Focus on the Role of Proteasome

Inhibitors in the Management of

Multiple Myeloma
Sagar Lonial, MD
Editor-In-Chief for Multiple Myeloma @Point of Care
Professor, Vice Chair of Clinical Affairs
Department of Hematology and Medical Oncology
Winship Cancer Institute, Emory University
Atlanta, Georgia

Kenneth C. Anderson, MD
Kraft Family Professor of Medicine, Harvard Medical School
Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for
Myeloma Therapeutics, Dana-Farber Cancer Institute
Boston, Massachusetts

Historical Perspective of
Multiple Myeloma Therapies1
Proteasome
Proteasome
4-6
inhibitors
inhibitors4-6
Other
Other immunoimmunomodulatory
modulatory
7-9
agents
agents7-9

High-dose
High-dose therapy
therapy
with
with autologous
autologous
3
stem
cell
stem cell support
support3

ABMT2
ABMT2

22

5
VAD
VAD5
11
Bisphosphonates
Bisphosphonates11

High-dose melphalan2
High-dose
High-dose
12
dexamethasone
dexamethasone12

Thalidomide13

14
Oral
Oral melphalan
melphalan14
15
and
and prednisone
prednisone15

1962

1983 1984

1986

1987 1996 1999 2000+

1. Kyle RA, Rajkumar SV. Blood. 2008;111:2962-2972. 2. McElwain TJ, Powles RL, Lancet. 1983;2:822-824. 3. Barlogie B, et al. Blood. 987;70:869-872.
4. Richardson PG, et al. N Engl J Med. 2003;348:2609-2617. 5. Richardson PG, et al. N Engl J Med. 2005;352:2487-2498. 6. Siegel DS, et al. Blood.
2012;120:2817-2825. 7. Dimopoulos M, et al. N Engl J Med. 2007;357: 2123-2132. 8. Weber DM, et al. N Engl J Med. 2007;357:2133-2142.
9. Richardson PG, et al. Blood. 2014;123: 1826-1832. 10. Barlogie B, et al. N Engl J Med. 1984;310:1353-1356. 11. Berenson JR, et al. N Engl J Med.
1996;334:488-493. 12. Alexanian R, et al. Ann Intern Med. 1986;105:8-11. 13. Singhal S, et al. N Engl J Med. 1999;341:1565-157 14. Bergsagel DE,
et al. Cancer Chemother Rep. 1962;21:87-99. 15. Mass RE. Cancer Chemother Rep. 1962;16:257-259. Slide courtesy of Dr. Anderson.

Targeting Growth, Survival, and Drug Resistance

of MM in Bone Marrow
MM
Microenvironment
migration
CD40

Cell surface
targets

FGFR3

CS1

BAFF-R
VEGFR

Cytokines
IL-6, VEGF
IGF-1, SDF-1
BAFF, APRIL
BSF-3

TNF
TGF
VEGF

GSK-3
FKHR
PKC
Survival
Caspase-9 Anti-apoptosis
Akt
NF-B
Cell cycle
mTOR
PI3-K
Bad
Survival
Bcl-xL
JAK/STAT3
Anti-apoptosis
Mcl-1
proliferation
Raf
MEK/ERK
Survival
Bcl-xL
Anti-apoptosis
NF-B
IAP
Cell cycle
Cyclin-D
MEK/ERK
p27Kip1

Smad, ERK

cytokines

BMSC

NF-B

Proliferation
Anti-apoptosis

Adhesion

NF-B

NF-B

SC

adhesion
molecules

ICAM-1
VCAM-1
Fibronectin

LFA-1
MUC-1
VLA-4

Anderson KC. J Clin Oncol. 2012;30:445-452. Reprinted with permission. 2012 American Society of Clinical Oncology. All rights reserved.

ProteasomePresent and Future Therapies

Bortezomib: 1st proteasome inhibitor
2nd generation proteasome inhibitors moving from bench
to bedside
Carfilzomib
Ixazomib
Marizomib
Can block ubiquitin proteasome cascade upstream of the
proteasome
Deubiquitylating enzyme inhibitors

Anderson KC. J Clin Oncol. 2012;30:445-452.

Review of Proteasome Inhibitors

(PIs)
Currently Approved PIs and
PIs in Phase III Development

Review of Proteasome Inhibitors (PIs)

Currently approved PIs

Bortezomib
Carfilzomib
PIs in development
Ixazomib citrate phase III
Marizomib phase II/III

BortezomibThe First Approved

Proteasome Inhibitor
A covalent, reversible inhibitor of
proteasome chymotryptic activity1,2
Induces apoptosis in solid tumors and hematologic
cancers, including multiple myeloma3
Alters the bone marrow microenvironment to reduce
tumor cell growth3
Efficacy in both previously untreated and relapsed
multiple myeloma1
1. Bortezomib Prescribing Information. 2. Adams J, et al. Cancer Res. 1999;59:2615-2622. 3. Adams J. Cancer Cell. 2004;5:417421.

Mechanisms Mediating Anti-MM Activity

ofAntiangiogenic
Bortezomib
&
ER-Stress Induction

Antiosteoclastic Activity

Caspase-12 cleavage;
phospo-PERK;
GADD-153, ATF4, GRP
78, & XBP-1 splicing

Migration, VEGF,
Proangiogenic MMP-9, &
Caveolin-1;
Osteoclastogenesis via
MIP1, BAFF
Osteoblast formation

Bortezomib

Microenvironment
MM-BMSCs interaction;
ICAM, VCAM, V3
IGF-1, IL-6,
BAFF,RANKL

Slide courtesy of Dr. Anderson.

JNK; Caspases & PARP cleavage;

ROS; m
Cyto-c & Smac release; IAPs;
Mitochondrial Ca+2 influx;
Bid cleavage, Fas & FasL, BH-3
only proteins: Bim, Bik, & NOXA

Heat Shock Proteins

& DNA Repair

Growth & Survival

NF-B, MAPK,JAK/STAT
IGF-1/IL-6 PI3K-Akt

Apoptosis

Heat shock proteins-27, -70, 90;

DNA-PK

Cell-Cycle
Proteasome
Chymotrypsin- and caspaselike
proteasome activities;
Mono-ubiquitination;
26S Proteasome subunits

Cdk inhibitors:
P21 & p27, p53
Cyclins: D1, E1, A, B.

CarfilzomibA Novel Proteasome

(Chymotryptic) Inhibitor
Novel chemical class with highly selective
and irreversible proteasome binding1
Improved antitumor activity with
consecutive day dosing1
O
No neurotoxicity in animals2

Tetrapeptide

H
N

N
O

O
N
H

H
N
O

O
N
H

Epoxyketone
23.7% responses lasting 7.8 months with
survival 15.6 months in relapsed and relapsed/refractory MM3
Mechanisms of action1
Induction of apoptosis
Cell cycle arrest
Activation of stress response pathways (hsp27, hsp70)

1. Demo SD, et al. Cancer Res. 2007; 67:6383-6391. 2. Kirk CJ, et al, Blood. 2008;112:abstract 2765. 3. Siegel DS, et al. Blood
2012:120:2817-2825.

IxazomibOral Chymotryptic Inhibitor

In in vivo studies, ixazomib1
Decreased MM cell viability
Overcame resistance to bortezomib
Blocked MM cell growth more potently than
bortezomib
Currently in phase I/II studies for relapsed/refractory
and newly diagnosed multiple myeloma2

1. Chauhan D, et al. Clin Cancer Res. 2011;17:5311-5321.

2. ClinicalTrials.gov. Accessed 5/29/14.

Marizomib (NPI-0052)
Isolated from Salinispora tropica, a marine bacterium1,2
Inhibits chymotrypsin-like, trypsin-like, and caspase-like
proteasome activity in MM cells3
Lack of cross-resistance with other proteasome inhibitors1,2
Cytotoxic mechanisms include caspse-8-dependent apoptosis
and oxidative stress1-3
Currently in phase I/II studies for relapsed/refractory multiple
myeloma4

1.
2.
3.
4.

Moreau P, et al. Blood. 2012;120:947-959.

Allegra A, et al. Leuk Res. 2014;38:1-9.
Chauhan D, et al. Cancer Cell. 2005;8:407-419.
ClinicalTrials.gov. Accessed 5/5/14.

Response Criteria and Clinical Trial

Results for PI Therapy in MM
Route of Administration,
Efficacy, Safety

PI Therapy in MM
Route of Administration

Currently approved Pis

Bortezomib SC, IV
Carfilzomib IV
PIs in phase III development
Ixazomib citrate oral
Marizomib IV

BortezomibKey Clinical Trials in

Relapsed/Refractory MM Patients

Patient population
N
Treatment arms

Primary endpoint

SUMMIT1
(Phase II)

CREST2
(Phase II)

APEX3
(Phase III)

Pegylated
Liposomal
Doxorubicin +
Bortezomib
(Phase III)

Relapsed/refractory

Relapsed/refractory
(1 prior therapy)

Relapsed/refractory
(1-3 prior therapies)

Relapsed/refractory
(1 prior therapy)

193

54

669

646

BTZ 1.3 mg/m2

BTZ 1.3 mg/m2

BTZ 1.3 mg/m2

PLD 30 mg/m2 + BTZ

1.3 mg/m2

BTZ 1.0 mg/m2

High-dose DEX
40 mg

BTZ 1.3 mg/m2

ORR: 50%
(1.3 mg/m2)

TTP: 6.22 mo
(BTZ)

TTP: 9.3 mo
(PLD + BTZ)

ORR: 33%
(1.0 mg/m2)

TTP: 3.49 mo
(High-dose DEX)

TTP: 6.5 mo
(BTZ)

ORR: 35%

Abbreviations: BTZ, bortezomib; DEX, dexamethasone; ORR, overall response rate; PLD, pegylated liposomal doxorubicin;
TTP, time to progression.
1. Richardson PG, et al. N Engl J Med. 2003;348:2609-2617. 2. Jagannath S, et al. Br J Haematol. 2004;127: 165-172.
3. Richardson PG, et al. N Engl J Med. 2005;352:2487-2498. 4. Orlowski RZ, et al. J Clin Oncol. 2007; 25:3892-3901.

BortezomibKey Clinical Trials in

Previously Untreated MM Patients

N
Treatment
arms

HOVON-65/
GMMG-HD44
(Phase III)

VISTA
(Phase III)

IFM 2005-01
(Phase III)

Previously untreated

Previously untreated

Previously untreated

Previously untreated

682

482

480

827

BTZ 1.3 mg/m2 + MP

VD (BTZ 1.3 mg/m2 +

DEX 40 mg)

VTD
(BTZ 1.3 mg/m2 +
THAL + DEX 40 mg)

PAD
(BTZ 1.3 mg/m2 + DOX
+ DEX 40 mg)

TD

VAD
PFS: 35 mo (PAD)

Patient
population

GIMEMA Italian
Myeloma
Network3
(Phase III)

MP alone
VAD
Primary
endpoint

TTP: 24.0 mo (BTZ +

MP)

Postinduction CR/nCR:
14.8% (VD)

Postinduction CR/nCR:
31% (VTD)

TTP: 16.6 mo (MP

alone)

Postinduction CR/nCR:
6.4% (VAD)

Postinduction CR/nCR:
11% (TD)

PFS: 28 mo (VAD)

Abbreviations: BTZ, bortezomib; CR, complete response; DEX, dexamethasone; DOX, doxorubicin; MP,
melphalan/prednisone; nCR, near complete response; PFS, progression-free survival; TD, thalidomide/dexamethasone;
THAL, thalidomide; TTP, time to progression; VAD, vincristine/doxorubicin/dexamethasone.
1. San Miguel JF, et al. N Engl J Med. 2008;359:906-917. 2. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629.
3. Cavo M, et al. Lancet. 2010;376:2075-2085. 4. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.

CarfilzomibKey Clinical Trials in

Relapsed/Refractory MM Patients with
Prior Bortezomib
PX-171-0043
Cohort 1
(Phase II)

PX-171-003-A01
(Phase II)

PX-171-003-A12
(Phase II)

Relapsed/refractory
(2 prior therapies
including BTZ + IMiD)

Relapsed/refractory
(99.6% prior BTZ)

46
(42 evaluable for
efficacy)

266
(257 evaluable for
efficacy)

35

Treatment arms

CFZ 20 mg/m2

CFZ 20/27 mg/m2

CFZ 20 mg/m2

Primary endpoint

ORR: 16.7%

ORR: 23.7%

ORR: 17.1%

Patient population

Relapsed/refractory
(1-3 prior therapies,
including BTZ)

Abbreviations: BTZ, bortezomib; CFZ, carfilzomib; IMiD, immunomodulatory drug; ORR, overall response rate.
1. Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2012;12:310-318. 2. Siegel DS, et al. Blood. 2012;120: 2817-2825.
3. Vij R, et al. Br J Haematol. 2012;158:739-748.

CarfilzomibKey Clinical Trials in

Bortezomib-Naive Relapsed/Refractory
MM Patients
PX-171-0041
Cohort 1
(Phase II)

PX-171-0041
Cohort 2
(Phase II)

Relapsed/refractory
(BTZ naive)

Relapsed/refractory
(BTZ naive)

59

70
(67 evaluable for efficacy)

Treatment arms

CFZ 20 mg/m2

CFZ 20/27 mg/m2

Primary endpoint

ORR: 42.4%

ORR: 52.2%

Patient population

Abbreviations: BTZ, bortezomib; CFZ, carfilzomib; ORR, overall response rate.

1. Vij R, et al. Blood. 2012;119:5661-5670.

IxazomibKey Clinical Trials

Single-Agent Ixazomib1
(Phase I)

Ixazomib Lenalidomide
Dexamethasone2
(Phase I/II)

Relapsed/refractory

Newly diagnosed

60
(50 evaluable for efficacy)

64
(56 treated at RP2D)

Cohorts

Dose escalation cohort:

Ixazomib 0.24-3.95 mg/m2

Phase I: Ixazomib 3.0 or 3.7 mg

+ Len 25 mg + Dex 20/10 mg

Dose expansion cohort:

Ixazomib 2.97 mg/m2

Phase II: Ixazomib RP2D (3.0 mg)

+ Len 25 mg + Dex 20/10 mg

Patient population

Followed by ixazomib maintenance

Results

ORR: 18%

ORR: 95%*
61%* had 100% decreases in Mprotein or serum FLC from baseline

*Patients treated at RP2D.

Abbreviations: Dex, dexamethasone; FLC, free light chain; Len, lenalidomide; ORR, overall response rate; RP2D,
recommended phase II dose.
1. Kumar SK, et al. Blood. 2014 [Epub ahead of print] 2. Richardson PG, et al. Blood. 2013;122:abstract 535.
2. Richardson PG, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.

Ixazomib/Lenaldiomide/Dexamethasone in Newly
Diagnosed Multiple Melanoma1,2
In a phase I/II study of ixazomib, lenalidomide, and dexamethasone in
newly diagnosed MM patients
Response was evaluated in 56 patients receiving ixazomib at the
recommended phase II dose (3.0 mg)
Phase I cohort: n = 7
Phase II cohort: n = 49
There was a complete resolution of M-protein in many patients
(61% had 100% decreases in M-protein)

1. Richardson PG, et al. Blood. 2013;122:abstract 535.

2. Richardson PG, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.

Marizomib Clinical Data

2 phase I trials (N = 34) of marizomib twice weekly (days 1, 4, 8,
and 11 of 21-day cycles) low-dose dexamethasone
Relapsed/refractory MM (88% prior bortezomib)
Maximum tolerated dose
0.4 mg/m2 over a 60-minute infusion
0.5 mg/m2 over a 120-minute infusion
Most common adverse effects: fatigue, nausea, vomiting, dizziness,
headache, diarrhea, constipation, insomnia, anorexia, dyspnea
No peripheral neuropathy, myelosuppression, or
thrombocytopenia
Overall response rate: 20%

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

Approaches to Therapy
Timing/Sequencing of
Treatment

Approaches to Therapy
Timing/Sequencing of Treatment

Induction therapy
Maintenance therapy
Treating relapsed/refractory MM
PIs in combination therapy to improve
outcomes
Managing adverse effects

The Good News

Outcomes for patients are clearly improved

The use of high-dose therapy or melphalan-based novel agent
inductions have doubled median survival for nearly all patients
With permission from Kumar SK, et al. Blood. 2008;111:2516-2520.

Integration of Novel Therapy

Into Myeloma Management
Bortezomib, lenalidomide, thalidomide, liposomal doxorubicin,
carfilzomib, pomalidomide
Target MM in the BM microenvironment to overcome conventional
drug resistance in vitro and in vivo
Effective in relapsed/refractory, relapsed MM and now part of
induction, consolidation, and maintenance therapy
9 FDA approvals in the last decade and median survival prolonged
from 2-3 years to at least 5-7 years, with additional prolongation seen
from maintenance
New approaches needed to treat and ultimately prevent relapse

Chromosomes and Prognosis

in Multiple Myeloma
For conventional low- and high-dose therapy
Nonhyperdiploid worse prognosis than hyperdiploid1,2
t(11;14), hyperdiplody - standard risk2
t(4;14), t(14;16), t(14;20), del(17p), del(13q14) -high risk1-4
For novel treatments
Bortezomib, but not lenalidomide, can at least partially overcome
t(4;14), del(13q14)5,6
del(17p), p53 remains high risk5

1. Avet-Loiseau H, et al. Leukemia. 2013;27:711-717. 2. Mikhael JR, et al. Mayo Clin Proc. 2013;88:360-376. 3. Palumbo A,
et al. J Clin Oncol. 2014;32:587-600. 4. Munshi NC, et al. Blood. 2011;117:4696-4700. 5. Avet-Loiseau H, et al. J Clin Oncol.
2010; 28:4630-4634. 6. Jagannath S, et al. Leukemia. 2007;21:151-157.

Induction Therapy

Impact of Novel Agents in the Treatment of

Elderly Pts with Newly Diagnosed MM
Substantial improvements in PFS and OS
Median PFS (mo)

Median OS (mo)

MP1-10

1120

29.149.4

MPT1-6

1527.5

2751.6

VMP7,8,11

21.727.4

68.5% (3-y OS)*

MPR-R9

31

N/A

VMP-VT/VP12

34

74% (3-y OS)*

37.2

85% (3-y OS)*

VMPT-VT11
*Median OS not reached.

Abbreviations: MP, melphalan/prednisone; MPR-R, melphalan/prednisone/lenalidomide followed by lenalidomide

maintenance; MPT, melphalan/prednisone/thalidomide; N/A, not available; VMP, bortezomib/melphalan/prednisone; VMPVT/VP, bortezomib/melphalan/prednisone followed by bortezomib/thalidomide or bortezomib/prednisone maintenance; VMPTVT, bortezomib/melphalan/prednisone/thalidomide followed by bortezomib/thalidomide maintenance.
1. Palumbo A, et al. Blood. 2008; 112:310-3114.
2. Facon T, et al. Lancet. 2007; 370:1209-1218.
3. Hulin C, et al. J Clin Oncol. 2009; 27:3664-3670.
4. Waage A, et al. Blood. 2010;116:1405-1412.
5. Wijermans P, et al. J Clin Oncol. 2010; 28:3160-3166.
6. Beksac M, et al. Eur J Haematol. 2011;86:16-22.

7. San Miguel JF, et al. N Engl J Med. 2008;359:906-917.

8. Mateos MV, et al. J Clin Oncol. 2010;28:2259-2266.
9. Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.
10. Mateos MV, et al. Haematologica. 2008;93:560-565.
11. Palumbo A, et al. Blood. 2010;116:abstract 620.
12. Mateos MV, et al. Lancet Oncol. 2010;11:934-941.

Carfilzomib in Elderly Patients

with Newly Diagnosed MM
Phase II study of carfilzomib/cyclophosphamide/dexamethasone
in newly diagnosed MM patients 65 years old (N = 58)
Up to nine 28-day cycles followed by carfilzomib maintenance
Response rates
PR: 95%
VGPR: 71%
nCR: 49%
sCR: 20%
2-year PFS: 76%
2-year OS: 87%
Abbreviations: nCR, near complete response; OS, overall survival; PFS, progression-free survival; PR, partial response;
sCR, stringent complete response; VGPR, very good partial response.
Bringhen S, et al. Blood. 2014;124:63-69 .

FIRST TrialStudy Design1,2

Arm A: Continuous Rd
LEN + Lo-DEX continuously
LEN

25 mg D1-21/28

Lo-DEX

40 mg D1,8,15, & 22/28

Screening

Arm B: Rd18

Randomization
1:1:1

LEN + Lo-DEX: 18 Cycles (72 weeks)

Patients were
stratified by:
Age
Country
ISS stage

LEN

25 mg D1-21/28

Lo-DEX

40 mg D1,8,15, & 22/28

PD or
unacceptabl
e toxicity

PD, OS, and

subsequent
MM Tx

Arm C: MPT
MEL + PRED + THAL: 12 Cycles (72 weeks)
MEL

0.25 mg/kg D1-4/42

PRED

2 mg/kg D1-4/42

THAL

200 mg D1-42/42

Active treatment + PFS follow-up phase

LT follow-up

Abbreviations: ISS, International Staging System; LEN, lenalidomide; Lo-DEX, low-dose dexamethasone; LT, long-term; MEL,
melphalan; PD, progressive disease; PFS, progression-free survival; PRED, prednisone; OS, overall survival.
1. Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans,
LA. Oral presentation.

FIRST Trial
Final Progression-Free Survival1,2
Median PFS
Rd (n = 535): 25.5 months
Rd18 (n = 541): 20.7 months
MPT (n = 547): 21.2 months
3-year PFS
Rd (n = 535): 42%
Rd18 (n = 541): 23%
MPT (n = 547): 23%
Hazard ratio
Rd vs MPT: 0.72, P = .00006
Rd vs Rd18: 0.70, P = .00001
Rd18 vs MPT: 1.03, P = .70349
Abbreviations: MPT, melphalan/prednisolone/thalidomide; PFS, progression-free survival; Rd, lenalidomide/low-dose
dexamethasone.
1. Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans,
LA. Oral presentation.

FIRST TrialConsistent PFS Benefit Across

Subgroups1,2

Age
Gender
ISS
Renal dysfunction
ECOG PS
LDH
Cytogenetics high risk

Cytogenetics high-risk included t(4;14), t(14;16), del(17p)

Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA.
Oral presentation.

FIRST TrialTTP and Time to 2nd Antimyeloma Therapy1,2

Median time to progression (TTP)
Rd (n = 535): 32.5 months
Rd18 (n = 541): 21.9 months
MPT (n = 547): 23.9 months
Hazard ratio
Rd vs MPT: 0.68, P = .00001
Rd vs Rd18: 0.62, P .00001
Rd18 vs MPT: 1.11, P = .21718
Median time to 2nd antimyeloma therapy (measure of whether a more malignant
relapse may have been selected)
Rd (n = 535): 39.1 months
Rd18 (n = 541): 28.5 months
MPT (n = 547): 26.7 months
Hazard ratio
Rd vs MPT: 0.66, P = .00001
Rd vs Rd18: 0.74, P = .00067
Rd18 vs MPT: 0.88, P = .12333
Abbreviations: MPT, melphalan/prednisone/thalidomide; Rd, lenalidomide/low-dose dexamethasone.
1. Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans,
LA. Oral presentation.

FIRST TrialResponse Endpoints

Overall response rate ( partial response)
Continuous Rd (n = 535): 75.1%
Rd18 (n = 541): 73.4%
MPT (n = 547): 62.3%
Duration of response (median)1,2
Continuous Rd (n = 535): 35.0 months
Rd18 (n = 541): 22.1 months
MPT (n = 547): 22.3 months

Response assessment for Rd obtained q4wk and for MPT q6wk; response and progression rate based on IRAC assessment.
Abbreviations: MPT, melphalan/prednisone/thalidomide; Rd, lenalidomide/low-dose dexamethasone.
1. Facon T, et al. Blood. 2013;122:abstract 2.
2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.

FIRST TrialConclusions1,2
Continuous lenalidomide/low-dose dexamethasone (Rd) is a new
standard of care for newly diagnosed, transplant-ineligible MM patients
Progression-free survival (PFS)
Continuous Rd vs melphalan/prednisone/thalidomide (MPT): HR = 0.72
(P = .00006): consistent across most subgroups
Continuous Rd vs Rd18: HR = 0.70 (P = .00001)
3-year PFS: 42% continuous Rd vs 23% Rd18 and MPT

Overall survival (planned interim analysis)

Continuous Rd vs MPT: HR = 0.78 (P = .0168)

Rd was superior to MPT for secondary efficacy endpoints

Adverse effects (hematologic and nonhematologic) for Rd and MPT
were as expected
Hematologic secondary primary malignancies: lower with
continuous Rd vs MPT

1. Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans,
LA. Oral presentation.

Combinations in the Upfront

Treatment of MM

Abbreviations: CR, complete response; CVD, cyclophosphamide/bortezomib/dexamethasone; CVRD,

cyclophosphamide/bortezomib/lenalidomide/dexamethasone; nCR, near complete response; ORR, overall response rate;
PAD, bortezomib/doxorubicin/dexamethasone; RD, lenalidomide/dexamethasone; RVD,
lenalidomide/bortezomib/dexamethasone; TD, thalidomide/dexamethasone; VAD, vincristine/doxorubicin/dexamethasone;
VGPR, very good partial response; VTD, bortezomib/thalidomide/dexamethasone.
With permission from Stewart AK, et al. Blood. 2009:114:5436-5443.

Bortezomib Induction and

Maintenance in ASCT
Maintenance
PAD
3 cycles

Patients with
NDMM
Transplantationeligible
Age 1865

CAD +
GCSF

MEL 200 +
ASCT

Randomization

VAD
3 cycles

MEL 200 +
2nd ASCT

Bortezomib
1.3 mg/m2/2 wk
2y

Allogeneic SCT

CAD +
GCSF

MEL 200 +
ASCT

MEL 200 +
2nd ASCT

Thalidomide
50 mg/d 2 y

Bortezomib 1.3 mg/m2 IV

Doxorubicin 9 mg/m2
Dexamethasone 40 mg
Abbreviations: ASCT, autologous stem cell transplantation; CAD, cyclophosphamide/doxorubicin/dexamethasone; GCSF,
granulocyte colony-stimulating factor; MEL, melphalan; NDMM, newly diagnosed multiple myeloma; PAD,
bortezomib/doxorubicin/dexamethasone; VAD, vincristine/doxorubicin/dexamethasone.
Sonneveld P, et al. J Clin Oncol. 2012;30\:2946-2955.

Results
Bortezomib-based treatment in newly diagnosed,
transplant-eligible MM patients
Progression-free survival (PFS): HR = 0.78 (P = .002)*
Overall survival (OS): HR = 0.80 (P = .047)*
Bortezomib significantly improved PFS (P = .003) and OS
(P <.001) in patients presenting with renal failure
*Adjusted for ISS stage

Sonneveld P, et al, Blood. 2013;122:abstract 404.

Bortezomib/Lenalidomide-Based Consolidation
Phase II (N = 31; age <65 years)
VRD induction (3 cycles)
ASCT
VRD consolidation (2 cycles)
Lenalidomide maintenance (1 year)
Results:
VGPR
58% postinduction
70% post-ASCT
87% postconsolidation
Complete response: 58%
3-year progression-free survival: 77%
3-year overall survival: 100%
Abbreviations: ASCT, autologous stem cell transplantation; VGPR, very good partial response; VRD,
bortezomib/lenalidomide/dexamethasone.
Roussel M, et al. J Clin Oncol. 2014 Jul 14. [Epub ahead of print]

Carfilzomib with Thalidomide and

Dexamethasone in ASCT1,2
Intensification* (1 cycle)

Phase II
open-label
doseescalation
trial
(N = 70)

Induction
(four 28-day cycles)

Consolidation
(four 28-day cycles)

Carfilzomib, 20/27 mg/m2

Days 1,2,8,9,15,16

Carfilzomib, 27 mg/m2
Days 1,2,8,9,15,16

Thalidomide, 200 mg
Days 1-28

Thalidomide, 50 mg
Days 1-28

Dexamethasone, 40 mg
Days 1,8,15,21

Dexamethasone, 20 mg
Days 1,8,15,21

Carfilzomib 27 mg/m2 dose escalation: Cohort 1 treatment as above;

Cohort 2 to 36 mg/m2; Cohort 3 to 45 mg/m2; Cohort 4 to 56 mg/m2.
*High-dose melphalan 200 mg/m2 plus ASCT.
Abbreviation: ASCT, autologous stem cell transplantation.
1. Sonneveld P, et al. Blood. 2013;122:abstract 688. 2. Sonneveld P, et al. Presented at: 55th ASH; December 7-10, 2013;
New Orleans, LA. Oral presentation.

Carfilzomib/Thalidomide/Dexamethasone
Response and Adverse Effects1,2
All patients
CR/sCR:

51%

VGPR:

84%

PR:

96%

Standard-risk patients
CR/sCR:

48%

VGPR:

76%

PR:

90%

High-risk patients*
CR/sCR:

57%

VGPR:

90%

PR:

90%

Grade 3/4 adverse effects 5% by

carfilzomib dose
20/27 mg/m2 = gastrointestinal
(GI) toxicity, 16%, skin, 12%;
metabolism, 10%;
myelotoxicity, 8%;
fatigue, 8%;
cardiovascular, 6%
20/36 mg/m2 = metabolism, 10%;
myelotoxicity, 8%;
GI toxicity, 5%
Neuropathy <5% in both cohorts

*t(4;14) and/or del(17p) and/or 1q and/or ISS3.

Abbreviation: CR, complete response; PR, partial response; sCR, stringent complete response; VGPR, very good partial
response.
1. Sonneveld P, et al. Blood. 2013;122:abstract 688. 2. Sonneveld P, et al. Presented at: 55th ASH; December 7-10, 2013;
New Orleans, LA. Oral presentation.

Maintenance Therapy

CALGB 100104LEN Maintenance

Significantly Prolonged PFS & OS vs Placebo
Post-ASCT randomized to lenalidomide or placebo
Progression-free survival
Median time to progression with lenalidomide vs
placebo: 46 vs 27 mo
HR = 0.48, P <.001
Overall survival
HR = 0.62, P = . 03 (improved)

Abbreviations: ASCT, autologous stem cell transplantation; CALGB, Cancer and Leukemia Group B; HR, hazard ratio.
McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781.

Lenalidomide Maintenance Therapy

Meta-Analysis
Meta-analysis of data from four phase III trials
IFM 05-02
CALGB 100104
MM-015
RV-MM-P1209
There was significant prolongation of both PFS and OS with
lenolidomide maintenance vs placebo/no maintenance
PFS (HR 0.49, 95% CI, 0.410.58, P <0.001)
OS (HR 0.77, 95% CI, 0.620.95, P = .013)

Abbreviations: LM, lenalidomide maintenance; PFS, progression-free survival; OS, overall survival.
Singh M, et al. Blood. 2013:122:abstract 407.

Progression-Free and Overall Survival

All Patients
Study in elderly patients (65 years of age) with newly diagnosed MM
Median progression-free survival
MPR-R: 31 months
MPR: 14 months
MP: 13 months
HR
MPR-R vs MPR: 0.49, P <.001
MPR-R vs MP: 0.40, P <.001
3-yr overall survival
MPR-R: 70%
MPR: 62%
MP: 66%
HR
MPR-R vs MPR: 0.79, P = .25
MPR-R vs MP: 0.40, P = .81
Abbreviations: MP, melphalan/prednisone; MPR, melphalan/prednisone/lenalidomide; MPR-R, melphalan/prednisone/
lenalidomide followed by lenalidomide maintenance.
Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.

Second Primary Malignancies

All Patients
Risk of relapse or death from progression is greater
than risk of second primary malignancies in all 3 arms
MPR-R
(n = 150)

MPR
(n = 152)

MP
(n = 153)

7%

7%

3%

Hematologic

n=7

n=5

n=1

Solid tumors

n=5

n=4

n=3

Total invasive second

primary malignancies

Abbreviations: MP, melphalan/prednisone; MPR, melphalan/prednisone/lenalidomide; MPR-R,

melphalan/prednisone/lenalidomide followed by lenalidomide maintenance.
Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.

Maintenance Therapy with Bortezomib

Relevant Trials1
Single-agent
bortezomib

Key Results

Transplant-eligible patients after

induction therapy and ASCT
(HOVON trial)2,3

Primary results (median 41 mo):

CR: 49% with BTZ (with PAD induction) vs 34%
with thalidomide (with VAD induction)
PFS: 35 vs 28 mo (P = .002)
5-y OS: 61% vs 55% (P = .11)*
Long-term results (median 67 mo):
Significant benefit in both PFS (P = .002) and OS
(P = .047)

Non-transplant-eligible patients after

induction therapy (UPFRONT trial)4

Increased response rates with maintenance therapy

Bortezomib +
thalidomide (VT)

Transplant-eligible patients after

induction therapy and ASCT
(PETHEMA/GEM trial)5

2-y PFS: 78% with VT vs 63% with T vs 49% with

alfa2-interferon (P = .01)

Bortezomib +
thalidomide (VT) vs
Bortezomib +
prednisone (VP)

Non-transplant-eligible patients
after induction therapy
(GEM2005MAS65 trial)6

PFS: 39 mo with VT vs 32 mo with VP

5-y OS: 69% vs 50%

Bortezomib +
lenalidomide +
dexamethasone

High-risk patients after ASCT7

sCR: 51% (VGPR: 96%)

Median PFS: 32 mo
3-y OS: 93%

*Median OS not reached.

Abbreviations: ASCT, autologous stem cell transplantation; BTZ, bortezomib; CR, complete response; OS, overall survival; PAD,
bortezomib/doxorubicin/dexamethasone; PFS, progression-free survival; sCR, stringent complete response; VAD,
vincristine/doxorubicin/dexamethasone.
5. Rosiol L, et al. Blood. 2012;120:1589-1596.
1. NCCN
Guidelines. Multiple Myeloma Version 2.2014.
6. Mateos MV, et al. Blood. 2012;120:2581-2588.
2. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.
7. Nooka AK, et al. Leukemia. 2014;28:690-693.
3. Sonneveld P, et al. Blood. 2013;122:abstract 404.
4. Niesvizky R, et al. Blood. 2010;116:abstract 619.

Maintenance Therapy with Carfilzomib

Phase II study in newly diagnosed elderly MM patients
Carfilzomib/cyclophosphamide/dexamethasone followed by carfilzomib
maintenance (36 mg/m2)
25 patients evaluable for maintenance
During maintenance therapy
Most frequent adverse effect: fever (24%; 8% grade 3)
Peripheral neuropathy: 8% (grade 1-2)
Response rates after 6 months of maintenance
24% sCR
68% nCR
80% VGPR
100% PR

Abbreviations: nCR, near complete response; PR, partial response; sCR, stringent complete response; VGPR, very good
partial response.
Bringhen S, et al Blood. 2013;122:abstract 685.

Relapsed/Refractory MM

The Landscape Is Changing

Many new treatment options
Treatment of relapse for most patients can be very
successful
Unfortunately, the pattern for most patients is
recurrent relapse followed by development of
refractory disease
When interpreting clinical trials, need to be clear on
what patients, and how much they have received

Definitions
Definition

Description

Primary refractory

A population that has never achieved a

minimal response or better to therapy

Refractory (to prior

treatment)

Progressive disease (PD) on last

prior therapy
OR
Best response of stable disease to
last prior therapy
OR
PD within 3 months of therapy

Relapsed (but not

refractory)

Clinically active disease

In patients who have received 1
prior therapy
With disease not refractory to the
most recent treatment

Anderson KA, et al. Leukemia. 2008;22:231-239.

Options in the Relapsed Setting

Existing novel agents
Thalidomide, bortezomib, lenalidomide, carfilzomib,
pomalidomide

Existing older agents

Dexamethasone/prednisone, cyclophosphamide,
melphalan, anthracyclines

Clinical trial options

Single agent vs combination
How do we as clinicians decide??

Factors in Selecting Treatment

in Relapsed Myeloma
Disease-related factors
Duration of response to initial therapy
FISH or cytogenetics data (p53, t(4:14))
Regimen-related factors
Prior drug exposure (relapsed vs refractory)
Toxicity of regimen (combination vs single agent)
Mode of administration (eg, oral or intravenous)
Patient-related factors
Pre-existing toxicity from therapy (peripheral
neuropathy, myelosuppression)

What are the tools we use to treat Relapse?

Combinations vs Sequenced Therapy

In relapse is there a role for combo vs single
agents?
Current phase III studies for full approval of new
agents are testing 2 vs 3 (pomalidomide, carfilzomib,
panobinostat, elotuzumab)
Is the possible benefit in early relapse the same as
in late relapse (refractory)?

Once Treatment Fails, Trouble Begins

Patients with bortezomib- and lenalidomiderefractory MM have very short median OS and EFS
Median EFS: 5 months
Median OS: 9 months
These were the benchmarks for testing new drugs
(eg, carfilzomib)

Abbreviations: EFS, event-free survival; OS, overall survival.

Kumar S. 2010 (unpublished)

Targets In Clinical Development

New immunomodulatory drugs
Proteasome pathway
Histone deacetylase inhibitors
Monoclonal antibodies
Other new targets in development

Carfilzomib in Relapsed/Refractory MM
003-A1 Single-Arm Pivotal Study (N = 266)

Patients (%)

35
30
25
20
15
10
5
0

Progressive disease required (>2 lines of therapy)

Median 5.4 years from diagnosis (range, 0.5-22.3)
99.6% prior bortezomib
80% refractory or intolerant to bortezomib and lenalidomide
DCR = 69%

31.5%

CBR = 37%

26.8%

ORR = 24%

18.3%
13.2%
5.1%
0.4%
CR*
(n = 1)

VGPR
(n = 13)

PR
(n = 47)

MR
(n = 34)

SD
(n = 81)

Well tolerated
Very low rate
of neuropathy
G1/2 11.3%
G3/4 1.1%

PD
(n = 69)

Responses not affected by prior treatment or cytogenetics

Abbreviations: CBR, clinical benefit rate; DCR, disease control rate; ORR, overall response rate; PD, progressive disease;
SD, stable disease.
Siegel DS, et al. Blood. 2012;120:2817-2825. Slide courtesy of Dr. Lonial.

PIs in Combination Therapy

CRd in Relapsed and Upfront MM

Response to CRd therapy in RRMM was high, with an overall
response rate (ORR) of 78%1
40% VGPR or better1
CRd well-tolerated with durable responses1,2
ASPIRE phase III open-label, international, multicenter trial
comparing CRd to Rd in RRMM fully enrolled3
Remarkable extent and frequency of response to CRd upfront
in newly diagnosed MM (98% ORR, with 72% CR, nCR after
12 cycles in a subset of patients)2

Abbreviations: CR, complete response; CRd, carfilzomib/lenalidomide/low-dose dexamethasone; nCR, near complete
response; RRMM, relapsed/refractory MM; VGPR, very good partial response.
1. Wang M, et al. J Clin Oncol. 2011;29:abstract 8025.
2. Jakubowiak AJ, et al, Blood. 2012;120:1801-1809.
3. ClinicalTrials.gov. 2014. Accessed 7/29/14 at: http://clinicaltrials.gov/ct2/show/NCT01080391.

Phase I MTDCarfilzomib, Pomalidomide,

and Low-Dose Dexamethasone
Maximum tolerated dose
Carfilzomib 27 mg/m2
Pomalidomide 4 mg
Dexamethasone 40 mg
Cohort level 1: Carfilzomib 27 mg/m2, pomalidomide 4 mg,
dexamethasone 40 mg
1/6 patients had dose-limiting toxicity (DLT) (febrile neutropenia)
Cohort level 2: Carfilzomib 36 mg/m2, pomalidomide 4 mg,
dexamethasone 40 mg
2/6 patients had DLTs (grade 4 thrombocytopenia: grade 3 rash)
Shah J, et al. Blood. 2013;122:abstract 690.

Treatment-Related Nonhematologic
Adverse Effects (N = 79)
Adverse event, n

All grades,
n (%)

Fatigue

33 (42%)

Dyspnea

22 (28%)

Muscle spasms

14 (18%)

Diarrhea

13 (16%)

Peripheral sensory neuropathy

5 (6%)

DVT/PE/VTE*

5 (6%)

Cardiac failure, congestive

2 (3%)

*1 grade 5 pulmonary embolism event; treatment-related.

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.
Shah J, et al. Blood. 2013;122:abstract 690.

Carfilzomib, Pomalidomide, and

Low-Dose Dexamethasone
Heavily pretreated patients (median 5 prior lines of therapy); 49% had
high/intermediate risk cytogenetics at baseline
Response rates
very good partial response: 27%
Overall response rate: 70%
Clinical benefit rate: 83%
Duration of response: median 17.7 months
Progression-free survival (PFS): median 9.7 months
Overall survival (OS): median >18 months
Response rates, PFS, and OS were independent of fluorescence in
situ hybridization/cytogenetic risk status
Carfilzomib/pomalidomide/low-dose dexamethasone was well tolerated
No unexpected toxicities
Shah J, et al. Blood. 2013;122:abstract 690.

Study DesignCarfilzomib, Cyclophosphamide,

and Low-Dose Dexamethasone
Phase II multicenter trial (10 centers)
28-day cycles

Carfilzomib/Cyclophosphamide/Low-Dose
Dexamethasone Induction
(9 cycles)

Carfilzomib
Maintenance
(Until Progression
or Intolerance)

Cycle 1

Cycles 29

Maintenance

Carfilzomib
20 mg/m2 IV (days 1,2)
36 mg/m2 (days 8,9,15,16)

Carfilzomib
36 mg/m2 IV
(days 1,2,8,9,15,16)

Carfilzomib
36 mg/m2 IV
(days 1, 2, 15, 16)

Cyclophosphamide
300 mg/m2
(days 1,8,15)

Cyclophosphamide
300 mg/m2
(days 1,8,15)

Dexamethasone
40 mg
(days 1,8,15,22)

Dexamethasone
40 mg
(days 1,8,15,22)

Bringhen S, et al Blood. 2013;122:abstract 685.

CCd Study Results

And Comparison with Other Regimens
100%
80%
60%
40%
20%

CCd
CCd 1
VMP 2
VMP
Rd3
Rd

0%

Abbreviations: CCd carfilzomib/cyclophosphamide/dexamethasone; CR, complete response; nCR, near-complete response;

OS, overall survival; PFS, progression-free survival; Rd, lenalidomide/dexamethasone; sCR, stringent complete response;
VGPR, very good partial response; VMP, bortezomib/melphalan/prednisone.
1. Bringhen S, et al Blood. 2013;122:abstract 685.
2. San Miguel JF, et al. N Engl J Med. 2008;359:906-917.
3. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

Pomalidomide with Low-Dose

Dexamethasone in Relapsed and
Refractory Multiple Myeloma
Heavily pretreated patients: received 2 prior therapies
(including lenalidomide and bortezomib) with disease
progression on last regimen
Overall response rate (ORR)
Pomalidomide (POM) + low-dose dexamethasone (LoDEX), 33%
POM alone, 18%

Duration of response
POM + LoDEX, 8.3 months
POM alone, 10.7 months

Low rate of discontinuation due to treatment-related adverse

effects (3%)
No impact of age (65 years vs > 65 years) on ORR or duration
of response
Richardson PG, et al. Blood. 2014;123:1826-1832.

MM-003 DesignPOM + LoDEX vs HiDEX

POM + LoDEX
POM: 4 mg/day (days 121)
DEX: 40 mg* (days 1, 8, 15, 22)
PD or
unacceptable
toxicity

Randomization
2:1
HiDEX
DEX: 40 mg* (days 14, 912, 1720)
Patients were stratified by:
Age ( 75 vs > 75 yrs)
Number of prior treatments ( 2 vs 3)

Disease population (refractory vs relapsed/refractory vs bortezomib intolerance)

* 20 mg > 75 yrs

Progression of disease was independently adjudicated in real time.

Abbreviations: HiDEX, high-dose dexamethasone; LoDEX, low-dose dexamethasone; PD, progressive disease; POM,
pomalidomide.
San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

POM + LoDEX vs. HiDEX

PFS
POM + LoDEX: 4.0 months (95% CI 3.64.7)
HiDEX: 1.9 months (95% CI 1.92.2)
HR = 0.48 (95% CI 0.390.60), P <.0001
OS
POM + LoDEX: 12.7 months (95% CI 10.415.5)
HiDEX: 8.1 months (95% CI 6.910.8)
HR = 0.74 (95% CI 0.560.97), P = .0285

Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; OS, overall survival;
PFS, progression-free survival; POM, pomalidomide.
San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

PFS Based on Cytogenetic Profile

POM + LoDEX

HiDEX

ITT population

233/302

133/153

HR = 0.48
(95% CI 0.390.60)

Non-high risk
cytogenetics

72/91

41/47

HR = 0.50
(95% CI 0.330.74)

Moderate high risk

cytogenetics

64/77

30/35

HR = 0.46
(95% CI 0.300.72)

Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; PFS,
progression-free survival; POM, pomalidomide.
San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

PFS Based on Prior Treatment

POM + LoDEX

HiDEX

ITT population

233/302

133/153

HR = 0.48
(95% CI 0.390.60)

Refractory

191/249

107/125

HR = 0.50
(95% CI 0.390.63)

4/8

5/5

HR = 0.18
(95% CI 0.040.81)

Bortezomib intolerant

38/45

21/23

HR = 0.48
(95% CI 0.280.84)

2 prior treatments

12/17

7/8

HR = 0.47
(95% CI 0.181.25)

>2 prior treatments

221/285

126/145

HR = 0.48
(95% CI 0.390.61)

Lenalidomide refractory

224/286

121/141

HR = 0.50
(95% CI 0.400.62)

Lenalidomide and
bortezomib refractory

176/225

95/113

HR = 0.52
(95% CI 0.410.68)

Lenalidomide was last

prior treatment

64/85

42/49

HR = 0.38
(95% CI 0.260.58)

Bortezomib was last prior

treatment

97/132

56/66

HR = 0.52
(95% CI 0.370.73)

Relapsed and refractory

Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; PFS,
progression-free survival; POM, pomalidomide.
San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

OS Based on Prior Treatment

POM + LoDEX

HiDEX

ITT population

145/302

82/153

HR = 0.74
(95% CI 0.560.97)

Refractory

120/249

67/125

HR = 0.76
(95% CI 0.561.03)

3/8

2/5

HR = 0.85
(95% CI 0.145.13)

Bortezomib intolerant

22/45

13/23

HR = 0.59
(95% CI 0.291.20)

2 prior treatments

7/17

5/8

HR = 0.44
(95% CI 0.141.40)

>2 prior treatments

138/285

77/145

HR = 0.76
(95% CI 0.581.01)

Lenalidomide refractory

140/286

77/141

HR = 0.73
(95% CI 0.550.96)

Lenalidomide and
bortezomib refractory

113/225

62/113

HR = 0.77
(95% CI 0.561.05)

29/49

HR = 0.53
(95% CI 0.330.87)

Relapsed and refractory

Lenalidomide was last

prior treatment
Bortezomib was last prior
treatment

41/85
56/132

30/66

HR = 0.87
(95% CI 0.561.36)

Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; OS, overall
survival; POM, pomalidomide.
San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

MM-005 Study Design: POM + BORT + LoDEX

Phase 1, multicenter, open-label, dose-escalation study; 3 + 3 design; 21-day cycles
POM: days 1-14
BORT: days 1, 4, 8, 11
LoDEX: days 1-2, 4-5, 8-9, 11-12
April 2013: study amended to allow SC BORT in 6 patients
Cohort 1
(n=3)

Cohort 2
(n=3)

Cohort 3
(n=3)

Cohort 4
(n=3)

Cohort 5
(n=3)

POM:
1 mg/day

POM:
2 mg/day

POM:
3 mg/day

POM:
4 mg/day

POM:
4 mg/day

BORT:
1 mg/m2 IV

BORT:
1 mg/m2 IV

BORT:
1 mg/m2 IV

BORT:
1 mg/m2 IV

BORT:
1.3 mg/m2 IV

LoDEX:
20 mg*

LoDEX:
20 mg*

LoDEX:
20 mg*

LoDEX:
20 mg*

LoDEX:
20 mg*

Expansion
cohort
(n=6)

SC BORT
(n=6)
POM:
4 mg/day

MTD/MPD

BORT:
1.3 mg/m2 SC
LoDEX:
20 mg*

*10 mg for patients age >75

Abbreviations: BORT, bortezomib; IV, intravenous; LoDEX, low-dose dexamethasone; MPD, maximum planned dose; MTD,
maximum tolerated dose; OS, overall survival; POM, pomalidomide; RBC, red blood cell; SC, subcutaneous; SPM, second
primary malignancy.
Richardson PG, et al. Blood. 2013;122:abstract 1969.

Pom + LoDEX + Bortezomib in

Relapsed MM
Cohort

ORR

Cohort 1 (n=3)

2 (67%)

Cohort 2 (n=3)

1 (33%)

Cohort 3 (n=3)

3 (100%)

Cohort 4 (n=3)

3 (100%)

Cohort 5 + Exp Cohort (n=9)

6 (67%)*

* 8 of 9 patients were evaluable for response; one patient discontinued study treatment in cycle 2 due to treatment-unrelated
metastatic pancreatic cancer.
Abbreviations: Exp, expansion; ORR, overall response rate.
Richardson PG, et al. Blood. 2013;122:abstract 1969.

Development of Rationally Based

Combination Therapies (HDAC and
Proteasome Inhibitors)
HDAC inhibitors
Examples include vorinostat, panobinostat, and
ricolinostat (ACY-1215)
Block accessory pathway for protein degradation,
which becomes activated when you block the
proteasome using proteasome inhibitors

Hideshima T, et al. Clin Cancer Res. 2005;11:8530-8533. Catley L, et al. Blood. 2006;108:3441-3449. Anderson KC. J Clin
Oncol. 2012;30:445-452.

VANTAGE 088
International, Multicenter, Randomized, Double-Blind
Study of Vorinostat or Placebo with Bortezomib
in Relapsed MM
Vorinostat + bortezomib in patients with relapsed and refractory MM
Results (vs placebo + bortezomib)
Overall response rate: 56.2% vs 40.6% (P <.0001)
Progression-free survival: 7.63 months (6.87-8.40) vs 6.83 months
(5.67-7.73)
HR = 0.77 (P = .01)
Increase in grade 3/4 diarrhea, fatigue, and thrombocytopenia with
vorinostat vs placebo

Dimopoulos M, et al. Lancet Oncol. 2013;14:1129-1140 .

Clinical Data with Histone Deacetylases

Panobinostat
Panobinostat + bortezomib (BTZ) + dexamethasone (PANORAMA2)1
Phase II (N = 55)
2 previous therapies, including an immunomodulatory drug,
BTZ-refractory
Results
Objective response rate (ORR): 34.5% (near complete response
[nCR]): 1.8%)
Progression-free survival (PFS): 5.4 months
Panobinostat + BTZ + dexamethasone (PANORAMA1)2
Phase III (N = 768)
1-3 previous therapies
Results (vs placebo + BTZ + dexamethasone)
PFS: 12 vs 8.1 months (HR 0.63, P <.0001)
ORR: 61% vs 55% (nCR/CR: 28% vs 16%)
Duration of response: 13.1 vs 10.9 months
1. Richardson PG, et al. Blood. 2013;122:2331-2337. 2. Richardson PG, et al. J Clin Oncol. 2014;32(5s):abstract 8510.

Ricolinostat (HDAC 6 inhibitor)

Alone and in Combination with Bortezomib in
Relapsed/Refractory MM
Ricolinostat monotherapy1

SD: best response in 6/15 patients

Ricolinostat + bortezomib and dexamethasone1,2
20/22 evaluable for response (6 cohorts; heavily pretreated)
ORR: 25%; CBR: 60%
2 VGPR, 3 PR, 2 MR, 2 SD*
5 patients withdrew after 1 cycle; 3 had PD after 2 cycles
6/10 patients refractory to bortezomib had SD
1 VGPR, 1 MR, 4 SD
MR in all patients (n = 3) in 240 mg/day cohort
Patients with response have been on study 2-16 cycles
Monotherapy response data from Final CSR. Combination response data pulled from live database Nov 8, 2013.
*One patient had a 26% decrease in M protein after Cycle 2 and withdrew after 2 subsequent cycles with SD.
Abbreviations: CBR: clinical benefit rate; MR, minimal response; ORR, overall response rate; PR, partial response; SD,
stable disease; VGPR, very good partial response.
1. Raje N, et al. Blood. 2013;122:abstract 759. 2. Raje N, et al. Presented at: 55th ASH; December 7-10, 2013; New
Orleans, LA. Oral presentation.

Managing Adverse Effects

Management of Adverse Effects with

Proteasome Inhibitors
Dose Modifications
Bortezomib

Dose modifications for peripheral neuropathy

(PN)1
Grade 1 with pain or grade 2: reduce to
1 mg/m2
Grade 2 with pain or grade 3: withhold until
toxicity resolves and reinitiate with reduced
dose (0.7 mg/m2)
Grade 4: discontinue
Dose modifications recommended for1
Grade 3 nonhematologic AEs (except for PN)
Grade 4 hematologic AEs

Carfilzomib

Dose modifications recommended for3

Grade 3-4 nonhematologic AEs (including PN)
Grade 3-4 neutropenia
Grade 4 thrombocytopenia

Other Recommendations
Hematologic adverse effects (AEs)
Transfusion, hematologic growth factors2
Nonhematologic AEs
PN: gabpapentin, amitriptyline, vitamin
supplements, topical capsaicin
Fatigue: low-dose prednisone, hydration2
GI: antiemetics, antidiarrheals, fluid and
electrolyte replacement1,2
Infections: consider anti-infective prophylaxis2

Hematologic AEs4
Transfusion, hematologic growth factors
Nonhematologic AEs4
Fatigue: 250-500 mL saline prior to carfilzomib
(and after if needed)
Gastrointestinal: antinausea medication prior
to carfilzomib
Infections: antiviral or antibacterial
prophylaxis

1. Bortezomib Prescribing Information. 2. San Miguel J, et al. Oncologist. 2006;11:51-61. 3. Carfilzomib Prescribing
Information. 4. Siegel DS. Ther Adv Hematol. 2013;4:354-365.

PIs in Treatment Guidelines

NCCN Treatment Guidelines

NCCN Guidelines
Primary Therapy for Transplant Candidates
Bortezomib-containing regimens
Preferred (category 1)
Bortezomib/dexamethasone
Bortezomib/doxorubicin/dexamethasone
Bortezomib/thalidomide/dexamethasone
Preferred (category 2A)
Bortezomib/cyclophosphamide/dexamethasone
Bortezomib/lenalidomide/dexamethasone
Carfilzomib-containing regimens
Other regimens (category 2A)
Carfilzomib/lenalidomide/dexamethasone

NCCN Guidelines. Multiple Myeloma Version 2.2014.

NCCN Guidelines
Primary Therapy for Non-Transplant Candidates
Bortezomib-containing regimens
Preferred (category 1)
Melphalan/prednisonebortezomib
Preferred (category 2A)
Bortezomib/dexamethasone

NCCN Guidelines. Multiple Myeloma Version 2.2014.

NCCN Guidelines
Maintenance Therapy
Bortezomib-containing regimens
Preferred (category 2A)
Bortezomib
Other regimens (category 2B)
Bortezomib plus prednisone
Bortezomib plus thalidomide

NCCN Guidelines. Multiple Myeloma Version 2.2014.

NCCN Guidelines
Salvage Therapy
Bortezomib-containing regimens
Preferred regimens (category 1)
Bortezomib
Bortezomib/liposomal doxorubicin
Preferred regimens (category 2A)
Bortezomib/dexamethasone
Bortezomib/lenalidomide/dexamethasone
Bortezomib/thalidomide/dexamethasone
Cyclophosphamide/bortezomib/dexamethasone
Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide
(DT-PACE) bortezomib (VTD- PACE)
Other regimens (category 2A)
Bortezomib/vorinostat
Carfilzomib-containing regimens
Preferred regimens (category 2A)
Carfilzomib
NCCN Guidelines. Multiple Myeloma Version 2.2014.

Concluding Remarks
Proteasome inhibitors have shown efficacy as initial,
salvage, and maintenance therapy
Bortezomib was the first approved proteasome inhibitor for
multiple myeloma
Second-generation proteasome inhibitors offer advantages,
including tolerability (carfilzomib and lack of neuropathy) as
well as convenience (ixazomib as oral agent)
Proteasome inhibitor combinations show increased extent
and frequency of response
Proteasome inhibitors have validated targeting the protein
homeostasis with novel therapies (deubiquitylating agent
inhibitors, HDAC 6 inhibitors)