Module 1

Current Approaches to Relapsed/ Refractory Multiple Myeloma

Shaji Kumar, MD Professor of Medicine Consultant, Division of Hematology Department of Internal Medicine Mayo Clinic Cancer Center Rochester, MN

Relapsed MM: Scope of the Problem

• Median time to first relapse with current therapies: 3-4 years

Kumar. Leukemia. 2014;28:1122-1128.

>100,000 patients

living with MM

2006-2011

2006-2011

2

Pro

po

rtio

n S

urv

ivin

g

Follow-Up From Diagnosis (years)

3

Definition of RRMM

a If lowest M component ≥5 g/dL, increase must be ≥1 g/dL. b In patients without measurable serum/urine M-protein. c In patients without measurable serum/urine M-protein or involved FLC.

1. Kumar. Lancet Oncol. 2016;17:e328. 2. Nooka. Blood. 2015;125:3085. 3. Rajkumar. Blood. 2011;117:4691.

• IMWG criteria for PD1

• ≥25% increase from nadir in:

• Serum/Urine M-protein (absolute increase ≥0.5 g/dLa and ≥200 mg per 24 h, respectively) or

• Difference between involved and uninvolved FLC levelsb (absolute increase >100 mg/L) or

• BM plasma cellsc (absolute increase ≥10%) or

• New lesions (≥50% increase in SPD of >1 lesion or longest diameter of previous lesion >1 cm in short axis) or

• Circulating plasma cells (≥50% increase [minimum 200 cells/μL] if only measure of disease)

• Criteria for RRMM2,3

• Meets IMWG criteria for PD1

• RRMM: Progression on tx in patients who obtain at least minor response or progression within 60 d on most recent tx

• Primary refractory MM: Not achieving at least minor response on a given tx

• Relapsed MM: Meets IMWG criteria for PD but not RRMM or primary refractory MM

Confronting Disease Relapse in Myeloma

4

1. Kumar. Mayo Clin Proc. 2004;79:867.

Me

dia

n R

esp

on

se

Du

rati

on

(m

o)

Response Duration With

Increasing Treatment1

10

8

6

0

2

Treatment Regimen

4

First Second Third Fourth Fifth Sixth

12

Effect of Drug Class Refractoriness

5

1. Kumar. Leukemia. 2012;26:149. 2. Gandhi. Leukemia. 2019;33:2266.

Pa

tie

nts

(%

)

0 12 24 36 48 60

Months

Survival Outcomes in RRMM Refractory

to Bortezomib (2012)2 100

80

60

40

0

20

Events, n/N Median, mo (range)

OS 170/286 9 (7-11)

EFS 217/286 5 (4-6)

Pro

po

rtio

n S

urv

ivin

g

0 10 20 30 40 50

Months

1.0

0.8

0.6

0.4

0

0.2

P=0.002

■ Not triple-refractory (n=57)

■ Triple- and quad-refractory (n=148)

■ Penta-refractory (n=70)

6

When Should We Start Treatment for Relapse?

• Patients with clinical progression/CRAB clearly need treatment

• Those with biochemical progression only may not need immediate treatment

• Standard-risk disease with slow trend upward

Indications

for treatment

High-risk disease with

any progression

Presentation with renal or neurologic

complications

Rapid doubling

of M spike

7

General Principles

• Duration of initial response defines biology

• Triplet (2 active classes + DEX) preferred over doublet

• ≥1 drug from a nonrefractory class

• Treat to maximum response and maintain on 1 drug until progression or intolerability

How Do We Select Treatment?

8

Considerations when selecting

drug/doses

Previous drug exposure/

refractory status High risk vs

standard risk

Age, frailty, comorbidities

Toxicity with previous drugs

Transplant eligibility/

prior transplant

Patient preference/ goals of care

Logistics of drug administration

Recommended Regimens in RRMM

9

a Relapse occurring while off all tx, on small doses of single-agent LEN, or on BTZ maintenance. b For those intolerant of LEN, with aggressive relapse, or with high-risk disease. c Consider salvage ASCT in eligible patients if first PFS >2 y off maintenance or >4 y with maintenance, or for patients with pancytopenias and heavy BM involvement.

1. Dimopoulos. Haematologica. 2018;103:2088. 2. Stewart. ASH 2017. Abstr 743. 3. Moreau. NEJM. 2016;374:1621. 4. Lonial. ASCO 2018. Abstr 8040. 5. Lentzsch. ASCO 2017. Abstr 8036. 6. Chari. Blood. 2017;130:974. 7. Chari. ASCO 2018. Abstr 8002. 8. Bringhen. Leukemia. 2018;32:1803. 9. Richardson. ASCO 2018. Abstr 8001. 10. Dimopoulos. EHA 2018. Abstr LBA2606. 11. San Miguel. Lancet Oncol. 2013;14:1055. 12. Krishnan. Leukemia. 2018;32:1567-1574. 13. Rajkumar. Am J Hematol. 2014;89:999. 14. Baz. Blood. 2016;127:2561. 15. Vogl. J Clin Oncol. 2018;36:859. 16. Richardson. ASH 2018. Abstr 600.

Treatment at first relapse

Not refractory to LENa Refractory to LEN

Considerb

DRd1 or

KRd2

Frail: IRd,3

ERd4

DVd,5 DPd,6

DKd,7 KPd,8

VPd,9 EloPd10

Frail: Pd,11

IPd,12 VCd,13

PCd14

Treatment after multiple relapses

Any first relapse options not yet used

(2 new drugs; triplet preferred)

Investigational options: BCMA-targeting therapy on clinical

trial; melphalan flufenamide, venetoclax

Additional approved options: selinexor,15 VTd-PACE,

panobinostat-based tx, bendamustine-based tx16

Agents in Relapsed MM

Outcomes POLLUX

DRd vs Rd1

ASPIRE

KRd vs Rd2

ELOQUENT-2

ERd vs Rd3,4

TOURMALINE-MM1

IRd vs Rd5

PFS HR

(95% CI) 0.37

(0.27-0.52) 0.69

(0.57-0.83) 0.73

(0.60-0.89) 0.74

(0.59-0.94)

ORR, % 93 87 79 78

≥VGPR, % 76 70 34 48

≥CR, % 43 32 5 14

DoR, mo NE 28.6 20.7 20.5

OS HR

(95% CI) 0.64

(0.40-1.01) 0.79

(0.63-0.99) 0.77

(0.61-0.97) NE

10

1. Dimopoulo. EHA 2016. Abstr LB238. 2. Stewart. NEJM. 2015;372:142. 3. Lonial. NEJM. 2015;373:621. 4. Dimopoulos. ASH 2015. Abstr 28. 5. Moreau. NEJM. 2016;374:1621.

Lenalidomide-Based Studies

Agents in Relapsed MM

Outcomes CASTOR

DVd vs Vd1

ENDEAVOR

Kd vs Vd2

Panobinostat

PVd vs Vd3,4

OPTIMISSM

POM+BTZ+DEX5

PFS HR

(95% CI)

0.39

(0.28-0.53)

0.53

(0.44-0.65)

0.63

(0.52-0.76)

0.61

(0.49-0.77)

ORR, % 83 77 61 82

Median PFS, mo NR 18.7 12.0 11.2

≥VGPR, % 59 54 28 53

≥CR, % 19 13 11 16

DoR, mo NE 21.3 13.1 13.7

OS HR

(95% CI)

0.77

(0.47-1.26)

0.79

(0.58-1.08)

0.94

(0.78-1.14)

0.98

(0.73-1.32)

11

1. Palumbo. N Engl J Med. 2016;375:754. 2. Dimopoulos. Lancet Oncol. 2016;17:27. 3. San-Miguel. Lancet Oncol. 2014;15:1195. 4. San-Miguel. ASH 2015. Abstr 3026. 5. Richardson. Lancet Oncol. 2019;20:781-794.

PI-Based Studies

POM-Based Salvage Therapy for RRMM

Trial Patient Population Primary

End Point(s) ORR, % ≥VGPR, %

Median PFS,

mo Median OS,

mo

POM/DEX (N=302)1

Phase 3 trial vs high-dose DEX RR; ≥2 lines of tx including LEN and BTZ PFS 31 vs 10 6 vs <1 4 vs 1.9 12.7 vs 8.1

BTZ + POM/DEX (N=559)2

Phase 3 trial vs Vd 1-3 lines of tx with LEN exposure;

prior PI ok PFS 82 vs 50 53 vs 18 11 vs 7 NR

CFZ + POM/DEX (N=57)3 RR to most recent tx; 1-3 lines of tx;

LEN-refractory MTD,

PR rate 62 23 10.3 NR

(1 y: 67%)

dara + POM/DEX (N=103)4 RR; ≥2 lines of tx including LEN and BTZ MTD 60 42 8.8 17.5

Ixazomib + POM/DEX (N=32)5 1-5 lines of rx including LEN and PI;

LEN-refractory MTD

activity 48;

High-risk, 58 20 – –

Elotuzumab + POM/DEX (N=60)6

Phase 2 trial vs POM/DEX ≥2 lines of tx including IMiD and PI;

refractory to last tx PFS 53 vs 26 20 10.3 vs 4.8 –

Isatuximab+POM/DEX (N=307)7

Phase 3 ICARIA-MM vs Pd ≥2 lines of tx including LEN and PI;

not refractory to anti-CD38 PFS 60.4 vs 35.3 31.8 vs 8.5 11.5 vs 6.5 –

12

1. San Miguel. Lancet Oncol. 2013;14:1055. 2. Richardson. ASCO 2018. Abstr 8001. 3. Bringhen. Leukemia. 2018;32:1803. 4. Chari. Blood. 2017;130:974. 5. Krishnan. Leukemia. 2018;32:1567. 6. Dimopoulos. EHA 2018. Abstr LBA2606. 7. Attal. Lancet. 2019;394:2096.

Administration Considerations for PIs

Bortezomib Carfilzomib Ixazomib

Route SC IV po

Dosing schedule 1.3 mg/m2 q1wk OR on days 1, 4,

8, 11 of 28-d cycle

20/27 mg/m2 on days 1, 2, 8, 9, 15, 16 or

20/70 mg/m2 q1wk for 3 wk of 28-d cyclea

4 mg on days 1, 8, 15

of 28-d cycle

Select AEs

to watch

• PN

• Hypotension

• Cardiac toxicity

• Pulmonary toxicity

• GI toxicity

• Thrombocytopenia

• Neutropenia

• Cardiac failure

• Renal insufficiency

• Pulmonary toxicity, dyspnea

• Hypertension

• Venous thrombosis

• Thrombocytopenia

• Hepatic toxicity

• Thrombocytopenia

• GI toxicity

• PN

• Rash

• Hepatotoxicity

Rate of PN

with PI + Rd, %

• Any grade, 35

• Grade ≥3, 12

• Any grade, 11

• Grade ≥3, 2

• Any grade, 28

• Grade ≥3, 2

Management

considerations

Safe in renal failure Hydration, cardiopulmonary Reduce dose for hepatic/

renal disease

13

a CFZ dosing depends on tx regimen.

Patients should receive VZV prophylaxis when receiving PIs

Administration Considerations for IMiDs

14

a Generally seen only in the context of maintenance tx after transplantation or with po melphalan.

VTE prophylaxis for individual (age, obesity) or MM-related risk factors (immobilization, hyperviscosity) allowed

Lenalidomide Pomalidomide Thalidomide

Route po po po

Dosing schedule 25 mg/d 3 wk on, 1 wk off (induction);

10 mg/d (maintenance) 4 mg/d 3 wk on, 1 wk off 200 mg once daily

Select AEs

to watch

• VTE

• Neutropenia

• Thrombocytopenia

• Fatigue

• Hepatotoxicity

• Skin rash

• GI disturbance

• Impaired stem cell mobilization

• SPMa

• VTE

• Neutropenia

• Fatigue

• Hepatotoxicity

• Skin rash

• VTE

• Constipation

• PN

• Dizziness/Orthostatic

hypotension

• Bradycardia

• Skin rash

• Somnolence

Management

considerations

ASA (81-325 mg/d) or LMWH (enoxaparin 40 mg/d equivalent) or full-dose warfarin (target INR, 2-3)

if high risk for clots; weekly CBC×8 wk

POLLUX: PFS With dara-Rd vs Rd in RRMM

Dimopoulos. NEJM. 2016;375:1319. Bahlis. Leukemia. 2020;34:1875.

Outcome Rd

(n=276)

Dara-Rd

(n=281)

ORR, % 76.4 92.9

Best overall response, %

sCR 10.5 29.2

CR 12.7 27.4

VGPR 26.1 23.8

PR 27.2 12.5

MRD negative (10–5) 5.3 30.4

Median DoR, mo 25.2 NR

HR, 0.44; 95% CI, 0.35-0.55; P<0.0001

PF

S (

%)

dara-Rd:

median,

44.5 mo

Rd:

median,

17.5 mo

20

40

60

80

100

At risk, n

0

0 3 6 9

Months

Rd

dara-Rd 283

286

249

266

206

249

144

215

12 15

181

238

160

229

18 21 24 27 30 33 36 39 42 45 48 51

127

204

112

195

102

184

91

168

83

156

75

151

66

143

63

135

53

123

20

54

4

11

0

0

15

EQUULEUS: dara/POM/DEX in RRMM

• Single-arm phase 1b study (N=103; median of 4 prior lines [range: 1-13]; 71% refractory to PIs and IMiDs; 25% with high-risk cytogenetics

Chari. Blood. 2017;130:974.

• Of 17 patients in ≥CR, 35%, 29%, and 6% were MRD-negative at thresholds of 10–4, 10–5, and 10–6, respectively

• Median OS, 17.5 mo (95% CI, 13.3-NE)

• Median PFS with high-risk cytogenetics (n=22), 3.9 mo (95% CI, 2.3-NE)

70

OR

R (

%)

20

40

50

60

0 dara + POM/DEX (N=103)

PR VGPR CR sCR

10

30

8%

9%

25%

18%

ORR, 60%

17% CR or better

42% VGPR or better

PFS

PFS

(%

)

Median, 8.8 mo (95% CI, 4.6-15.4) 20

40

60

80

100

At risk, n

0 0 3

Months 6 9 12 15 18

103 71 53 42 28 12 1

21

0

16

CASTOR: PFS in Total Study Population

Palumbo. N Engl J Med. 2016;375:754.

PF

S (

%)

0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15

Months

1-y PFS

60.7%

26.9%

DVd

Vd

Median (mo)

NR

7.2

HR, 0.39; 95% CI, 0.28-0.53; P<0.0001

17

CASTOR: Other Efficacy Outcomes

Efficacy Outcome DVd

(n=251)

Vd

(n=247)

HR

(95% CI) P-value

Median PFS after 1 prior tx, mo

1-y PFS, %

NR

77.5

7.5

29.4

0.31

(0.18-0.52) <0.0001

Median TTP, mo

1-y PFS, %

NR

65.4

7.3

28.8

0.30

(0.21-0.43) <0.0001

ORR, %

≥VGPR

≥CR

83

59

19

63

29

9

--

<0.0001

<0.0001

0.0012

MRD negative, % 14 3 -- --

Palumbo. ASCO 2016. Abstr LBA4.

18

CANDOR: Study Design

• Multicenter, randomized phase 3 study (N=466)

• Primary end point: PFS

• Key secondary end points

• ORR

• MRD

• OS

19

a 56 mg/m2 administered twice weekly; 20 mg/m2 administered on days 1 and 2 of cycle 1; 28-d cycles. b First dose split over 2 d (8 mg/kg each).

Usmani. ASH 2019. Abstr LBA6.

CFZa 56 mg/m2 + DEX 40 mg

+ Darab 16 mg/kg2

(n=312)

CFZa 56 mg/m2 + DEX 40 mg

(n=154)

tx until

disease

progression

MRD

sample

Month 12:

MRD sample

Month

32

Month 24:

MRD sample

2:1

Patients with RRMM

and:

1-3 lines of prior tx

≥PR to ≥1 prior tx

ECOG PS 0-2

CrCl ≥20 mL/min

LVEF ≥40%

20

CANDOR: Response Rates

a P=0.0040. b P<0.0001.

Usmani. ASH 2019. Abstr LBA6.

Response, % KdD

(n=312) Kd

(n=154)

ORR 84.3a 74.7a

≥VGPR 69.2 48.7

≥CR 28.5 10.4

MRD negative at 12 mo

(10–5 threshold) 17.6 3.9

MRD negative CR at 12 mo

(10–5 threshold) 12.5b 1.3b

Best MRD negative CR

(10–5 threshold) 13.8 3.2

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

+ + + + + + + + +

+ +

+ + + + + + +

+ + + + +

+ + + Median PFS: NE vs 15.8 mo

Pro

po

rtio

n S

urv

ivin

g

Wit

ho

ut

Pro

gre

ssio

n

0 3 6 12 15 18

Months After Randomization

1.0

0.8

0.6

0.4

0.0

0.2

9 21 24

302

154

KdD

Kd

At risk, n

279

122

236

100

211

85

189

70

165

55

57

13

14

2

0

0

KdD

Kd

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

+

+ +

CANDOR: PFS

• Prolonged PFS with KdD vs Kd

• Median, NR vs 15.8 mo

• HR, 0.63

• 95% CI, 0.46-0.85

• P=0.0014

21

Usmani. ASH 2019. Abstr LBA6.

Subgroup HR KdD vs Kd

(95% CI)

ISS stage • 1 or 2

• 3 0.61 (0.43-0.85)

0.71 (0.37-1.36)

Baseline

age, y • ≤64

• 65-74

• ≥75

0.57 (0.38-0.86)

0.72 (0.43-1.20)

0.97 (0.39-2.43)

Region • North America

• Europe

• Asia Pacific

0.04 (0.01-0.34)

0.86 (0.60-1.23)

0.49 (0.25-0.93)

Baseline

ECOG PS • 0 or 1

• 2

0.69 (0.51-0.94)

0.31 (0.08-1.19)

Baseline

CrCl,

mL/min

• ≥15 to <50

• ≥50 to <80

• ≥80

0.46 (0.21-1.02)

0.78 (0.45-1.33)

0.67 (0.44-1.02)

Subgroup HR KdD vs Kd

(95% CI)

Cytogenic

risk group • High

• Standard

• Unknown

0.58 (0.30-1.12)

0.55 (0.31-0.97)

0.72 (0.47-1.11)

Number of

prior tx • 1

• ≥2

0.70 (0.42-1.17)

0.63 (0.44-0.92)

Prior LEN

exposure • No

• Yes

0.87 (0.56-1.35)

0.52 (0.34-0.80)

Refractory

to LEN • No

• Yes

0.85 (0.57-1.27)

0.45 (0.28-0.74)

Prior PI

exposure • No

• Yes

0.93 (0.29-3.02)

0.64 (0.47-0.88)

Refractory

to BTZ • No

• Yes

0.59 (0.40-0.85)

0.83 (0.49-1.41)

ELOQUENT-2: Study Design

• Randomized, open-label, multicenter phase 3 trial

• Primary end points: PFS, ORR

• Secondary endpoints: OS, safety, DoR, health-related QoL

• Threshold for interim OS significance, 0.014

Dimopoulos MA, et al. ASH 2015. Abstract 28.

Elotuzumab 10 mg/kg IV q1wk

cycles 1, 2 then q2wk + LEN 25 mg

po days 1-21 + DEX 40 mg po q1wk

(n=321) Patients

with

RRMM

and 1-3

prior tx

(N=646)

LEN 25 mg po days 1-21

+ DEX 40 mg po q1wk

(n=325)

28-d cycles

tx until

PD or

unacceptable

toxicity

22

ELOQUENT-2: Efficacy

Outcome Elotuzumab + LEN/DEX

(n=321)

LEN/DEX

(n=325)

HR (95% CI)

PFS

Median, mo 19.4 14.9

0.73 (0.60-0.89)

P=0.0014 1 y, % 68 57

2 y, % 41 27

3 y, % 26 18

Median time to next tx, mo 33 21 0.62 (0.50-0.77)

ORR, % 79 66

Interim OS, mo 43.7 39.6 0.77 (0.61-0.97)

P=0.0257

Dimopoulos. ASH 2015. Abstr 28.

• PFS benefit seen with elotuzumab in all predefined subgroups

23

Phase 2 ELOQUENT-3: Elotuzumab/POM/DEX vs POM/DEX (N=117)

Dimopoulos. NEJM. 2018;379:1811.

Pa

tie

nts

Su

rviv

ing W

ith

ou

t

Pro

gre

ssio

n (

%)

18 11 9 5 4 2 3 1

PFS 100

80

60

40

20

0

Months Since Randomization

22 0 6 10 12 14 15

HR, 0.54; 95% CI, 0.34-0.86; P=0.008

16 17 19

Elotuzumab

Controls

7 8 20 21 13

Su

rviv

ing P

ati

en

ts (

%)

18 11 9 5 4 2 3 1

OS 100

80

60

40

20

0

Months Since Randomization

22 0 6 10 12 14 15

HR, 0.62; 95% CI, 0.30-1.28

16 17 19

Elotuzumab

Controls

7 8 20 21 13

24

Administration Considerations for mAbs

Daratumumab Daratumumab Elotuzumab Isatuximab

Route IV SC IV IV

Dosing schedule 16 mg/kg q1wk in cycles 1 and 2;

q2wk in cycles 3 and 6; q4wk in

cycles 7+

1800 mg dara + 30,000 units

hyaluronidase into abdomen

10 mg/kg q1wk in cycles 1 and 2;

q2wk in cycle 3+

10 mg/kg q1wk×4; q2wk+POM/

DEX until PD or toxicity

Prophylaxis Before/after, medicate with

corticosteroids, antipyretics, and

antihistamines ± inhaled steroids

(COPD)

Corticosteroid, acetaminophen,

histamine-1 receptor antagonist

Before/after, medicate with

corticosteroids, diphenhydramine,

ranitidine, acetaminophen

Dexamethasone, acetaminophen,

histamine-2 antagonist,

diphenhydramine

Select AEs

to watch

• Infusion reactions

• Interference with cross-

matching, red blood cell

antibody screening,

determination of CR

• Infections

• Upper respiratory tract infection

• Constipation

• Nausea

• Fatigue

• Pyrexia

• Cytopenia

• Infusion reactions

• Infection

• SPM

• Hepatotoxicity

• Interference with determination

of CR

• Infusion reactions

• Neutropenia

• SPM

• Pneumonia

• Upper respiratory tract

infections

• Diarrhea

Management

considerations

For infusion reaction risk: medicate as directed before and after; interrupt infusion if reaction occurs --

25

• HDAC inhibitor, po administration

• HDAC overexpression promotes a closed chromatin structure, which may reduce expression of tumor-suppressor genes, increasing myeloma cell growth and proliferation

• PAN may promote an open chromatin structure, increasing gene expression of tumor-suppressor genes that induce cell cycle arrest and/or apoptosis

26

Panobinostat

FDA-Approved in 2015

panobinostat

Panobinostat

Phase 3 PANORAMA 1: BTZ/DEX ± PAN

• Randomized, double-blind trial (N=768)

a Reduced frequency.

San-Miguel. Lancet Oncol. 2014;15:1195.

PAN 20 mg TIW

+ BTZ 1.3 mg/m2 IV days 1, 4, 8, 11

+ DEX 20 mg days 1, 2, 4, 5, 8, 9, 11, 12

(n=387)

Placebo TIW

+ BTZ 1.3 mg/m2 IV days 1, 4, 8, 11

+ DEX 20 mg days 1, 2, 4, 5, 8, 9, 11, 12

(n=381)

Stratified by prior lines of

tx and prior BTZ

PAN 20 mg TIW

+ BTZa 1.3 mg/m2 IV

+ DEXa 20 mg

Placebo TIW

BTZa 1.3 mg/m2 IV

+ DEXa 20 mg

Treatment phase I

8×21-d cycles (24 wk)

Treatment phase II

4×42-d cycles (24 wk)

Patients with ≥SD in phase I can proceed to phase II

Patients with

symptomatic RRMM

after 1-3 prior tx

(BTZ-refractory excluded)

27

• Primary end point reached: median PFS ↑ by 3.9 mo • Interim OS analysis; final analysis forthcoming

PANORAMA 1: BTZ/DEX ± PAN

Overall Population

San-Miguel. Lancet Oncol. 2014;15:1195.

100

80

60

40

20

0

0 4 8 12 16 20 24 28 32 36

Pro

ba

bilit

y o

f P

FS

(%

)

PFS

100

80

60

40

20

0

Pro

ba

bilit

y o

f O

S (

%)

0 4 8 12 16 20 24 28 32 36 40

OS

Month Month

PAN/BTZ/DEX

Placebo/BTZ/DEX

PAN/BTZ/DEX

Placebo/BTZ/DEX

28

BTZ/DEX ± PAN

• Subgroup analysis of patients who received ≥2 previous tx, including BTZ and an IMiD

• FDA-approved indication based on subgroup analysis

San-Miguel. ASCO 2015. Abstr 8526.

Patients With Prior BTZ and IMiD Exposure

100

PF

S P

rob

ab

ilit

y (%

)

Time (mo)

80

60

40

20

0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

PAN/BTZ/DEX

Placebo/BTZ/DEX

Events, n/N

Median PFS,

mo (95% CI)

HR

(95% CI)

44/73 12.5 (7.3-14.0) 0.47

(0.31-0.72) 54/74 4.7 (3.7-6.1)

29

Conclusion

• Timing of therapy initiation of for relapsed disease should be based on disease characteristics, patient symptoms, end-organ effects, and tempo of progression

• Risk stratification should be done at relapse

• Triplets should be employed when possible, ensuring at least 1 new class of drug and a new drug from the same class

• Patients should be continued on treatment until maximum response and then maintained on one of the drugs

• Regimens should be selected to limit any worsening of preexisting toxicities

30