upper respiratory tract infection and
pneumonia. dIncludes patients treated with active doses ( 150–800 ×106CAR+ T cells; N=40). Median and 95% CI from Kaplan-Meier estimate. eTime from first bb2121 i nfusion to the first grade ≤2 event after day 32.
Neutropenia
(n=9)
Thr ombocytopenia
(n=18)
Events
710
Median (95% CI), mo
2 (1.2–2.6) 3 (1.9–NE)
Time to Recovery of Grade 3/4 Cytopenias in Patients
Without Recovery by Month 1d
Probability of Recovery, %
Time After bb2121 Infusion, monthse
•No grade 4 CRS events
•No fatal CRS or neurotoxicity events
•31/40 (78%) recovered ANC to ≥1000/µL by Day 32
•22/40 (55%) recovered PLT to ≥50,000/µL by Day 32
CYTOKINE RELEASE SYNDROME: MOSTLY LOW GRADE
AND MANAGEABLE
Parameter
Dosed Patients
(N=43)
Patients with a CRS event, n (%)
27 (63)
Maximum CRS
gradea
None
1
2
3
4
16 (37)
16 (37)
9 (21)
2 (5)
0
Median (min, max) time to onset, d
2 (1, 25)
Median (min, max) duration
, d 6 (1, 32)
Tocilizumab use, n (%)
9 (21)
Corticosteroid
use, n (%) 4 (9)
Cytokine Release Syndrome Parameters
Data cutoff: Ma rch 29, 2018. aCRS uniformly graded accordin g to Lee DW, et al. Blood. 2014;124(2):188-195.b3 patients were treated at the 50 x 106 dose level for a total of 43 patients.
Cytokine Release Syndrome By Dose Level
Dose Levelb
16.7
50.0
22.2
22.7
9.1
0
10
20
30
40
50
60
70
80
90
100
150 x 106 >150 x 106
Patients, %
3 2 1
39%
82%
>150 × 106
(n=22)
150 ×106
(n=18)
Maximum Toxicity Gradea
6/18/2018
4
12.5 9.1
50.0
27.3
37.5
54.5
0
10
20
30
40
50
60
70
80
90
100
450 x 106 low 450 x 106 high
Objective Response Rate, %
sCR/CR
VGPR
PR
33.3
7.1 9.1
7.1
36.4
42.9
50.0
0
10
20
30
40
50
60
70
80
90
100
50 x 106 150 x 106 >150 x 106
Objective Response Rate, %
sCR/CR
VGPR
PR
TUMOR RESPONSE: DOSE-RELATED; INDEPENDENT OF TUMOR
BCMA EXPRESSION
Data cutoff: March 29, 201 8. CR, complete response; mDOR, median duration of response; ORR, objective response rate; PD, progr essive disease; PR, partial response; sCR, stringent CR; VGPR, very good partial
response. aPatients with ≥2 months of response data or PD/death within <2 months. ORR is defined as attaining sCR, CR, VGPR, or PR, including confirmed and unconfirmed responses. Low BCMA is <50% bone
marrow plasma cells expression of BCMA; high BCMA is defined as ≥50%.
Tumor Response By DoseaTumor Response By BCMA Expressiona
ORR=33.3%
mDOR=1.9 mo
ORR=57.1%
mDOR=NE
150 ×106
(n=14) >150 × 106
(n=22)
50 ×106
(n=3)
ORR=95.5%
mDOR=10.8 mo
450 ×106
High BCMA
(n=11)
Median follow-up
(min, max), d 87
(36, 638)
84
(59, 94) 194
(46, 556) Median follow-up
(min, max), d
450 ×106
Low BCMA
(n=8)
311
(46, 556)
ORR=100%
ORR=91%
168
(121, 184)
PROGRESSION-FREE SURVIVAL
PFS at Inactive (50 ×106) and Active (150–800 ×106) Dose LevelsaPFS in MRD-Negative Patients
Data cutoff: March 29 , 2018. Median and 95% CI from Kaplan-Meier estimate. NE, not estimable. aPFS in dose escalation cohort.
50 ×106
(n=3)
150
–800 ×106
(n=18)
Events
310
mPFS
(95% CI),
mo
2.7
(1.0–2.9)
11.8
(8.8–NE)
150–800 ×106
(n=16)
mPFS
(95% CI),
mo
17.7
(5.8–NE)
•mPFS of 11.8 months at active doses (≥150 ×106CAR+ T cells) in 18 subjects in dose escalation phase
•mPFS of 17.7 months in 16 responding subjects who are MRD-negative
mPFS = 11.8 mo
mPFS = 2.7 mo
mPFS = 17.7 mo
Summary of ongoing BCMA CAR-T Trials for
MM Name Anti-BCMA CAR Bb2121 LCAR-B38M CART-BCMA
Group NCI Bluebird/Celgene Nanjng/Legend
Biotech Novartis/Penn
Binder/co-
stimulatory
signal
Murine/CD3ζ, CD28
Murine/CD3
ζ, 4-
1BB
Murine/CD3ζ, 4-
1BB
Fully human/CD3ζ,
4-1BB
Transfection γ-retroviral Lentiviral Lentiviral Lentiviral
BCMA
expression
required?
Yes Yes Yes No
Median prior
lines of tx 7, 11 7 3 9
Efficacy
1 sCR (relapsed), 1
VGPR, 2 PR, 8 SD
Responses in highest
cell dose;
9/11 in top
dose
10 CRs, 6 VGPR, 1
PRs (4 eventual PD),
n=18
at >5 e7 : 94% RR
9 MRD neg
33 CR or VGPR,
n=35, 1 relapse; 5
MRD neg > 1 yr
6/9, 2/5, 5/6
responses in 3
cohorts
Safety
Toxicity substantial
(Gr3-4CRS) but
reversible esp in
highest doses (9
e6/kg); protocol
modified to pts with
lower tumor burden
CRS in 71%;
transient Gr3 10%; 5
deaths (cardio
-
pulm
arrest, unrelated, 1
MDS, 3 PD at lowest
dose)
Early report of 1 Gr
4 neurotoxicity
Transient CRS
29/35, no
neurotox
CRS in 17/21 pts (6
with Gr2), with
neurotox in 3 pts
1 death –
candidemia/PD
6/18/2018
5
16
JNJ-68284528 (LCAR-B38M CAR-T cells)
Genetically modified autologous T-cell immunotherapy directed at B-cell maturation antigen (BCMA) which is being developed for the treatment of
Multiple Myeloma
VHH VHH
Linker = (Glycine)4Serine
2 different anti-BCMA VHH
domains for enhanced
avidity –T cell function is
avidity driven
4-1BB: built-in “2nd
Signal” costimulatory
signaling
CD3z: TCR-like
activation
JNJ-528 is a unique bispecific CAR that binds with high affinity to 2 different epitopes on BCMA, enabling tight
binding of the CAR to the BCMA-expressing cells Courtesy of Janssen
JNJ-68284528 (LCAR-B38M) CAR T cell: designed for high affinity interaction
with BCMA-expressing tumor cells
Conventional CAR-T LCAR-B38M VHH multi-specific CAR
scFv-Conventional CAR VHH-Bi-epitope CAR VHH-multi-specific CAR
BCMA Target A Target B
Courtesy of Janssen
Summary of ongoing BCMA CAR-T Trials for
MM Name Anti-BCMA CAR Bb2121 LCAR-B38M CART-BCMA
Group NCI Bluebird/Celgene Nanjng/Legend
Biotech Novartis/Penn
Binder/co-
stimulatory
signal
Murine/CD3ζ, CD28
Murine/CD3
ζ, 4-
1BB
Murine/CD3ζ, 4-
1BB
Fully human/CD3ζ,
4-1BB
Transfection γ-retroviral Lentiviral Lentiviral Lentiviral
BCMA
expression
required?
Yes Yes Yes No
Median prior
lines of tx 7, 11 7 3 9
Efficacy
1 sCR (relapsed), 1
VGPR, 2 PR, 8 SD
Responses in highest
cell dose;
9/11 in top
dose
ORR= 57% , 96% in
pts @>150 e6
;
mPFS
11.8
mo, 17.7 mo
in
MRD neg pts
33 CR or VGPR,
n=35, 1 relapse; 5
MRD neg > 1 yr
6/9, 2/5, 5/6
responses in 3
cohorts
Safety
Toxicity substantial
(Gr3-4CRS) but
reversible esp in
highest doses (9
e6/kg); protocol
modified to pts with
lower tumor burden
CRS in 71%;
transient Gr3 10%; 5
deaths (cardio
-
pulm
arrest, unrelated, 1
MDS, 3 PD at lowest
dose)
Early report of 1 Gr
4 neurotoxicity
Transient CRS
29/35, no
neurotox
CRS in 17/21 pts (6
with Gr2), with
neurotox in 3 pts
1 death –
candidemia/PD
6/18/2018
6
Challenges in CAR T therapy for MM
•CRS (hopefully not as much of an issue as with ALL)
•Persistence
•Lymphodepletion
•Cytokine-based T-reg elimination
•Virus-specific T cells as primary CAR-T population
Virus-specific T cells as primary CAR-T
population
1. Maus et al, CCR 2016
Challenges in CAR T therapy for MM
•CRS (hopefully not as much of an issue as with ALL)
•Persistence
•Lymphodepletion
•Cytokine-based T-reg elimination
•Virus-specific T cells as primary CAR-T population
•Optimizing co-stimulatory signaling
•41BB>CD28
•Nature of MM is waxing and waning, should the cells be that way as
well?
•“ON-switch” CARs
•Targeting multiple antigens
•T cells redirected for universal cytokine-mediated killing (TRUCKs)
6/18/2018
7
“On” switch CAR T cells
1. Roybal et al, Cell 2016
T cells redirected for universal cytokine-
mediated killing (TRUCKs)
1. Chiemelewski et al, Immunological Reviews, 2013
Cellectis Universal SLAMF7-Specific CAR T
(abs 502)
•“Off-the-shelf”
•Normal healthy PB donors
•Inactivation of the TCRα constant (TRAC)
gene using TALEN®gene-editing technology
to prevent GVHD and expression of T cell
SLAMF7.
6/18/2018
8
Poseida: CARTyrin (abs 3068)
•DNA transposon system
•iCasp9-based safety switch
•Anti-BCMA CARTyrin
•Selection gene (~ 100% pure CAR+product)
•Enrich stem cell memory T cell subset
But where are we really going…?
•Timing of CART
•Disease burden
•Position relative to autologous transplant
•Cost
•Time and financial cost of proving superiority
•Clinical trial design
•MRD as endpoint
“It’s my CAR-T and I’ll cry if I want to…”
•Persistence
•Inducibility
6/18/2018
9
Case
•65 YO M without significant PMH presents with new back pain and
incidentally found abnormal protein level
•Further work-up shows IgG kappa M-spike 3.8 g/dL
•Additional labs: normal Cr, Ca; Hb=11.8 g/dL
•MRI shows new L4 compression fracture
•BM biopsy: 60% kappa-restricted plasma cells, normal cytogenetics, FISH
positive for t(11;14)
Treatment course
•VRD induction→achieves VGPR after 6 cycles
•Mel 200 ASCT→sCR at day 100 with MRD negativity
•Len maintenance x 2.5 y--> biochemical progression
•KRD with PR; Goes 18 months but then presents with new bone
lesions
•Starts DRD→Stable x 12 months but then presents wit new anemia.
BM with 70% plasma cells and clonal evolution (-16)
Now what??
Thank you!
nina.shah@ucsf.edu
