1. Update on Novel Combinations for Relapsed/Refractory Disease: Approved Drugs
James R. Berenson, MD
Medical & Scientific Director
Institute for Myeloma & Bone Cancer Research
Los Angeles, CA

2. Treatment Choices + + + + + + + Anthracyclines Thal Bortezomib
Doxorubicin
PLD
Thal
Bortezomib
Carfilzomib
Chemotherapy
IMiDs
Proteasome
inhibitors
Pom + + + + + +
Len
Steroids
Clarithromycin
Alkylating agents
Melphalan
Cyclophosphamide
Bendamustine
Dex
Methylpred +
Prednisone
Clinical Trials
Novel Combinations
Investigational Drugs

3. Individualize your choice for the myeloma patient based on:
How active is the patient?
Mobility?
Is potential neuropathy an issue? (e.g.- surgeon, pianist)
Responseand for how long?
Side effects and tolerability
Work/ Lifestyle
Prior Treatments
Diabetes mellitus (steroids)
Cardiac (Doxorubicin, PLD)
Neuropathy
(Thalidomide)
Renal,
Bone,
Marrow,
Subjective,
Rate of ProgressionGenetics?
Disease characteristics
Co-morbid conditions

4. Principles of Treating Relapsed/Refractory Multiple Myeloma
Be sure a patient has really progressed before changing therapy
REPEAT MYELOMA LABS!
Try to use drugs patient has not seen before
HOWEVER,
progression on one drug in combination does not mean that drug will not be effective w/ another agent
e.g., pts progressing from bortezomib w/ melphalan often respond to bortezomib w/ PLD
Even different drugs in the same class may be active so that
bortezomib+melphalan failures may respond to other alkylating agents- cyclophosphamide or bendamustine
LEN failures may respond to THAL and vice versa
pts progressing from a drug at one dose may respond to the same drug at a higher dose- e.g., LEN
the same combination may be effective again if the patient has not seen the combination in a long time

5. Single Agent Bortezomib Relapsed/Refractory Multiple Myeloma
Initial approval in multiple myeloma based on phase II data
Only single agent to demonstrate a statistically significant survival advantage (APEX)
Study
Regimen
Evaluable Patients (n)
Overall Response*
Median OS (mos)
SUMMIT
Bortezomib
1.3 mg/m2
202
27% 17
CREST
1.0 mg/m2 54
30%
38%
26.7
Not yet reached
APEX
Dex
40 mg
315
312
43%
18%
29.8
23.7
PHASE II
PHASE III
P = .0272
*EBMT criteria 5

6. Efficacy and Safety of Bendamustine plus Bortezomib in R/RMM: A Phase 1/2 trial
Patients were assigned to one of 3 cohorts receiving doses of intravenous bendamustine at 50 mg/m2 (cohort 1), 70 mg/m2 (cohort 2), or 90 (cohort 3) mg/m2 in combination with a fixed dose of intravenous bortezomib (1.0 mg/m2) according to the schedule in Figure 1.
Berenson et al., Brit J Haematol, in press

7. Bendamustine & Bortezomib: Results
No DLT was observed at any dose level.
50 mg/m2 (n = 5)
70 mg/m2 (n = 4)
90 mg/m2 (n = 5)
The maximum dose of bendamustine (90 mg/m2) was well tolerated in combination with bortezomib 1.0 mg/m2 and was designated as the MTD
Overall response rate
Overall 48% (1 CR, 2 VGPR, 9 PR, & 7 MR)
At MTD (90 mg/m2) 52%
Bortezomib-exposed (n=31) 42%
Alkylator-exposed (n=28) 46%
Berenson et al., Brit J Haematol, in press

8. Bendamustine (B) w/ Lenalidomide (L) and Dexamethasone (D): Phase 1/2 Trial
R/R MM patients
N=29
Regimen (28-day cycles)
B mg/m2 d1 & 2
L 5-10 mg qd d1-21
Dex 40 mg PO weekly
MTD: B 75/ L 10/ D 40
Results (only 25 considered evaluable for response)
ORR (> PR): 52% w/ 24% VGPR
MR 24%
PFS: 6.1 mo
Lentzsch et al. Blood 2012

9. Bortezomib + PLD vs. Bortezomib in Previously Treated MM
1° Endpoint: TTP 2° Endpoints: OS*, ORR
N=646
(n=322)
RANDOMI ZE
q 3 weeks up to 8 cycles
Days 1 4 8 11
q 3 weeks up to 8 cycles
(n=324)
BORT 1.3 mg/m2 PLD 30 mg/m2
*Not enough events to determine statistical significance in overall survival.
ORR=overall response rate; OS=overall survival; TTP=time to progression.
Doxorubicin HCl liposome injection Prescribing Information, Rev’d May 2007 9

10. Bortezomib ± PLD MMY-3001 Trial
*By EBMT criteria
Response* B
(n = 322)
B+D
(n = 324)
P value
CR + nCR
11%
13% PR
39%
40%
ORR
41%
44%
0.43
Efficacy
DOR, months
7.0
10.2
0.0008
TTP, months
6.5
9.3
An overall survival advantage was observed for the combination arm (P=0.0476)
Survival rate (15 months)
65%
76%
0.03
Orlowski et al. J Clin Oncol 25: (2007) 10

11. More Frequent Dosing with PLD Improves Anti-Myeloma Effect in a SCID-hu MM Model
Weekly Dosing1
Daily Dosing2
1Twenty days post-implantation, mice received i.p. injection of PLD once weekly. Human IgG was measured weekly in the mouse serum by ELISA.
2Seventeen days post-implantation, mice received i.p. injection of PLD once daily for three consecutive days weekly. Human IgG was measured weekly in the mouse serum by ELISA.
Campbell et al. Br J Haematol 2006

12. Bortezomib + PLD + Dexamethasone for Patients with Previously Untreated Myeloma: A Phase II Trial
Dexamethasone 40 mg IV
Bortezomib: 1.0 mg/m2 IV
Cycle repeats
PLD: 5 mg/m2 IV infusion
Days
Berenson et al. Brit J Haematol, 2011 12

13. DVD: Response Rates Response Type Number of Patients (N = 35)
Complete Response (CR)
(no serum M-protein)
7 (20%)
Very Good Partial Response (VGPR)
(≥ 90% decrease in serum M-protein)
3 (8.6%)
Partial Response (PR)
(50-74% decrease in serum M-protein)
15 (42.9%)
Minor Response (MR)
(25-49% decrease in serum M-protein)
5 (14.3%)
Objective Response (CR+VGPR+PR+MR)
30 (85.8%)
Stable Disease (SD)
Disease Control (CR+VGPR +PR+MR+SD)
33 (94.4%)
Progressive Disease (PD)
(>25% increase in serum M-protein)
2 (5.7%)
Berenson et al. Brit J Haematol, 2011

14. Comparison of Adverse Events w/ Modified DVD vs Conventional Dosing
Adverse Event Comparison Between DVD (Current Study) and Standard Dosing (Jakubowiak et al., Blood 2009).

15. Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up1
Endpoints: Primary: PFS; Secondary: ORR (≥MR), DOR, TTP, OS, safety
Patients: 64 pts with relapsed/refractory MM; median age 65 years (range 32–83); ISS stage I/II/III/unknown (%): 27/25/23/25; median 2 (range 1–3) prior therapies
Study design:
Anticoagulation with aspirin ± warfarin or LMWH, and antiviral prophylaxis against herpes zoster were required 15
Richardson PG et al. ASH 2010, abstract #3049 15

16. Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up
Results: 62 pts evaluable for response
Outcomes
Median, mos
1-yr, %
2-yr, %
TTP
9.5 37 16
PFS 36 15 OS 26 86 55
Best response,%
CR/nCR
11/14
PR/VGPR
36/3
ORR (≥MR) 78
Median duration of ≥MR: 8.3 months
Median duration of ≥PR: 8.4 months
Gr ≥3 AE, %
VRD (n=64)
Neutropenia 30
Thrombocytopenia 22
Lymphopenia 11
Leukopenia 9
Hyperglycemia
Hyponatremia 8
Hypophosphatemia
Fatigue 5
Diarrhea 3
Limb edema
Pain in extremity 2
Safety:
Median cycles received: 11 (range 1–48)
Median treatment duration: 7.9 months (range 0.4–36); 66% of pts completed ≥8 cycles with all three drugs
Richardson PG et al. ASH 2010, abstract #3049 16 16

17. DVD-R (Bortezomib + PLD + Dexamethasone + Lenalidomide) for Patients with R/R MM: A Phase II Trial
Dexamethasone 40 mg IV
Bortezomib: 1.0 mg/m2 IV
Cycle repeats
PLD: 4 mg/m2 IV infusion
Days
Len 10 mg po qd d1-14
Berenson et al., Leukemia 2012

18. Percent w/o Progression
DVD-R: Response Rate
N=39
Complete Response (CR)
8* (21%)
(no serum M-protein)
Very Good Partial Responses (VGPR)
4 (10%)
(> 90% decrease in serum M-protein)
Partial Response (PR)
7 (18%)
(50-74% decrease in serum M-protein)
Minor Response (MR)
14 (36%)
(25-49% decrease in serum M-protein)
Objective Response (CR+VGPR+PR+MR)
30 (85%)
Stable Disease (SD)
(change in M-protein + 25%)
Disease Control (CR+VGPR+PR+MR+SD)
37 (95%)
Progressive Disease (PD)
2 (5%)
(>25% increase in M-protein)
*Based on the modified Blade’ criteria
Percent w/o Progression
*Based on the modified Blade’ criteria
*Based on the modified Blade’ criteria
*Based on the modified Blade’ criteria

19. DVD-R Study: Adverse Events
Grade 3 adverse events included:
6 reversible neutropenia, 4 reversible anemia, 4 pneumonia,
1 dyspnea, 3 reversible thrombocytopenia,
1 reversible peripheral neuropathy, 1 mental confusion,
1 hypophosphatemia, 1 fall, 1 skin BCC, 1 allergic reaction to moxifloxacin,
1 dysphagia, 1 syncope, 1 respiratory distress.
Grade 4 adverse events included:
1 reversible thrombocytopenia & 1 anemia
No cases of stomatitis or hand-foot syndrome reported!
Treatment-emergent peripheral neuropathy (25%):
Grade 1: n=8 (20%)
Grade 2: n=1 (2.5%)
Grade 3: n=1 (2.5%)
Percent w/o Progression

20. Retreatment w/ IMiDs for MM Patients
Retrospective study in 140 pts treated firstline w/
THAL/DEX- 58%
LEN/DEX- 42%
Retreatment w/ a regimen containing
THAL- 24%
LEN- 76%
# of treatments before retreatment median of 2 (range 1-6)
89% received IMiD w/ DEX
113 considered evaluable for response
44% > PR
MR not reported
LEN
(n=48)
THAL
(n=11)
(n=58)
THAL (n=23)
> PR
54%
20%
48%
30%
Madan et al. Blood 2011

22. PX-171-003: Study Overview Phase 2 Study Population
Study expanded to registration trial
Phase 2 Study Population
PX A1 (N=266)
PX A0 (N=46)
Progressive disease required at study entry
Relapsed from ≥2 prior lines of therapy
Must include bortezomib
Must include thalidomide or lenalidomide
Refractory to last regimen
Carfilzomib for Injection*
days 1,2,8,9,15,16
(28-day cycles)
Maximum 12 cycles
Dosing regimen, premedication, and hydration were defined in 003-A0
*Cycle 1, 20 mg/m2
Cycle 2 and beyond, 27 mg/m2
Primary endpoint: Overall response rate
Assessed by an Independent Review Committee, using International Myeloma Working Group criteria
Adapted from Siegel D, et al. ASCO Abstract 8027 (poster presentation). 22

23. PX-171-003-A1 (N=266): Disease characteristics
Median prior regimens (range)
5 (1-20)
Median years since diagnosis (range)
5.35 ( )
Prior transplant
74.4%
Refractory status to most recent therapy
Refractory: Progression during most recent therapy
Refractory: Progression within 60 days after completion of most recent therapy
Refractory: ≤25% response to treatment
Relapsed: Progression after 60 days post treatment
14.3%
6.0%
5.3%
Creatinine clearance <30 mL/min
2.3%
Median serum b2-microglobulin (range)
4.3 ( )
Cytogenetics
Normal/Favorable
Unfavorable
Unknown
59.8%
28.2%
12.0% 23

24. PX-171-003-A1: Response N=266 Response rates*
Overall response rate (ORR)
Complete response
Very good partial response
Partial response
61 (22.9%)
1 (0.4%)
13 (4.9%)
47 (17.7%)
Median duration of response
(95% CI)
7.8 months
( )
*As assessed by the Independent Response Review Committee 24

25. Carfilzomib in MM Patients Following 1-3 Prior Therapies
Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
Carfilzomib in MM Patients Following 1-3 Prior Therapies
004, Phase II
1:1
Carfilzomib
Cohort 1
20 mg/m2
Relapsed / Refractory Multiple Myeloma
1-3 Prior Therapies
N = 165
Cohort 2
20 mg/m2→27 mg/m2
Bortezomib-treated
Bortezomib-naïve
Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles
Bortezomib-naïve
Bortezomib-treated N
129 36
Median age
65 years
63 years
Median # prior therapies 2 3
Stewart AK, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8026. Stewart K, et al. Hematologica. 2010;95(S2). Abstract Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813. 25

26. Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies
Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies
Bortezomib-Treated
Cohort 1 (20 mg/m2 Carfilzomib)
n = 34
ORR
21%
CBR (> MR)
33%
Median TTP
8.1 months
Median DOR (> PR)
11.5 months
Bortezomib-naïve
Cohort 1 (20 mg/m2)
n = 59
Cohort 2 (20→27 mg/m2)
n = 70
ORR
42%
52%
CBR
59%
64% CR 3% 2%
VGPR
14%
27%
Median TTP
8.3 mo
Not reached
Median DOR
13.1 mo
Median PFS
8.2 mo
Stewart K, et al. Hematologica. 2010;95(S2). Abstract Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813. 26

28. Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed / Refractory MM
Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed / Refractory MM
Carfilzomib
Lenalidomide
Low-dose dex
MM: 1-3 Prior Therapies
N = 52
1o Endpoint
ORR
2o Endpoint
DOR, TTP, OS, PFS, Safety
CRd
N = 51
Median age
63 years
Median # of prior therapies
Prior bortezomib
Prior lenalidomide
Prior lenalidomide and bortezomib
Prior thalidomide 2
85%
73%
50%
44%
Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025. 28

29. Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed/Refractory MM
Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed/Refractory MM
Response
CRd
N = 51
ORR
78%
CR / nCR
24%
VGPR
18% PR
37%
Grade 3/4 Adverse Events
CRd
N = 51
Neutropenia
23%
Thrombocytopenia
15%
Anemia
Hypophosphatemia
13%
Fatigue
12%
ORR, overall response rate; CR, complete response; nCR, near complete response; VGPR, very good partial response; PR, partial response.
Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025. 29

30. Nontraditional intrapatient Phase I/II trial
A Phase I/II Study of Carfilzomib as a Replacement for Bortezomib for Multiple Myeloma Patients Failing Bortezomib-Containing Regimens
Nontraditional intrapatient Phase I/II trial
Eligibility: Progressive disease while on bortezomib or relapsed within 12 wks of the last dose of bortezomib in a combination regimen
Carfilzomib replaces bortezomib in combination with:
Alkylating agent
Anthracycline
Glucocorticosteroid
IMiD

31. Study Design (cont’d) Study treatment
Carfilzomib
starting at 20 mg/m2 for the 1st cycle
increased to 27, 36 and 45 mg/m2 during cycles 2, 3 and 4, respectively if no DLT is observed
DLT considered > Grade 2
administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle
Cycle length, schedule(s) and dose(s) of other drugs identical to that of the previous bortezomib-containing regimen
A patient must complete a minimum of a full cycle without DLT before continuing onto a subsequent cycle (cycles 1-4 only)
Maximum # of cycles- 8

32. Results Demographics Enrolled (N) 32 Efficacy (N) 24 Age (median) 67
Sex (M:F)
21:11
Prior Regimens
Number of prior regimens- median (range)
6 (1-18)
Number of prior bortezomib-containing regimens- median (range)
2 (1-13)
Regimen Details
Cycle length
8 pts day
24 pts- 28-day
Cycles completed, median (range)
(range 0-12)
Follow-up median
(range)
5.9 mo
( mo)
Number of DLTs
8 (25%)

33. Regimen in addition to carfilzomib (N=32)
Dexamethasone
9 (28%)
Cyclophosphamide+ ascorbic acid
5 (16%)
Cyclophosphamide+ascorbic acid+dexamethasone
1 (3%)
Melphalan
Bendamustine
3 (9%)
Bendamustine+methylprednisolone
PLD
PLD+dexamethasone
Lenalidomide
2 (6%)
Lenalidomide + dexamethasone
Lenalidomide + dexamethasone + PLD
1 (3%
Thalidomide + dexamethasone
Thalidomide + lenalidomide + bendamustine + clarithromycin + methylprednisolone

34. Efficacy (N=24) PD 2 8% SD 4 17% MR 5 21% PR 7 29% VGPR CR
Best Response
# of Patients % PD 2 8% SD 4
17% MR 5
21% PR 7
29%
VGPR CR
Overall Response Rate
(PR+VGPR+CR) 13
54%
Clinical Benefit Rate
(MR+PR+VGPR+CR) 18
75%

35. Summary
Intrapatient Phase I/II trial of MM patients refractory to bortezomib combination therapy with and without IMiDs
Treatment with same regimen w/ carfilzomib (CAR) replacing bortezomib
CAR escalated from 20 to 27, 36, and 45 mg/m2 during cycles 1-4; maximum of 8 cycles
MTD for one regimen (CY+CAR) reached at the maximum dose of CAR (45 mg/m2) with no DLT
Well tolerated
Clinical benefit rate 75% including 8% CR, 17% VGPR, 29% PR, & 21% MR
Responses observed with all drugs!

36. A Phase I/II Trial of Weekly Carfilzomib in Combination With IV Dexamethasone for R/R Multiple Myeloma
Phase I/II, open-label, multi-center trial investigating weekly carfilzomib + dexamethasone in R/R MM patients
Phase I:
28-day cycle
Carfilzomib 45, 56 or 70 mg/m2 on days 1, 8 & 15
Dexamethasone IV at 40 mg days 1, 8, 15, & 22
Phase II:
Carfilzomib at MTD on days 1, 8 & 15
Enrollment: second cohort (56 mg/m2) currently being treated!

37. Bortezomib + Vorinostat
HDAC Inhibitor Vorinostat & Bortezomib for R/R MM: VANTAGE 088: Phase III Trial
Bortezomib + Vorinostat
Multiple Myeloma
1-3 Prior Therapies
N = 637 R
Bortezomib + Placebo
Bortezomib + Vorinostat
Bortezomib + Placebo P
ORR
56%
41%
<
CBR
71%
54%
Median PFS
7.63 mo
6.83 mo
< 0.01
Median OS NR
28.1 mo
0.35
ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival.
Dimopoulos MA, et al. ASH Annual Meeting Abstracts. 2011;118(21):811.

38. Vorinostat, Lenalidomide & Dexamethasone for R/R MM
Vorinostat (300 or 400 mg, 1x daily)
Lenalidomide (10, 20, 25 mg daily)
Dexamethasone (40 mg weekly)
Relapsed / Refractory MM
N = 28
1:1
Response
Vorinostat / Lenalidomide / Dexamethasone
N = 28
ORR
46% CR 7%
> SD
86%
Serious AE
Neutropenia, diarrhea, ↑ QTc, extrasystole, dehydration, ↑ troponin, fever
Grade 3 DVT in 2 patients
No treatment-related deaths
Siegel D, et al. Blood. 2009;114(22). Abstract 305. Vorhees PM, et al. Blood. 2009;114(22). Abstract 306.

39. Novel Combinations of Approved Drugs Greatly Expand the Therapeutic Options for R/R Myeloma Patients!
Approved drugs
Novel combinations
Modifications of dose and schedule
Improve efficacy
Better tolerability
Many new drugs in development
Similar targets
Proteasome inhibitors- carfilzomib (FDA-approved!)
IMiDs- pomalidomide
New classes of agents
HDAC inhibitors- vorinostat, panobinostat
Monoclonal antibodies
Anti-CS-1- elotuzumab
Anti-CD40- dacetuzumab
MTOR inhibitors- temsirolimus
PI3K inhibitors- perifosine