focus on the role of proteasome inhibitors in the management of multiple myeloma sagar lonial, md...

Focus on the Role of Proteasome Inhibitors in the Management of

Multiple Myeloma

Sagar Lonial, MDEditor-In-Chief for Multiple Myeloma @Point of Care

Professor, Vice Chair of Clinical AffairsDepartment of Hematology and Medical Oncology

Winship Cancer Institute, Emory UniversityAtlanta, Georgia

Kenneth C. Anderson, MDKraft 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

1962 1983 1986 1996 1999 2000+

Oral melphalan14 and prednisone15

High-dose dexamethasone12

Proteasome inhibitors4-6

Other immuno-modulatory

agents7-9

Historical Perspective of Multiple Myeloma Therapies1

Thalidomide13

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.

1987

High-dose therapy with autologous

stem cell support3

ABMT22

High-dose melphalan2

Bisphosphonates11

1984

VAD5

Targeting Growth, Survival, and Drug Resistance of MM in Bone Marrow Microenvironment

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

VCAM-1Fibronectin

ICAM-1LFA-1

MUC-1

VLA-4

CytokinesIL-6, VEGFIGF-1, SDF-1BAFF, APRILBSF-3

TNFTGFVEGF

NF-B

NF-BBMSC

adhesion molecules

NF-B

Smad, ERK

JAK/STAT3

MEK/ERK

PI3-K

GSK-3FKHRCaspase-9NF-BmTORBad

PKC

Bcl-xLMcl-1

MEK/ERKp27Kip1

NF-BBcl-xLIAPCyclin-D

MM

SurvivalAnti-apoptosisCell cycle

SurvivalAnti-apoptosisCell cycle

proliferation

SurvivalAnti-apoptosis

Akt

migration

ProliferationAnti-apoptosis

cytokines

Raf

FGFR3

Adhesion

SC

CD40

CS1

BAFF-R

Cell surfacetargets

VEGFR

Proteasome—Present and Future Therapies

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

• 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

Review of Proteasome Inhibitors (PIs)

Currently Approved PIs and

PIs in Phase III Development

Currently approved PIs— Bortezomib— Carfilzomib

PIs in development— Ixazomib citrate – phase III— Marizomib – phase II/III

Review of Proteasome Inhibitors (PIs)

Bortezomib—The 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;5:417-421.

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

Apoptosis

Migration, VEGF,Proangiogenic MMP-9, &Caveolin-1;

Osteoclastogenesis viaMIP1, BAFF

Osteoblast formation

Antiangiogenic &Antiosteoclastic Activity

Caspase-12 cleavage; phospo-PERK; GADD-153, ATF4,

GRP 78, & XBP-1 splicing

ER-Stress Induction

Cdk inhibitors: P21 & p27, p53Cyclins: D1, E1, A, B.

Cell-Cycle MM-BMSC’s interaction; ICAM, VCAM, V3 IGF-1, IL-6,

BAFF,RANKL

Microenvironment

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

Growth & Survival

Heat shock proteins-27, -70, 90; DNA-PK

Heat Shock Proteins& DNA Repair

Chymotrypsin- and caspase-likeproteasome activities;

Mono-ubiquitination; 26S Proteasome subunits

Proteasome

Mechanisms Mediating Anti-MM Activityof Bortezomib

Slide courtesy of Dr. Anderson.

Bortezomib

Carfilzomib—A Novel Proteasome (Chymotryptic) Inhibitor

• Novel chemical class with highly selective

and irreversible proteasome binding1

• Improved antitumor activity with

consecutive day dosing1

• No neurotoxicity in animals2

• 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.

HN

NH

O HN

O

O

NHO

NO O

O

Epoxyketone

Tetrapeptide

Ixazomib—Oral 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.

• 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

Marizomib (NPI-0052)

1. Moreau P, et al. Blood. 2012;120:947-959. 2. Allegra A, et al. Leuk Res. 2014;38:1-9. 3. Chauhan D, et al. Cancer Cell. 2005;8:407-419. 4. ClinicalTrials.gov. Accessed 5/5/14.

Response Criteria and Clinical Trial Results for PI Therapy in MM

Route of Administration, Efficacy, Safety

Currently approved Pis

– Bortezomib – SC, IV

– Carfilzomib – IV PIs in phase III development

– Ixazomib citrate – oral

– Marizomib – IV

PI Therapy in MMRoute of Administration

SUMMIT1

(Phase II)CREST2

(Phase II)APEX3

(Phase III)

Pegylated Liposomal

Doxorubicin + Bortezomib(Phase III)

Patient population Relapsed/refractory Relapsed/refractory (1 prior therapy)

Relapsed/refractory(1-3 prior therapies)

Relapsed/refractory(≥1 prior therapy)

N 193 54 669 646

Treatment arms BTZ 1.3 mg/m2 BTZ 1.3 mg/m2

BTZ 1.0 mg/m2

BTZ 1.3 mg/m2

High-dose DEX 40 mg

PLD 30 mg/m2 + BTZ 1.3 mg/m2

BTZ 1.3 mg/m2

Primary endpoint ORR: 35% ORR: 50% (1.3 mg/m2)

ORR: 33% (1.0 mg/m2)

TTP: 6.22 mo (BTZ)

TTP: 3.49 mo (High-dose DEX)

TTP: 9.3 mo (PLD + BTZ)

TTP: 6.5 mo (BTZ)

Bortezomib—Key Clinical Trials in Relapsed/Refractory MM Patients

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.

VISTA1

(Phase III)IFM 2005-012

(Phase III)

GIMEMA Italian Myeloma Network3

(Phase III)

HOVON-65/ GMMG-HD44

(Phase III)

Patient population

Previously untreated Previously untreated Previously untreated Previously untreated

N 682 482 480 827

Treatment arms

BTZ 1.3 mg/m2 + MP

MP alone

VD (BTZ 1.3 mg/m2 + DEX 40 mg)

VAD

VTD (BTZ 1.3 mg/m2 +

THAL + DEX 40 mg)

TD

PAD(BTZ 1.3 mg/m2 + DOX

+ DEX 40 mg)

VAD

Primary endpoint

TTP: 24.0 mo (BTZ + MP)

TTP: 16.6 mo (MP alone)

Postinduction CR/nCR: 14.8% (VD)

Postinduction CR/nCR: 6.4% (VAD)

Postinduction CR/nCR: 31% (VTD)

Postinduction CR/nCR: 11% (TD)

PFS: 35 mo (PAD)

PFS: 28 mo (VAD)

Bortezomib—Key Clinical Trials in Previously Untreated MM Patients

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.

PX-171-003-A01 (Phase II)

PX-171-003-A12

(Phase II)

PX-171-0043

Cohort 1(Phase II)

Patient populationRelapsed/refractory (≥2 prior therapies

including BTZ + IMiD)

Relapsed/refractory (99.6% prior BTZ)

Relapsed/refractory(1-3 prior therapies,

including BTZ)

N46

(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%

Carfilzomib—Key Clinical Trials in Relapsed/Refractory MM Patients with

Prior Bortezomib

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.

PX-171-0041

Cohort 1(Phase II)

PX-171-0041

Cohort 2(Phase II)

Patient population Relapsed/refractory (BTZ naive)

Relapsed/refractory (BTZ naive)

N 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%

Carfilzomib—Key Clinical Trials in Bortezomib-Naive Relapsed/Refractory

MM Patients

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

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

Single-Agent Ixazomib1

(Phase I)

Ixazomib Lenalidomide Dexamethasone2

(Phase I/II)

Patient population Relapsed/refractory Newly diagnosed

N 60(50 evaluable for efficacy)

64(56 treated at RP2D)

Cohorts Dose escalation cohort: Ixazomib 0.24-3.95 mg/m2

Dose expansion cohort:Ixazomib 2.97 mg/m2

Phase I: Ixazomib 3.0 or 3.7 mg + Len 25 mg + Dex 20/10 mg

Phase II: Ixazomib RP2D (3.0 mg)+ Len 25 mg + Dex 20/10 mg

Followed by ixazomib maintenance

Results ORR: 18% ORR: 95%*

61%* had 100% decreases in M-protein or serum FLC from baseline

Ixazomib—Key Clinical Trials

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.

*Patients treated at RP2D.

Ixazomib/Lenaldiomide/Dexamethasone in Newly Diagnosed Multiple Melanoma1,2

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.

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)

• 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%

Marizomib Clinical Data

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

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

Approaches to TherapyTiming/Sequencing of Treatment

• 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

The Good News

With permission from Kumar SK, et al. Blood. 2008;111:2516-2520.

• 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

Integration of Novel Therapy Into Myeloma Management

• 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

Chromosomes and Prognosis in Multiple Myeloma

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 OS not reached.

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.

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.

Median PFS (mo) Median OS (mo)

MP1-10 11–20 29.1–49.4

MPT1-6 15–27.5 27–51.6

VMP7,8,11 21.7–27.4 68.5% (3-y OS)*

MPR-R9 31 N/A

VMP-VT/VP12 34 74% (3-y OS)*

VMPT-VT11 37.2 85% (3-y OS)*

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; VMP-VT/VP, bortezomib/melphalan/prednisone followed by bortezomib/thalidomide or bortezomib/prednisone maintenance; VMPT-VT, bortezomib/melphalan/prednisone/thalidomide followed by bortezomib/thalidomide maintenance.

• 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%

Carfilzomib in Elderly Patients with Newly Diagnosed MM

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 .

Patients were stratified by: • Age• Country• ISS stage

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.

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.

FIRST Trial—Study Design1,2

Randomization 1:1:1

Screening

PD, OS, and subsequent

MM Tx

Active treatment + PFS follow-up phase LT follow-up

Arm A: Continuous Rd

LEN + Lo-DEX continuously

LEN 25 mg D1-21/28

Lo-DEX 40 mg D1,8,15, & 22/28

Arm B: Rd18

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

LEN 25 mg D1-21/28

Lo-DEX 40 mg D1,8,15, & 22/28

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

PD or unacceptabl

e toxicity

Abbreviations: MPT, melphalan/prednisolone/thalidomide; PFS, progression-free survival; Rd, lenalidomide/low-dosedexamethasone.


• 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

FIRST Trial—Final Progression-Free Survival1,2

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.

• Age• Gender• ISS• Renal dysfunction• ECOG PS• LDH• Cytogenetics high risk

FIRST Trial—Consistent PFS Benefit Across Subgroups1,2

• 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.


FIRST Trial—TTP and Time to 2nd Antimyeloma Therapy1,2

• 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

FIRST Trial—Response Endpoints

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.


• 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

FIRST Trial—Conclusions1,2


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.

Combinations in the Upfront Treatment of MM

Bortezomib Induction and Maintenance in ASCT

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.

Randomization

CAD + GCSF

CAD + GCSF

MEL 200 + ASCT

MEL 200 + 2nd ASCT

Maintenance

MEL 200 + 2nd ASCT

MEL 200 + ASCT

Allogeneic SCT

Bortezomib 1.3 mg/m2 IVDoxorubicin 9 mg/m2

Dexamethasone 40 mg

Thalidomide50 mg/d 2 y

Bortezomib 1.3 mg/m2/2 wk

2 y

Patients with NDMM

Transplantation-eligible

Age 18−65

PAD3 cycles

VAD3 cycles

• 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

Results

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

*Adjusted for ISS stage

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

*High-dose melphalan 200 mg/m2 plus ASCT.

Induction (four 28-day cycles)

Carfilzomib, 20/27 mg/m2

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

Dexamethasone, 40 mgDays 1,8,15,21

Thalidomide, 200 mgDays 1-28

Intensification* (1 cycle)

Phase IIopen-labeldose-escalationtrial (N = 70)

Carfilzomib, 27 mg/m2

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

Dexamethasone, 20 mgDays 1,8,15,21

Thalidomide, 50 mgDays 1-28

Consolidation(four 28-day cycles)

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.

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

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

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

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.

High-risk patients*

CR/sCR: 57%

≥VGPR: 90%

PR: 90%

Standard-risk patients

CR/sCR: 48%

≥VGPR: 76%

PR: 90%

All patients

CR/sCR: 51%

≥VGPR: 84%

PR: 96%

Maintenance Therapy

CALGB 100104—LEN Maintenance Significantly Prolonged PFS & OS vs Placebo

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.

• 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)

Lenalidomide Maintenance Therapy Meta-Analysis

Abbreviations: LM, lenalidomide maintenance; PFS, progression-free survival; OS, overall survival.

Singh M, et al. Blood. 2013:122:abstract 407.

• 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, 0.41–0.58, P <0.001) – OS (HR 0.77, 95% CI, 0.62–0.95, P = .013)

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.

Progression-Free and Overall SurvivalAll 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

Second Primary MalignanciesAll Patients

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.

MPR-R(n = 150)

MPR(n = 152)

MP(n = 153)

Total invasive second primary malignancies 7% 7% 3%

Hematologic n = 7 n = 5 n = 1

Solid tumors n = 5 n = 4 n = 3

• Risk of relapse or death from progression is greater than risk of second primary malignancies in all 3 arms

Relevant Trials1 Key Results

Single-agent bortezomib

• 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) vsBortezomib + 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%

Maintenance Therapy with Bortezomib

1. NCCN Guidelines. Multiple Myeloma Version 2.2014. 2. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 3. Sonneveld P, et al. Blood. 2013;122:abstract 404. 4. Niesvizky R, et al. Blood. 2010;116:abstract 619.

*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. Rosiñol L, et al. Blood. 2012;120:1589-1596.

6. Mateos MV, et al. Blood. 2012;120:2581-2588. 7. Nooka AK, et al. Leukemia. 2014;28:690-693.

• 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

Maintenance Therapy with Carfilzomib

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 refractoryA 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.

• 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??

Options in the Relapsed Setting

• 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)

Factors in Selecting Treatment in Relapsed Myeloma

What are the tools we use to treat Relapse?

• 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)?

Combinations vs Sequenced Therapy

Once Treatment Fails, Trouble Begins

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

Kumar S. 2010 (unpublished)

• Patients with bortezomib- and lenalidomide-refractory 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)

• New immunomodulatory drugs

• Proteasome pathway

• Histone deacetylase inhibitors

• Monoclonal antibodies

• Other new targets in development

Targets In Clinical Development

Carfilzomib in Relapsed/Refractory MM003-A1 Single-Arm Pivotal Study (N = 266)

• 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

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.

• Well tolerated• Very low rate

of neuropathy• G1/2 11.3%• G3/4 1.1%

Responses not affected by prior treatment or cytogenetics

30

25

20

5

0

Pat

ien

ts (

%)

15

10

35

CR*(n = 1)

VGPR(n = 13)

PR(n = 47)

MR(n = 34)

SD(n = 81)

PD(n = 69)

0.4%5.1%

18.3%

13.2%

31.5%

26.8%

DCR = 69%

CBR = 37%

ORR = 24%

PIs in Combination Therapy

• 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

CRd in Relapsed and Upfront MM

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 MTD—Carfilzomib, 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)

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

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.


Adverse event, nAll 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%)

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


Study Design—Carfilzomib, Cyclophosphamide, and Low-Dose Dexamethasone

• Phase II multicenter trial (10 centers)• 28-day cycles

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

Carfilzomib/Cyclophosphamide/Low-Dose Dexamethasone Induction

(9 cycles)

Carfilzomib Maintenance

(Until Progression or Intolerance)

Cycle 1 Cycles 2–9 Maintenance

Carfilzomib20 mg/m2 IV (days 1,2)

36 mg/m2 (days 8,9,15,16)

Cyclophosphamide300 mg/m2

(days 1,8,15)

Dexamethasone40 mg

(days 1,8,15,22)

Carfilzomib36 mg/m2 IV

(days 1,2,8,9,15,16)

Cyclophosphamide300 mg/m2

(days 1,8,15)

Dexamethasone40 mg

(days 1,8,15,22)

Carfilzomib36 mg/m2 IV

(days 1, 2, 15, 16)

CCd Study ResultsAnd Comparison with Other Regimens

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.

≥VGPR nCR/CR/sCR

2-yr PFS 2-yr OS0%

20%

40%

60%

80%

100%

CCdVMPRd

CCd1

VMP2

Rd3

• 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

Pomalidomide with Low-Dose Dexamethasone in Relapsed and

Refractory Multiple Myeloma

Richardson PG, et al. Blood. 2014;123:1826-1832.

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.

MM-003 Design—POM + LoDEX vs HiDEX

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.

Randomization 2:1

PD† or unacceptable

toxicity

POM + LoDEX

POM: 4 mg/day (days 1–21)DEX: 40 mg* (days 1, 8, 15, 22)

HiDEX

DEX: 40 mg* (days 1–4, 9–12, 17–20)

• PFS– POM + LoDEX: 4.0 months (95% CI 3.6–4.7)– HiDEX: 1.9 months (95% CI 1.9–2.2) – HR = 0.48 (95% CI 0.39–0.60), P <.0001

• OS– POM + LoDEX: 12.7 months (95% CI 10.4–15.5) – HiDEX: 8.1 months (95% CI 6.9–10.8)– HR = 0.74 (95% CI 0.56–0.97), P = .0285

POM + LoDEX vs. HiDEX

Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; OS, overall survival; PFS, progression-free survival; POM, pomalidomide.


PFS Based on Cytogenetic Profile

Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; PFS, progression-free survival; POM, pomalidomide.


POM + LoDEX HiDEX

ITT population 233/302 133/153 HR = 0.48 (95% CI 0.39–0.60)

Non-high risk cytogenetics 41/47 HR = 0.50

(95% CI 0.33–0.74)

Moderate high risk cytogenetics

64/77 30/35 HR = 0.46 (95% CI 0.30–0.72)

72/91

PFS Based on Prior TreatmentPOM + LoDEX HiDEX

ITT population 233/302 133/153HR = 0.48

(95% CI 0.39–0.60)

Refractory 191/249 107/125 HR = 0.50

(95% CI 0.39–0.63)

Relapsed and refractory 4/8 5/5HR = 0.18

(95% CI 0.04–0.81)

Bortezomib intolerant 38/45 21/23HR = 0.48

(95% CI 0.28–0.84)

2 prior treatments 12/17 7/8HR = 0.47

(95% CI 0.18–1.25)

>2 prior treatments 221/285 126/145HR = 0.48

(95% CI 0.39–0.61)

Lenalidomide refractory 224/286 121/141HR = 0.50

(95% CI 0.40–0.62)

Lenalidomide and bortezomib refractory

176/225 95/113HR = 0.52

(95% CI 0.41–0.68)

Lenalidomide was last prior treatment

64/85 42/49HR = 0.38

(95% CI 0.26–0.58)

Bortezomib was last prior treatment

97/132 56/66HR = 0.52

(95% CI 0.37–0.73)

Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; PFS, progression-free survival; POM, pomalidomide.


OS Based on Prior TreatmentPOM + LoDEX HiDEX

ITT population 145/302 82/153HR = 0.74

(95% CI 0.56–0.97)

Refractory 120/249 67/125 HR = 0.76

(95% CI 0.56–1.03)

Relapsed and refractory 3/8 2/5HR = 0.85

(95% CI 0.14–5.13)

Bortezomib intolerant 22/45 13/23HR = 0.59

(95% CI 0.29–1.20)

2 prior treatments 7/17 5/8HR = 0.44

(95% CI 0.14–1.40)

>2 prior treatments 138/285 77/145HR = 0.76

(95% CI 0.58–1.01)

Lenalidomide refractory 140/286 77/141HR = 0.73

(95% CI 0.55–0.96)

Lenalidomide and bortezomib refractory

113/225 62/113HR = 0.77

(95% CI 0.56–1.05)

Lenalidomide was last prior treatment

41/8529/49

HR = 0.53 (95% CI 0.33–0.87)

Bortezomib was last prior treatment

56/132 30/66 HR = 0.87 (95% CI 0.56–1.36)

Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; OS, overall survival; POM, pomalidomide.


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

*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.


Cohort 1 (n=3)

Cohort 2(n=3)

Cohort 3(n=3)

Cohort 4(n=3)

Cohort 5(n=3)

Expansion cohort(n=6)

POM: 1 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*

POM: 2 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*

POM: 3 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*

POM: 4 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*

POM: 4 mg/day

BORT: 1.3 mg/m2 IV

LoDEX: 20 mg*

MTD/MPD

SC BORT(n=6)

POM: 4 mg/day

BORT: 1.3 mg/m2 SC

LoDEX: 20 mg*

Pom + LoDEX + Bortezomib in Relapsed MM

* 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.


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%)*

Development of Rationally Based Combination Therapies (HDAC and

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.

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

VANTAGE 088International, 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 .

• 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

Clinical Data with Histone DeacetylasesPanobinostat

1. Richardson PG, et al. Blood. 2013;122:2331-2337. 2. Richardson PG, et al. J Clin Oncol. 2014;32(5s):abstract 8510.

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

Ricolinostat (HDAC 6 inhibitor) Alone and in Combination with Bortezomib in

Relapsed/Refractory MM

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

Dose Modifications Other Recommendations

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

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

Carfilzomib Dose modifications recommended for3

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

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

Management of Adverse Effects with Proteasome Inhibitors

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

• 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 GuidelinesPrimary Therapy for Transplant Candidates

NCCN Guidelines. Multiple Myeloma Version 2.2014.

• Bortezomib-containing regimens– Preferred (category 1)

■Melphalan/prednisonebortezomib – Preferred (category 2A)

■Bortezomib/dexamethasone

NCCN GuidelinesPrimary Therapy for Non-Transplant Candidates


• Bortezomib-containing regimens – Preferred (category 2A)

■Bortezomib– Other regimens (category 2B)

■Bortezomib plus prednisone ■Bortezomib plus thalidomide

NCCN GuidelinesMaintenance 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 GuidelinesSalvage Therapy


• 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)

Concluding Remarks

focus on the role of proteasome inhibitors in the management of multiple myeloma sagar lonial, md...

Documents

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role of proteasome inhibitors

adams j

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relapsed multiple myeloma