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6/18/2018

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

1

6/18/2018

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


Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting

2

6/18/2018

Overall Response Rates

Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting

Adverse Events Summary


Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting

Adverse Events of Interest

Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting

3

6/18/2018

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?

4

6/18/2018

Maintenance Therapy with 25 versus 5 mg Lenalidomide after Prolonged Lenalidomide Consolidation Therapy 
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

5

6/18/2018

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

6/18/2018

Conclusions

Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting

Targeted therapy

Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma

Presented By Luciano Costa at 2018 ASCO Annual Meeting

7

6/18/2018

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

8

6/18/2018

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

9

6/18/2018

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

10

6/18/2018

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

11

6/18/2018

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 refractory myeloma (abstract 8012)


Presented By Rachid Baz at 2018 ASCO Annual Meeting

12

6/18/2018

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

13

6/18/2018

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.

14

6/18/2018

Thank you!
Slides from ASCO meeting library

kpatel1@mdanderson.org

15

6/18/2018

Smoldering Myeloma
Irene Ghobrial, MD
Associate Professor of Medicine
Harvard Medical School
Dana Farber Cancer Institute
Boston, MA

Is it time to treat patients with Smoldering MM
Ductal Carcinoma in Situ

Metastatic breast cancer

Treat as early
as possible
CURE
Watch and
wait until end
organ damage
NO CURE

MGUS
Multiple Myeloma

Which patient population to consider for SMM?
Probability of Progression (%)

100

Smoldering MM
MGUS

80
60
51

27% will convert in 15 years
Roughly 2% per year

78
73
66
27% more will convert in remaining 15 yrs
~ 2% per yr

40
51% will convert in first 5 yrs
~ 10% per yr

20

4
0

0

5

10

21

16

10
15

20

25

Yrs Since Diagnosis
Kyle R. N Engl J Med 2007; 356:2582-90; Greipp RR, et al. J Clin Oncol 2005;23:3412–3420

1

6/18/2018

What is the definition of MM or SMM?

Rajkumar et al. Lancet Oncology 2014; 15: e538-48

What is high risk SMM?
Identification of high-risk SMM 50% 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)

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

Dispenzieri A. Blood 2008; 111:785-9

2

6/18/2018

Evolution pattern of the M-spike:
evolving vs nonevolving (n:207)
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
Median TTP 3 years

Evolving SMM
• Risk progression at 2 years: 45%

Mediana TTP 19,4 years

p < 0,001

• Risk progression at 5 years: 78%
• IgA isotype:
(41,2% frente a 23,8%, p=0,02)

Fernández Larrea C et al. ASH 2014

Which patient population to consider for high risk SMM?
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

Rajkumar et al, Blood 2015

Should we consider therapeutic interventions in SMM

Manier, Salem, et al. Nat Rev Clin Oncol, 2016

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6/18/2018

Should we use single agents or combination
therapy to treat high-risk SMM
Whole-exome and targeted sequencing of SMM BM samples

Genomic profile of high risk SMM indicates that it is similar to overt MM
A.

B.

C.

Non-progressors 26

Progressors - 37

D.

Bustoros et al, Unpublished data

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

4

6/18/2018

Phase II trial of Elotuzumab/Len/Dex in high risk SMM
Stem Cell Mobilization and Collection

Arm A
2 Months

6 Months

Elotuzumab Days 1, 8,
15, 22

16 Months

Elotuzumab Days 1, 15

Revlimid Days 1-21

Revlimid Days 1-21

Decadron Days 1, 8,
15, 22

Decadron Days 1, 8, 15

Elotuzumab Day 1
Revlimid Days 1-21

End of
Treatment

Event
Monitoring
(Up to 3 years)

As of 08/14/2015 11 patients were enrolled on Arm B (Elotuzumab
amended to
Event
End of
enrollment
to Arm
Monitoring
Elotuzumab Days
1, 15 A (Elotuzumab,
Elotuzumab Day 1Revlimid, and
Treatment
Dexamethasone)
and
halt
Arm
Revlimid
Days
1-21 enrollment
Revlimidto
Days
1-21 B . To date, 40 patients
(Up to 3 years)
have been enrolled on Arm A.

and Revlimid). As
of 1/15/16, the protocol
was
2 Months
6 Months
16 Months

Elotuzumab
Days 1, 8,
continue
15, 22
Revlimid Days 1-21

Arm B
Stem Cell Mobilization and Collection

Ghobrial I, et al. ASH 2016. Abstract 976

GEM-CESAR: Study Design
•

Multicenter, open-label, phase II trial
Consolidation
2 x 28-day
cycles

Induction
6 x 28-day
cycles

High-risk*
Smouldering
MM patients
N=90

Carfilzomib i.v.
20/36 mg/m2
Days 1, 2, 8, 9, 15,
16
Lenalidomide
25 mg
Days 1–21

High-dose
Melphalan
[200 mg/m2]
Followed by
ASCT

Dexamethasone
40 mg
Days 1, 8, 15 & 22

Carfilzomib i.v.
20/36 mg/m2
Days 1, 2, 8, 9, 15,
16
Lenalidomide
25 mg
Days 1–21
Dexamethasone
40 mg
Days 1, 8, 15 & 22

Maintenance
24 x 28-day
cycles

Lenalidomide
10 mg
Days 1–21
Dexamethaso
ne
20 mg
Days 1, 8, 15
& 22

*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
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 smoldering5
• Randomized Ph III AQUILA (sc)6
Recruitment status: Recruiting
Start date: November 2017
Estimated completion date: December 2025
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.

5

6/18/2018

Center for Prevention of Progression of Blood Cancers
www.dana-farber.org/cpop
PCROWD

Retrospective
Studies

Therapeutic

Biology

Screening

pcrowd.dana-farber.org/

Predicting progression of developing Myeloma in a
High-Risk screened population
(PROMISE)

6

6/18/2018

http://ghobriallab.danafarberdev.org/

Aldo Roccaro, Salomon Manier, Jihye Park, Antonio Sacco, Yujia Shi, Yuji Mishima, Oksana Zavidij, Marzia Capelletti, Daisy Huynh, Karma
Salem, Yawara Kawano, Sioban Glavey , Jiantao Shi, Michele Moschetta, Adriana Perilla-Glen, Patrick Henrick, Kim Noonan, Kaitlen
Reyes,, Joe Cappuccio, Aaron Caola.

Gad Getz, Viktor Adelsteinsson, Ken Anderson, Rob Soiffer, Nikhil Munshi, Paul Richardson, 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 Daley, Jon Licht, Gad Getz, David Root. Viktor Adalsteinsson

7

6/18/2018

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

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6/18/2018

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

Murine/CD3ζ, 41BB

Murine/CD3ζ, 41BB

Fully
human/CD3ζ, 41BB

Binder/costimulatory Murine/CD3ζ, CD28
signal
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,1 Jesus Berdeja, MD,2 Yi Lin, MD, PhD,3 Nikhil Munshi, MD,4 David Siegel, MD, PhD,5 Michaela Liedtke, MD,6 Sundar Jagannath, MD,7
Deepu Madduri, MD,7 Jacalyn Rosenblatt, MD,8 Marcela Maus, MD, PhD,1 Ashley Turka,9 Lyh Ping Lam, PharmD,9 Richard A. Morgan, PhD,9
M. Travis Quigley,9 Monica Massaro, MPH,9 Kristen Hege, MD,10 Fabio Petrocca, MD,9 and James N. Kochenderfer, MD11

1Massachusetts

General Hospital Cancer Center, Boston, MA; 2Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; 3Mayo Clinic, Rochester, MN;
Institute, Boston, MA; 5Hackensack University Medical Center, Hackensack, NJ; 6Stanford University Medical Center, Palo Alto, CA; 7Mount Sinai
Medical Center, New York, NY; 8Beth Israel Deaconess 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

4Dana-Farber Cancer

CRB-401 PHASE 1 STUDY DESIGN

Flu 30 m/m 2
Cy 300 mg/m2

Dose Escalation (N=21)

Dose Expansion (N=22)

≥50% BCMA expression
<50% BCMA expression (n=10)
50 × 106

150 × 106

450 × 106

800 × 106

≥50% BCMA expression (n=12)
Dose range: 150–450 × 106 CAR+ cells

Manufacturing success rate of 100%

2

6/18/2018

TREATMENT HISTORY
Escalation
(N=21)
7 (3, 14)
21 (100)
0
15 (71)
6 (29)
Escalation (N=21)

Median (min, max) prior regimens
Prior autologous SCT, n (%)
0
1
>1

Expansion
(N=22)
8 (3, 23)
19 (86)
3 (14)
14 (64)
5 (23)
Expansion (N=22)

Exposed

Refractory

Exposed

Refractory

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)

Prior therapies, n (%)
Bortezomib

Daratumumab
Exposed/Refractory, n (%)
Bort/Len

15 (71)

10 (48)

22 (100)

19 (86)

21 (100)

14 (67)

22 (100)

14 (64)

Bort/Len/Car/Pom/Dara

15 (71)

6 (29)

21 (96)

7 (32)

Data cutoff: March 29, 2018. SCT, stem cell transplant.

ADVERSE EVENTS OF SPECIAL INTEREST

TEAE, n (%)

Overall

Grade ≥3

Cytokine release syndromea

27 (63)

2 (5)

Neurotoxicityb

14 (33)

1 (2)

Neutropenia

35 (81)

34 (79)

Thrombocytopenia

26 (61)

22 (51)

Anemia

24 (56)

19 (44)

Infectionc
Overall
First Month

26 (61)
10 (23)

9 (21)
2 (5)

• No grade 4 CRS events
• No fatal CRS or neurotoxicity events

Time to Recovery of Grade 3/4 Cytopenias in Patients
Without Recovery by Month 1d

Probability of Recovery, %

CAR T Treatment-Emergent Adverse Events
All Infused Patients (N=43)

Events
Median (95% CI), mo

Neutropenia
(n=9)
7
2 (1.2–2.6)

Thrombocytopenia
(n=18)
10
3 (1.9–NE)

Time After bb2121 Infusion, monthse

• 31/40 (78%) recovered ANC to ≥1000/µL by Day 32
• 22/40 (55%) recovered PLT to ≥50,000/µL by Day 32

Data cutoff: March 29, 2018. NE, not estimable. aCRS uniformly graded per Lee DW, et al. Blood. 2014;124(2):188-195. bEvents occurring in first 28 d and including dizziness, bradyphrenia, somnolence, confusional state, nystagnmus,
insomnia, memory impairment, depressed level of consciousness, neurotoxicity, lethargy, tremor and hallucination. cIncludes the SOC Infections and Infestations. Events observed in >10% include upper respiratory tract infection and
pneumonia. dIncludes patients treated with active doses (150–800 × 106 CAR+ T cells; N=40). Median and 95% CI from Kaplan-Meier estimate. eTime from first bb2121 infusion to the first grade ≤2 event after day 32.

CYTOKINE RELEASE SYNDROME: MOSTLY LOW GRADE
AND MANAGEABLE
Cytokine Release Syndrome By Dose Level

Cytokine Release Syndrome Parameters

Patients with a CRS event, n (%)

Dosed Patients
(N=43)

100

27 (63)

80

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)

90

Patients, %

Parameter

Maximum Toxicity Gradea
3

2

1

82%
9.1

70
22.7

60
50
40

30

39%
22.2

50.0

20
10
0

16.7
150x×106
106
150
(n=18)

>150 x× 106
106
>150
(n=22)

Dose Levelb

Data cutoff: March 29, 2018. a CRS uniformly graded according 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.

3

6/18/2018

TUMOR RESPONSE: DOSE-RELATED; INDEPENDENT OF TUMOR
BCMA EXPRESSION
Tumor Response By Dosea

Objective Response Rate, %

90
80
60
40

ORR=33.3%
mDOR=1.9 mo

10

36.4
33.3

7.1
7.1

9.1

50 ×x 106
106
(n=3)

150 x× 106
106
(n=14)

>150 x× 106
106
(n=22)

84
(59, 94)

87
(36, 638)

194
(46, 556)

0

Median follow-up
(min, max), d

50.0

42.9

30
20

ORR=100%

100

ORR=91%

90
ORR=57.1%
mDOR=NE

70
50

Tumor Response By BCMA Expressiona

ORR=95.5%
mDOR=10.8 mo

sCR/CR
VGPR
PR

Objective Response Rate, %

100

37.5

80

sCR/CR
VGPR
PR

70
54.5

60
50
40

50.0

30
27.3

20
10

0

Median follow-up
(min, max), d

12.5

9.1

6
450x ×106
10low
450
Low BCMA
(n=8)

6
450x 106
× 10high
450
High BCMA
(n=11)

311
(46, 556)

168
(121, 184)

Data cutoff: March 29, 2018. CR, complete response; mDOR, median duration of response; ORR, objective response rate; PD, progressive 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%.

PROGRESSION-FREE SURVIVAL
• mPFS of 11.8 months at active doses (≥150 × 106 CAR+ T cells) in 18 subjects in dose escalation phase
• mPFS of 17.7 months in 16 responding subjects who are MRD-negative
PFS at Inactive (50 × 106) and Active (150–800 × 106) Dose Levelsa

Events
mPFS (95% CI), mo

50 × 106
(n=3)

150–800 × 106
(n=18)

3
2.7
(1.0–2.9)

10
11.8
(8.8–NE)

PFS in MRD-Negative Patients
150–800 × 106
(n=16)
mPFS (95% CI), mo

mPFS = 11.8 mo

17.7
(5.8–NE)

mPFS = 17.7 mo

mPFS = 2.7 mo

Data cutoff: March 29, 2018. Median and 95% CI from Kaplan-Meier estimate. NE, not estimable.

aPFS

in dose escalation cohort.

Summary of ongoing BCMA CAR-T Trials for
MM
Name

Anti-BCMA CAR

Bb2121

Group

NCI

Bluebird/Celgene

Murine/CD3ζ, CD28

Murine/CD3ζ, 4-1BB

Murine/CD3ζ, 41BB

Fully human/CD3ζ,
4-1BB

γ-retroviral

Lentiviral

Lentiviral

Lentiviral

Yes

Yes

Yes

No

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

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

10 CRs, 6 VGPR, 1
PRs (4 eventual PD),
n=18
at >5 e7 : 94% RR
9 MRD neg
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

Binder/costimulatory
signal
Transfection
BCMA
expression
required?
Median prior
lines of tx

LCAR-B38M
Nanjng/Legend
Biotech

CART-BCMA

Novartis/Penn

4

6/18/2018

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

2 different anti-BCMA VHH
domains for enhanced
avidity –T cell function is
avidity driven

VHH

4-1BB: built-in “2nd
Signal” costimulatory
signaling
CD3z: TCR-like
activation
Linker = (Glycine)4Serine

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

16

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
Target A

BCMA

scFv-Conventional CAR

Target B

VHH-Bi-epitope CAR

VHH-multi-specific CAR

Courtesy of Janssen

Summary of ongoing BCMA CAR-T Trials for
MM
Name

Anti-BCMA CAR

Bb2121

Group

NCI

Bluebird/Celgene

Murine/CD3ζ, CD28

Murine/CD3ζ, 4-1BB

Murine/CD3ζ, 41BB

Fully human/CD3ζ,
4-1BB

γ-retroviral

Lentiviral

Lentiviral

Lentiviral

Yes

Yes

Yes

No

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

Binder/costimulatory
signal
Transfection
BCMA
expression
required?
Median prior
lines of tx

LCAR-B38M
Nanjng/Legend
Biotech

CART-BCMA

Novartis/Penn

5

6/18/2018

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

6/18/2018

“On” switch CAR T cells

1. Roybal et al, Cell 2016

T cells redirected for universal cytokinemediated 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.

7

6/18/2018

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

8

6/18/2018

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

9



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