Therapeutic sequencing in Myeloma at relapsecme-utilities.com/mailshotcme/Material for...

Therapeutic sequencing in Myeloma at relapse

Xavier Leleu

Hôpital la Milétrie, PRC, CHUInserm U1402 CIC

Laboratoire d’Immunologie Oncologie et dormance tumoralePoitiers, France

Disclosures

• Honorarium, Grants/research support, and Consulting fees:

Amgen, Celgene, Janssen, Takeda, Novartis, Sanofi, Merck, Pierre Fabre, Mundipharma, Karyopharm, Roche, Abbvie, Bristol-Myers Squibb, Gilead, Incyte

Main questions

1. Switch vs. re-treatment2. Doublet vs Triplet3. Treatment until progression

Main questions

1. Which line is best for pomalidomide2. Doublet vs Triplet3. Treatment until progression

1–3 prior lines of therapyProgressing after at least 2 lines of

therapy incl. 1 IMiD + BTZ and refractory to the last line

Lenalidomide-dexamethasoneBortezomib-dexamethasone

Pomalidomide-dexamethasone-Daratumumab-

Approved drugs in RRMM in EU until 2016

RRMM, relapsed/refractory multiple myeloma.

Lenalidomide prescribing information, available at: http://www.ema.europa.euBortezomib prescribing information, available at: http://www.ema.europa.eu

Pomalidomide prescribing information, available at: http://www.ema.europa.eu

Pomalidomide-dexamethasone

+ Cyclo or Ixa or Bort or

Dara or Elo

Daratumumab(single agent or

combination)

Clinicaltrial

At second or subsequent relapse

IMiD-based induction

PI-based doubletsKd / Vd

Bortezomib-based tripletsDaraVDPanoVDEloVDVCD

Bortezomib-based induction

Rd-based tripletsDaraRd

KRdIRdERd

Rd doublet

First relapse after

Moreau P, et al;.Ann Oncol. 2017

ESMO Guidelines 2017: RRMM

IMiDs/Lenalidomide backbone

Rd+

proteasome inhibitorCarfilzomibIxazomib

Bortezomib

Rd+

therapeutic antibodyanti-CD38 (daratumumab, isatuximab)

anti-SLAMF7 (elotuzumab)

• Triplet better by PFS median 1 to possibly 3 years +

• High risk improves

• MRD becomes a new objective

K, carfilzomib; E, elotuzumab; I, ixazomib.

1. Dimopoulos MA, et al. N Engl J Med 2016; 375:1319-13312. Stewart AK, et al. N Engl J Med. 2015;372(2):142-152.

3. Lonial S, et al. N Engl J Med. 2015;373(7):621-631.4. Dimopoulos MA, et al. Blood. 2015;126(23):Abstract 28.

5. Moreau P, et al. N Engl J Med. 2016;374(17):1621-1634.

Studies evaluating Rd-based triplets

POLLUXDRd vs Rd1

PFS HR (95% CI)

0.41 (0.31-0.53)

ORR 93%

≥ VGPR 76%

≥ CR 43%

Duration of response, mo NE

OS HR (95% CI)

0.64(0.40-1.01)

ASPIREKRd vs Rd2

ELOQUENT-2ERd vs Rd3,4

TOURMALINE-MM1

IRd vs Rd5

0.69 (0.57-0.83)

0.73 (0.60-0.89)

0.74 (0.59-0.94)

87% 79% 78%

70% 33% 48%32% 4% 14%

28.6 20.7 20.5

0.79(0.63-0.99)

0.77 (0.61-0.97) NE

INTENDED FOR INTERNAL USE. ALL MATERIALS/CONTENT ARE SUBJECT TO RELEVANT LOCAL REVIEW PROCESSES (IE, MEDICAL, LEGAL, COMPLIANCE, PRIVACY AND REGULATORY). 7

Updated PFSa of POLLUX

Median follow-up: 32.9 months (range, 0-40.0 months)

Progression‐Free Survival in the ITT Population

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 15 18 42Months

30

283286

249266

206249

181238

160229

143214

126203

00

100183

No. at riskRd

DRd

21 24 36

89167

3667

111194

DRd

Rd

3927 33

516

80145

12

Median: not reached

Median: 17.5 months

HR 0.44; 95% CI, 0.34-0.55; P <0.0001

30-month PFSb

58%

35%

aExploratory analyses based on clinical cut-off date of October 23, 2017; bKaplan-Meier estimate.

Stewart AK, et al. N Engl J Med 2015; 372:142-52 Dimopoulos MA, et al. N Engl J Med 2016; 375:1319-1331

Triplet until Progression (1)

POLLUXAnti-CD38 + IMiD + Dex

Until progression

ASPIREPI + IMiD + Dex

18 months then Rd until progression

Rd(n = 396)

KRd(n = 396)

17.626.30.69 (0.57–0.83)

< 0.0001

Median PFS, moHR (KRd/Rd) (95% CI)

p value (one-sided)

0

0.2

0.6

1.0

Prop

ortio

n su

rviv

ing

with

out

prog

ress

ion

Months since randomization

0.8

0.4

0.06 18 24 30 36 42 4812

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 15 18 33Months

21 24 30

Rd (n = 283)

DRd (n = 286)

27

24-month PFS

68%

41%

HR, 0.41 (95% CI, 0.31-0.53; P <0.0001)

Median: 17.5 mo

Median not reached 24-month PFSDRd until PDK stopped


Time to MRD Negativity PFS by MRD Status (10-5)

POLLUX. Time to MRD Negativity and PFS by MRD Status

DRdMRD–

Rd MRD–

DRdMRD+

Rd MRD+

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 15 18 42Months

3021 24 36 3927 33

Rd

DRd

MR

D-n

egat

ive

patie

nts,

%

0

10

20

30

40

0 3 6 9 12 15 18 42Months

30

283286

272271

252255

242235

229208

219186

209172

00

183151

No. at riskRd

DRd

21 24 36

181153

7765

193167

3927 33

166139

2218

12

1476269210

1476235190

1476192173

1375168163

1372147157

1269131145

1269114134

0000

126688117

No. at riskRd MRD negative

DRd MRD negativeRd MRD positive

DRd MRD positve

106279105

8547291

126999125

0111

0759

6263041

PI - Imids -DexPFS by risk group

Aspire Tourmaline-MM1 Pollux

Median, months KRd Rd IRd Rd DRd Rd

High 23.1 13.9 21.4 14.7 22.6 10.2

Standard 29.6 19.5 20.6 9.7 NR 18.5

Avet-Loiseau H, et al. Blood. 2016;128:1174-80.Moreau P, et al. Blood. 2015;126:727. Presented at ASH 2015.

Moreau P, et al. N Engl J Med. 2016;374:1621-34.Weisel K, et al. Presented at ASCO 2017

Prolonged PFS in ASPIRESurvie sans progression chez

les patients en rechute précoce

Progression/décès, n (%)SSP médiane, moisHR (KRd/Rd) (IC à 95 %)Valeur p (test unilatéral)

KRd (n = 113)70 (61,9 %)

21,4

Rd (n = 104)64 (61,5 %)

10,7

0,714 (0,508, 1,004)0,0257

Nombre à risque :KRdRd

Pro

porti

on e

n su

rvie

sa

ns p

rogr

essi

on1,0

0,8

0,6

0,4

0,2

0,00 6 12 18 24 30 36 42

Mois depuis la randomisation113104

8661

7238

5531

4322

2117

77

KRd

Rd

Progression/décès, n (%)SSP médiane, moisHR (KRd/Rd) (IC à 95 %)Valeur p (test unilatéral)

KRd (n = 263)130 (49,4 %)

29,7

Rd (n = 257)150 (56,2 %)

18,2

0,675 (0,533, 0,854)0,0005

Nombre à risque :KRdRd

Pro

porti

on e

n su

rvie

sa

ns p

rogr

essi

on

1,0

0,8

0,6

0,4

0,2

0,0

Survie sans progression chez les patients en rechute tardive

0 6 12 18 24 30 36 48Mois depuis la randomisation

263267

228204

195149

157110

12787

8549

1510

42

11

KRd

Rd

EARLY

LATE

Weisel K et al., ASCO 2017

**P = 0.0009. ***P = 0.0001. aPercentage of patients within a given risk group and treatment arm.

21

32

0

12

0

5

10

15

20

25

30

35

High risk Standard risk

MR

D-n

egat

ive

patie

nts

per r

isk

grou

p, %

a

** ***

DRdn = 28

Rdn = 37

DRdn = 133

Rdn = 113

MRD-negative rates PFS in high-risk patients

% s

urvi

ving

with

out p

rogr

essi

on0

20

40

60

80

100

0 3 6 9 12 15 18 33Months

21 24

Rd MRD positive

DRd MRD negative

27

DRd MRD positive

30

In POLLUX, high-risk patients treated with daratumumab achieve MRD negativity and remain progression free

ClinicalTrials.gov Identifiers: NCT02136134

POLLUX: MRD by Cytogenetic Risk Status (10–5)

CR, complete response; DOR, duration of response; MPT, melphalan-prednisone-thalidomide; PR, partial response; Rd, lenalidomide and low-dose dexamethasone; Rd18, Rd for 18 cycles; VGPR, very good partial response. Bahlis N et al. Presented at EHA 2015

Rd (FIRST): Impact of depth of response on duration of response

• Median DOR was prolonged with Rd continuous

• vs Rd18 or MPT

PI-dex backbone

PI-dex+

LenalidomidePomalidomide

PI-dex+

Therapeutic antibodyanti-CD38 (daratumumab, isaruximab…)

anti-SLAMF7 (elotuzumab)

• Triplet does better by PFS median 1–x years

• High risk improves

• MRD becomes a new objective

Historically• Used upfront• Not optimal, as re-treatment

2017• Lenalidomide moves upfront• Novel combination

1. Palumbo et al. Presented at ASCO 2016 (Abstract LBA4)2. Dimopoulos MA, et al. Lancet Oncol. 2016;17(1):27-38.

3. San-Miguel JF, et al. Lancet Oncol. 2014;15(11):1195-1206.4. San-Miguel JF, et al. Blood. 2015;126(23):Abstract 3026.

5. Jakubowiak A, et al. Blood. 2016. Epub ahead of print.

Efficacy of PI-based triplets

DaratumumabDVd vs Vd1

PFS HR (95% CI) 0.39 (0.28-0.53)

PFS median, mo NE

VGPR 59%

CR 19%

Duration of response,mo NE

OS HR (95% CI) 0.77 (0.47, 1.26)

CarfilzomibKd vs Vd2

PanobinostatPVd vs Vd3,4

ElotuzumabEVd vs Vd5

0.53 (0.44-0.65) 0.63 (0.52-0.76) 0.72 (0.59-0.88)

18.7 12.0 9.7

54% 28% 36%

13% 11% 4%

21.3 13.1 11.4

0.79 (0.58-1.08) 0.94 (0.78-1.14) 0.61 (0.32-1.15)

CASTOR: 1-Year Update

Weisel K et al., ASCO 2917

SOC, standard of care.aExploratory analyses based on 1-year update: clinical cut-off date of January 11, 2017. 1. Lentzsch S, et al. Poster presentation at ASCO 2017. Abstract 8036.

18-month PFSa

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

0 3 6 9 12 15 18 30Months

21 24 27

Median 16.7 moDVd (n = 251)

Vd (n = 247)Median 7.1 mo

48%

8%HR: 0.31 (95% CI, 0.24-0.39; P <0.0001)

100

Adding daratumumab to SOC regimens significantly prolongs PFS

• Median follow-up of 19.4 months

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 15 18 27Months

21 24

Vd MRD positive

DVd MRD negative

DVd MRD positive

PFS in high-risk patients

Median follow‐up : 12 months

Dimopoulos et al. Lancet Oncol 2016

Btz Dex versus Kd (ENDEAVOR trial)

Dimopoulos et al. Lancet Oncol 2017

Median follow‐up : 3 yearsmedian OS : 40 (Vd) vs 47 (Kd)

months

Btz Dex versus Kd (ENDEAVOR trial)

IMiD/PI grey zone

IMiD-based PI-based

IMiD-basedPI-based

Re-treatment• Relapsed not refractory• Long PFS/DoR• Safety

Reuse upfront regimenlikely in a triplet-based combo

Example:VMP x9/12 / W§W: PFS of 4 yearsRd x24 / W§W: PFS of 4 years

Why not re-treatment?Why not VRd?

Module 2 Part 2 data: Scenario C: Retreat with LEN (6/13)

20.6 20.6

14.7

17.5

13.9

0

5

10

15

20

25

30

Overall population Prior LEN No prior LEN

Med

ian

PFS,

mos

Rd+I RdPrior LEN: 12%

LEN refractory: not eligible

360 16362 318n

Mateos M-V, et al. Presented at ASCO 2016:abstr 8039;Moreau P, et al. N Engl J Med. 2016;374:1621–1634.

TOURMALINE-MM1 IRd in patients who received prior LEN

4444 316

NE

0.74 (0.59–0.94) 0.58

(0.28–1.23)

HR (95% CI)0.77

(0.60–1.00)

Prior LEN exposure was permitted if:

• NOT refractory to prior LEN therapy (refractory disease was defined as disease progression on treatment or progression within 60 days after the last dose of LEN)

Stewart AK, et al. N Engl J Med 2015; 372:142-52 Dimopoulos MA, et al. N Engl J Med 2016; 375:1319-1331

Triplet until Progression (2)

POLLUXAnti-CD38 + IMiD + Dex

Until progression

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 15 18 33Months

21 24 30

Rd (n = 283)

DRd (n = 286)

27

24-month PFS

68%

41%

HR, 0.41 (95% CI, 0.31-0.53; P <0.0001)

Median: 17.5 mo

Median not reached

18-month PFSa

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

0 3 6 9 12 15 18 30Months

21 24 27

Median 16.7 moDVd (n = 251)

Vd (n = 247)Median 7.1 mo

48%

8%HR: 0.31 (95% CI, 0.24-0.39; P <0.0001)

100

CASTORAnti-CD38 + PI + Dex

DARA Until progression

DRd until PD

D until PD

Current and future treatment options in RRMM

Pd/Nivolumab +/-Elotuzumab

Pd/Nivolumab +/-Elotuzumab

Pomalidomide regimens

PVdPVd

Pd/IsatuximabPd/Isatuximab

Pd/PembrolizumabPd/Pembrolizumab

Pd/DaratumumabPd/Daratumumab

KRdKRd

ERdERd

IRdIRd

DRdDRd

DVdDVd

Lenalidomide regimens PI regimens

Venetoclax/VdVenetoclax/Vd

Selinexor/VdSelinexor/VdKdKd

Pd/OprozomibPd/Oprozomib

3rd line +2nd line +

OPTIMISMM (MM007) STUDY DESIGN: Ongoing

(n = 391)POM+BTZ+DEX (PVd) 21

day-cycle until PD or unacceptable

toxicity

RA

ND

OM

IZA

TIO

N (n

=782

) 1:

1

Follow-Up for OS , MM tx, SPM

5 years post last randomization(n = 391)

BTZ+DEX (Vd) 21 day-cycle until PD or

unacceptable toxicity

Tx D/Cprior to PD

Tx D/C due to PDOngoing

evaluationEvery 21(± 3) days

PFS follow-upEvery 21 (± 3) days

PDStratification•Age (≤ 75 vs. > 75 yrs)

•Number of prior anti-MM regimens ( 1 vs. > 1)

•β2M at screening (< 3.5 mg/L vs. ≥ 3.5 mg/L ; ≤ 5.5 mg/L vs. > 5.5 mg/L)

Bortezomib = Velcade™, D/C: discontinuation, PD: progressive disease

A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide, Bortezomib and Low-Dose Dexamethasone versus Bortezomib and Low-Dose Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma

1-3 prior linesNo refractary to bortezomib

Fresh biopsyFresh biopsy

Patient encounter

Genomicprofiling

Data interpretation

Management decision

Clinical response?

Drug resistance?

Salvage or new therapy?

What is precision cancer medicine?

• A large proportion of cancers may contain at least one plausibly actionable genetic alteration

• Therapies designed to target the molecular alteration (BRAF) or pathways that aid cancer development

975. Venetoclax Combined with Bortezomib and Dexamethasone for Patients with Relapsed/Refractory Multiple Myeloma

Philippe Moreau, Asher A. Chanan‐Khan, Andrew W. Roberts, Amit B. Agarwal, Thierry Facon, Shaji Kumar, CyrilleTouzeau, Jaclyn Cordero, Jeremy Ross, Wijith Munasinghe, Jia Jia, Ahmed H. Salem, Joel Leverson, Paulo Maciag, Maria Verdugo, and Simon J. Harrison

Monday, December 5, 2016, 3:15 PM

Venetoclax* with bortezomib + dexamethasone for RRMM: Open-label Phase 1b study

Objectives: Assessment of safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose, and efficacy (ORR, time to progression, and duration of response) of the combination therapy in RRMM

RRMM

Dose escalation (N=54)

Venetoclax50–1200 mg per dose cohort

BortezomibDexamethasone

Dose escalation (N=54)

Venetoclax50–1200 mg per dose cohort


RRMMpatients

Safety expansion (N=12)

Venetoclax800 mg


Safety expansion (N=12)

Venetoclax800 mg


Patient characteristics Venetoclax (N=66)

Median age, years 64

ISS stage II/III, n (%) 39 (59)

Median number of prior therapies, n (range)Bortezomib refractory, n (%)Lenalidomide refractory, n (%)

3 (1–13)21 (32)37 (56)

Prior ASCT, n (%) 41 (62)

* Potent and selective, orally bioavailable small-molecule inhibitor of BCL-2.ASCT, autologous stem cell transplant; ISS, International Staging System; ORR, overall response rate; RRMM, relapsed or refractory multiple myeloma.Moreau P, et al. 58th American Society of Hematology Annual Meeting 2016, Abstract 975.

28 3219 26 35

20 26

2332

5

34 15 3612

18 20

5

235

7 9 10

0

20

40

60

80

100

Pat

ient

s (%

)

PR VGPR CR sCR

Venetoclax+bortezomib+dexamethasone efficacy response rates in RRMM

* Numbers are based on evaluable patients per subgroup.CR, complete response; DoR, duration of response; ORR, overall response rate; PR, partial response; RRMM, relapsed or refractory multiple myeloma; sCR,stringent complete response; TTP, time to progression; VGPR, very good partial response.Moreau P, et al. 58th American Society of Hematology Annual Meeting 2016, Abstract 975.

RRMM

DoR in months

TTP in months

All patients (n=65)

8.8 8.6

Bortezomib refractory and 1-3 prior therapies (n=31)

10.6 11.3

Bortezomibnaïve and 1-3 prior therapies

15.8 17.1

• Response rates were higher in patients non-refractory to bortezomib and/or with 1–3 prior therapies (ORR 89–94%) compared to all patients

• In patients non-refractory to prior bortezomib but refractory to lenalidomide, the ORR was 86% compared with 91% in those who were non-refractory to lenalidomide

• Clinical responses were comparable in patients with t(11;14) MM (ORR 78%) and without t(11;14) MM (ORR 66%)

• Median follow-up: 4.9 months

ORR for patients with RRMM*

ORR 68%

ORR 89%

ORR 24%

ORR 89%

ORR 55%

ORR 20%

ORR 94%

All evaluable patients (N=65)

Bortezomib non-refractory and

1-3 prior therapies (n=31)

Bortezomib Prior therapiesNon-refractory

(n=44)Refractory

(n=21)1-3

(n=35)4-6

(n=20)>6

(n=10)

Harnessing the immune system to fight myeloma

ADCC, antibody-dependent cellular cytotoxicity;ADCP, antibody-dependent cellular phagocytosis;

CDC, complement-dependent cytotoxicity;WBC, white blood cell.Rodríguez-Otero P, et al. Haematologica 2016;102:423–32.

Monoclonal antibodies CAR-T cells Therapeutic vaccines

• Direct effects

• CDC

• ADCC

• ADCP

• Effector cell engagement

1. Extract WBCs

2. Modify and expand cells ex vivo

3. Infuse MM-targeted cells back into patient

Passive Active

CD138

CD20

CD40

CD56

CD38

CS1

IGF1-R

Il-6

Plasmocyte

Monoclonal antibodies in multiple myelomaTargets ?

- Rituximab

- Lucatumumab : Humanized Anti CD40

- Lorvotuzumab: Humanized Anti CD56 + maytansine

- AVE1642: Humanized Anti IGF1-R (CD221)

- BT062: Chimeric Anti CD138 + maytansine

- RadioimmunotherapyAnti CD138 conjugated with 213Bi

- Siltuximab: Chimeric Anti Il-6

Daratumumab: Mechanisms of Action• CD38 is highly and ubiquitously expressed on myeloma cells1,2

• DARA is a human IgG1 monoclonal antibody that binds CD38-expressing cells

• DARA binding to CD38 induces tumor cell death through direct and indirect mechanisms3-5

Immunomodulation

Adenosine

cADPRADPRNAADP

Ca2+

NAD

CD8+

T cell

CD38

MM cellCD38

DARA

NK cellMacrophageComplement

CD38

MDSC

Immune-mediated activity

Directanti-tumor

effect

ADPC ADCCCDC

MM cell

Adenosine

AMPCa2+

Ca2+

Ca2+

B reg

CD38+

T reg

DARA

Tumor celldeath

DARA

CD38

Apo

ptos

is v

ia

cros

s-lin

king

CD

38 e

nzym

atic

in

hibi

tion

Dec

reas

ed

imm

unos

uppr

essi

on

1. Lin P, et al. Am J Clin Pathol. 2004;121(4):482-488.2. Santonocito AM, et al. Leuk Res. 2004;28(5):469-477.3. de Weers M, et al. J Immunol. 2011;186(3):1840-1848.4. Overdijk MB, et al. MAbs. 2015;7(2):311-321.5. Krejcik J, et al. Presented at: 57th ASH Annual

Meeting; December 5-8, 2015; Orlando, FL. Abstract 3037.

INTENDED FOR INTERNAL USE. ALL MATERIALS/CONTENT ARE SUBJECT TO RELEVANT LOCAL REVIEW PROCESSES (IE, MEDICAL, LEGAL, COMPLIANCE, PRIVACY AND REGULATORY).

Daratumumab Monotherapy for Patients With Intermediate or High‐risk Smoldering Multiple Myeloma (SMM):

CENTAURUS, a Randomized, Open‐Label, Multicenter Phase 2 Study

Craig C. Hofmeister, Ajai Chari, Yael C. Cohen, Andrew Spencer, Peter Voorhees, Jane Estell, Christopher Venner, Irwindeep Sandhu,Matthew Jenner, Catherine Williams, Michele Cavo, Niels

W.C.J. van de Donk, Meral Beksac, Steven Kuppens, Rajesh Bandekar, Tobias Neff, Christoph Heuck, Ming Qi, Hartmut Goldschmidt, C. Ola Landgren

Oral presentationSession Name: Myeloma: Therapy, Excluding Transplantation: Immunotherapy in Myeloma and AmyloidSession Date: Sunday, 10 December 2017 Session Time: 4:30 – 6:00PM

Presenter: Tobias Neff, MD


Scre

enin

g

1:1:

1 R

AN

DO

MIZ

ATI

ON Cycle 1:

QWCycles 2 & 3:

Q2WCycles 4-7:

Q4WCycles 8-20:

Q8W

Cycle 1: QW

Cycles 2-20: Q8W

n = 41

n = 41

n = 41

Arm A (16 mg/kg IV; 8-week cycles); Long Intense (max 3 years)

Arm B (16 mg/kg IV; 8-week cycles); Intermediate (max 3 years)

Arm C (16 mg/kg IV; one 8-week cycle); Short Intense

Following until PD or end of study

(4 years from LPFD)

Primary endpoints:• CR• % patients with PDa

or death per patient-yearCycle 1:

QW

1. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

CENTAURUS Study Design

aAs defined by 2014 IMWG criteria for smoldering multiple myeloma.

• CR rate: proportion of subjects who achieve a CR in each arm– First assessed 6 months after last patient randomized

• PD/death rate: ratio of subjects with an event (PD or death) to the total follow-up for all patients– Assessed 12 months after last patient randomized– Disease progression to MM assessed according to IMWG guidelines1


Progression-Free Survival

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 15 18 24Months

21

Arm B: IntermediateArm A: Long intense

Arm C: Short intense

414141

414140

403635

393631

373224

211916

1286

000

111

No. at riskLong intenseIntermediate

Short intense Post-hoc analysis comparing Arm A + Arm B versus

Arm C: P value = 0.0398

Extended Daratumumab Therapy Prolongs PFS

Study arm 12-month PFS rate

Progression to MM based on SLiMCRABcriteria, n

Arm ALong Intense 95% 3

Arm BIntermediate 88% 5

Arm CShort Intense 81% 9


Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D‐VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for

Transplant (ALCYONE)

Maria Victoria Mateos, Meletios A. Dimopoulos, Michele Cavo, Kenshi Suzuki, Andrzej Jakubowiak, Stefan Knop, Chantal Doyen, Paulo Lucio, Zsolt Nagy, Polina Kaplan, Ludek Pour, Mark Cook,

Sebastian Grosicki, Andre Crepaldi, Anne Marina Liberati, Philip Campbell, Tatiana Shelekhova, Sung‐Soo Yoon,Genadi Iosava, Tomoaki Fujisaki,Mamta Garg, Christopher Chiu, Jianping Wang,

Robin Carson, Wendy Crist, William Deraedt, Marie Nguyen, Ming Qi, Jesus San‐Miguel

Oral presentationSession Name: Late‐Breaking AbstractsSession Date: Tuesday, 12 December 2017 Session Time: 7:30 AM – 9:00 AM

Presenter: Marie Nguyen, MD


ALCYONE Study Design

Key eligibility criteria:

• Transplant-ineligible NDMM

• ECOG 0-2• Creatinine

clearance ≥40 mL/min

• No peripheral neuropathy grade ≥2

Stratification factors• ISS (I vs II vs III)• Region (EU vs other)• Age (<75 vs ≥75 years)

1:1

Ran

dom

izat

ion

(N =

706

)

D-VMP × 9 cycles (n = 350)

Daratumumab: 16 mg/kg IVCycle 1: once weeklyCycles 2-9: every 3 weeks

+

Same VMP schedule

Follow-up for PD and

survival

Primary endpoint:• PFS

Secondary endpoints:• ORR• ≥VGPR rate• ≥CR rate• MRD (NGS; 10–5)• OS• Safety

VMP × 9 cycles (n = 356)Bortezomib: 1.3 mg/m2 SC

Cycle 1: twice weeklyCycles 2-9: once weekly

Melphalan: 9 mg/m2 PO on Days 1-4 Prednisone: 60 mg/m2 PO on Days 1-4

DCycles 10+

16 mg/kg IV

Every4 weeks: until PD

Statistical analyses• 360 PFS events: 85% power for

8-month PFS improvement• Interim analysis: ~216 PFS events

• Cycles 1-9: 6-week cycles• Cycles 10+: 4-week cycles


% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

0 3 6 9 12 15 18 27Months

356350

303322

276312

261298

231285

127179

6193

00

210

No. at riskVMP

D-VMP

21 24

1835

12-monthPFSa

18-monthPFSa

HR, 0.50 (95% CI, 0.38-0.65; P <0.0001)

VMPMedian: 18.1 months

D-VMPMedian: not reached

87%

72%

76%

50%

100

Pre-specified interim analysis after 231 PFS events Median (range) follow-up: 16.5 (0.1-28.1) months

PFS

aKaplan-Meier estimate.


6

22

0

5

10

15

20

25

VMP (n = 356) D-VMP (n = 350)

MR

D-n

egat

ive

rate

, %

P <0.00013.6X

% s

urvi

ving

with

out p

rogr

essi

on0

20

40

60

80

100

0 3 6 9 12 15 18 27Months

2278

334272

2278

281244

2278

254234

2277

239221

2175

210210

1458

113121

8315362

0000

0228

No. at riskVMP MRD negative

D-VMP MRD negativeVMP MRD positive

D-VMP MRD positive

21 24

4141421

VMP MRD negative

VMP MRD positive

D-VMP MRD negativeD-VMP MRD positive

MRD‐negative Rates and PFS by MRD Status


Interim Safety Analysis of a Phase 2 Randomized Study of Daratumumab (Dara), Lenalidomide (R), Bortezomib (V), and Dexamethasone (d; Dara‐Rvd) Vs. Rvd in Patients (Pts) With Newly Diagnosed Multiple Myeloma (MM) Eligible for High‐

Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)

Peter M. Voorhees, Brandi Reeves, Nitya Nathwani, Cesar Rodriguez, Yana Lutska, Laura Hydutsky, Huiling Pei, Jon Ukropec, Ming Qi, Thomas Lin, Luciano J. Costa

Poster presentationSession Name: Myeloma: Therapy, Excluding Transplantation: Poster ISession Date: Saturday, 9 December 2017 Session Time: 5:30 – 7:30PM

Presenter: Daniela Hoehn, MD, PhD

Cassiopeia IFM/Hovon


Daratumumab (DARA) in Combination with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) in Patients With Newly Diagnosed Multiple Myeloma (MMY1001): Updated

Results From an Open‐label, Phase 1b Study

Ajai Chari, Saad Z. Usmani, Amrita Krishnan, Sagar Lonial, Raymond L. Comenzo, Kaida Wu, JianpingWang, Parul Doshi, Brendan Weiss, Jordan M. Schecter, Andrzej Jakubowiak

Poster presentationSession Name: Myeloma: Therapy Excluding Transplantation: Poster IISession Date: Sunday, 10 December 2017 Session Time: 6:00 – 8:00PM


MMY1001: DARA Kd Study Design

EndpointsPrimary• Safety, tolerabilitySecondary• ORR, duration of CR,

duration of response, overall survival

Dosing Schedule (28-d cycles)Daratumumab• Single dose: 16 mg/kg QW on Cycles 1-2, Q2W on

Cycles 3-6, and Q4W thereafter (n = 10)• Split dose: 8 mg/kg on Days 1-2 of Cycle 1 and 16

mg/kg QW on Cycle 2, Q2W on Cycles 3-6, and Q4W thereafter

Carfilzomib• 20 mg/m2 Cycle 1 Day 1• Escalated to 70 mg/m2 Cycle 1 Day 8+; weekly (Days 1,

8, 15)Dexamethasone: 40 mg/weeka

Eligibility/Treatment• Relapsed MM• 1-3 prior LOTs

including bortezomiband an IMiD

• Carfilzomib-naive• ECOG score ≤2• LVEF ≥40%• ANC ≥1 x 109/L• Platelet count ≥75 x

109/L

a20 mg if >75 years of age. On DARA dosing days, dexamethasone 20 mg IV was administered as premedication on infusion day and 20 mg PO the day after infusion; for DARA as a split first dose, dexamethasone 20 mg IV was administered as a premedication on Cycle 1 Day 1 and Cycle 1 Day 2; on Cycle 1 Day 3, administration of low-dose methylprednisolone (≤20 mg PO) was optional. On weeks when no DARA infusion was administered, dexamethasone was given as a single dose on Day 1; if dexamethasone was reduced to 20 mg, methylprednisolone (≤20 mg PO) was administered the day after DARA infusion to prevent delayed IRRs. Montelukast was required before first DARA dose and was optional for subsequent doses.

Open-label, nonrandomized, multicenter, phase 1b study


ORR MRD-negative Rates in All Treated Pts

ORR and MRD‐negative Rates


PFS: All Patients and Len‐refractory Patients

52

All Treated Patients

Lenalidomide-refractory Patients

Phase 1b Study of Daratumumab Plus Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple

Myeloma (RRMM) With ≥2 Prior Lines of Therapy

Ajai Chari,1 Attaya Suvannasankha,2 Joseph W. Fay,3 Bertrand Arnulf,4 Jonathan Kaufman,5 Jainulabdeen J. Ifthikharuddin,6 Brendan Weiss,7 Amrita Krishnan,8

Suzanne Lentzsch,9 Raymond Comenzo,10 Jianping Wang,11 Tara Masterson,12

Kerri Nottage,11 Jordan Schecter,11 Christopher Chiu,12 Nushmia Khokhar,12

Tahamtan Ahmadi,12 Sagar Lonial5

ClinicalTrials.gov Identifier: NCT01998971

1Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA; 2Indiana University School of Medicine and Simon Cancer Center, Richard L. Roudebush VAMC, Indianapolis, IN, USA; 3Baylor Institute for Immunology Research, Dallas, TX, USA; 4Hôpital Saint Louis, Paris, France; 5Department of

Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA; 6James P. Wilmot Cancer Center, University of Rochester Strong Memorial Hospital,

Rochester, NY, USA; 7Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 8The Judy and Bernard Briskin Myeloma

Center, City of Hope, Duarte, CA, USA; 9Columbia University Medical Center, New York, NY, USA; 10Division of Hematology-Oncology, Tufts Medical Center, Boston, MA, USA;

11Janssen Research & Development, Raritan, NJ, USA; 12Janssen Research & Development, Spring House, PA, USA.

18

25

9

8

0

10

20

30

40

50

60

70

DARA + POM-D (N =103)

OR

R, %

PR VGPR

CR sCR

ORRa: DARA + POM-D

54

DARA + POM-D(N = 103)

n (%) 95% CIORR(sCR+CR+VGPR+PR) 62 (60) 50.1-69.7

Best responsesCRCRVGPRPRMRSDPDNE

8 (8)9 (9)

26 (25)19 (18)2 (2)

26 (25)3 (3)

10 (10)

3.4-14.74.1-15.917.2-34.811.5-27.30.2-6.8

17.2-34.80.6-8.34.8-17.1

VGPR or better (sCR+CR+VGPR) 43 (42) 32.1-51.9

CR or better (sCR+CR) 17 (17) 9.9-25.1

ORR = 60%

42%VGPR

or better

17%CR or better

aBased on independent safety monitoring board assessment. Daratumumab IFE reflex assay was used to mitigate DARA-mediated interference with assessment of CR

Among patients with CR or better, the minimal residual disease negative rate at:– 10–4 threshold = 6/17 (35%)

– 10–5 threshold = 5/17 (29%)

– 10–6 threshold = 1/17 (6%)

Deep responses were observed with DARA + POM-D

OS: DARA + POM-D

12-month OS rate: 66.2% (95% CI, 55.6-74.8)

55Patients with SD/MR derive survival benefit with DARA

+ POM-D

% s

urvi

ving

pat

ient

s

0

20

40

60

80

100

0 3 6 9 12 15 18 27

No. at risk

Months

21 24

103 88 75 63 49 18 5 03 2

NE, not evaluable.

% s

urvi

ving

pat

ient

s0

20

40

60

80

100

0 3 6 9 12 15 18 27

622813

62224

59151

52110

4360

1710

410

110

≥PRSD/MRPD/NE

No. at risk Months

≥PR SD/MR

24

000

PD/NE

21

210

Median: 17.5 months (95% CI, 13.3-NE)

Median: NE (95% CI, 17.5-NE)

Median: 8.5 months (95% CI, 5.0-12.3)Median: 2.3

months (95% CI, 0.6-5.4)

OS OS by Response Category


Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (RRMM): PAVO, an

Open‐label, Multicenter, Dose Escalation Phase 1b Study

Ajai Chari, Hareth Nahi, Maria‐Victoria Mateos, Henk Lokhorst, Jonathan L. Kaufman, Philippe Moreau, Albert Oriol, Torben Plesner, Lotfi Benboubker, Peter Hellemans, Tara Masterson, Pamela

L. Clemens, Kevin Liu, Jesus San‐Miguel, Saad Z. Usmani

Oral presentationSession Name: Myeloma: Therapy, Excluding Transplantation: Studies in Relapsed and Refractory Multiple MyelomaSession Date: Monday, 11 December 2017 Session Time: 4:30 – 6:00PM

Presenter: Jordan Schecter, MD


PAVO Study Design

PAVO, an Open‐label, Multicenter, Dose Escalation Phase 1b Study

Key eligibility criteria • RRMM with measurable disease

• ≥2 prior lines of treatment

• Not received anti‐CD38 therapy

aGroup 2 comprises 4 distinct cohorts, each treated with DARA 1,800 mg and rHuPH20 45,000 U. Ctrough on Cycle 3/Day 1 in Group 1 supported dose selection for Group 2. The study evaluation team reviewed safety after Cycle 1 and PK after Cycle 3/Day 1 for each group.bAdministered 1 hour prior to infusion. c100 mg for the first and second infusions; dose may be reduced to 60 mg thereafter.

Group 1 (n = 8)DARA‐MD: 1,200 mgrHuPH20: 30,000 U

Group 2a (n = 45)DARA‐MD: 1,800 mgrHuPH20: 45,000 U

Dosing schedule Approved schedule for IV 1 Cycle = 28 days

Group 3 (n = 25)DARA‐SC: 1,800 mgrHuPH20: 30,000 U

Part 1: mixed

formulation

Part 2: concentrated co-

formulation

Primary endpoints• Ctrough of DARA at Cycle 3/Day1

• SafetySecondary endpoints• ORR• CR• Duration of response• Time to response

Pre-b/post-infusion medication• Acetaminophen• Diphenhydramine• Montelukast• Methylprednisolonec

Infusion time• DARA-MD 1,200 mg: 20-min (60 mL)• DARA-MD 1,800 mg: 30-min (90 mL)• DARA-SC 1,800 mg: 3-5 min (15 mL)


Pharmacokinetics Findings

Nominal time after first dose (hours)

First dose Last weekly dose (8th dose)

Max CtroughDA

RA

con

cent

ratio

n (µ

g/m

L)

0

500

1000

2 24 72 168 (7 days)10

1,200 mg MD 1,800 mg MD16 mg/kg IVa 1,800 mg SC

Nominal time after last QW dose (hours)

DA

RA

con

cent

ratio

n (µ

g/m

L)

0

200

100

300

2 24 72 168 (7 days)10 12 48

400 1500

aFrom study GEN501.


DARA-SC 1,800 mg(n = 25)

OR

Ra

(%)

DARA-MD 1,800 mg(n = 45)

≥VGPR: 28%

42%38%

44%

≥VGPR: 20%

4.3 monthsb 8.3 months 4.6 monthsMedian follow-up:

≥VGPR: 9%

Response Rates

aResponse-evaluable set; bData presented by Usmani SZ, et al. 58th Annual Meeting and Exposition of the American Society of Hematology. Abstract: 1149.

ELOQUENT-2 Study Design • Open-label, international, randomized, multicenter, phase 3 trial (168 global sites)

• Endpoints:– Co-primary: PFS and ORR– Other: overall survival (data not yet mature); duration of response, quality of life, safety

• All patients received premedication to mitigate infusion reactions prior to Elo administration

Key inclusion criteria

•RRMM•1–3 prior lines of therapy

•Prior Len exposure permitted in 10% of study population (patients not refractory to Len)

Elo plus Len/Dex (E-Ld) schedule (n=321)

Elo (10 mg/kg IV): Cycle 1 and 2: weekly; Cycles 3+: every other weekLen (25 mg PO): days 1–21

Dex: weekly equivalent, 40 mg

Elo plus Len/Dex (E-Ld) schedule (n=321)

Elo (10 mg/kg IV): Cycle 1 and 2: weekly; Cycles 3+: every other weekLen (25 mg PO): days 1–21

Dex: weekly equivalent, 40 mg

Len/Dex (Ld) schedule (n=325)Len (25 mg PO): days 1–21;

Dex: 40 mg PO days 1, 8, 15, 22

Len/Dex (Ld) schedule (n=325)Len (25 mg PO): days 1–21;

Dex: 40 mg PO days 1, 8, 15, 22

Repeat every 28 days

Assessment

•Tumor response: every 4 wks until progressive disease•Survival: every 12 wks after disease progression

ELOQUENT-2: Extended 4 years follow-up

Isatuximab

CD38

ISATUXIMAB TCD1407

A Phase Ib Study of Isatuximab plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma

(RRMM)

Joseph Mikhael,1 Paul Richardson,2 Saad Usmani,3Noopur Raje,4 William Bensinger,5 Dheepak Kanagavel,6

Lei Gao,7 Samira Ziti-Ljajic,6 Kenneth Anderson2

1Mayo Clinic, Phoenix, AZ, USA; 2Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 3Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC, USA; 4Massachusetts

General Hospital, Boston, MA, USA; 5Swedish Cancer Institute, Seattle, WA, USA; 6Sanofi R&D, Vitry-Alfortville, France; 7Sanofi Oncology, Cambridge, MA, USA

symptomatic MM 1st line treatment

18-70a

4 x VRD

2 x VRD consolidation

Cy + G-CSF + leukapheresis

4 x VRD + Elotuzumab

HDM + TPL

2. HDM + TPL (if no nCR/CR)

Rev. MT

Randomization

A-I A-II B-I B-II

A-I + A-II B-I + B-II

1) 1)

HD6-Trial

1) high risk patients, optional in phase II trial

GMMGstandardintensification

Rev. MTRev. MT + Elotuzumab

Rev. MT + Elotuzumab

2 x VRD + Elo. consolidation

2 x VRD consolidation 2 x VRD + Elo. consolidation

N 500 patients 3 years recruitment

MRD1

Questions to ask MRD2

Standard Risk

PI+Rd‐antiCD38 X4‐6

‐‐ Transplant or not‐ Consolidation or

Maintenance ‐‐ Consolidation or Maintenance‐ Duration of maintenanceObj. Cure?

+ HDT1 +PI+Pd‐anti CD38 X6

+HDT 2

‐ High risk? / MGUS like profile‐ More chemo?‐ Consolidation post ASCT #2?‐ Triplet maintenance‐ Duration: until PD

‐ ‐ Good risk?‐ Consolidation?‐ Maintenance, mono or combined?‐ Duration of maintenance

High RiskPI+RD‐anti CD38 X6

→ HDT 1 + PI+PD‐Dara X 6

→ HDT 2 → REV + Dara Maint

IFM to come

Obj. PFS/OS

Obj. PFS/OSDo your best…

70Optimising High-Risk MM OutcomesMUK9 Trial: OPTIMUM (CI M Kaiser/M Jenner)

MAb+PI+IMiD

Central MRDPFS + PFS2

Statistically FormalisedComparison

620 NDMM patientsCentral Risk Profiling

GEP + Genetics

PI+MEL-ASCT

High-Risk

Induction

Augmented ASCT

MAb+PI+IMiD

Intensified Consolidation & Maintenance

Standard-RiskData recording of ‘real-world’ outcomes

NCRI Myeloma XI

‚winning‘ arm

High-RiskMolecularly &

Clinically Matched

GEM2017FITFit elderly newly diagnosed MM patients non-transplant candidates

Primary end-point: Immunophenotypic CR after 18 induction cyclesSecondary end-point: PFS

New Startegies…CAR-T cells

76

CAR : Chimeric antigen receptor Adoptive transfer of T lymphocytes CAR expressing

CD19- CAR T cells in MM

Garfall AL, et al. NEJM 2015

BCMA- CAR T cells in MM

Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome

Both patients had prolonged cytopenias

Ali SA, et al. Blood 2015

ANTI-BCMA T CELLS IN RRMM (PHASE 1 TRIAL)OUTCOMES

• For most patients, LCAR-B38M cells were undetectable in peripheral blood > 4 months post-infusion

• Grade ≥ 3 AEs, n = 2 (5.7%)• No SAEs or deaths have occurred to date

79Zhang W, et al. EHA 2017: Abstract S103. Oral presentation.

OutcomesAnti-BCMA CAR T Cells

(N = 35)Response >1 year, n 5Progressive disease, n 2Relapse of extramedullary lesion, n 1

AE, adverse event; BCMA, B cell maturation antigen; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; ORR, overall response rate; PR, partial response; SAE, serious AE; sCR, stringent complete response; VGPR, very good PR.

AUTHOR CONCLUSIONS• LCAR-B38M CAR-T cell technology exert rapid and reproducible therapeutic effects in RRMM• 12-month follow-up shows durable sCR• US clinical trial ongoing

CRS, n N = 35CRS free 6Grade 1 17Grade 2 10Grade 3 2Grade 4 0Grade 5 (death) 0

2

9

19

0%10%20%30%40%50%60%70%80%90%

100%

Best response

Patie

nts

sCRVGPRPR

• ORR: 100%

• The most common AE was CRS

Never give up!

Thank you for your attention

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