Treating Early Relapse

Dr. A. Keith StewartMayo Clinic

Single Agent and Doublet Efficacy are Modest

Trial Phase nIMiD

exposedPI

exposed ORR PFS (months)

OS (months)

Thalidomide 2 169 0% 0% 30% 2y: 20% 2y: 48%

BTZ vs DEX 3 669 49% 0% 38% 6.22 30

BTZ + doxil 3 646 41% 0% 43% 9.3 33

Len Dex MM009 3 177 41% 10% 61% 11.1 29.6

Len Dex MM010 3 349 30% 4.5% 60% 11.3 38

CFZ (+dex 8) 2 266 100% 99% 23.7% 3.7 15.6

Pom D vs Dex 3 302 100% 95% 31% 4.2 13.1

Dara 2 106 100% 100% 29.2% 3.7 17.5

Barlogie B et al. Blood. 2001;98:492. Richardson PG et al. N Engl J Med. 2005;352:2487.Orlowski RZ et al. J Clin Oncol. 2007;25:3892. Weber D et al. N Engl J Med. 2007;357:2133.

Dimopoulos M et al. N Engl J Med. 2007;357:2123. Siegel DS et al. Blood. 2012;120:2817. San Miguel J et al. Lancet Oncol. 2013;14:1055. Lonial S et al. Lancet. 2016;387:1551.

Key Numbers to Remember

•VD - 9

•RD - 17

High rate of attrition

Br J Haematol. 2016 Oct;175(2):252-264

61% 38% 15% 1%

Randomized Trials at Relapseü ASPIRE: KRd vs Rdü TOURMALINE-MM1: IRd vs Rdü ELOQUENT-2: ERd vs Rdü POLLUX DaraRd vs Rdü PANORAMA: PanVd vs Vdü CASTOR DaraVd vs Vdü ENDEAVOR Kd vs Vdü OPTIMMISM PVd vs Vdü ELOQUENT- 3 EPd vs Pdü ARROW K weekly vs K biweeklyü CANDOR KDara verus Kdü ICARIA ISA-PD vs. PD

ENDEAVOR: Carfilzomib/Dexamethasone Versus Bortezomib/Dexamethasone1

0

100

80

60

20

40

0 12 3018

Prog

ress

ion-

Free

Surv

ival

, %Carfilzomib group

(n = 464)

246

Bortezomib group(n = 465)

18.7 (95% CI, 15.6-NE) 9.4 (95% CI, 8.4-10.4)Median PFS, mo:

Carfilzomib groupBortezomib group

464 144 041 4331No. at RiskCarfilzomib groupBortezomib group 465 81 012 1252

HR = 0.53 (95% CI, 0.44-0.65); P < .0001

1. Dimopoulos MA et al. Lancet Oncol. 2016;17:27-38.

ASPIRE: Carfilzomib, Lenalidomide,and Dexamethasone1

0

0.2

0.4

0.6

0.8

1.0

480 6 12 24 30 36 42Time Since Randomization, mo

Prop

ortio

n Su

rviv

ing

With

out P

rogr

essi

on

18

HR: 0.69 (0.57-0.83)

0

0.2

0.4

0.6

0.8

1.0

480 6 12 24 30 36 42Time Since Randomization, mo

Prop

ortio

n Su

rviv

ing

Control group

18

Carfilzomib group

HR: 0.79 (0.63-0.99)P = .0001 P = .04

1. Stewart AK et al. N Engl J Med. 2015;372:142-152.

Median PFSCarfilzomib/RD: 26.3 monthsPlacebo/RD: 14.7 months

A.R.R.O.W. Study Design

Arm B: Twice-weekly carfilzomib + dex(10 min infusion of K)

Carfilzomib 20 mg/m2 IV D1, 2 (Cycle 1)Carfilzomib 27 mg/m2 IV D8, 9, 15, 16 (Cycle 1), D1, 2, 8, 9, 15, 16 (Cycle 2+)Dexamethasone 40 mg IV/PO D1, 8, 15 (All cycles)Dexamethasone 40 mg IV/PO D22 (Cycles 1-9 only)

Arm A: Once-weekly carfilzomib + dex(30 min infusion of K)

Carfilzomib 20 mg/m2 IV D1 (Cycle 1)Carfilzomib 70 mg/m2 IV D8, 15 (Cycle 1), D1, 8, 15 (Cycle 2+)Dexamethasone 40 mg IV/PO D1, 8, 15 (All cycles)Dexamethasone 40 mg IV/PO D22 (Cycles 1-9 only)

1:1 Randomization N = 478

•Relapsed and Refractory MM

•2-3 prior lines

•Prior exposure to IMiD & PI (except carfilzomib or oprozomib)

•PS 0-1

•CrCl of ≥30 mL/min

Stratification:

•ISS stage

•Refractory to bortezomib

•Age (<65 vs. ≥65)

28-day cycles

Follo

w-u

p fo

r D

isea

se S

tatu

s un

til

Conf

irm

ed P

D

Long

-ter

m F

ollo

w-u

p fo

r Su

rviv

al

Primary end point: PFS

María-Victoria Mateos

CrCl, creatinine clearance; D, day; IMiD, immunomodulator; ISS, international staging system; IV, intravenous; K, carfilzomib; PD, progressive disease; PI, proteasome inhibitor; PO, by mouth

Primary Endpoint: PFS

Data cutoff date: June 15, 2017; Median follow-up: 12.6 (once-weekly) and 12.0 (twice-weekly) months

CI, confidence interval; HR, hazard ratio

238 164 119 86 41 15 4 0Kd 20/27

Number of Patients at Risk:

++++++ + ++++

+++ +++ ++++ ++++ +++ ++++++++++++++++++++++ +++++++ +++++++++ ++++ ++++++ +++++ ++++ + +++ +

++++ ++++ + + +++ +++ ++++ ++++ +++++++++++++++++++++++++++ ++++++++++++++++++ +++++++++ +++++++++++ +++++ +++++++ ++++ +++++ +

+++

0 3 6 9 12 15 18 21Months from Randomization

0

20

40

60

80

100Pr

opor

tion

Sur

vivi

ngW

itho

ut P

rogr

essi

on

Kd Once-weekly (70 mg/m2)

Kd Twice-weekly (27 mg/m2)

Once-weekly Kd 20/70 mg/m2

(n=240)

Twice-weekly Kd 20/27 mg/m2

(n=238)

Progression/Death, n (%) 126 (53%) 148 (62%)

Median PFS, months 11.2 7.6

HR (Kd 20/70/Kd 20/27) (95% CI) 0.693 (0.544, 0.883)

p-value (2-sided) 0.0029

240 178 145 114 69 24 5 0Kd 20/70

María-Victoria Mateos

Overall Response RatesO

RR,

%

CR 5%

ORR=62.9%

≥VGPR 34%

≥VGPR 13%

ORR=40.8%

CI, confidence interval; CR, complete response; OR, odds ratio; VGPR, very good partial response.

OR (95% CI); p-value (2-sided): 2.49 (1.72, 3.60); p<0.0001

CR 2%

María-Victoria Mateos

Adverse Events of Interest

AE, % (SMQN) Once-weekly Kd(n=238)

Twice-weekly Kd(n=235)

All grades Grade ≥3 All grades Grade ≥3

Peripheral neuropathy 4 0 7 <1

Acute renal failure 7 4 7 6

Cardiac failure 4 3 5 4

Ischemic heart disease 2 1 1 1

Pulmonary hypertension 2 0 1 <1

• Safety findings were consistent with the known safety profile of carfilzomib, and no new risks were identified.

AE, adverse event; SMQN, standardized MedDRA Query, narrow scope

María-Victoria Mateos

TOURMALINE: PFS Summary

No. at RiskIxazomib/RDPlacebo/Rd

360 345 332 315 298 283 270 248 233 224 206 182 145 119 111 95 72 58 44 34 26 14 9 1 0362 340 325 308 288 274 254 237 218 208 188 157 130 101 85 71 58 46 31 22 15 5 3 0 0

1.0

0.8

0.6

0.4

0.2

0.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Prog

ress

ion-

Free

Su

rviv

al, P

roba

bilit

y

Time Since Randomization, Months

Log rank P = .012HR = 0.742 (95% CI, 0.587-0.939)Number of events: Ixazomib/RD, 129; placebo/RD, 157

Median PFSIxazomib/RD: 20.6 monthsPlacebo/RD: 14.7 monthsMedian follow-up: ~15 months

1. Moreau P et al. Blood. 2015;126:727.

Phase 3 Studies of Daratumumab Combinations in in Patients With MM and ≥1 Prior Line of Therapy

DRd (n = 286)D 16 mg/kg IVEvery week: cycles 1-2Every 2 weeks: cycles 3-6Every 4 weeks until PDR 25 mg PO (similar to Rd alone)d 40 mg

Rd (n = 283)R 25 mg PO

Days 1-21 of each cycle until PDd 40 mg weekly until PD

RANDOMIZE

POLLUX

DVd (n = 251)D 16 mg/kg IVEvery week: cycles 1-3Every 3 weeks: cycles 4-8Every 4 weeks: cycles 9+V 1.3 mg/m2 SC (similar to Vd alone)d 20 mg

Vd (n = 247)V 1.3 mg/m2 SC on days 1, 4, 8, and 11 for 8 cyclesd 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 for 8 cycles

CASTOR

RANDOMIZE

MRD Assessments•At suspected CR•3 and 6 months after CR

MRD Assessments•At suspected CR•6 and 12 months after first study dose

Patient characteristics • Median (range) prior lines: 1 (1-11)• Prior V: 84%• Prior R: 18%

Patient characteristics• Median (range) prior lines: 2 (1-10)• Prior V: 66%• Prior R: 42%

1. Avet-Loiseau H et al. ASH 2016. Abstract 246.

POLLUX: Daratumumab, Lenalidomide, and Dexamethasone1

0

20

40

60

80

100

210 3 6 9 12 15 18Time, MonthsPr

ogre

ssio

n-Fr

ee S

urvi

val,

%

N286283

Median PFS, monthsNE

18.4Daratumumab groupControl group

12-month PFS83.2 (95% CI, 78.3-87.2)

Daratumumabgroup

Control group

60.1 (95% CI, 54.0-65.7)

HR for progression or death = 0.37 (95% C, 0.27-0.52)P < .001

1. Dimopoulos MA et al. N Engl J Med. 2016;375:1319-1331.

CASTOR: Daratumumab, Bortezomib, and Dexamethasone1

1. Palumbo A et al. N Engl J Med. 2016;375:754-776.

Daratumumab Group(n = 251)

NE

Control Group(n = 247)

7.2Median PFS, months

0

0.20

0.40

0.60

0.80

1.00

150 3 6 9 12Time, Months

Prop

ortio

n Su

rviv

ing

With

out P

rogr

essi

on

HR for progression or death = 0.39 (95% CI, 0.28 -0.53)P < .001

Daratumumabgroup

Control group

MRD Negativity in Daratumumab Combination Studies (Cont’d)1

a P < .005. b P < .05.1. Avet-Loiseau H et al. ASH 2016. Abstract 246.

• Percent of MRD-negative patients among those who achieved ≥CR

CASTORPOLLUX

ITT

Popu

latio

n, %

05

1015

2520

DVD VD10-4

DVD VD DVD VD10-5 10-6

60

35

37

22 169IT

T Po

pula

tion,

%

010203040

DRD RD10-4

MRD negative MRD positive

DRD RD DRD RD10-5 10-6

65

42

52

2726

13

MRD negative MRD positive

• Efficacy and PK coprimary endpoints were not met, demonstrating noninferiority of daratumumab subQ to daratumumab IV

Phase 3 COLUMBA: Noninferiority Comparison of SubQ Versus IV Daratumumab in R/R MM1

Daratumumab subQ significantly decreased IRR rate and administration time with a safety profile comparable with daratumumab IV

1. Mateos MV et al. ASCO 2019. Abstract 8005.

• Open-label, randomized phase 2 trial• ORR: 53% for elotuzumab group vs 26% for control group;

odds ratio: 3.25 (95% CI, 1.49-7.11) • Elotuzumab 10 mg/kg IV every wk in cycles 1-2 and 20 mg/kg IV every 4 wk thereafter• Pomalidomide 4 mg PO on d 1-21 of each cycle• Dexamethasone 40- or 20-mg equivalent every wk for patients aged ≤75 or >75 y, respectively• Primary endpoint: PFS• Secondary endpoint: ORR

ELOQUENT-3: Addition of Elotuzumab to Pomalidomide/Dexamethasone Backbone1

1. Dimopoulos MA et al. N Engl J Med. 2018;379:19.

Patients with R/R MM who received ≥2 prior lines and are refractory or R/R to lenalidomide and a PI(N = 559)

28-d cyclesR

Elotuzumab + pomalidomide + dexamethasone

Pomalidomide + dexamethasone

ELOQUENT-3: PFS1

• In this population of lenalidomide- and PI-refractory patients, risk of progression or death was significantly lower among those who received elotuzumab + pomalidomide/dexamethasone vs pomalidomide + dexamethasone alone

1. Dimopoulos MA et al. N Engl J Med. 2018;379:19.

• Stratification• Age (≤ 75 y vs > 75 y)• Prior regimens (1 vs > 1)• β2-microglobulin at screening

(< 3.5 mg/L vs ≥ 3.5 to ≤ 5.5 mg/L vs > 5.5 mg/L)

Phase 3 OPTIMISMM Study Design

Richardson PG et al. ASCO 2018; Abstract 8001.

Vd (n = 278)BORT 1.3 mg/m2 sc

cycles 1-8: D 1, 4, 8, 11cycle 9+: D 1 and 8

LoDEX 20 mg (≤ 75 y) or 10 mg (> 75 y)day of and day after BORT

PD, subsequent

antimyeloma Tx,

and survival

PD or unacceptabl

e toxicity

PVd (n = 281)POM 4 mg D 1-14BORT 1.3 mg/m2 sc

cycles 1-8: D 1, 4, 8, 11cycles 9+: D 1 and 8

LoDEX 20 mg (≤ 75 y) or 10 mg (> 75 y)day of and day after BORT

RRMM

•1-3 prior regimens, ≥ 2 cycles of LEN•ECOG PS ≤ 2•Prior BORT allowed (PD with 1.3 mg/m2 twice weekly dose excluded)a

N = 559

LT follow-upFollow-up visit 28 days after Tx discontinuation

Enter PFS follow-up periodb

21-day cycles

Progression-Free Survival (ITT)Pr

obab

ility

of

Prog

ress

ion-

Free

Su

rviv

alEvents/N

Median PFS,

monthsHR (95% CI)

P Value

PVd 154/281 11.20 0.61 (0.49-0.77) < .0001Vd 162/278 7.10

278 176 112 66 42 30 20 14 4 4 3 2 2 0281 233 182 128 94 67 47 28 13 7 4 2 1 0

01

01

No. at RiskPVd

0.00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Months

1.00.90.80.70.60.50.40.30.20.1

49%

32%

36%

22%

• Primary endpoint: PFS• Key secondary endpoints: ORR, OS, safety

Phase 3 ICARIA-MM Study: Isatuximab Plus Pomalidomide/Dexamethasone in R/R MM1,2

a Isatuximab 10 mg/kg IV on d 1, 8, 15, and 22 in the first cycle; d 1 and 15 in subsequent cycles. Pomalidomide 4 mg on d 1-21. Dexamethasone 40 mg for patients aged <75 y and 20 mg for patients aged ≥75 y on d 1, 8, 15, and 22.1. Richardson PG et al. ASCO 2019. Abstract 8004. 2. https://clinicaltrials.gov/ct2/show/NCT02990338. Accessed September 6, 2019.

R/R MM•≥2 prior lines of therapy•Prior IMiD and PI•Progressed ≤60 d of prior therapy(N = 300)

R

Isatuximaba + pomalidomide + dexamethasone 28-d cycles

(n = 150)

Pomalidomide + dexamethasone(n = 150)

Until disease progression, occurrence of unacceptable

AEs, or patient’s

decision to discontinue the study

ICARIA-MM: PFS (by IRC)1

1. Richardson PG et al. ASCO 2019. Abstract 8004.

• Median time to first response: Isa/Pd = 35 days vs Pd = 58 days

• True CR rate in Isa/Pd underestimated because of isatuximab interference with M-protein measurement

ICARIA-MM: Response1

1. Richardson PG et al. ASCO 2019. Abstract 8004.

Isa/Pd(n = 154)

Pd(n = 153)

nCR, % 15.6 3.3

• MRD negativity at 10-5 (ITT): 5.2% for Isa/Pd vs 0% for Pd

Isa/Pd(n = 154)

Pd(n = 153)

ORR = 60.4%

ORR = 35.3%

P < .001

Usmani SZ, et al. ASH 2019. Abstract LBA6.

CANDOR: Car/Dara/Dex vs Car/Dex

PatientsN = 466

Key Eligibility Criteria:•RRMM•1 to 3 prior therapies with ≥ PR to ≥ 1 prior therapy•ECOG PS 0 to 2•CrCI ≥ 20 mL/min•LVEF ≥ 40%

R2:1

Carfilzomib at 56 mg/m2

Dexamethasone 40 mgDaratumumab 16 mg/kg

N = 312

N = 154

28-daycycles

Carfilzomib at 56 mg/m2

Dexamethasone 40 mg

Trea

tmen

t Unt

il D

isea

se

Prog

ress

ion

MRD sample:Baseline

MRD sample:Landmark

analysis MRD-negative CR

rate

MRD sample:Landmark analysis

Sustained MRD-negative CR rate

Primary Endpoint:

PFS

Key Secondary:ORR, MRD,

OS

0 4 8 12

16

20

24

28

32Months

26

Usmani SZ, et al. ASH 2019. Abstract LBA6.

CANDORResponse and PFS

KdD (n = 312)

Kd (n = 154)

Median follow-up time, months 16.9 16.3

Progression/death, n (%) 110 (35%) 68 (44%)

Median PFS, months NE 15.8

HR (KdD/Kd) (95% CI) 0.63 (0.46, 0.85)

P value (1-sided) .0014

Response

MRD

– 30 fatal events (9.7%) on Car/Dara/Dex vs 8 (5.2%) on Car/Dex • 14 (4.5%) due to infections vs 5 (2.6%) with Car/Dex; 4 (1.4%) due to cardiac disorders vs 0 with

Car/Dex

CANDOR: AEs of Interest

AE, n (%)

Car/Dara/Dex( n = 308)

Car/Dex ( n = 153)

All Grades Grade ≥ 3 All Grades Grade ≥ 3Acute renal failure 18 (5.8) 9 (2.9) 12 (7.8) 10 (6.5)Cardiac failure* 23 (7.5) 12 (3.9) 16 (10.5) 13 (8.5)Ischemic heart disease 13 (4.2) 9 (2.9) 5 (3.3) 4 (2.6)

Respiratory tract infection 225 (73.1) 89 (28.9) 84 (54.9) 24 (15.7)

Peripheral neuropathy 53 (17.2) 3 (1.0) 13 (8.5) 0Hypertension 98 (31.8) 55 (17.9) 44 (28.8) 21 (13.7)

IRR (on same day as any K) 126 (40.9) 38 (12.3) 43 (28.1) 8 (5.2)

Dara-related infusion reactions 56 (18.2) 7 (2.3) 0 0Viral infections 63 (20.5) 19 (6.2) 22 (14.4) 3 (2.0)

Usmani SZ, et al. ASH 2019. Abstract LBA6.

• Car/Dara/Dex resulted in – Significantly longer PFS

• 37% reduction in risk of progression or death– Deeper responses

• 10x higher MRD negative at 12 mo– PFS benefit across pre-specified subgroups– Consistent safety profile

• Increase in treatment-emergent fatal AEs on Car/Dara/Dex arm

Usmani SZ, et al. ASH 2019. Abstract LBA6. 29

CANDOR: Conclusions

Harrison SJ, et al. ASH 2019. Abstract 142.

Venetoclax/Bor/Dex vs Bor/DexBELLINI, Study Design

N = 291

Key Eligibility:• RRMM• 1 to 3 prior

lines of therapy• PI

nonrefractory

R2:1

Venetoclax (800 mg once daily) +

Bortezomib + Dexamethasone

PDN = 194

N = 97

Cycles 1 to 8: 21-day, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20 mg days 1, 2, 4, 5, 8, 9, 11, 12Cycles 9+: 35-day, bortezomib 1.3 mg/m2 days 1, 8, 15, 22 and dexamethasone 20 mg days 1, 2, 8, 9, 15, 16, 22, 23

Placebo +Bortezomib +

Dexamethasone

Primary endpoint:•PFS (per IRC)Key secondary endpoints:•ORR•≥ VGPR•OS•QoL/PRO parameters

PD

Stratification factors • Bortezomib sensitive vs naive• Prior lines of therapy: 1 vs 2 to 3

Nonranked secondary endpoints PFS in BCL2high (IHC), DOR, TTP, MRD negativity rate, other PROs (GHS, fatigue)

Key subgroup analyses t(11;14), high/standard-risk cytogenetics, and BCL2 gene expression

4

30

Data cutoff Jul 15, 2019.

Harrison SJ, et al. ASH 2019. Abstract 0142.

Venetoclax/Bor/Dex vs Bor/DexBELLINI, Subgroup Analysis

31

PFS was significantly prolonged in the venetoclax arm vs placebo arm in patients with t(11;14) or BCL2high gene expression

– The addition of venetoclax to bor/dex resulted in significant efficacy in patients with RRMM harboring either t(11;14) or tumor cells expressing high levels of BCL2, with a favorable benefit-risk profile

• BCL2high gene expression was associated with prolonged PFS and higher response rates in the venetoclax arm independently of t(11;14)

• OS in patients with t(11;14) or BCL2high gene expression was not inferior with venetoclax

– PFS was not significantly improved with venetoclax, and OS favored placebo in those with tumor cells also negative for t(11;14) and expressing low levels of BCL2

– Biomarker selected trials in MM with t(11;14) or BCL2high gene expression

Harrison SJ, et al. ASH 2019. Abstract 0142.

Venetoclax/Bor/Dex vs Bor/DexBELLINI, Conclusions