1. Developments in the Treatment of Multiple Myeloma
Kenneth C. Anderson, M.D.
Kraft Family Professor of Medicine
Harvard Medical School
Director, Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute

2. Conflict of Interest: Kenneth C. Anderson, M.D.
Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead
Scientific Founder: Acetylon, Oncopep

3. Integration of Novel Therapy Into Myeloma Management
Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib, Pomalidamide
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
Nine FDA approvals in the last decade and median survival prolonged from 2-3 yrs to at least 5-7 yrs, with additional prolongation seen from maintenance
New approaches needed to treat and ultimately prevent relapse

5. Chromosomes and Prognosis
in Multiple Myeloma
For conventional low and high dose theapy:
Nonhyperdiploid worse prognosis than hyperdiploid
t(11;14), hyperdiplody -standard risk
t(4;14), t(14;16),t(14;20), del(17p), del(13q14)-high risk
For novel treatments
Bortezomib, but not lenalidomide, can at least partially overcome t(4;14), del(13q14)-
del(17p) p53 remains high risk

6. Combinations in the Upfront Treatment of MM
Stewart AK, Richardson PG, San Miguel JF Blood 2009

7. Lenalidomide and Bortezomib/Lenalidomide-Based Consolidation
Study details
Response data
IFM
Len consolidation (2 mos)
Maintenance randomization: Len vs placebo
IFM 20082
VRD induction
ASCT
VRD consolidation (2 cycles)
Len maintenance
n=572
Pre-consolidation
Post-consolidation p
CR (IF–)
14%
20%
<0.0001
≥ VGPR
58%
67%
n=31
Post-induction
Post-ASCT
Post-consolidation
sCR
13%
26%
38% CR
10%
≥ VGPR
62%
68%
84%
≥PR
94%
91%
1Attal et al. Haematologica 2011; 96 (s1): S23; oral presentation at IMW 2011
2Roussel et al. ASH 2010 (Abstract 624), oral presentation

8. CALGB 100104:LEN Maintenance significantly prolonged PFS & OS vs
CALGB :LEN Maintenance significantly prolonged PFS & OS vs. placebo
PFS OS
ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo. McCarthy PL. N Engl J Med. 2012;366:

9. Lenalidomide Maintenance Therapy Meta-Analysis
Oral Abstract #407 - Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized Trials Monday, December 9, 2013: 11:30 AM
There was significant prolongation of both PFS (HR 0.49, 95% CI, 0.41–0.58, p<0.001) and OS (HR 0.77, 95% CI, 0.62–0.95, p=0.013) with LM vs. placebo/no maintenance
Singh M, et al. ASH Abstract 407.

10. Bortezomib induction and maintenance in ASCT
NDMM, TE, sge 18–65 y
Bortezomib
1.3 mg/m2
i.v.
Doxorubicin
9 mg/m2
Dexameth
40 mg
Randomization
3 x VAD
3 x PAD
CAD + GCSF
CAD + GCSF
MEL PBSCT
MEL PBSCT
In GMMG 2nd
MEL PBSCT
Allogeneic Tx
In GMMG 2nd
MEL PBSCT
Thalidomide
maintenance 50 mg/day for 2 years
Bortezomib
Maintenance
1.3 mg/m2 / 2 weeks for 2 years
Sonneveld et al, ASH 2013 10

11. Results
Bortezomib-based treatment consistently improves PFS (median 27 m vs 36 m) and OS (median 84 m vs not reached, p=0.05) in patients with newly diagnosed MM who are transplant eligible
Bortezomib significantly improves the long-term outcome of patients presenting with renal failure (p<0.001)
Sonneveld et al, ASH 2013

12. Carfilzomib With Thalidomide and Dexamethasone in ASCT
Intensification* (1 cycle)
Induction (4 28-day cycles)
Consolidation (4 28-day cycles)
Carfilzomib, 20/27 mg/m2
Days 1,2,8,9,15,16
Carfilzomib, 27 mg/m2
Days 1,2,8,9,15,16
Phase II open-label
dose-
escalation
trial (N=70)
Thalidomide, 200 mg
Days 1-28
Thalidomide, 50 mg
Days 1-28
C, cyclophosphamide; CPR, cyclophosphamide/prednisone/lenalidomide; d, low-dose dexamethasone; M, melphalan; MPR, melphalan/prednisone/lenalidomide; NDDM, newly diagnosed multiple myeloma; P, prednisone; qod, every other day; R, lenalidomide; Rd, lenalidomide/low-dose dexamethasone.
Dexamethasone, 40 mg
Days 1,8,15,21
Dexamethasone, 40 mg
Days 1,8,15,21
*High-dose melphalan 200 mg/m2 plus ASCT
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.
Sonneveld P, et al. ASH Abstract 688.

13. Carfilzomib/Thalidomide/ Dexamethasone: Response and AEs
Patient Response, %
High-risk* Patients
Standard Risk Patients
All Patients
CR/sCR 57 48 51
≥VGPR 90 76 84 PR 96
*t(4;14) and/or del(17p) and/or 1q and/or ISS3.
Grade 3/4 AEs ≥ 5% by carfilzomib dose:
20/27 mg/m2=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
Sonneveld P, et al. ASH Abstract 688.

14. Substantial improvements in PFS and OS
Impact of Novel Agents in the Treatment of Elderly Pts with Newly Diagnosed MM
Substantial improvements in PFS and OS
Median PFS (mos)
Median OS (mos)
MP1-8
11–20
29.1–49.4
MPT1-6
15–27.5
29–51.6
VMP7,8,11
21.7–27.4
68.5% (3-yr OS)*
MPR-R9 31
N/A
VMP-VT/VP10 34
74% (3-yr OS)*
VMPT-VT11
37.2
85% (3-yr OS)*
*Median OS not reached
N/A: not available
1Palumbo et al. Blood 2008; 112:3107–3114
2Facon et al. Lancet 2007; 370:1209–1218
3Hulin et al. J Clin Oncol 2009; 27:
4Waage et al. Blood 2010; 116:
5Wijermans et al. J Clin Oncol 2010; 28:3160-6
6Beksac et al. Eur J Haematol 2011;86:16-22
7San Miguel et al. N Engl J Med 2008; 359(9): 906–917; Supplementary Appendix
8Mateos et al. J Clin Oncol 2010; 28(13):
9Palumbo et al. ASH 2010 (Abstract 622)
10Mateos et al. Lancet Oncol 2010; 11(10):
11Palumbo et al. ASH 2010 (Abstract 620)

15. Active Treatment + PFS Follow-up Phase PD or Unacceptable Toxicity
FIRST Trial: Study Design
Screening
Active Treatment + PFS Follow-up Phase
LT Follow-Up
RANDOMIZATION 1:1:1
LEN + Lo-DEX Continuously
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
Continuous Rd
Arm B
Rd18
LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE mg D1-21/28
Lo-DEX mg D1,8,15 & 22/28
MEL + PRED + THAL 12 Cycles1 (72 wks)
MELPHALAN mg/kg D1-4/42
PREDNISONE mg/kg D1-4/42
THALIDOMIDE mg D1-42/42
Arm C
MPT
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
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL mg/kg D1–4
Stratification: age, country and ISS stage
ISS, 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 al. Blood. 2013;122:abstract 2.

16. FIRST Trial: Final Progression-free Survival
Median PFS
Rd (n=535)
25.5 mos
Rd18 (n=541)
20.7 mos
MPT (n=547)
21.2 mos
100 80 60 40 20
Hazard ratio
Rd vs. MPT: 0.72; P =
Rd vs. Rd18: 0.70; P =
Rd18 vs. MPT: 1.03; P =
Patients (%)
42% (Rd)
23% (Rd18)
23% (MPT)
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. 6 12 18 24 30 36 42 48 54 60
Time (months) 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 al. Blood. 2013;122:abstract 2.

17. FIRST Trial: Consistent PFS Benefit Across Subgroups
Hazard ratio (HR) and 95% CI
HR (95% Cl)
Age > 75
Age ≤ 75
Gender: female
Gender: male
Asia
Europe
North America and Pacific
ISS stage: I or II
ISS stage: III
CrCI < 30 ml/min
CrCI 30 – 50 ml/min
CrCI 50 – 80 ml/min
CrCI ≥ 80 ml/min
ECOG PS Grade 0
ECOG PS Grade 1
ECOG PS Grade 2
LDH < 200 IU/l
LDH ≥ 200 IU/l
Cytogenetics High-risk
Cytogenetics Non-high Risk
ITT patients
0.81 ( )
0.68 ( )
0.73 ( )
0.71 ( )
0.61 ( )
0.77 ( )
0.64 ( )
0.70 ( )
0.75 ( )
0.76 ( )
0.66 ( )
0.74 ( )
0.71 ( )
0.54 ( )
0.81 ( )
0.80 ( )
0.69 ( )
0.96 ( )
1.23 ( )
0.69 ( )
0.72 ( )
The PFS benefit of continuous Rd over MPT was independent of most baseline characteristics, including age, gender, race, geographic region, ISS stage, renal function, beta-2-microglobulin level, albumin level, ECOG performance status, and cytogenetic risk (please confirm High-risk cytogenetics)
0.125
0. 25
0.5 1 2 4 8
Favoring Rd
Favoring MPT
ITT, intention to treat; ITT comparison for continuous Rd vs. MPT
Facon T, et al. Blood. 2013;122:abstract 2.
Cytogenetics high-risk included t(4;14), t(14;16), del(17p)

18. FIRST Trial: TTP and Time to 2nd Anti-myeloma Therapy
Time to Progression
Time to 2nd AMT
Median Time to 2nd AMT
Rd (n=535)
39.1 mos
Rd18 (n=541)
28.5 mos
MPT (n=547)
26.7 mos
Median TTP
Rd (n=535)
32.5 mos
Rd18 (n=541)
21.9 mos
MPT (n=547)
23.9 mos
TTP (months)
Patients (%)
100 80 60 40 20 6 12 18 24 30 36 42 48 54
Hazard ratio
Rd vs. MPT: 0.68; P=
Rd vs. Rd18: 0.62; P≤
Rd18 vs. MPT: 1.11; P=
100 80 60 40 20
Patients (%)
Hazard ratio
Rd vs. MPT: 0.66; P<
Rd vs. Rd18: 0.74; P=
Rd18 vs. MPT: 0.88; P=
Similar results were seen in terms of time to progression (TTP) and time to 2nd line antimyeloma therapy (TAMT)
Continuous Rd significantly prolonged TTP and TAMT compared with MPT
TTP: 32.5 vs 23.9 months; hazard ratio 0.68; P =
TAMT: 39.1 vs 26.7 months; hazard ratio 0.66; P <
Continuous Rd also significantly prolonged TTP and TAMT compared with Rd given for 72 weeks
There was no significant difference in TTP and TAMT between Rd given for 72 weeks and MPT
Curves are separating early for Time to 2nd AMT continuous Rd vs. MPT
Time to 2nd AMT clearly illustrates that the choice of prior Tx matters 6 12 18 24 30 36 42 48 54 60
Time to 2nd AMT (months) Rd
Rd18
MPT
535
541
547
398
389
379
318
317
303
263
265
242
218
167
169
108
115
105 56 58 55 30 28 19 7 6 2 1 Rd
Rd18
MPT
535
541
547
445
451
422
371
375
351
319
331
293
275
266
239
224
181
177
142
111
101 77 61 42 28 16 9 3 2 1
Facon T, et al. Blood. 2013;122:abstract 2.

19. FIRST Trial: Conclusions
Continuous Rd significantly extended PFS, with an OS benefit vs. MPT
PFS:
HR= 0.72 (P= )
Consistent benefit across most subgroups
Rd better than Rd18 (HR= 0.70, P= )
3 yr PFS: 42% Rd vs. 23% Rd18 and MPT
Planned interim OS: HR= 0.78 (P= )
Rd was superior to MPT across all other efficacy secondary endpoints
Safety profile with continuous Rd was manageable
Hematological and non-hematological AEs were as expected for Rd and MPT
Incidence of hematological SPM was lower with continuous Rd vs. MPT
In NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care
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 al. Blood. 2013;122:abstract 2.

22. A total of one hundred fifty two of patients were enrolled, we performed at baseline a geriatric assessement using 3 scales: Charlson index, ADL, IADL.
Bortezomib was administrated subcutaneously at 1.3 mg/sqm with the weekly schedule with prednisone 50 3 times for week or plus melphalan 2 mg 3 times for week or with ciclofosfamide 50 3 times for week. All patients underwent to the maintenance phase with bortezomib days 1 and 15 until progression disease or intolerance
Larocca et al ASH 2013

23. The same trend was seen in term of PFS and OS

24. Taking in account that mean age of global population is increasing and comorbidities, frailty and disability are growing consequently; in our study of elderly MM patients PFS and OS appeared similar between the 2 drug and three drug combinations, in term of safety melphalan is more toxic then ciclofosfamide.
Geriatric assessment permitted to find out 3 different patient categories that could help clinical decision of therapeutic strategies, in particular fit patients who could benefit from full dose therapy, unfit patients who could receive a reduced-dose therapy and frail patients for whom we should consider a further reduced strategy.
Larocca et al, ASH 2013

25. Bringhen et al ASH 2013

26. Bringhen et al ASH 2013

27. Oral MLN 9708 Len Dex in Newly Diagnosed MM
Induction: up to 16 x 21-day treatment cycles
Maintenance 1 2 4 5 8 9 11 12 15 21
MLN9708
MLN9708
MLN9708
MLN9708
MLN9708 maintenance
Days 1, 4, 8, 11
21-day cycles
Dex*
Dex*
Dex*
Dex*
Lenalidomide 25 mg, days 1–14
*Dex 20/10 mg cycles 1–8 / 9–16
Thromboembolism prophylaxis with aspirin 81–325 mg QD or LMWH while receiving len-dex mandatory
Phase 1: oral MLN9708 dose-escalation (dose of 3.0 and 3.7 mgs)
Standard 3+3 schema, 33% dose increments, based on cycle 1 DLTs
Phase 2: oral MLN9708 at the RP2D from phase 1
Stem cell collection allowed after cycle 4, with ASCT deferred until after 8 cycles
MLN9708 maintenance continued at tolerated dose until progression or unacceptable toxicity
Richardson et al ASH 2013

28. % decreases in M-protein Subject identifier for the study
Ixazomib lenalidomide dexamethasone in newly diagnosed multiple myeloma
Dose level (cohort): Ph 1, 3.0 mg Ph 2, 3.0 mg
–20
–25%
–40
% decreases in M-protein
–50%
–60
–80
–90%
–100
Subject identifier for the study
56 pts treated at the RP2D were evaluable for response (7 phase 1, 49 phase 2)
61% of pts had 100% decreases in M-protein or serum free light chain from baseline
Richardson et al ASH 2013

30. Pomalidomide With Low-Dose Dexamethasone Relapsed and Refractory Multiple Myeloma
POM was effective in heavily pretreated patients who had already received LEN and bortezomib and who progressed on their last line of therapy
The combination of POM with LoDEX improves the ORR due to synergy between immunomodulatory agents and glucocorticoids
POM + LoDEX, 34%; POM alone, 15%
Response was durable with POM regardless of the addition of LoDEX
POM + LoDEX, 8.3 months ; POM alone, 8.8 months
POM is generally well tolerated, with low rates of discontinuations due to AEs
Age had no impact on ORR, DoR, or safety
Jagannath S, et al. ASH 2012 abstract 450.

31. MM-003 Design: POM + LoDEX vs. HiDEX
POM: 4 mg/day D1-21 +
LoDEX: 40 mg (≤ 75 yrs) mg (> 75 yrs) D1, 8, 15, 22
RANDOMIZATION 2:1
Follow-Up for OS and SPM Until 5 Years Post Enrollment
(n = 153)
HiDEX: 40 mg (≤ 75 yrs) mg (> 75 yrs) D1-4, 9-12, 17-20
28-day cycles
PDa or Unacceptable AE
Companion trial MM-003C
POM 21/28 days
PDa or Unacceptable AE
Thromboprophylaxis was required for those receiving POM or at high risk for DVT
Stratification
Age (≤ 75 vs. > 75 yrs)
Number of prior Tx ( 2 vs. > 2)
Disease population (primary refractory vs. relapsed/refractory vs. intolerance/failure)
a Progression of disease was independently adjudicated in real time. Dimopoulos MA, et al. ASH 2013 [abstract 408].

32. PFS Based on Cytogenetic Profile
POM + LoDEX significantly improved PFS vs. HiDEX regardless of the presence of del17p or t(4;14)
POM + LoDEXa
Subgroup
HiDEXa
HR (95% CI)
ITT Population
253/302
138/153
0.49 ( )
del(17p)/t(4;14)
71/77
32/35
0.44 ( )
Standard-Risk Cytogenetics
126/148
63/72
0.55 ( )
0.25
0.5 1 2
Favors POM + LoDEX
Favors HiDEX
Note: Data shown only for pts with available cytogenetics; totals will not sum. a Number of events/number of patients. Dimopoulos MA, et al. ASH 2013 [abstract 408].

33. Forest Plot of OS Based on Prior Treatment
Subgroup
POM + LoDEXa
HiDEXa
HR (95% CI)
ITT Population
176/302
101/153
0.72 ( )
≤ 3 Prior Tx
41/70
22/33
0.56 ( )
> 3 Prior Tx
135/232
79/120
0.76 ( )
Prior THAL
102/173
64/93
0.75 ( )
No Prior THAL
74/129
37/60
0.66 ( )
LEN Ref
168/286
94/141
0.70 ( )
BORT Ref
142/238
79/121
0.77 ( )
LEN and BORT Ref
135/225
74/113
0.77 ( )
LEN as Last Prior
47/85
32/49
0.56 ( )
BORT as Last Prior
76/134
39/66
0.92 ( )
0.25
0.5 1 2
a Number of events/number of pts. San Miguel JF, et al. ASH 2013 [abstract 686].
Favoring POM-LoDex
Favoring HiDEX

34. Proportion of Patients
MM-003: PFS and OS by M-Protein Reduction Patients Assigned to POM + LoDEX
M-Protein Reduction
Median PFS
≥ 25 % (n = 163)
7.4 mos
≥ 50 % (n = 113)
8.4 mos
< 25% (n = 96)
2.3 mos
M-Protein Reduction
Median OS
≥ 25 % (n = 163)
17.2 mos
≥ 50 % (n = 113)
19.9 mos
< 25% (n = 96)
7.5 mos
0.0
0.2
0.4
0.6
0.8
1.0 4 8 12 16 20 24
0.0
0.2
0.4
0.6
0.8
1.0 4 8 12 16 20 28 24
Proportion of Patients
PFS (mos)
OS (mos)
Median PFS was 4.0 mos and median OS was 13.1 mos overall for POM + LoDEX
San Miguel JF, et al. ASH 2013 [abstract 686].

35. Pom low dose dex and bortezomib in relapsed MM
Table 4. Summary of Best Response (IMWG) in Intravenous BORT Cohorts
Outcome
Cohort 1
(n = 3)
Cohort 2
Cohort 3
Cohort 4
Cohort 5 + Exp Cohort
(n = 9)a
Overall response, n (%)
2 (67)
1 (33)
3 (100)
6 (67)
sCR/CR
1 (11)
VGPR
4 (44) PR SD
3 (33)
Median cycles received (range)
5 (4-16)
6 (4-18)
16 (5-20)
10 (4-13)
11 (6-15)
a 8 of 9 patients were evaluable for response; one patient discontinued study treatment in cycle 2 due to treatment-unrelated metastatic pancreatic cancer. CR, complete response; Exp, expansion; IMWG, International Myeloma Working Group; PR, partial response; SC, subcutaneous; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.
Richardson et al, ASH 2013

36. Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor
Novel chemical class with highly selective
and irreversible proteasome binding
Improved antitumor activity with
consecutive day dosing
No neurotoxicity in animals
23% Responses lasting 7.8 months with survival 15.4 months in relapsed and relapsed/ refractory MM w/o
Epoxyketone
Tetrapeptide
Demo et al Cancer Res 2007; 67:6383
Kirk et al, Blood 2008, 112: 2765 ; Siegel et al Blood 2012:120:2817.

37. CRd in Relapsed and Upfront MM
Response to CRd therapy in RRMM was high, with an ORR of 78%
41% VGPR or better
CRd well-tolerated with durable responses
ASPIRE phase 3 open-label, international, multicenter trial comparing CRd to Rd in R/R MM fully enrolled.
Remarkable extent and frequency of response to CRd upfront in ND MM (94% ORR, with 80% CR,nCR after 12 cycles in a subset of pts)
Wang et al ASCO 2011; Jakubowiak et al, Blood 2012 37 37

38. Carfilzomib Pomalidomide Low dose Dex
Median of 5 prior lines of therapy; 49% of patients had high/intermediate risk cytogenetics at baseline
Response rates, PFS, and OS were preserved independent of FISH/cytogenetic risk status
Well tolerated with no unexpected toxicities
≥ VGPR 27%
ORR 70%
CBR 83%
DOR (median) months
PFS (median) 9.7 months
OS (median) > 18 months
Shah et al ASH 2013

39. MAb-Based Therapeutic Targeting of Myeloma
Antibody-dependent
Cellular cytotoxicity (ADCC)
Apoptosis/growth arrest
via targeting
signaling pathways
Complement-dependent
Cytotoxicity (CDC)
Effector cells: MM
FcR MM
C1q MM
CDC
ADCC
Daratumumab (CD38)
huN901-DM1 (CD56)
nBT062-maytansinoid
(CD138)
1339 (IL-6)
BHQ880 (DKK1)
RAP-011 (activin A)
Daratumumab (CD38)
Lucatumumab or Dacetuzumab (CD40)
Elotuzumab (CS1)
Daratumumab (CD38)
XmAb5592 (HM1.24)
Tai & Anderson Bone Marrow Research 2011

40. Elotuzumab Anti-CS MoAb in MM
CS1 is highly and uniformly expressed on MM cells
Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting CS1
Clinical trial of Elo in MM achieved SD
Anti-MM activity of Elo enhanced by lenalidomide (len) in preclinical models
Phase I/II trials: 80-90% response to len dex elo in relapsed MM with prolonged (> month 33 PFS)
Phase III trial of len dex elo versus len dex in relapsed MM for new drug approval
Hsi ED et al. Clin Cancer Res. 2008;14: ; Tai YT et al. Blood. 2008;112: ; Van Rhee F et al. Mol Cancer Ther. 2009;8: ; Lonial S et al. Blood. 2009;114:432; Richardson et al Blood 2010:864 Lonial et al, ASH 2012 40

41. Martin et al ASH 2013

42. Martin et al 2013

43. PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN RELAPSED/REFRACTORY MM
Favorable safety profile as monotherapy
In 15 of 32 (47%) showed benefit
4 patients achieving PR (13%)
6 patients achieving MR (19%)
5 patients achieving SD (16%)
At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%)
To be combined with lenalidomide dexamethasone
Plesner et al ASH 2012

44. Daratumumab and lenalidomide dexamethasone in relapsed MM
The best change in response paraprotein evaluated according to IMWG 2011.
A: serum M-protein, B: urine-M-protein 44
Plesner et al ASH 2013 44

45. Kelley et al ASH 2013

46. Kelly et al ASH 2013

47. Background: Targeting KSP with ARRY-520 (Filanesib)
Array BioPharma Inc.
9/10/2012
Background: Targeting KSP with ARRY-520 (Filanesib)
Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitor
KSP is a microtubule motor protein critical to the function of proliferating cells
KSP inhibition induces aberrant mitotic arrest and rapid cell death
Novel mechanism of action for MM
Preferentially acts on MCL-1 dependent cells including MM
Not expected to be cross-resistant with other drugs
Cancer cell image from ELN page E
ARRY-520 is a new mechanism for the treatment of multiple myeloma. ARRY-520 is a highly selective allosteric inhibitor of KSP. The KSP protein is not found in differentiated cells, so there's no expectation of neuropathy with this particular mechanism. And because it is a novel mechanism, we believe there would be less or no cross resistance to other mechanisms in this area.
We've done significant work in trying to link why KSP is active in multiple myeloma. It appears to be highly active because of the role of Mcl-1 in myeloma specifically, and the dependence of Mcl-1 levels on KSP activity.
We've also demonstrated preclinically that ARRY-520 has synergistic efficacy with both lenalidomide and bortezomib, both standards of care in this disease.
Lonial et al ASH 2013

48. Low AAG is Associated with Higher ORR
Lonial et al ASH 2013
Low AAG is Associated with Higher ORR
Filanesib Single-agent
 Filanesib + Dex
All Pts1
AAG-High
AAG-Low
All Pts2 n 32 6 21 55 15 36
ORR (≥ PR)
5 (16%)
0 (0%)
5 (24%)
8 (15%)
7 (19%)
CBR (≥ MR)
7 (22%)
7 (33%)
11 (20%)
10 (28%)
Duration of Response (months)
8.6 -
5.1
Time to Next Treatment (months)
3.7
2.6
5.3
3.4
2.0
OS (months)
19.0
4.5
23.3
10.5
2.9
10.8 
1 5 patients did not have a baseline AAG measurement
2 4 patients did not have a baseline AAG measurement, including 1 responder

49. Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
Development of Rationally-Based Combination Therapies (HDAC and Proteasome Inhibitors)
Protein Ub
protein aggregates
(toxic) Ub Ub Ub Ub
26S proteasome
HDAC6
Bortezomib, Carfilzomib, NPI0052,
MLN9708, ONX 0912 Ub
Panibinostat,
Vorinostat, ACY1215
HDAC6
dynein Ub
Lysosome
Aggresome
HDAC6 Ub Ub
dynein
Microtubule
Autophagy
Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:

50. PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4)
VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat or Placebo with Bortezomib in Relapsed MM
The combination of vorinostat + bortezomib is active in patients with relapsed and refractory MM
Significant improvement in response rate
ORR 54% vs 41% (P<0.0001); CBR 71% vs 53% (P<0.0001)
PFS and TTP were prolonged in the combination arm compared with bortezomib alone
PFS hazard ratio reduction of 23% (P=0.01); months (6.9–8.4)
versus 6.83 months (5.7–7.7)
Diarrhea, fatigue, and thrombocytopenia limited tolerability.
Time-to-progression hazard ratio reduction of 21% (P=0.02)
Dimopoulos et al Lancet Oncol
2013; 14: 50 50

51. Ricolinostat (HDAC 6 inhibitor) alone and in combination with bortezomib in relapsed refractory MM
Monotherapy
6/15 patients had stable disease (SD) as their best response.
Combination with bortezomib and dexamethasone
20/22 were evaluable for response assessment in six combination cohorts
Overall response rate (≥PR): 25% in heavily pretreated patients
5 patients withdrew after one cycle and 3 had progressive disease after 2 cycles
Clinical benefit rate (≥SD): 60%
6/10 patients refractory to bortezomib had ≥SD (1 VGPR, 1 MR, 4 SD)
Responding patients have been on study 2 to 16 cycles
All 3 patients treated 240 mg QD cohort had MR or better
VGPR 2 PR 3
MR1 SD 5
Should we add the PDs? Did the 5 who withdrew after 1 cycle have PD??Do we need to say seperately about 240mgs??
Have kept the table but would probably take out
Monotherapy response data from Final CSR. Combination response data pulled from
live database Nov 8, 2013
1 One patient had a 26% decrease in M Protein after Cycle 2 and withdrew after two
subsequent cycles with SD

52. Ricolinostat (HDAC 6 inhibitor) lenalidomide dexamethasone in relapsed refractory MM
M protein % change CR 1
VGPR 3
PR1 7 MR 2 SD
11/16 pts (69%) had PR or better
16/16 pts (100%) had clinical benefit (including MR and SD)
Yee, et al, Poster #3190, ASH 2013

53. PKB115125 Akt Inhibitor: Dose Limiting Toxicities
Afur / Bor / Dex
dose (mg) n
DLT
Comment 4
None - 6
1/6
LFT elevation G2
Erythema Multiforme G3
2/6
Rash G3
Rash G3 / Diarrhea G3 /Thrombocytopenia G3 NA
MTD / RP2D:
Afuresertib mg PO daily
Bortezomib mg/m2 IV/SC on days: 1,4,8,11
Dexamethasone 40 mg PO on days: 1,4,8,11
All DLTs were reversible
Voorhees et al ASH 2013

54. Maximum % change in M-protein or FLC from baseline
Voorhees et al ASH 2013

55. Treatment of Multiple Myeloma: Conclusions
In newly diagnosed transplant candidates, three drug regimens incorporating immunomodulatory drugs and proteasome inhibitors before and after transplant can prolong PFS and OS.
Lenalidomide dex until progression is standard of care for non transplant patients with newly diagnosed myeloma.
Lenalidomide maintenance until progression prolongs PFS and OS, with an increased risk of secondary cancers in patients who have received MP or high dose therapy and ASCT.

56. Treatment of Multiple Myeloma: Conclusions
Pomalidomide low dose dex is active in relapsed refractory MM, (including 17p deletion)
Bortezomib or Carfilzomib and pomalidomide low dose dex increases response and is tolerated in relapsed refractory MM
Novel agents including oral proteasome inhibitor ixazomib, monoclonal antibodies SAR and daratumumab, immunotoxin indatuximab, KSP inhibitor filanesib, Akt inhibitor afuresertib, and HDAC6 inhibitor ricolinostat demonstrate promising activity in relapsed refractory MM
Incorporation of novel therapies at all stages of disease is further improving patient outcome in MM