1. Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
Challenges and Novel Approaches to Treating Myeloma… AZMN Roundtable March 2014
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Joseph Mikhael, MD, MEd, FRCPC, FACP
Staff Hematologist, Mayo Clinic Arizona

2. Managing myeloma: the components
Initial Therapy
Consolidation
Maintenance
Treatment of Relapsed disease
Transplant Eligible
Patients
Consolidation/ Maintenance/ Continued therapy
Transplant Ineligible
patients
Supportive Care

3. Treatment sequence NEW OLD
Thal/Dex VD
Rev/Dex
CyBorD
VTD
VRD
SCT
VD/VRD
Nothing
Thalidomide?
Bortezomib?
Lenalidomide?
Bortezomib
Lenalidomide
Thalidomide
Carfilzomib
Pomalidomide
Monoclonal Ab (CD38)
Elotuzumab
HDAC
Bendamustine
NEW
Front line treatment
Maintenance
Relapsed
Induction
Consolidation
Post consolidation
Rescue
VAD
DEX
SCT
Nothing
Prednisone
Thalidomide
Few options
OLD 3 3

4. 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

5. mSMART Newly Diagnosed Myeloma Website: www.msmart.org
Mayo Stratification for Myeloma And Risk-adapted Therapy
Newly Diagnosed Myeloma
Website: 5

6. mSMART 2.0: Classification of Active MM
High-Risk 20%
Intermediate-Risk 20%
Standard-Risk 60%
FISH
Del 17p
t(14;16)
t(14;20)
GEP
High risk
signature
FISH
t(4;14)*
Cytogenetic Deletion 13 or hypodiploidy
PCLI >3%
All others including:
Hyperdiploid
t(11;14)
t(6;14)
3 years years years
Mikhael et al Mayo Clinic Proceedings April 2013 6 6

7. mSMART – Off-Study Transplant Eligible High Risk Intermediate Risk
Standard Risk
4 cycles of VRd
4 cycles of CyBorD
4 cycles of Rda or CyBorD
Collect Stem Cellsb
Autologous stem cell transplant, especially if not in CR
Autologous stem cell transplant
Autologous stem cell transplant
Figure 1
2 cycles of Rd consolidation; Then Len maintenance if not in VGPR and Len responsive*
Continue
Rd;c or CyBorD for ~12 months
V or VCd for minimum of 1 year
Bortezomib based therapy for minimum of 1 year
a Bortezomib containing regimens preferred in renal failure or if rapid response needed
b If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixafor
c 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 months
Dispenzieri et al. Mayo Clin Proc 2007;82: ; Kumar et al. Mayo Clin Proc : ; Mikhael et al. Mayo Clin Proc 2013;88: v //last reviewed Dec 2013 7 7

8. mSMART – Off-Study Transplant Ineligible High Risk Intermediate Risk
Standard Risk*
MP + weekly Bortezomib or weekly CyBorD for ~12 months
VRd* for ~12 months,
Rda, b
Bortezomib based therapy for minimum of 1 year
Continue VRd as maintenance for minimum of 1 year
Figure 1
a Dex is usually discontinued after first year
b Bortezomib containing regimens preferred in renal failure or if rapid response needed
*Clinical trials strongly recommended as the first option
Dispenzieri et al. Mayo Clin Proc 2007;82: ; Kumar et al. Mayo Clin Proc : ; Mikhael et al. Mayo Clin Proc 2013;88: v //last reviewed Dec 2013 8 8

9. Active Treatment + PFS Follow-up Phase PD or Unacceptable Toxicity
FIRST Design: Lenalidomide and Low-dose Dexamethasone (Rd/Rd18) vs. MPT
Screening
LT Follow-Up
Active Treatment + PFS Follow-up Phase
RANDOMIZATION 1:1:1
LEN + Lo-DEX until Progressive Disease
LENALIDOMIDE mg D1-21/28
Lo-DEX mg D1,8,15 & 22/28
PD or Unacceptable Toxicity
Subsequent anti-MM Tx
PD, OS and
Arm A Rd
ARM A
N = 535
n=535
LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE mg D1-21/28
Lo-DEX mg D1,8,15 & 22/28
Arm B
Rd18
n=541
MEL + PRED + THAL 12 Cycles1 (72 wks)
MELPHALAN mg/kg D1-4/42
PREDNISONE mg/kg D1-4/42
THALIDOMIDE mg D1-42/42
The FIRST trial was a randomized multicentre, open-label, pivotal phase III trial with 3 comparison arms.
FIRST was designed to compare the efficacy and safety of Rd, given continuously or for a fixed number of cycles, with MPT.
Patients were stratified according to age (≤75 years vs. >75 years), ISS disease stage (I and II vs. III), and country.
Starting doses of LEN were adjusted based on renal function (20 mg/D  10 mg/D  15 mg/every other day).
Starting doses of DEX were adjusted based on age (40 mg  20 mg).
Starting dose of MEL was adjusted based on age and ANC, platelet count, and renal function (0.25/0.125 mg/kg  0.20/0.10 mg/kg)
Starting dose of THAL was adjusted based on patient age (200 mg  100 mg)
All patients received low-dose aspirin ( mg/day) or other prophylactic anticoagulation throughout the study.
The active treatment and PFS follow-up phase was followed by a long-term follow-up phase to assess OS and the impact of subsequent therapy
Arm C
MPT
n=547
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL mg D1-42/42, Melphalan mg/kg D1–4
n= 1, countries from North America, Asia-Pacific, and Europe represented from 246 Centers
Stratification: age, country and ISS stage
International Staging System; LT, long-term; PD, progressive disease; OS, overall survival
1Facon T, et al. Lancet 2007;370: ; 2Hulin C, et al. JCO. 2009;27:
Facon T. et._ASH 2013: Abstract 2

10. FIRST Trial: Final PFS Continuous Rd  the risk of PFS events (PD or death) by 28% vs. MPT
Median PFS
Rd (n= 535)
25.5 mos
Rd18 (n= 541)
20.7 mos
MPT (n= 547)
21.2 mos
Hazard ratio
Rd vs. MPT: 0.72; P =
Rd vs. Rd18: 0.70; P =
Rd18 vs. MPT: 1.03; P =
Time (months)
Patients (%)
100 80 60 40 20 6 12 18 24 30 36 42 48 54
72 wks
With regard to the primary endpoint, continuous Rd significantly reduced the risk of disease progression by 28% compared with MPT (hazard ratio 0.72; P = )
Continuous Rd also significantly reduced the risk of disease progression by 30% compared with giving Rd for 72 weeks (hazard ratio 0.70; P = )
There was no significant difference in PFS between Rd given for 72 weeks and MPT (hazard ratio 1.03; P = ).
Median PFS was 25.5 months with continuous Rd, compared with 20.7 months with Rd for 72 weeks and 21.2 months with MPT
The benefit was independent of age, gender, race, geographic region, ISS stage, renal function, beta-2-microglobulin level, albumin level, ECOG performance status, lactate dehydrogenase level, and cytogenetic risk. Rd
535
400
319
265
218
168
105 55 19 2
Rd18
541
391
167
108 56 30 7
MPT
547
380
304
244
170
116 58 28 6 1
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone.
Facon T. et._ASH 2013: Abstract 2

11. FIRST Trial: Overall Survival Interim Analysis 574 deaths (35% of ITT)
Overall survival (months)
100 80 60 40 20 6 12 18 24 30 36 42 48 54
Hazard ratio
Rd vs. MPT: 0.78; P = ( 22% risk of death with Rd)
Rd vs. Rd18: 0.90; P = 0.307
Rd18 vs. MPT: 0.88; P = 0.184
4-year OS
Rd (n= 535)
59.4%
Rd18 (n= 541)
55.7%
MPT (n= 547)
51.4%
Patients (%)
At an interim analysis of OS, after a median follow-up of 37 months, 574 deaths (35%) had occurred
Continuous Rd significantly reduced the risk of death by 22% compared with MPT (hazard ratio 0.78; P = 0.017)
4-year OS rates were 59.4% with continuous Rd, 55.7% with Rd given for 72 weeks, and 51.4% for MPT
The pre-specified boundary (p<0.0096) was not crossed for Rd_continuous vs MPT_18 months Rd
Rd18
MPT
535
541
547
488
505
484
457
465
448
433
425
418
403
393
375
338
324
312
224
209
205
121
124
106 43 44 30 5 6 3
Facon T. et._ASH 2013: Abstract 2

12. 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= ) 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
This is the largest registrational phase III trial conducted in transplant ineligible patients with newly diagnosed myeloma comparing Rd (an alkylator-free doublet) vs. the triplet MPT.
Efficacy
The study met its primary endpoint - PFS
Continuous administration of Rd, significantly reduced the risk of progression or death by 28% vs. MPT.
The PFS clinical benefit is associated with an OS advantage associated with continuous Rd vs. MPT.
All other secondary endpoints were positive
Safety
Rd is as good as MPT in regards to safety
Similar safety seen across the arms
Continuous Rd is not associated with increased safety concerns
SPM was higher with MPT vs Rd consistent with previous reports, in which it has been hypothesized that the increased SPM risk in patients treated with lenalidomide may be related to prior or concurrent melphalan use (Palumbo 2012; Attal 2012; McCarthy 2012; Dimopoulos 2012)
Implications & Perspective
Rd should be a new standard of care
Results with a 2-drug regimen at least comparable to that achieved with a 3-drug regimen
Reserve alkylating agents for later in treatment
Future development: novel agents in combination with Rd rather than alkylating agents
Facon T. et._ASH 2013: Abstract 2

13. Efficacy Comparisons CR PFS OS FIRST (Continuous Rd)
(Facon)
FIRST (Rd for 72 wks)
MM-015 (MPR-R)
(Palumbo)
VISTA (VMP arm for 54 wks)
(San Miguel)
VMP lite (for 45 wks)
VMPT-VT
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%
Use of Len maintenance does not increase CR rate
Facon et al. ASH 2013 (Abstract 2), plenary presentation
Palumbo et al. N Engl J Med 2012;366(19):
San Miguel et al. N Engl J Med 2008; 359:
San Miguel et al. J Clin Oncol 2013;31(4):448-55
Palumbo et al. ASH 2012 (Abstract 200), oral presentation
Mateos et al. Blood 2012; 120:

15. Relapsed Disease

16. NEWER THERAPIES: ASH 2013 TOP 8
Anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR (#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)

17. Monoclonal antibodies in MM
Target
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
Signaling molecules
IL-6
RANKL
B cell activating factor (BAFF)
VEGF
DKK1
Siltuximab
Denosumab
Tabalumab
Bevacizumab
BHQ880
Phase 3
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; Wong et al. ASH 2013 (Abstract 505), oral presentation; Hageman et al. Ann Pharmacother 2013;47: ;

18. SAR650984, A CD38 Monoclonal Antibody in Patients with Selected CD38+ Hematological Malignancies Data From a Dose-Escalation Phase I Study (TED10893)*
Thomas G. Martin III1, Stephen A. Strickland2, Martha Glenn3, Wei Zheng4, Nikki Daskalakis5 and Joseph R. Mikhael6
1University of California San Francisco, San Francisco, CA
2Vanderbilt-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
*NCT Trial Sponsored by Sanofi, Cambridge, MA

19. SAR650984: A Humanized IgG1 Monoclonal Antibody
1. Antibody-dependent
cellular cytotoxicity (ADCC) and phagocytosis (ADCP)
2. Complement-dependent cytotoxicity (CDC)
NK cell,
Macrophage
4. CD38 enzymatic activity inhibition
3. Direct apoptosis induction without crosslinking
NAD
cADPR
ADPR
Antibody
Fc Receptor
Complement 19

20. SAR650984: Phase I Dose Escalation Study
Primary Objective
Determine maximum tolerated dose (MTD)/maximum administered dose (MAD)
Secondary Objective
Characterize safety profile
Evaluate pharmacokinetic (PK) profile
Assess pharmacodynamics, immunogenicity, and preliminary disease response

21. SAR650984: Baseline Characteristics
39 treated patients
Median age = 65.0 ( )
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
Accelerated
Doses
0.3 mg/kg
Q2W
1 mg/kg
3 mg/kg
5 mg/kg
10 mg/kg
10 mg/kg QW
20 mg/kg
Overall
# of Patients (# of Myeloma patients)
6 (5)
7 (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)
(2 - 9)
8.5
(4 -13)
(4 - 7)
(1- 14)
Prior carfilzomib 3 1 2 12
Prior pomalidomide
At doses of 10mg/kg and higher; 69% received carfil & pom
Eight of them took carfilzomib before, with 1 CR, 1 PR and 1 MR. Three of them took pomalidomide before, but none of them responded.

22. Mandatory Prophylaxis in All Patients*
SAR650984: Patients with Infusion Reactions Patients treated at doses of 0.3 mg/kg Q2W or higher
Mandatory Prophylaxis in All Patients* 7
Number of Patients
No infusion reaction
Grade 1 6
Grade 2 5 4 3 2 1
C = Cycle C1
C>11 C1
C>1 C1
C>1 C1
C>1 C1
C>1 C1
C>1 C1
C>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
*methylprednisolone 100 mg IV, diphenhydramine 50 mg IV, ranitidine 50 mg IV, and acetaminophen mg po (or equivalents)
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)

23. CR PR MR SD PD NA
SAR650984: Time on Treatment by Best Response Myeloma Patients Treated at Doses of 1 mg/kg Q2W or higher CR * PR MR SD
1 mg/kg Q2W
3 mg/kg Q2W PD
5 mg/kg Q2W
As of 24Oct2013 Patient still in CR (24 weeks)
10 mg/kg Q2W
10 mg/kg QW
20 mg/kg Q2W NA 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Week
* Off study since 23May2013 due to patient decision.
Ongoing

24. SAR650984: Phase 1 Response Summary
CBR:38.5%
ORR: 30.8%

25. 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 ( )
6 patients still on treatment
Median duration of follow up is 6.5 months ( )

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