challenges and novel approaches to treating myeloma … azmn roundtable march 2014
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Scottsdale, Arizona. Rochester, Minnesota. Jacksonville, Florida. Challenges and Novel Approaches to Treating Myeloma … AZMN Roundtable March 2014. Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona. Managing myeloma: the components. Initial Therapy. Consolidation. - PowerPoint PPT PresentationTRANSCRIPT
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Challenges and Novel Approaches to Treating Myeloma…
AZMN Roundtable
March 2014
Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida
Joseph Mikhael, MD, MEd, FRCPC, FACPStaff Hematologist, Mayo Clinic Arizona
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Managing myeloma: the components
Supportive Care
Initial Therapy
Consolidation Maintenance
Treatment of Relapsed
disease
Transplant EligiblePatients
Transplant Ineligiblepatients
Consolidation/ Maintenance/ Continued therapy
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Treatment sequence
Induction Consolidation
Front line treatment
Post consolidation
Maintenance
Rescue
Relapsed
OLD VADDEX
SCTNothing
PrednisoneThalidomide
Few options
NEW
Thal/Dex VD
Rev/DexCyBorD
VTDVRD
SCTVD/VRD
NothingThalidomide?Bortezomib?
Lenalidomide?
BortezomibLenalidomideThalidomideCarfilzomib
PomalidomideMonoclonal Ab (CD38)
ElotuzumabHDAC
Bendamustine
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2006-2010 73% 56%
2001-2005 63% 31%
IMPACT OF NOVEL THERAPY 2012/2013
Median 7.3 years
5 YEAR SURVIVAL BY AGE
AGE≤ 65 YRS
AGE> 65 YRS
2012 ASH Abstract #3972 Kumar et al
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Mayo Stratification for Myeloma And Risk-adapted Therapy
Newly Diagnosed Myeloma
Website: www.msmart.org
mSMART
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mSMART 2.0: Classification of Active MM
FISH Del 17p t(14;16) t(14;20)
GEP High risk
signature
All others including: Hyperdiploid t(11;14) t(6;14)
FISH t(4;14)*
Cytogenetic Deletion 13 or hypodiploidy
PCLI >3%
High-Risk 20% Intermediate-Risk 20% Standard-Risk 60%
3 years 4-5 years 8-10 years
Mikhael et al Mayo Clinic Proceedings April 2013
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mSMART – Off-StudyTransplant Eligible
a Bortezomib containing regimens preferred in renal failure or if rapid response neededb If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixaforc Continue Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year* Consider risks and benefits; consider limited duration 12-24 months
Standard Risk
Autologous stem cell transplant
4 cycles of Rda or CyBorD
Collect Stem Cellsb
Continue Rd;
c or
CyBorD for ~12 months
High Risk
4 cycles of VRd
Intermediate Risk
Autologous stem cell transplant
Bortezomib based therapy for minimum of 1 year
4 cycles of CyBorD
Autologous stem cell transplant, especially if
not in CR
V or VCd for minimum of 1 year
2 cycles of Rd consolidation; Then Len maintenance if not in VGPR and Len responsive*
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v11 //last reviewed Dec 2013
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mSMART – Off-StudyTransplant Ineligible
a Dex is usually discontinued after first yearb Bortezomib containing regimens preferred in renal failure or if rapid response needed*Clinical trials strongly recommended as the first option
Intermediate Risk Standard Risk*
MP + weekly Bortezomib or weekly CyBorD for
~12 months
Bortezomib based therapy for minimum of 1 year
High Risk
VRd* for ~12 months, Rda, b
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v11 //last reviewed Dec 2013
Continue VRd as maintenance for minimum
of 1 year
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FIRST Design: Lenalidomide and Low-dose Dexamethasone (Rd/Rd18) vs. MPT
ARM A
Arm BRd18
Arm CMPT
N = 535
Arm ARd
LEN + Lo-DEX until Progressive DiseaseLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28
LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28
MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42
Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 100 mg D1-42/42, Melphalan2 0.2 mg/kg D1–4
• Stratification: age, country and ISS stage
1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.
International Staging System; LT, long-term; PD, progressive disease; OS, overall survival
n= 1,623 - 18 countries from North America, Asia-Pacific, and Europe represented from 246 Centers
n=535
n=541
n=547
Facon T. et._ASH 2013: Abstract 2
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FIRST Trial: Final PFSContinuous Rd the risk of PFS events (PD or death) by 28% vs. MPT
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone.
Median PFS
Rd (n= 535) 25.5 mos
Rd18 (n= 541) 20.7 mos
MPT (n= 547) 21.2 mos
Rd 535 400 319 265 218 168 105 55 19 2 0
Rd18 541 391 319 265 167 108 56 30 7 2 0
MPT 547 380 304 244 170 116 58 28 6 1 0
Hazard ratio
Rd vs. MPT: 0.72; P = 0.00006
Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349
Time (months)
Pat
ien
ts (
%)
100
80
60
40
20
00 6 12 18 24 30 36 42 48 54 60
72 w
ks
Facon T. et._ASH 2013: Abstract 2
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FIRST Trial: Overall Survival Interim Analysis574 deaths (35% of ITT)
Pat
ien
ts (
%)
RdRd18MPT
535541547
488505484
457465448
433425418
403393375
338324312
224209205
121124106
434430
563
000
4-year OS
Rd (n= 535) 59.4%
Rd18 (n= 541) 55.7%
MPT (n= 547) 51.4%
Overall survival (months)
100
80
60
40
20
00 6 12 18 24 30 36 42 48 54 60
Hazard ratio Rd vs. MPT: 0.78; P = 0.0168 ( 22% risk of death with Rd)
Rd vs. Rd18: 0.90; P = 0.307 Rd18 vs. MPT: 0.88; P = 0.184
The pre-specified boundary (p<0.0096) was not crossed for Rd_continuous vs MPT_18 months
Facon T. et._ASH 2013: Abstract 2
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FIRST Trial: Conclusions
• Continuous Rd significantly extended PFS, with an OS benefit vs. MPT• PFS:
• 3 yr PFS: 42% continuous Rd vs 23% Rd18 and MPT
• Planned interim OS: HR= 0.78 (P= 0.0168) but did NOT cross the pre-specified boundary (p<0.0096)
• Safety profile with continuous Rd was manageable • Hematological and non-hematological AEs were as expected for
Rd and MPT with more infections and cataract observed in the continuous Rd arm
• Incidence of hematological SPM was lower with continuous Rd vs. MPT
Facon T. et._ASH 2013: Abstract 2
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Efficacy Comparisons
FIRST (Continuous Rd) (Facon)
FIRST (Rd for 72 wks)(Facon)
MM-015 (MPR-R) (Palumbo)
VISTA (VMP arm for 54 wks) (San Miguel)
VMP lite (for 45 wks) (Palumbo)
VMPT-VT (Palumbo)
VMP-VT(Mateos)
CR 15.1% 14.2% 9.9% 30% 24% 38% 46%
PFS 25.5 mo 20.7 mo 31 mo 21.7 mo 24.8 mo 35.3 mo 39 mo
OS 4-yr OS; 59.4%
4-yr OS: 55.7%
3-yr OS: 70%
5-yr OS: 46%
Med OS: 56.4 mo
5-yr OS: 51%
Med OS: 60.6 mo
5-yr OS: 61%
5-yr OS: 69%
Facon et al. ASH 2013 (Abstract 2), plenary presentation Palumbo et al. N Engl J Med 2012;366(19):1759-69 San Miguel et al. N Engl J Med 2008; 359: 906-917
San Miguel et al. J Clin Oncol 2013;31(4):448-55Palumbo et al. ASH 2012 (Abstract 200), oral presentation
Mateos et al. Blood 2012; 120: 2581-2588
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Relapsed Disease
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NEWER THERAPIES: ASH 2013
TOP 8
Anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284)
MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983) ARRY 520 (abstracts #285 and #1982) ACY-1215 (abstracts #759 and #3190) Selinexor (also known as KPT-330, abstract #279) Anti-CD 138 monoclonal antibody (BT062, indatuximab
ravatansine, abstract #758) Panabinostat (abstract #1970) Bendamustine (abstract #1971)
Anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284)
MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983) ARRY 520 (abstracts #285 and #1982) ACY-1215 (abstracts #759 and #3190) Selinexor (also known as KPT-330, abstract #279) Anti-CD 138 monoclonal antibody (BT062, indatuximab
ravatansine, abstract #758) Panabinostat (abstract #1970) Bendamustine (abstract #1971)
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Monoclonal antibodies in MMTarget mAb Stage of development
Surface molecules
CS1
CD38
CD74 CD40 CD56 CD138
Elotuzumab
Daratumumab SAR650984 MOR202 Milatuzumab Dacetuzumab Lorvotuzumab mertansine BT062
Phase 2/3
Phase 1/2/3 Phase 1/2 Phase 1/2 Phase 1/2 Phase 1 Phase 1 Phase 1
Signaling molecules IL-6 RANKL B cell activating factor (BAFF) VEGF DKK1
Siltuximab Denosumab Tabalumab
Bevacizumab BHQ880
Phase 3 Phase 3 Phase 2/3
Phase 2 Phase 2
Richardson et al. et al. IMW 2013 (Abstract P-214), poster presentation; Plesner et al. ASH 2013 (Abstract 1987), poster presentation; Martin et al. ASH 2013 (Abstract 284), oral presentation; http://www.clinicaltrials.gov/ct2/show/NCT00421525; http://www.clinicaltrials.gov/ct2/show/NCT00079716;
http://www.clinicaltrials.gov/ct2/show/NCT00346255; http://www.clinicaltrials.gov/ct2/show/NCT01001442; Wong et al. ASH 2013 (Abstract 505), oral presentation; Hageman et al. Ann Pharmacother 2013;47:1069-74;
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Thomas G. Martin III1, Stephen A. Strickland2, Martha Glenn3,
Wei Zheng4, Nikki Daskalakis5 and Joseph R. Mikhael6
1University of California San Francisco, San Francisco, CA2Vanderbilt-Ingram Cancer Center, Nashville, TN 3University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 4Sanofi Oncology, Cambridge, MA 5Sanofi US, Bridgewater, NJ 6Mayo Clinic in Arizona, Scottsdale, AZ
*NCT01084252 Trial Sponsored by Sanofi, Cambridge, MA
SAR650984, A CD38 Monoclonal Antibody in Patients with Selected CD38+
Hematological MalignanciesData From a Dose-Escalation Phase I Study
(TED10893)*
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SAR650984: A Humanized IgG1 Monoclonal Antibody
Antibody
Fc Receptor
Complement
2. Complement-dependent
cytotoxicity (CDC)
2. Complement-dependent
cytotoxicity (CDC)3. Direct apoptosis induction without
crosslinking
3. Direct apoptosis induction without
crosslinking
1. Antibody-dependentcellular cytotoxicity (ADCC)
and phagocytosis (ADCP)
1. Antibody-dependentcellular cytotoxicity (ADCC)
and phagocytosis (ADCP)
NK cell,NK cell,MacrophageMacrophage
NK cell,NK cell,MacrophageMacrophage
NAD
4. CD38 enzymatic
activity inhibition
4. CD38 enzymatic
activity inhibition
cADPRADPR
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SAR650984: Phase I Dose Escalation Study
Primary ObjectivePrimary Objective
● Determine maximum tolerated dose (MTD)/maximum administered dose (MAD)
Secondary ObjectiveSecondary Objective● Characterize safety profile
● Evaluate pharmacokinetic (PK) profile
● Assess pharmacodynamics, immunogenicity, and preliminary disease response
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SAR650984: Baseline Characteristics
Accelerated Doses
0.3 mg/kgQ2W
1 mg/kgQ2W
3 mg/kgQ2W
5 mg/kgQ2W
10 mg/kgQ2W
10 mg/kg
QW
20 mg/kgQ2W
Overall
# of Patients (# of Myeloma patients) 6 (5) 7 (5) 3 (3) 6 (5) 3 (3) 7 (6) 2 (2) 5 (5) 39 (34)
# of Prior treatments,All pts - Median (range)
5(4 - 9)
6(1 - 12)
8(7 - 9)
7(3 -14)
4(4 - 10)
5(2 - 9)
8.5(4 -13)
5(4 - 7)
6(1- 14)
Prior carfilzomib 0 0 0 3 1 4 2 2 12
Prior pomalidomide 0 0 2 0 2 0 1 2 7
●39 treated patients● Median age = 65.0 (40 - 85)
●Prior therapies of myeloma patients (n=34)● Median = 6 (2 – 14)● At doses ≥ 0.3 mg/kg - all patients received prior lenalidomide and bortezomib● At doses ≥ 10 mg/kg - 69% of patient received carfilzomib and/or pomalidomide
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SAR650984: Patients with Infusion ReactionsPatients treated at doses of 0.3 mg/kg Q2W or higher
Symptoms of Infusion Reactions (N; max severity): Nausea (5; G 2); Pyrexia (4; G 1); Drug hypersensitivity, Chills (3; G 2); Headache (3; G 1); Vomiting , Hypoxia (2; G 2); Cytokine release syndrome, Dyspnea, Flushing, Nasal congestion, Bronchospasm, Tracheal stenosis, Laryngospasm (1; G 2); Influenza-like illness, Abdominal pain, Blurred vision, Lacrimation increased, Rhinorrhea, Cough, Restlessness (1; G 1)
C1 C>11
C1 C>1 C1 C>1 C1 C>1 C1 C>1 C1 C>1 C1 C>1
7
6
5
4
3
2
1
Dose level 0.3 mg/kg 1 mg/kg 3 mg/kg 5 mg/kg 10 mg/kg 10 mg/kg QW 20 mg/kg
No infusion reaction
Grade 1
Grade 2
Mandatory Prophylaxis in All Patients*
C = Cycle
*methylprednisolone 100 mg IV, diphenhydramine 50 mg IV, ranitidine 50 mg IV, and acetaminophen 650-1000 mg po (or equivalents)
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* Off study since 23May2013 due to patient decision. Ongoing
*CR
PR
MR
SD
PD
NA
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Week
5 mg/kg Q2W10 mg/kg Q2W10 mg/kg QW20 mg/kg Q2W
3 mg/kg Q2W1 mg/kg Q2W
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SAR650984: Phase 1 Response Summary
ORR: 30.8%
CBR:38.5%
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SAR650984: Phase 1 Response Summary
●Overall Response Rate (CR+PR)● Dosing cohorts ≥1mg/kg = 25% (2 CR, 4 PR of 24) ● Dosing cohorts ≥ 10 mg/kg = 31% (2 CR, 2 PR of 13)
● Clinical Benefit Rate (CR+PR+MR)● Dosing cohorts ≥ 1mg/kg = 33% (2 CR, 4 PR, 2 MR of 24) ● Dosing cohorts ≥ 10 mg/kg = 38% (2 CR, 2 PR, 1 MR of 13)
●Median Time to Initial Response (CR, PR, MR) = 6.1 weeks (3.4 – 12.3)
● In 8 responders the median duration of response 5.0 months (0 - 15.4)● 6 patients still on treatment
●Median duration of follow up is 6.5 months (1.9-16.3)
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