Post on 23-Dec-2015
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.
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.
• 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.
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—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.
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.
• 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
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: 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.
Shah J, et al. Blood. 2013;122:abstract 690.
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
Shah J, et al. Blood. 2013;122:abstract 690.
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.
San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.
PFS Based on Cytogenetic Profile
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.
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.
San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.
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.
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
*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.
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.
Richardson PG, et al. Blood. 2013;122:abstract 1969.
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
NCCN Guidelines. Multiple Myeloma Version 2.2014.
• Bortezomib-containing regimens – Preferred (category 2A)
■Bortezomib– Other regimens (category 2B)
■Bortezomib plus prednisone ■Bortezomib plus thalidomide
NCCN GuidelinesMaintenance Therapy
NCCN Guidelines. Multiple Myeloma Version 2.2014.
• 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
NCCN Guidelines. Multiple Myeloma Version 2.2014.
• 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