Multiple Myeloma UpdateIs Immunotherapy a Game Changer in Multiple Myeloma?

Professor of MedicineDirector, Myeloma Program

The University of Chicago

Andrzej J Jakubowiak, MD, PhD

…we have made tremendous progress in myeloma…

Barlogie et al, Blood. 2014 Nov 13;124(20):3043-51

Sustained CR duration in subsequent Total Therapies

Sustained MRD – negative status? Sustained MRD – negative status? Sustained MRD – negative status

Since the introduction of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs)

• Consistent and deeper responses

• Significantly improved overall survival

KRd +/- Transplant

KRd + High dose

KRd Conventional

Studies not designed for comparisons

Zimmerman et al, TT Meeting 2016; Jakubowiak et al, ASH 2017

Jakubowiak et al, manuscript in preparation

…and we keep making progress using more practical then Total Therapies regimens with new generation of IMiDs and PIs +/- transplant

Surv

ival

(%

)

100

75

50

25

00 30 40 60

Months

20 5010

KRd + ASCT (n=75)KRd w/o ASCT (n=46*)

Median f/u, mo

PFS rate1-yr 2-yr 3-yr 4-yr

47.6 100% 91% 80% 69%†

12.8 96% 90% 82% 80%

Attal et al. ASH 2015, N Eng J Med 2017:376:1311-20

PFS Rate3-yr 4-yr

Arm A—Conventional 47% 35%Arm B—High dose 61% 41%

Months since randomization

RVd +/- Transplant

1.0

0.7

0.5

0.2

00 18 24 4812 366 4230

0.9

0.6

0.4

0.1

0.8

0.3

Arm B – High dose

Arm A – Conventional

Pro

gre

ssio

n-f

ree

surv

ival

Pro

gre

ssio

n-f

ree

surv

ival

…however, even with as most promising like these KRd+transplant results

…can immunotherapy contribute to further improvements?

MRD (-) by NGS

Best ResponseMRD (-) by NGS

Sustained Response MRD (-) by NGS

Sustained Response

…at least 40% of patients are at risk of relapse

Jakubowiak et al ASH 2017; Jakubowiak et al, manuscript in preparation

Strategy #1

Adding monoclonal antibodies to target myeloma cells

…we started with elotuzumab, an anti-SLAMF7 (anti-CS1) antibodySingle agent was not active

Lonial et al, N Eng J Med 2015; 373:621-631

… which was subsequently confirmed in a positive Phase III ELOUENT-2 trial

…although with margin of improvement

smaller than anticipated,

…but based on MOA, elotuzumab was expected to work well with IMiDs

…but still resulting in elotuzumab (EmplicitiTM) approval

…next came anti-CD38 antibodies

Daratumumab as single agent emerged

as one of the most active drugs in myeloma

Basis for daratumumab

(Darzalex) approval

Lonial et al, Lancet 2016:387:1551-1560

…simultaneously, its combinations generated highly promising results

…providing support and very quick enrollment into two phase III studies in Relapsed/Refractory MM

Dimopoulos N Eng J Med 2016:375:1319-31

San Miguel J, et al. EHA 2017; Abstract S101

Palumbo N Eng J Med 2016;375:754-66

Weisel K, et al. EHA 2017, Abstract S459

HR: 0.31(95% CI, 0.24-0.39)p<0.0001

Vd Median: 7.1 months

DVd Median: 16.7 months

% s

urv

ivin

g w

ith

ou

t p

rogr

ess

ion

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 24 30MonthsNo. at risk

Median follow-up: 19.4 months

CASTOR trial

RdDRd

283286

No. at riskMonths

249266

206249

181238

160229

143214

127203

109189

86146

2346

00

HR: 0.41(95% CI, 0.31–0.53) p<0.0001

28

100

80

60

40

20

0Surv

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g w

ith

ou

t p

rogr

essi

on

(%)

0

DRdMedian: NR

3 6 9 12 15 18 21 24 27 33

RdMedian: 17.5 months

30

68%

41%

24-month PFS

Median follow-up: 25.4 months

POLLUX trial(VD +/- daratumumab) (RD +/- daratumumab)

…with hazard ratios and PFS for Rd-Dara exceeding anything we have seen before

…and quickly generating rationale for evaluation of daratumumab in frontline treatment with intent to cure

…with a hope that 2 players (KRd + dara) will

improve a chance to achieve this win

…the initial results were indeed very promising

Depth of response improved

with duration of treatment

• Median number of treatment cycles:

11.5 (range, 1.0-13.0)

10091

43

29

0

10

20

30

40

50

60

70

80

90

100

≥PR ≥VGPR ≥CR sCR

Resp

on

se r

ate

, %

Best Response (n = 21)

DARA (16 mg/kg) + KRd

• Median follow-up: 10.8 (range, 4.0-12.5) months

• Overall survival = 100%

12-month PFS ratea = 94%

No. at risk

% s

urv

ivin

g w

itho

ut

pro

gre

ssio

n

0

20

40

60

80

100

0 3 6 9 15Months

12

22 21 17 12 04

aKaplan-Meier estimate.

Jakubowiak et al, ASCO 2017, oral presentation, Chari ASH 2017, Abstract 3110 (updated results)

KRd+Daratumumab

…although no clear signal from this pilot study

…with several larger KRd-dara frontline studies in progress

…leading to recent approval of daratumumab with VMP in newly diagnosed myeloma

…but we now have the first evidence that daratumumab can improve the results

of standard of care in frontline myeloma from the ALCYONE phase III trial

…including an increase of MRD (-) disease

…so naked antibodies work,

…how about antibody conjugates

ORR = 60% (21/35; 95% CI: 42.1%, 76.1%)

• 1 sCR, 2 CR, 15 VGPR, 3 PR

…supporting further development of antibody conjugatesTrudel et al, ASH 2017, Oral Presentation (Abstract #741)

…the most advanced work is with antibody conjugate targeting BCMA

Strategy #2

Overcoming immune suppression

PD1/PDL-1 checkpoint inhibitors

…the promise of checkpoint inhibition is well established in many cancers

• Myeloma like other cancers cells express

“neo-antigens” that allow them to be

recognized by the immune system

• Immune evasion mechanisms are

prominent in myeloma

• The PD-1 / PD-L1 axis is a dominant

immune escape pathway across many

human cancers including myeloma

• PD-1 blocking antibodies have shown

remarkable activity across a growing

number of cancer types

…making future development of check-point inhibitors in

myeloma more challenging

…however, check-point inhibition does not seem to work in myeloma

Strategy #3

Activating myeloma-specific immunity

Cancer vaccines

…the strategy is pursued in several cell-based and non-cell based vaccine trials in myeloma in progress

TrialStudyPhase Site(s)

Survivin Vaccine 1 H. Lee Moffitt Cancer Center

Vaccination with PD-L1 Peptide 1 Non-US

Enhancing Anti-Myeloma Vaccine Response After Autologous Stem Cell Transplantation 2 Emory University

Dendritic Cell/Myeloma Fusion Vaccine 2National Heart, Lung, and Blood Institute (NHLBI) (CTN 1401)

SVN53-67/M57-KLH Peptide Vaccine in Treating Patients With Newly Diagnosed Multiple Myeloma Receiving Lenalidomide Maintenance Therapy

1 Roswell Park Cancer Institute

CT7, MAGE-A3, and WT1 mRNA-electroporated Autologous Langerhans-type Dendritic Cells as Consolidation

1 MSKCC

A Study of PVX-410, a Cancer Vaccine, and Durvalumab +/- Lenalidomide for Smoldering MM

1 Massachusetts General Hospital

Vaccine Therapy With or Without Cyclophosphamide in Treating Patients With Recurrent or Refractory Multiple Myeloma

1/2 Mayo Clinic

…they are all too early

to draw conclusions on the future role of this strategy in myeloma

Strategy #4

Directing T-cells to fight myeloma

BiTESCART cells

Other engineered T-cell strategies

CAR modified T cells are clearly “hot” as candidate cancer therapy

Chimeric Antigen

Receptors

CD28 or 4-1BB

…and the first results are highly promising

Berdeja et al, ASH 2017, Oral Presentation (Abstract #740)

…importantly, with manageable toxicity

1Data cut-off of October 2, 20172Neurotoxicity includes the preferred terms: depressed level of consciousness, confusional state, bradyphrenia, somnolence

Preferred TermOveralln (%)

Grade 3 or highern (%)

Cytokine release syndrome 15 (71) 2 (10)

Neurotoxicity2 5 (24) 0

Neutropenia 18 (86) 18 (86)

Thrombocytopenia 11 (52) 9 (43)

Anemia 14 (67) 12 (57)

Dose Escalation Patients

(N = 21)1

Berdeja et al, ASH 2017, Oral Presentation (Abstract #740)

PHASE I, OPEN-LABEL TRIAL OF ANTI-BCMA CHIMERIC ANTIGEN RECEPTOR T CELLS IN PATIENTS WITH RELAPSED/ REFRACTORY

MULTIPLE MYELOMA

LCAR-B38M CAR-T Cells designed based on proprietary

bispecific CAR platform

Zhang et al, first at ASCO 2017, updated at EHA 2017, Oral presentations

…and it is getting even better

…showing again very promising results

Patients treatedbefore April 5, 2017

Total PR VGPR sCR

Best efficacy 30 2 9 19

% 100% 6.7% 30% 63.3%

Objective response rate (ORR): 100%

1 year

Chance of cure ?

Zhang et al, EHA 2017, Oral Presentation

…which can be very durable

…in summary, immunotherapy is almost certainly a game changer in myeloma

• Anti-CD-38 antibodies (darumumab) and and CARTs are making great entry

• More developments are likely

• It will likely contribute to an increase of the rate of cure for myeloma

Thank you!

I would like to thank:

Members of the Myeloma Program at the

University of Chicago

The investigators, nursing staff, and research

support staff in participating institutions

The Multiple Myeloma Research Consortium and

PCCC, under whom our multi-site trials were

conducted.

Acknowledgments