NEW TREATMENT OPTIONS FOR PATIENTS WITH ADVANCED … · 3/15/2016 · Vd. Bortezomib 1.3 mg/m. 2 (IV bolus or subcutaneous injection) Days 1, 4, 8, 11. Dexamethasone 20 mg . Days

TIMER

NEW TREATMENT OPTIONS FOR PATIENTS WITH ADVANCED RELAPSE / REFRACTORY MULTIPLE

MYELOMA

Paula Rodríguez OteroClínica Universidad de Navarra

NEW TREATMENT OPTIONS FOR PATIENTS WITH ADVANCED RELAPSE /

REFRACTORY MULTIPLE MYELOMA

Paula Rodríguez Otero

University of Navarra

Natural History of Multiple Myeloma

MGUS or smoldering myeloma

Asymptomatic Symptomatic

ACTIVE MYELOMA

M-p

rote

in (g

/L)

20

50

100

1. RELAPSE

2. RELAPSE

REFRACTORY RELAPSE

First-line therapy

Plateau remission

Second-line Third-line

MGUS=monoclonal gammopathy of undetermined significance.

Kumar, Blood 2008

Despite the benefit observed with novel agents in the last years,… other drugs are still needed for relapsed/refractory patients

Evolution of MM OS over the years

1971–76

1994–001989–94

1977–821983–88

Time

0 20 40 60 80 100 120 140

Surv

ival

0.0

0.2

0.4

0.6

0.8

1.0

2001–06

Surv

ival

100%

80%

60%

40%

20%

0

60483624120

Months from Time Zero

Events/N Median (m)

— Overall Survival 170/286 9 (7.11)— Event-Free Survival 217/286 5 (4.6)

Kumar, Leukemia 2012

Outcome of pts refr to Btz & IMIDs*

Historical evolution of MM patients

* 286 pts refractory to BTZ and relapsed or refractory or ineligible to receive an IMiD

2006–10

Kumar, Leukemia 2014

Novel Drugs in MM

- Derivatives from the already approved

- Novel Proteasome Inhibitors

- Novel IMIDs

- Novel Alkylators

- Novel Mechanisms of action

- MoAb: anti CS1 & anti-CD38

- Deacetylase Inhibitors

- KSP inhibitors

- Checkpoint inhibitors

- XPO-1 inhibitors

Proteasome inhibitors

TypeCatalytic inhibition

Reversibilitypo/iv

DosingChymotryp Casp Tryp

Bortezomib Boronate X X Reversible Iv 1, 4, 8, 11

IxazomibMLN-9708

Boronate X X Reversible po 1, 8, 15

Carfilzomib Epoxi-ketone X Irreversible iv 1-2, 8-9, 15-16

Oprozomib Epoxi-ketone x Irreversible po BID

Marizomib Salinospore X X X Irreversible iv 1, 4, 8, 11

CEP-18770 Boronate X X Reversible iv 1, 4, 8, 11

β-subunit ring of the proteasome: Catalytic sites Caspase-L

β7β1

β2

β6

β5 β4

β3

Trypsin-L

Chymotrypsin-LCarfilzomib

NPI-0052

Bortezomib

MLN-9708

The proteasome is an intracellular enzyme complex responsible for the degradation of regulatory & misfolded and potentially toxic proteins.

Biological effects of proteasome inhibition: - Inhibition of Proliferation- Cell Cycle Arrest- ER stress and unfolded protein response- Blockade of NFkB pathway

Carfilzomib single agent in R/R MM: Summary efficacy data

Bortezomib (APEX) ≥ PR 43%6

PX-171-003 A01/A12: Relapsed after Btz & Len/Thal + Refr to last regimen

PX-171-0043,4: Relapsed to 1-3 prev. Lines

1. Jagannath S, et al. Clin Lymphoma Myeloma Leuk 2012;12:310-82. Siegel D, et al. Blood 2012; 120: 2817-25

3. Vij R, et al. Blood 2012; 119: 5661-704. Vij R, et al. Br J Haematol 2012; 158: 739-48

5. Siegel D, et al. ASCO 2012. Abstract 8035.6. Richardson PG, et al. Blood 2007;110:3557-60

Population Study NDose of

CarfilzomibORR (%)

PFS (mo) / OS (%)

BTZ-naïve 004004

5970

20 mg/m2

20/27 mg/m242.452

8.3 (TTP)

NR (TTP)

BTZ-treated003A0003A1

004

4625735*

20 mg/m2

20/27 mg/m2**20 mg/m2

16.723.717.1

3.7 / 15.6

BTZ-refractory

003A15 194 20/27 mg/m2 16.5

BTZ-treated FOCUS trial 30320/27 mg/m2

vs Pred/Cycl-Prd30% 3.7 vs 3.3

*Subgroup of patients included in 004 study and bortezomib-exposed

**1st cycle 20 mg iv QD x2 for 3 weeks (28-day cycle). Subsequently 27 mg

VdBortezomib 1.3 mg/m2 (IV bolus or subcutaneous injection)

Days 1, 4, 8, 11

Dexamethasone 20 mg

Days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycles until PD or unacceptable toxicity

KdCarfilzomib 56 mg/m2 IV

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)Infusion duration: 30 minutes for all doses

Dexamethasone 20 mg Days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycles until PD or unacceptable toxicity

N=929

Stratification:• Relapsed MM

• 1–3 prior treatments

• Prior treatment with V or K was allowed if:

• ≥PR to prior treatment

• ≥6 month PI treatment-free interval

• Was not removed owing to toxicity

• Creatinine clearance ≥15 mL/min

Carfilzomib-Dex vs Bortezomib-Dex in RMMPhase III ENDEAVOR trial : Study design

Dimopoulos MA et al, Lancet Oncol. 2016 Jan;17(1):27-38

Carfilzomib-Dex vs Bortezomib-Dex in RMMPhase III ENDEAVOR trial : PFS and OS data

1.0

0.8

0.6

0.4

0.2

0

Prop

orti

on S

urvi

ving

W

itho

ut P

rogr

essi

on

0

Months Since Randomization

KdVd

6 12 18 24 30

Kd Vd

Events, n 171 243

Median PFS, mo 18,7 9.4

HR (95% CI) 0.53 (0.44-0.65)p<0.0001

Primary endpoint: PFS

ORR (Kd vs Vd): 77% vs 63%. ≥CR: 13% vs 6%Median DOR (Kd vs Vd): 21.3 vs 10.4 months

KdVd

Prop

ortio

n Su

rviv

ing

0 6 12 18 24 30

1.0

0.8

0.6

0.4

0.2

0

Secondary endpoint: OSKd

(n=464)Vd

(n=465)Events, n 75 88

Median OS, mo NE 24.3

HR (95% CI) 0.79 (0.58-1.08)p=0.066


Carfilzomib-Dex vs Bortezomib-Dex in RMMPhase III ENDEAVOR trial: Safety profile

TreatmentKd

(n=464)Vd

(n=465)

Discontinuation due to AE, % 14.0 15.7

Death due to AE, % 3.9 3.4

Grade 3 AEs, %

Hypertension, % 8.9 2.6

Dyspnea, % 5.6 2.2

Cardiac failure, % 4.8 1.8

Acute renal failure, % 4.1 2.6

Grade ≥ 2 PN, % 6.3 32

Dimopoulos MA et al, Lancet Oncol. 2016 Jan;17(1):27-38

Berenson J, ASH 2015 Abst 373

Carfilzomib Days 1, 8, and 15 (30 minutes infusion)

Dexamethasone IV or PO Days 1, 8, 15, and 22 (day 22 omitted for cycles 9+)

Treatment Schedule (Phase 1 and 2)

28 day cycles - Both drugs given until PD or unacceptable toxicity

Champion-1: Carfilzomib-Dexamethasone weekly Study design

DOR (≥PR), median months (95% CI) 16.3 (12.7–NA)

TTR (≥PR), median months (range) 1.6 (0.7–7.2)

Median PFS (95% CI): 14.3 months (9.9–21.0) 1.00

0.75

0.50

0.25

0.00

Prop

orti

on P

rogr

essi

on-F

ree

0 6 12 18 24

Time (months)

30

ORR 77%; CBR 84%; sCR 5%, VGPR 30%.ORR and CBR in Btz refr: 63% & 76% respect.

MTD: 20/70 mg/m2

Phase III trial (ARROW) ongoing

Study population (N = 700)• Measurable disease

• Relapsed progressive MM after 1-3 prior therapies

• ECOG PS 0-2

Stratification:• Prior bortezomib

• Prior lenalidomide

• β2-microglobulin levels

1:1

KRdCarfilzomid 27mg/m2 IV

Day 1, 2, 8, 9, 15, 16 (20 mg/m2 on days 1 and 2 of cycle 1 only)

Lenalidomide 25 mgDays 1-21

Dexamethasone 40 mgOnce weekly days 1, 8, 15, and 22

RdLenalidomide 25 mg

Days 1-21

Dexamethasone 40 mgOnce weekly days 1, 8, 15, and 22

After cycle 12, CFZ given on days 1, 2, 15, 16After cycle 18, CFZ to be discontinued

Both arms to receive 28 day cycles until progression

Primary endpoint: PFS

National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT01080391. Accessed: October 28, 2014.

Carfilzomib-Len-Dex (KRd) in Relapsed MMPhase III ASPIRE trial

Phase III ASPIRE trial

Stewart et al. ASH 2014 (Abstract 79), oral presentationStewart et al. N Engl J Med 2014 Dec 6

No. at Risk:KRd

Rd396 332 272 222 179 112 24 1396 287 206 151 117 72 18 1

1.0


0.8

0.6

0.4

0.2

0.0

Prop

ortio

n Su

rviv

ing

With

out P

rogr

essi

on

KRdRd

0 6 12 18 24 30 36 42 48

The progression-free survival benefit in the carfilzomib group was observed across all predefined subgroups

Stewart et al. ASH 2014 (Abstract 79), oral presentation. Stewart et al. N Engl J Med 2014 Dec 6 [Epub ahead of print].

ORR (KRd vs Rd): 87.1 vs 66.7%. ≥CR: 31.8 vs 9.3%KRd Rd

(n=396) (n=396)

Median PFS, mo 26.3 17.6HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83)P value <0.0001

KRd Rd(n=396) (n=396)

Median OS, mo NE NEHR (KRd/Rd) (95% CI) 0.79 (0.63–0.99)P value (one-sided) 0.018

1.0

0.8

0.6

0.4

0.2

0.0Pr

opor

tion

Surv

ivin

g

KRdRd

0 6 12 18 24 30 36 42 48Months Since Randomization

KRdRd

396 369 343 315 280 191 52 2396 356 313 281 237 144 39 3

Carfilzomib-Len-Dex (KRd) in Relapsed MMPhase III ASPIRE trial: PFS* and OS results (N=792)

KRd Rd

Treatment discontinuation due to AE, % 15.3 17.7

Grade ≥3Anemia, %Neutropenia, %Thrombocytopenia, %PN, %Cardiac failure, %Ischemic heart disease, %

17.929.616.62.63.83.3

17.226.512.33.11.82.1

Stewart et al. ASH 2014 (Abstract 79), oral presentationStewart et al. N Engl J Med 2014 Dec 6 [Epub ahead of print]

Cardiovascular impact of CFZ in MM:Baseline elevated cardiac peptides and abnormal cardiac strain (60% at baseline)Arise in the NT-proBNP occurs immediately after Cfz based chemotherapy.5% of severe cardiac events attributable to cfz Rosental et al.ASH2014

Carfilzomib-Len-Dex (KRd) in Relapsed MMPhase III ASPIRE trial: Safety profile data

Tourmaline-MM1: Phase 3 study of weekly oral ixazomibplus lenalidomide-dexamethasone

Rand

omiz

atio

n

Ixazomib + Lenalidomide + DexamethasoneIxazomib: 4 mg on days 1, 8, and 15Lenalidomide: 25 mg* on days 1-21

Dexamethasone: 40 mg on days 1, 8, 15, 22

N=722

1:1

Placebo + Lenalidomide + DexamethasonePlacebo: on days 1, 8, and 15

Lenalidomide: 25 mg* on days 1-21Dexamethasone: 40 mg on days 1, 8, 15, 22

Repeat every 28 days until progression, or unacceptable toxicity

Stratification:• Prior therapy: 1 vs 2 or 3• ISS: I or II vs III• PI exposure: yes vs no

Global, double-blind, randomized, placebo-controlled study design

*10 mg for patients with creatinine clearance ≤60 or ≤50 mL/min, depending on local label/practice

1. Rajkumar S, et al. Blood 2011;117:4691–5.

Response and progression (IMWG 2011 criteria1) assessed by an independent review committee (IRC) blinded to both treatment and investigator assessment

Primary endpoint: • PFSKey secondary endpoints:

• OS

• OS in patients with del(17p)

Moreau P, ASH 2015 Abst 727


A significant, 35% improvement in PFS with IRd vs placebo-Rd

Number of patients at risk:

IRd

Placebo-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 0

362 340 325 308 288 274 254 237 218 208 188 157 130 101 85 71 58 46 31 22 15 5 3 0 0

1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3 4 5 6 7 8 9 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

Prob

abili

ty o

f pro

gres

sion

-fre

e su

rviv

al

Time from randomization (months)

Log-rank test p=0.012

Hazard ratio (95% CI): 0.742 (0.587, 0.939)

Number of events: IRd 129; placebo-Rd 157

Median PFS:

IRd: 20.6 months

Placebo-Rd: 14.7 months

Median follow-up: ~15 months

Interim OS analysis @ 23 months of FU: 81 and 90 deaths in ixazomib and placebo, respectively

Tourmaline-MM1: Ixazomib +/- Rd: Final PFS analysis

ORR (IRd vs Rd): 78.3% vs 71.5% CR (IRd vs Rd): 11.7% vs 6.6%


IRd (N=361), % Placebo-Rd (N=359), %

Preferred terms All-grade Grade 3-4 All-grade Grade 3AEs overlapping with lenalidomideDiarrhea 45 6 39 3Nausea 29 2 22 0Rash* 36 5 23 2Upper respiratory tract infection

23 <1 19 0

Thrombocytopenia 31 19 16 9AEs with proteasome inhibitorsPeripheral neuropathy* 27 2 22 2

Peripheral edema 28 1 20 1

AEs with lenalidomideThromboembolism* 8 2 11 3

Neutropenia* 33 23 31 24

*Represents multiple MedDRA preferred terms.

Tourmaline-MM1: Ixazomib +/- RD: SafetyIncreased rates with IRd driven by low-grade events

Activity of other Proteasome Inhibitors in RRMM

- MARIZOMIB + DEX (n = 21) (90% Btz exposed ):

- Twice weekly (≥0.4 mg/m2 ) x 4doses, 21 day cycles,

- ≥PR: 19% - Diarrhea (38/35%), nausea (10/30%)anemia (22%)

Richardson PG, et al. Blood. 2011;118: Abstract 302;.

- OPROZOMIB + DEX (n = 69) (38% Btz exposed ): Median number of prior lines: 4

≥PR: 31% (2/7 sched) & 23% (5/14 sched)

Diarrhea (38/35%), nausea (10/30%) anemia (22%)

Vij R, et al. Blood. 2014; 124(21): Abstract 34

- OPROZOMIB + POMA + DEX (n = ?). Median number of prior lines: 8. 2

different schedules: 150mg 5/14 or 210 mg 2/7: 210mg 2/7 chose for dose expansion.

ORR (2/7): 85.7% Shah J, ASH 2015 Abstract 378

Novel Drugs in MM



- Novel IMIDs- Novel Alkylators




- XPO-1 inhibitors


Activity of Poma + Dex in relapse and RRMM

Dex 40 mg weeklySchey (JCO 2004): 24 pts (2mg): 54%PR

Lenalidomide + Dex5 ≥ PR: 60% (15% CR) TTP: 13.4 m

Lacy1,2 34 Len refr 3.5 2 mg (1-28) 32 % PFS 5.0 m

Lacy1,2 60 Len refr 2 4 mg (1-28) 37% PFS 7.9 m

Leleu3 84 Prev. Len & Btz5

5

4 mg (1-21) 35 % PFS 5.5 m

4 mg (1-28) 34 % PFS 4.4 m

Lacy1,2 70 Len & Btz refr6 2 mg (1-28) 26 % PFS 6.5 m

6 4 mg (1-28) 29 % PFS 3.3 m

Richardson4 113 Prev Len & Btz. Refr to last line 5 4 mg (1-21) 34 % PFS 4.6 m

n Population No prior tx Dose ≥ PR PFS

Lacy1,2 60 60% prev IMIDs 2 2 mg (1-28) 65 % PFS 13 m

1. Lacy. ASH 2011. Abst 3963. 2. Lacy. ASH 2012. Abst 201.3. Leleu X, et al. Blood. 2013; 121:1968-75. 4. Richardson. IMW 2013. Abst O-15.

5. Dimopoulos MA, et al. Leukemia. 2009;23:2147-52.

Comparison of Pom-Dex trials (& combinations)

1. San Miguel, Lancet Oncology 2013; 2. Dimopoulos MA, et al. ASH 2014. Abstract 80; 3. Baz et al. ASH 2014. Abstract 303; 4. Richardson et al. ASH 2015. Abstract 3036

*EFS at 12 months

MM-0031 STRATUS(MM-010)2

Pom-Dex vsPom-Cyclo-Dex3 Pom-Btz-Dex4

Treatment PD PD PD PCD PVDn 302 604 36 34 34

Population Failed Bort & Len & refr to last lineAt least 2 prior lines & Len-

refractory1-4 prior lines & Len-refractory

ORR, % 31 35 39 65 65

≥ VGPR, % 14 12 45

PFS, months 4.0 4.2 4.4 9.5 -

OS, months 13.1 11.9 16.8 NR -

a Pts may have received POM + LoDEX following crossover.

POM + LoDEX(N = 300)

HiDEXa

(N = 150)

Grade 3/4 hematologic AEs (%)

Neutropenia 49 17

Febrile neutropenia 9 0

Anemia 33 39

Thrombocytopenia 22 26

Grade 3/4 non-hematologic AEs (%)

Infections 33 25

Pneumonia 14 8

Bone Pain 7 5

Fatigue 5 6

Asthenia 4 7

Glucose intolerance 4 7

Discontinuation due to AEs (%) 9 10

San Miguel J, et al. Patient Outcomes by Prior Therapies and Depth of Response: Analysis of MM-003, a Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) vs High-Dose Dexamethasone (HiDEX) in Relapsed/Refractory Multiple Myeloma (RRMM). Oral presentation at: American Society of Hematology. 2013; December 7-10; New Orleans, LA.

Pom-Dex vs HiDEX in RRMMPhase III MM-003 trial: Safety profile

Novel Drugs in MM



- Novel IMIDs

- Novel Alkylators




- XPO-1 inhibitors


Melflufen

Chauhan Clin Cancer Res 2013 & Wickström Invest New Drugs 2008

N=29. 4 (2-11) prior lines.

All prior IMiDs and PIs and 18 (62%) prior melphalan

4 /6 pts @ 55 mg had DLTs (haem.)MTD 40 mg

G 3/4 rel. TEAEs: Thromboc. (41%) & Neutropenia (31%)

Phase I/II

• Melflufen is a highly lipophilic alkylator, consisting of

melphalan + 4-fluoro-L-phenylalanine.

• Intracellular peptidases that are overexpressed in most

malignant cells, will rapidly cleave melflufen releasing the

hydrophilic, active metabolite melphalan.

• In vitro, equimolar treatment of tumor cells with melphalan

and melflufen, results in a 10-20 fold higher intracellular

concentration of melphalan.

Paba-Praba ASH 2014

ORR @ MTD 60%

1 VGPR & 2 PR

Median time on txfor responding pts 13

w.

Novel Drugs in MM



- Novel IMIDs

- Novel Alkylators


- MoAb: anti CS1 & anti-CD38- Deacetylase Inhibitors

- XPO-1 inhibitors


Elotuzumab (SLAMF7:Signaling Lymphocytic Activation Molecule F7: Anti-CS1)

- ELOTUZUMAB Single agent1 26% SD- ELOTUZUMAB + LEN-DEX (Phase II) ORR: 76-92%; PFS 18 - 33 m

Elotuzumab + Len + Dex in RRMM patients Phase III – Eloquent trial (646 patients): Study design

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: days 1, 8, 15, 22; Cycles 3+: days 1, 15

Len (25 mg PO): days 1–21Dex: 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

Repeat every 28 days

Assessment

• Tumor response: every 4 wks until progressive disease,

• Survival: every 12 wks after disease progression

Repeat every 28 days

• Endpoints:

– Co-primary: PFS and ORR

– Other endpoints: OS (data not yet mature); DOR, quality of life, safety

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

Lonial S et al, NEJM 2015 Aug 13;373(7):621-31

Eloquent-2: Extended Progression-Free Survival

Dimopoulos M, ASH 2015 Abst 28

ORR (ELd vs Ld): 79% vs 66%. ≥VGPR: 32.7% vs 27.9%

27% reduction in the risk of disease progression or death

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

480 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Prob

abili

ty p

rogr

essi

on fr

ee

E-LdLd

0.

1

1-year PFS 2-year PFS 3-year PFS

No. of patients at risk:E-LdLd

321325

293266

259215

227181

171130

144106

12580

10767

9460

8551

5936

3415

197

83

PFS (months)30

195157

00

68%

41%

26%

57%

27%

18%

PFS: 19.4 vs 14.9 HR 0.73 (95% CI 0.60, 0.89)

p=0.0014

PFS (19.4 vs 14.9 m)

460 2 4 6 1416 2022 2628 3234 36 40 448 1012

E-Ld

Ld

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time to next treatment (months)

Prob

abili

ty o

f pat

ient

s w

itho

ut n

ext

trea

tmen

t

18 24 30 38 4842

0.1

No. of patients at risk:E-LdLd 321

325315305

282251

259232

208174

198166

174135

165120

153105

13889

12685

9446

6530

4620

145

225193

31

294276

239206

182148

14496

11876

3213

63

00

TNT: 33 vs 21 mHR 0.62 (95% CI 0.50, 0.77)

TNT (33 vs 21 m)

Eloquent-2: Interim Overall Survival

Dimopoulos M, ASH 2015 Abst 28

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

510 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

No. of patients at risk:E-LdLd

321325

314305

303287

291269

283255

266241

250228

239218

224208

217200

196184

190171

152134

9588

4841

1517

1-year OS 2-year OS

OS (months)

Prob

abili

ty a

live

53

00

E-Ld

Ld

No. of patients at risk:

3-year OS E-Ld Ld

HR 0.77 (95% CI 0.61, 0.97; 98.6% CI 0.58, 1.03); p=0.0257

Median OS (95% CI)

43.7 m(40.3,NE)

39.6 m(33.3, NE)

Prespecified interim analysis for overall survival indicates a strong trend (p=0.0257) with early separation sustained over time for E-Ld vs Ld

TreatmentELd

(n=464)Ld

(n=465)

Grade 3 AEs, %

Fatigue, % 9 8

Neutropenia, % 35 44

Thrombocytopenia, % 21 20

Anemia, % 20 21

Infusion reactions, %11% gr 1/2

1% gr 3NA

Lonial S, ASCO 2015. Abstract 8508. Dimopoulos MA, ASH 2015 oral presentation 28.

- Addition of elotuzumab did not increase the incidence of AE compared to Len/Dex alone. - 70% of infusion reactions occur with the first dose.- Only 2 patients discontinue the study due to an infusion reaction.

Elotuzumab + Len + Dex in RRMMPhase III – Eloquent trial: Results

Anti CD38 in MM: single agent activity in RRMM

Daratumumab Isatuximab

Study details 3 studies: GEN5011, SIRIUS2 & combined analysis4

First in-human, phase 1 dose escalation3

Patients Pts with rel/ref MMn=148 (SIRIUS n=42 and GEN501 n=106)

Pts with rel/ref MMn=40

Dose 16 mg/kg Dose is not yet defined

Results

• ORR 31% (36% GEN501 & 29%SIRIUS)

• Median DOR: 7.6 m• 1 year OS: 77% / 69%• Median PFS: 5.6m , 3.7 m,

Infusion-related reactions gr 1-2

• At ≥ 10 mg/kg: 29%• At 20 mg/kg: 24%5

• Infusion-reactions mainlygrade 1/2, only with first dose

1Lokhorst HM et al, NEJM 2015, 363:8; 1Lokhorst et al. ASCO 2014; Abstract 8513; Lonial S JCO 2015, 3Martin et al. ASCO 2014; Abstract 8532; 4Usmani S, et al ASH 2015 oral presentation 29, 5Martin T, ASH 2015 oral presentation 509

Dara/SAAR are CD38 MoAB showing activity as single agents in RRMM patients

• For the combined analysis, median OS = 19.9 (95% CI, 15.1-NE) months

• 1-year overall survival rate = 69% (95% CI, 60.4-75.6)

Daratumumab in monotherapy: Two studies: GEN501 & SIRIUS – PFS and OS analysis

PD/NE: 3.7 (1.7-7.6) months

Responders: NE (7.4, NE)

MR/SD: 3.2 (2.8-3.7) months

PD/NE: 0.9 (0.9-1.0) months

0

Pati

ents

pro

gres

sion

-fre

e an

d al

ive,

%

2 6 8 12 14 18 20Time from first dose, months

Patients at riskResponders

MR/SDPD/NE

0

25

50

75

100

4 10 16

RespondersMR/SDPD/NE

467725

46450

35130

2730

1310

500

300

000

41210

1420

300

0

Pati

ents

aliv

e, %

2 6 8 12 14 18 22Time from first dose, months

Patients at riskResponders

MR/SDPD/NE

0

25

50

75

100

4 10 16

MR/SD

467725

467416

456311

44577

42475

29374

310

000

466712

43537

15101

20

1351

Responders: NE (19.9, NE)

MR/SD: 17.5 (15.1-NE) months

PD/NE: 3.7 (1.7-7.6) months

Responders

PD/NE

Progression-free survival Overall Survival

Usmani S, ASH 2015 Abst 29

Anti-CD38 MoAb plus Len/dex in RRMM

Daratumumab + Len/Dex SAR650984 + Len/Dex

Target CD38 CD38

Single-agent activity Yes Yes

Study details

Phase 1/2 dose escalation & expansion

Prior IMiDs: 80%Pts ref or intolerant to Len

excluded

Phase Ib dose escalation trialPts rel + ref to

IMiD:84%

Patients n=32 n=31

ResultsORR 81%

(35% CR, 28% VGPR, 19% PR)

ORR 58% (6% sCR, 23% VGPR,

29% PR)PFS 6.2 months

Plesner et al. ASH 2014 (Abstract 84); ASH 2015 (Abs 507); Martin et al. ASH 2014 (Abstract 83); oral presentation

Chari A, ASH 2015 Abst 508

• ORR = 71%

• ORR in double-refractory patients = 67%

• Clinical benefit rate (ORR + minimal response) = 73%

• Rates of grade ≥3 AEs were similar to those observed with POM-D alone

DARA + POM-D(N = 75)

n (%) 95% CI

Overall response rate (sCR+CR+VGPR+PR)

53 (71) 59.0-80.6

Best responsesCRCRVGPRPRMRSDPD

4 (5)3 (4)

25 (33)21 (28)

2 (3)17 (23)

3 (4)

1.5-13.10.8-11.2

22.9-45.218.2-39.6

0.3-9.313.8-33.80.8-11.2

VGPR or better (sCR+CR+VGPR)

32 (43) 31.3-54.6

CR or better (sCR+CR) 7 (9) 3.8-18.3

ORR = 71%

43%VGPR or better

9%CR or better

28%

33%

4%5%

0

10

20

30

40

50

60

70

80

16 mg/kg

OR

R, %

PR VGPR CR sCR

N = 75

MMY-1001: Daratumumab + Pomalidomide + DexOverall response rate

Novel Drugs in MM



- Novel IMIDs

- Novel Alkylators



- Deacetylase Inhibitors- Checkpoint inhibitors

- XPO-1 inhibitors

Inhibition of the aggresome and proteasome pathways causes a buildup of intracellular misfolded cytotoxic proteins, leading to MM cell apoptosis1-4

Accumulation of

Unfolded/ misfoldedproteins

Ubiquitinatedprotein aggregates

DACiRocilinostat, Vori &

Panobinostat

Bortezomib

1. Hideshima T, et al. Proc Natl Acad Sci USA. 2005;102:8567-8572. 2. Ocio EM, et al. Haematologica. 2010;95:794-803. 3. Catley L, et al. Blood. 2006;108:3441-3449. 4. Hideshima T, et al. Mol Cancer Ther. 2011;10:2034-2042.

Proteindegradation

Ubiquitinatedprotein

Proteasomal degradation

Dynein

Microtubule

Aggresomeformation

Lysosomal degradation

ProteindegradationHDAC6

Rationale for combining DACi + Bortezomib

No benefit in OS

PANORAMA 1: Panobinostat + Bort + Dex vs Bort + Dex

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

387 288 241 202 171 143 113 89 69 52 44 35 26 18 13 10 5 3 0

381 296 235 185 143 114 89 64 42 32 24 18 12 5 5 3 2 0 0

MonthsNumber of patients at riskPAN-BTZ-DexPbo-BTZ-Dex

100

80

60

40

20

0

PFS

Prob

abili

ty, %

PAN-BTZ-DexPbo-BTZ-Dex

San Miguel JF, et al. Lancet Oncol. 2014;15(11):1195-1206

PAN-BTZ-Dex Pbo-BTZ-Dex

Median PFS(m) 12 (10.3-12.9) 8.1 (7.6-9.2)

HR (95% CI) 0.63 (0.52 – 0.76)

ORR PanoBD vs PcboBD: 60.7% vs 54.6% CR: 27.6% vs 15.7%

PFS

73 57 42 36 32 25 20 15 10 6 4 3 2 2 1

74 54 37 23 11 9 5 4 2 2 2 2 2 0 0

Number of Patients at RiskPAN-BTZ-DexPbo-BTZ-Dex

PFS

Prob

abili

ty, %

100

80

60

40

20

00 2 4 6 8 10 12 1

416 18 20 22 24 26 28

Months

Censoring timesPAN-BTZ-Dex (n/N = 44/73)Pbo-BTZ-Dex (n/N = 54/74)

Subgroup Analysis by Prior Treatment:

PFS Prior BTZ + IMiDs w/ ≥ 2 Prior Lines

PAN-BTZ-Dex Pbo-BTZ-Dex

Median PFS(m) 12.5 (7.3-14.0) 4.7 (3.7-6.1)

HR (95% CI) 0.47 (0.31 – 0.72)

Other HDACi: Ricolinostat (ACY-1215) (HDAC6 inhibitor)

2. Yee, ASH 2014. Abstract 47721. Vogl, ASH 2014. Abstract 4764

- BORT + DEX1 ...........ORR 19% 1 VGPR, 2 PR In Btz refr. only 1 MR

n=16. 11 Btz refractory

G3/4 related AEs: Hemat. Amylase & creat incr.

- LEN+ DEX2 ORR 69%1 CR, In 6 Len refr. 1 VGPR, 1 PR, 2 MR

n=15. 14 prior Len. 6 Len refr

G3/4 related AEs: Hematologic and fatigue

Novel Drugs in MM



- Novel IMIDs

- Novel Alkylators




- XPO-1 inhibitors


XPO1-Inhibitors: Selinexor

Main AEs: Anorexia Nausea/Vomiting; Fatigue; Thrombocytopenia. Improve with Dex.

• Cancer cells (and MM) overexpress XPO1, causingincreased export of tumor suppressors and growthregulatory proteins from the nucleus

• Selinexor inhibit XPO1 mediated nuclear-cytoplasmic transport by transiently binding toXPO1 cargo binding site.

• Accumulation of Tumor suppressors in the nucleusamplifies the natural apoptotic function in cancercells with damaged DNA.

• Preclinical antitumoral & antiresorptive act. in MM

Chen et al. ASH 2014

First-in-class, oral Selective Inhibitor of Nuclear Export (SINE) that inhibits XPO1and activates Tumor Suppressor Proteins & reduces Oncoproteins

Tai et al. Leukemia 2014

PHASE I OF SELINEXOR PLUS/MINUS DEX IN RRMM

- Single agent (oral:3-45 mg twice/ w)….. 17% MR

- Plus Dex (45 mg)…………………………60% ORR (50% PR)

Under normal physiological conditions, immune checkpoints are crucial for: Maintenance of self-tolerance (prevent autoimmunity)

Protect tissues from damage

Activation of T-cell is a two-step process:

1- Interaction of TCR with a specific antigenic peptide-containing complex onAPC/tumor cells.

2- Co-stimulatorysignal, that induces activation and expansion of T-cells. In the absence of thissignal, T-cells fail to respondand are inactivated.

Overcoming tumour immune suppression

Topalian SL et al. Curr Opinion Immunol, 2012

Pembrolizumab: Targeting PD-1 (Programmed Cell Death 1) Releasing The Brakes

• Pembrolizumab is a potent and highly selective humanized monoclonal antibody of the IgG4/kappa isotype against PD-1

• Directly blocks the interaction between PD-1 and PD-L1/PD-L2

• Checkpoint Blockade of PD-1/PD-L1 signaling induces anti-MM immune responses, enhanced by lenalidomide. Gorgun ASH 2014: Ab 27

• PD-1 is overexpressed in T cells (at relapse & MRD) & PD-L1 in PC and MSC

• PD-1 blockade delays tumor progression (mouse model). Paiva B Leukemia 2015

1. Keir ME et al. Annu Rev Immunol. 2008;26:677-704; 2. Hallett WH et al. Biol Blood Marrow Transplant. 2011;17:1133-1145; 3. Homet Moreno B, Ribas A. Br J Cancer. 2015;112:1421-1427. Phase I of Nivolumab (BMS-936558) 67% SD

Pembrolizumab treatment in RRMM

KEYNOTE-023 (PhI):PEMBRO-LEN-DEX1

Ph I/II: PEMBRO – POMA –DEX2

Study designPEMBRO 200mg/2QW LEN 25mg 1-21 DEX 40mg weekly

PEMBRO 200mg/2QW POMA 4mg 1-21DEX 40mg weekly

Patient population- > 2 prior lines- PI & IMID exposure

- >2 prior lines- RRMM- PI & IMID exposure

Refractory status 76% Len-refractory30% Bort-refractory

50% double/triple/cuadruple refractory

89% Len-refractory82% Bort-refractory

70% double-refractory

ORRTotal (n=17): 76%

Len-refr (n=9): 56%Total (n=27): ORR: 60% Double refractory: 55%

SafetyAEs consistent with individual drug safety

profiles for approved indicationsIRAEs: no pneumonitis. No colitis.

Good safety profilePneumonia/Infection

Few cases pneumonitis / hepatitis

1San Miguel JF, ASH 2015 oral presentation 505; 2Badros A, ASH oral presentation 585

Type of relapse

Further options

Efficacy of previous

treatments

Toxicity of previous

treatments

Strategies at relapse: How to make the RIGHT CHOICE?

Intermediate relapse (1-3 years post ASCT)“Prolong survival until curative treatments are developed”

Sequential novel agent combinationsStarting with a different drug to that used in maintenance.( if less < 55 years & suboptimal response RIC-Allo?)

Late relapse (> 3 years post ASCT)Aggresive relapse: Reinduction (KRD) + 2nd ASCTBiological relapse: proceed direct to ASCT

Early relapse (< 1 year post ASCT)“Overcome drug resistance”

Combination of non cross-resistant agentsVTD-PACE or VRD +/- Adria & Cyclo RIC-Allo

60 year old man relapsing after ASCT: How to make the RIGHT CHOICE?

Decisions based on the duration of the previous response

Decisions based on treatment used up-front and its efficacy

Modest efficacy or progression under treatment

Switch drug class

IMiDProteasome inhibitor

or Alkylators if not used upfront

Biological progression

Increase dose/add a new drug

CR & Durable TFI (> 9-12m)

Re-treatment(1st or 2nd option)

75 year old man relapsing after frontline treatment: Can treatment be individualized at first relapse?

Type of relapseNumber of prior lines of therapy

Cytogenetic abnormalities,....

60y man 1st or 2nd relapse NOT LEN-refractory …

After Bortezomib based induction without maintenance(Lenalidomide or Bortezomib) until progression:

Lenalidomide – Dexamethasone until progression (PFS 15 m)

1Stewart AK, et al. NEJM 2015 Jan 8;372(2):142-52; 2Moreau P, ASH 2015 abst 727; 3Lonial S et al, NEJM 2015 Aug 13;373(7):621-31; 4Dimopoulos MA et al, Lancet Oncol. 2016 Jan;17(1):27-38

DoubletsKD (PFS 18 m)4

Kd (18 m) + Rd (15m) = 33 m

Triplets (with RD as backbone) KRD (PFS 26.3 m)1

IRD (PFS 20.6 m)2

EloRD (PFS 19.4 m)3

but

Type of relapse

Cytogenetic abnormalities

Age

Number/Typesof prior lines of

therapy

What are the factors influencing our decisions?

What are the factors influencing our decisions?: Age

ENDEAVOR trial (Kd vs Vd)2: Similar benefit among different ages

PFS in 65-74y ……… HR 0.53 (0.38–0.73)PFS in >75 y ……… HR 0.38 (0.23–0.65)

ASPIRE trial (KRd vs Rd)1: Only borderline benefit in patients older than 70y

PFS in >70 y ………… 23.8 vs 16 (HR 0.73, p=0.0521)PFS in < 70y .……….. 28.6 vs 17.6 (HR 0.66, p=0.0002)

ELOQUENT-2 trial (EloRd vs Rd)3: Significant benefit in patients older than 75y

PFS in < 75y ………… HR for PFS 0.76 (0.62-0.94)PFS in ≥ 75y ………… HR for PFS 0.59 (0.38-0.91)

TOURMALINE-MM1 (IRd vs Rd)4: No survival benefit in patients older than 65y

PFS in ≤ 65 y ……….. 20.6 vs 14.1 m (HR 0.689)PFS in 65-75y ……… 17.5 vs 17.6 m PFS in >75y ………… 18.5 vs 13.1 m (HR 0.86, p=n.s)

1Stewart AK, et al. N Engl J Med 2015;372:142–52; 2Dimopoulos MA, et al. Lancet Oncology 2016; 17: 27-38; 3Lonial S et al, NEJM 2015 Aug 13;373(7):621-31; 4Moreau P, ASH 2015 abst 727;

What are the factors influencing our decisions?: Prior lines of therapy

ENDEAVOR trial (Kd vs Vd)2: Better used at first relapse.

1 prior line ……… PFS (Kd vs Vd): 22.2 vs 10.1 (HR 0.45)

≥ 2 prior lines ……… PFS 14.9 vs 8.4 (HR 0.60)

ASPIRE trial (KRd vs Rd)1: Similar results after 1 or 2 or more prior lines

1 prior line ……… PFS 29.6 vs 17.6 (HR 0.69) ≥ 2 prior lines ……… PFS 25.8 vs 16.7 (HR 0.69)

ELOQUENT-2 trial (EloRd vs Rd)3: Better results after 2 or more prior lines. 1 prior line ..……… HR 0.79 (0.60 - 1.05) Prior IMID .………. HR 0.55 (0.21 – 1-25)≥ 2 prior lines ……… HR 0.68 (0.52 – 0.88)

TOURMALINE-MM1 (IRd vs Rd)4: Better results after three lines of therapy1 prior line ……… PFS 20.6 vs 15.9 (HR 0.83, n.s) 2 prior lines ……… PFS 17.5 vs 14.1 (HR 0.75, n.s)3 prior lines ………. PFS NE vs 10.2 (HR 0.36)


What are the factors influencing our decisions?: Cytogenetic abnormalities

ENDEAVOR trial (Kd vs Vd)2: KD does NOT OVERCOME adverse prongnosis of HR cytogenetics

Standard risk ……… PFS NE vs 10.2 (HR 0.44) (0.33 – 0.57) High risk ……..……… PFS 8.8 vs 6.0 (HR 0.66) (0.45 – 0.92)

ASPIRE trial (KRd vs Rd)1: KRD improves but does NOT OVERCOME the -ve prongnosis

Standard risk ……… PFS 29.6 vs 19.5 (HR 0.66) (0.48 – 0.90) High risk ……..……… PFS 23.1 vs 13.9 (HR 0.70) (0.43 – 1.13)

ELOQUENT-2 trial (EloRd vs Rd)3: EloRd improves but does NOT OVERCOME the –ve prognosisDel(17p) ……..……… HR 0.70 (0.49 – 0.99) t(4;14) ………………… HR 0.52 (0.29 – 0.93)

TOURMALINE-MM1 (IRd vs Rd)4: IRD OVERCOMES the adverse prognosis of HR cyto.Standard risk ..……… PFS 20.6 vs 25.6 (HR 0.64)High risk ……………… PFS 21.4 vs 9.4 (HR 0.54)


65 year old woman first or second relapse…

Following continuous Lenalidomide – Dexamethasone(Lenalidomide refractory)

1Dimopoulos MA et al, Lancet Oncol. 2016 Jan;17(1):27-38; 2San Miguel JF et al, Lancet Oncol 2014;15(11):1195-1206; 3Palumbo A, AHS 2015 abst 510.

Carfilzomib-dex PFS (18 m)1Triplets with Pom-Dex(as backbone)

PVD (PFS ? MM-007 trial)

Triplets based on bortezomib:PanobinostatVd (PFS 12m)2

EloVD (9.7m) ?

Treatment at second/subsequent relapse

Pomalidomide - Dexa(as a backbone)

+ Cyclophosphamide+ Ixazomib+ Bortezomib+ Daratumumab+ Elotuzumab

Daratumumab(single agent orcombination)

Clinicaltrial

NEW TREATMENT OPTIONS FOR PATIENTS WITH ADVANCED RELAPSE /

REFRACTORY MULTIPLE MYELOMA

Paula Rodríguez Otero

University of Navarra

Documents

NEW TREATMENT OPTIONS FOR PATIENTS WITH ADVANCED … · 3/15/2016 · Vd. Bortezomib 1.3 mg/m. 2 (IV bolus or subcutaneous injection) Days 1, 4, 8, 11. Dexamethasone 20 mg . Days