1. Meletios A. Dimopoulos, MD
Emerging therapeutic options for relapsed/refractory multiple myeloma
Meletios A. Dimopoulos, MD
Department of Clinical Therapeutics,
National and Kapodistrian University of Athens,
School of Medicine, Athens, Greece

2. Prompt treatment initiation needed
Relapse situations
Two clear scenarios
Slow, asymptomatic relapse
No symptoms
Slowly progressing disease
Low tumor burden
Cytogenetic low risk
Good performance status
Fast, symptomatic relapse
Symptoms
Radiply progressing disease
High tumor burden
Organ involvement
Cytogenetic high risk
Poor performance status
Observation
Prompt treatment initiation needed
The challenge: Identify appropriate time to initiate treatment for situations ‘in between‘

3. Multiple factors drive treatment choice in relapsed/refractory MM
Prior therapies received†
Tolerance to prior therapies
Time interval since last therapy
Influential
factors
Side effects
Subtype e.g. t(4;14)
Comorbidity e.g. renal impairment*
Age
Previous SCT
Treatment availability
Pre-existing toxicities e.g. PN
Performance status
*Occurs in up to 50% MM patients; †Can repeat induction therapy where relapse occurs >6 mo. after treatment
PN, peripheral neuropathy; SCT, stem cell transplant
Moreau P, et al. Ann Oncol 2013;24:vi133–vi137; Lonial S. Hematology Am Soc Hematol Educ Program 2010;2010:303–309

4. Main Randomized Trials of Treatment of Relapsed/Refractory Myeloma
Regimen
ORR, %
CR, %
TTP, mo OS
Bort vs Dex1
38 vs 18
6 vs 1
6.2 vs 3.5
80% vs 66% at 1 year
Bort + Doxil vs Bort2
44 vs 41
4 vs 2
9.3 vs 6.5
76% vs 65%
at 15 months
Len/Dex vs Dex3
61 vs 19.9
14.1 vs 0.6
11.1 vs 4.7
29.6 vs 20.2 months
Len/Dex vs Dex4
60.2 vs 24
15.9 vs 3.4
11.3 vs 4.7
Not reached vs 20.6 months
1. Richardson PG, et al. N Engl J Med. 2005;352:
2. Orlowski RZ, et al. J Clin Oncol. 2007:
3. Weber DM, et al. N Engl J Med. 2007;357:
4. Dimopoulos M, et al. N Engl J Med. 2007;357:

5. Phase 1/2: VRD for first relapse or primary refractory disease
n=70
Phase 1 dose escalation
MTD: Btz 1.6 mg/m2 once weekly
Len 10 mg day 1-21
Dex 20 mg days 1,2,8,9,15, 16
Phase 2 at MTD
ORR: 89%, ≥ VGPR 64%, PFS 19 months, OS 42 months
Grade 3/4 AEs: Hematological 30%, infection (grade 3) 16%, PN 17%
PFS OS
Broijl et al. ASH 2014 (Abstract 4735), poster presentation

6. ...But IMiDs (thalidomide mainly) and bortezomib are used in first line therapy
What are the implications for treatment at relapse?
How can relapse under treatment, e.g. maintenance treatment, be managed?
Is retreatment feasible?

7. Is retreatment with novel agents feasible?

8. Overall response* rate (%)
2nd-line combinations after bortezomib-based therapies: data from VISTA trial
MPV (n = 129)
MP (n = 194)
Overall response* rate (%)
Lenalidomide combination (n = 36)
Thalidomide combination (n = 155)
Bortezomib mono or combination (n = 107)
* Responses  PR.
Mateos MV, et al. J Clin Oncol 2010;28: 8 8

9. Retreatment with IMiDs
Retrospective study
Median of 2 treatments prior to IMiD based salvage therapy
Median time from diagnosis to repeat exposure to IMiD: 28 months
n=140
Len  Len
n=48
Len  Thal
n=11
Thal  Len
n=58
Thal  Thal
n=23
ORR (≥PR) to repeat IMiD therapy
54%
20%
48%
30%
Median TTP from start of repeat IMiD therapy
16 months
3 months
9 months
6 months
Repeat therapy with IMiDs feasible
Response rates with lenalidomide retreatment higher than with repeat thal administration
Madan et al. Blood 2011;118:1763-5

10. What is the role for transplantation at relapse or in refractory disease?

11. Phase 3 prospective study: ASCT at relapse Myeloma X – Final results
Pts (n= 174), median age 61, in relapse following prior ASCT
Treatment
PAD induction (bortezomib, doxorubicin, dexamethasone)
Randomization: MEL200-ASCT versus cyclophosphamide weekly x 12
Cook et al. ASH 2013 (Abstract 765), oral presentation

12. Phase 3 prospective study: ASCT at relapse Myeloma X – Final results
Results (median follow-up 12 months)
Response to PAD induction
79.2% ORR: 16.5% sCR/CR, 20.9% VGPR
Conclusion
First prospective study to demonstrate superior duration of response for salvage ASCT
ASCT
(n=89)
Cyclophosphamide weekly
(n=85) P
Median TTP
19 months
11 months
<
3-year OS
80.3%
62.9%
0.2332
Cook et al. ASH 2013 (Abstract 765), oral presentation

13. Novel Treatment Options for Relapsed/Refractory Myeloma after 1-3 prior lines of therapy

14. ASPIRE Study Design KRd Rd Randomization 28-day cycles N=792
Category (XX)
11/9/2018
28-day cycles
Randomization
N=792
Stratification:
β2-microglobulin
Prior bortezomib
Prior lenalidomide
KRd
Carfilzomib 27 mg/m2 IV (10 min)
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)
Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
After cycle 12, carfilzomib given on days 1, 2, 15, 16
After cycle 18, carfilzomib discontinued Rd
Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
Stewart et al. N Engl J Med 2015;372:142-52

15. Primary Endpoint: Progression-Free Survival
KRd Rd
(n=396) (n=396)
Median PFS, mo
HR (KRd/Rd) (95% CI) (0.57–0.83)
P value (one-sided) <0.0001
1.0
0.8
0.6
Proportion Surviving
Without Progression
0.4
0.2
KRd Rd
0.0 6 12 18 24 30 36 42 48
Months Since Randomization
No. at Risk:
KRd Rd
Stewart et al. N Engl J Med 2015;372:142-52

16. Secondary Endpoints: Response
Percentage of Patients
sCR
14.1% vs 4.3%
P<.0001
Median duration of response was 28.6 months in the KRd group and 21.2 months in the Rd group
Stewart et al. N Engl J Med 2015;372:142-52

17. Months Since Randomization
Secondary Endpoints: Interim Analysis for OS Median Follow-Up 32 Months
1.0
KRd Rd
(n=396) (n=396)
Median OS, mo NE NE
HR (KRd/Rd) (95% CI) (0.63–0.99)
P value (one-sided)
0.8
0.6
Proportion Surviving
0.4
0.2
KRd Rd
0.0 6 12 18 24 30 36 42 48
Months Since Randomization
No. at Risk:
KRd Rd
Median OS was not reached; results did not cross the prespecified stopping boundary (P=0.005) at the interim analysis
Stewart et al. N Engl J Med 2015;372:142-52

18. AEs Occurring in ≥25% of Patients in Either Arm
11/9/2018
AEs Occurring in ≥25% of Patients in Either Arm
AE, %
KRd (n=392)
Rd (n=389)
All Grade
Grade ≥3
Hematologic AEs
Anemia
42.6
17.9
39.8
17.2
Neutropenia
37.8
29.6
33.7
26.5
Thrombocytopenia
29.1
16.6
22.6
12.3
Non-hematologic AEs
Diarrhea
42.3
3.8
33.7
4.1
Fatigue
32.9
7.7
30.6
6.4
Cough
28.8
0.3
17.2
Pyrexia
28.6
1.8
20.8
0.5
Upper respiratory tract infection
19.3
1.0
Hypokalemia
27.6
9.4
13.4
4.9
Muscle spasms
26.5
21.1
0.8
Stewart et al. N Engl J Med 2015;372:142-52

19. PANORAMA 1 (Phase 3)
Panobinostat + BTZ + DEX (PanVD) in relapsed or relapsed and refractory MM
PANORAMA 1: multicenter, randomised, double-blind, placebo- controlled Phase 3 study
Primary endpoint: PFS
Study population
N=768
1–3 lines prior therapy
Measurable M component in serum or urine at study screening
ECOG ≤ 2
Treatment Phase 1 (TP1)
PanVD (21-day cycle)
PAN
20 mg PO on D1,3,5,8,10,12
BTZ
1.3 mg/m2 IV on D1,4,8,11
DEX
20 mg PO on D1,2,4,5,8,9,11,12
Treatment Phase 2 (TP2)
PanVD (42-day cycle)
20 mg PO as TP1 plus on D22,24,26,29,31,33
1.3 mg/m2 IV D1,8,22,29
20 mg PO on D1,2,8,9,22,23,29,30
Placebo + VD (21-day cycle)
Placebo
As above
Placebo + VD (42-day cycle) R
*The study treatment consisted of 12 cycles max: TP1 (8 cycles) + TP2 (4 cycles); PAN, panobinostat
San Miguel JF, et al. Lancet Oncol 2014;15:

20. Progression-free survival Probability (%)
Primary Endpoint: PFS
PANORAMA 1
Events
Median PFS (95% CI)
months
HR (95% CI)
P value
PAN-BTZ-Dex
207/387
12.0 (10.3, 12.9)
0.63 ( )
< .0001
Pbo-BTZ-Dex
260/381
8.1 (7.6, 9.2)
100 80 60 40 20
Progression-free survival Probability (%)
PAN-BTZ-Dex
Pbo-BTZ-Dex 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Number of patients at risk
Months
PAN-BTZ-Dex
Pbo-BTZ-Dex
387
288
241
202
171
143
113 89 69 52 44 35 26 18 13 10 5 3
381
296
235
185
114 64 42 32 24 12 2
Primary endpoint was met (P < .0001), with clinically relevant increase in median PFS of 3.9 months for PAN-BTZ-Dex arm
San Miguel JF, et al. Lancet Oncol 2014;15:

21. Overall Survival (Interim Analysis) Key Secondary Endpoint
PANORAMA 1
Overall Survival (Interim Analysis) Key Secondary Endpoint
Events
Median OS, months (95% CI)
HR (95% CI)
P value
PAN-BTZ-Dex
134/387
33.64 (31.34, NE)
0.87 ( ) NS
Pbo-BTZ-Dex
152/381
(26.87, NE)
100 80 60 40 20
Overall survival Probability (%)
PAN/BTZ/Dex
Pbo/BTZ/Dex 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Number of patients at risk
Months
PAN-BTZ-Dex
Pbo-BTZ-Dex
387
362
333
315
306
295
284
276
265
241
210
178
147
118 92 64 40 25 12 7 4
381
365
344
326
314
297
273
251
234
211
164
140
115 90 59 39 24 15 9
Final OS analysis after 415 events reached
San Miguel JF, et al. Lancet Oncol 2014;15:

22. PANORAMA 1
Efficacy: Response
PAN-BTZ-Dex (n = 387)
Pbo-BTZ-Dex
(n = 381)
P value
ORR (PR or better) [95% CI]
60.7% [55.7, 65.6]
54.6% [49.4, 59.7]
.087
CR/nCR rate [95% CI]
27.6% [23.2, 32.4]
15.7% [12.2, 19.8]
.00006*
Median DoR [95% CI]
13.1 mos [11.8, 14.9]
10.9 mos [9.2, 11.8]
N/A
Median TTR [95% CI]
1.5 mos [1.4, 1.6]
2.0 mos
[1.6, 2.8]
Median TTP [95% CI]
12.7 mos
[ ]
8.5 mos
[ ]
CR/nCR rate was nearly doubled vs control arm (sCR in PAN arm 2%, vs 0% Pbo arm)
Clinically meaningful improvements in median DoR and TTP
San Miguel JF, et al. Lancet Oncol 2014;15:

23. Non-Hematologic AEs Grade 3/4 Diarrhea and Asthenia/Fatigue Observed
PANORAMA 1
Non-Hematologic AEs Grade 3/4 Diarrhea and Asthenia/Fatigue Observed
PAN-BTZ-Dex (n = 381)
Pbo-BTZ-Dex (n = 377)
Preferred term – %
All grades
Grade 3/4
Diarrhea
68.2
25.5
41.6
8.0
Peripheral neuropathy
60.6
17.6
67.1
14.6
Asthenia/fatigue
57.0
23.9
40.6
11.9
Nausea
36.2
5.5
20.7
0.5
Peripheral edema
28.6
2.1
19.1
0.3
Decreased appetite
28.1
3.1
12.5
1.1
Constipation
26.8
1.0
32.6
Pyrexia
26.0
1.3
14.9
1.9
Vomiting
25.7
7.3
13.0
Cough
21.3
18.6
Discontinuation due to diarrhea (4.5%) and fatigue (2.9%) on PAN arm
San Miguel JF, et al. Lancet Oncol 2014;15:

24. Hematologic Lab Abnormalities
PANORAMA 1
Hematologic Lab Abnormalities
PAN-BTZ-Dex (n = 381)
Pbo-BTZ-Dex (n = 377)
Laboratory abnormality – %
All grades
Grade 3/4
Thrombocytopenia
97.6
67.4
83.5
31.4
Lymphopenia
82.6
53.2
73.7
39.8
Neutropenia
75.0
34.5
35.5
11.4
Anemia
62.0
17.7
52.3
19.1
Discontinuation due to thrombocytopenia on PAN 1.6% (vs 0.5%)
Grade 3/4 hemorrhages on PAN 4.2% (vs 2.4%)
Grade 4 neutropenia on PAN 6.6% (vs 2.4%)
Febrile neutropenia on PAN 1% (vs 0.5%)
San Miguel JF, et al. Lancet Oncol 2014;15:

25. Phase Ib/II: Single-Agent Oprozomib in Relapsed/Refractory MM
Open-label, phase Ib/II dose-escalation study of oprozomib
Oprozomib is a selective, irreversible oral epoxyketone proteasome inhibitor with promising antitumor activity
In pts who relapsed after ≥ 1 prior lines of therapy
Trial Parameter
2/7 Schedule
(n = 21)
5/14 Schedule
(n = 47)
2/7 Step-up
Schedule
(n = 10)
5/14 Step-up
(n = 9)
Phase Ib
Ib/II II
Schedule, every 2 wks
Days 1, 2, 8, 9
Days 1-5
Dose, mg/day
240/300
150/180
Median tx duration, wks (range)
23.4 ( )
6.7 ( )
5.6 ( )
6.7 ( )
Vij R, et al. ASH Abstract 34.

26. Single-Agent Oprozomib in Relapsed/ Refractory MM: Summary of EfficacyPD SD MR PR
VGPR CR
CBR: 50.0%
2/7 Schedule
ORR: 31.3%
Phase Ib mg/day (n = 16) 44 19 19 13
CBR: 32.6%
5/14 Schedule
ORR: 23.3%*
Phase Ib + II mg/day (n = 43) 9 42 9 9 12 2 50
100
*ORR in 11 carfilzomib-refractory pts (phase II): 18.2%
Response data not shown for step-up cohorts due to limited treatment exposure
Vij R, et al. ASH Abstract 34.

27. Single-Agent Oprozomib in Relapsed/ Refractory MM: Safety
Phase Ib study identified MTD of oprozomib for 2/7 dosing schedule (300 mg/day) and 5/14 dosing schedule (240 mg/day)
4 dose-limiting AEs observed: grade 3 diarrhea and grade 4 thrombocytopenia (2/7 schedule), grade 3 tumor lysis syndrome and grade 3 vomiting (5/14 schedule)
Overall safety improved in phase II, step-up dosing with introduction of extended-release oprozomib
Incidence of grade ≥ 3 hematologic AEs declined
Incidence of gastrointestinal AEs declined, except for grade 1/2 nausea and diarrhea in the 5/14 schedule
Serious AEs occurred in approximately 30% to 33% of pts in phase II study (3 pts with each schedule)
Overall fewer pts required dose reductions, discontinuations in phase II, but more discontinued treatment in phase II vs phase Ib with 2/7 schedule
Vij R, et al. ASH Abstract 34.

28. Ixazomib + Dexamethasone (n = 20)
Ixazomib in rel/ref MM
Response
Ixazomib (n = 32)
Ixazomib + Dexamethasone (n = 20)
ORR
≥ PR, n (%)
5 (16) --
11 (34)
≥ Minor response, n (%)
8 (25)
13 (41)
Stable CR,* n 1
CR,† n
Very good PR,† n
PR, n 3
6 (2 minor response, 4 SD‡) 9
Minor response, n
3 (2 SD, 1 PD‡) 4
SD, n 16 10
PD, n
Not assessed, n
Kumar SK, et al. Blood 2014;124:

29. Ixazomib in rel/ref MM: Safety
Kumar SK, et al. Blood 2014;124:

30. Novel Regimens for Relapsed/Refractory Myeloma Patients

31. Follow-up for OS and SPM Until 5 Years Post Enrollment
MM-003 Design: Pomalidomide + LoDEX vs. HiDEX Refractory MM Pts Who Have Failed BORT and LEN
(n = 302)
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
PD* or intolerable AE
PD*
Companion trial MM-003C
POM 21/28 days
Thromboprophylaxis was indicated for those receiving POM or with DVT history
Stratification
Age (≤75 vs >75 yrs)
Number of prior Tx (2 vs >2)
Disease population
San Miguel et al. Lancet Oncol 2013;14:

32. MM-003: Clinical benefit with Pomalidomide + LoDex in 40% of patients
ORR = 32%
ORR = 11%a
Patients (%)
Median DoR,b
(95% CI)
7.5 months
(6.0–9.5)
5.1 months
(1.7–8.5)
p = 0.031
Based on IMWG criteria.
a Patients (n = 11) who crossed over to receive POM were analysed per original randomised arm.
b Kaplan–Meier estimate; patients with ≥ PR.
San Miguel et al. Lancet Oncol 2013;14:

33. MM-003 Final Analysis: Pomalidomide/ LoDex vs. HiDex: PFS and OS
Median PFS, Mos
POM + LoDex (n = 302)
4.0
HiDex† (n = 153)
1.9
Median OS, Mos
POM + LoDex (n = 302)
13.1
HiDex† (n = 153)
8.1
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
HR: 0.72
P = .009
HR: 0.50
P < .001
Proportion of Patients
Proportion of Patients
PFS (Mos)
OS (Mos)
*Primary endpoint. †85 pts (56%) on the HiDex arm received subsequent POM.
San Miguel et al. Lancet Oncol 2013;14:

34. MM-010 (STRATUS) Design: POM + LoDEX in RRMM
Study Treatment
POM: 4 mg D1-21
LoDEX: 40 mg (≤ 75 yrs) or
20 mg (> 75 yrs)
D1, 8, 15, 22
28-day cycles
Treatment until PD or intolerable AE
Patients with refractory or relapsed and refractory MM
(up to 720)a
Follow-up for subsequent Tx, OS, and SPM until 5 yrs post enrollment of last patient
Thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent was required for all pts
a 604 pts enrolled as of September 15, 2014.
Registered at ClinicalTrials.gov as NCT and at EudraCT as
AE, adverse event; D, days; LoDEX, low-dose dexamethasone; MM, multiple myeloma; OS, overall survival; PD, progressive disease; POM, pomalidomide; RRMM, relapsed/refractory multiple myeloma; SPM, second primary malignancy; Tx, treatment.
Dimopoulos MA, et al. ASH 2014 [abstract 80].

35. Investigator-Assessed IMWG Criteria
MM-010: Response
Investigator-Assessed IMWG Criteria
ORR = 35% with 7% VGPR and 1% CR
Median DOR = 6.8 mos (95% CI: )
Patients (%)
ITT population
(N = 604)
LEN-refractory
(n = 572)
BORT-refractory
(n = 498)
LEN+BORT-refractory
(n = 473)
Dimopoulos MA, et al. ASH 2014 [abstract 80].

36. MM-010: Efficacy by Prior Treatment
Patient Population
ORR (%; 95% CI)
Median PFS (mos; 95% CI)
Median OS (mos; 95% CI)
ITT population
35 (31-39)
4.2 ( )
11.9 ( )
LEN-refractory
34 (30-38)
12.0 ( )
BORT-refractory
36 (31-40)
4.2 ( )
11.9 ( )
LEN + BORT refractory
35 (30-39)
4.1 ( )
12.0 ( )
BORT, bortezomib; ITT, intent to treat; LEN, lenalidomide; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
Dimopoulos MA, et al. ASH 2014 [abstract 80].

37. Pomalidomide Combinations with Cyclo or Bortezomib
Phase 2:
Pom-Dex vs Pom-Cyclo-Dex
(n=34)1
Pom-Btz-Dex
(n=47)2
Pom-Dex
Pom-Cyclo-Dex p
PVD
ORR, %
38.9
64.7
0.03 85
≥ VGPR, %
13.8
11.8 NA 45
PFS, months
4.4
9.5
0.1078
10.7
OS, months
16.8
Not reached
0.1308
94*
*Event-free survival at 12 months
1. Baz et al. ASH 2014 (Abstract 303), oral presentation
2. Lacy et al. ASH 2014 (Abstract 304), oral presentation

38. Study 003-A1: phase 2b study of single-agent carfilzomib in relapsed and refractory myeloma
Study population
003-A1 (n=266)
Relapsed from ≥2 prior lines of therapy
Must include BTZ
Must include THAL or LEN
Refractory to last regimen
Carfilzomib on days 1, 2, 8, 9, 15 and 16 every 28 days
20 mg/m2 in Cycle 1
and 27 mg/m2 from Cycle 2 and beyond
(maximum 12 cycles)
Primary endpoint: ORR
IMWG response criteria (IRC assessed)
Secondary endpoints
CBR (ORR+ MR), DOR, OS, PFS, TTP, safety
CBR, combined response rate; DOR, duration of response; IRC, independent review committee; LEN, lenalidomide; MR, molecular response; ORR, objective response rate; OS, overall survival; PFS, progression-free survival THAL, thalidomide; TTP, time to progression
Siegel D, et al. Blood 2012;120:2817–25

39. Study 003-A1: efficacy response-evaluable population (n=257†)
TTR: 1.9 mo (≥PR) and 1.0 mo (≥MR)
DOR: 7.8 mo (≥PR) and 8.3 mo (≥MR)
DCR = 69%
Percentage of Patients
CBR = 37%
ORR = 24%
Subset analyses of higher risk populations showed similar response rates (eg, unfavorable cytogenetics, baseline peripheral neuropathy)
†12 patients were not evaluable; *CR IRC determined CR, complete response; DCR, disease control rateSD, stable disease; VGPR, very good partial response
Siegel D, et al. Blood 2012;120:2817–25; Siegel D, et al. ASCO Abstract 8027 (poster presentation); Wang M, et al. ASH Abstract 3969 (poster presentation)

40. Proportion without progression
Study 003-A1: progression-free survival response-evaluable population (n=257)
Median PFS* = 3.7 months (95% CI )
1.0
0.8
0.6
Proportion without progression
0.4
0.2
0.0 3 6 9 12 15 18
Months
*Interpretation of time to event endpoints are limited in a single arm trial
Siegel D, et al. Blood 2012;120:2817–25 40

41. Study 003-A1: overall survival response-evaluable population (n=257)
Median OS* = 15.6 months (95% CI )
1.0
0.8
0.6
Proportion surviving
0.4
0.2
0.0 3 6 9 12 15 18 21 24 27
Months
*Interpretation of time to event endpoints are limited in a single arm trial
Siegel D, et al. Blood 2012;120:2817–25 41

42. Treatment-emergent adverse events ≥25% and carfilzomib-related adverse events ≥10%
Any grade, %
Grade 3/4, %
All grade related*, %
Haematologic
Anaemia
Thrombocytopenia
Lymphopenia
Neutropenia
Leukopenia 46 39 23 18 14 24 29 20 11 7 22 17 15 12
Non-haematologic
Fatigue
Nausea
Dyspnea
Diarrhea
Pyrexia
Headache
Upper respiratory tract infection
Blood creatinine increased 49 45 34 32 31 28 27 25
7.5
1.9
3.4
0.8
1.5
4.5
2.6 37 6
*≥10% incidence, considered to be probably or possibly related to study drug
Siegel D, et al. Blood 2012;120:2817–25 42

43. Induction (cycles 1-6, 28-day cycle)
Phase II: carfilzomib/pomalidomide/ dexamethasone in patients with RRMM
Induction (cycles 1-6, 28-day cycle)
Carfilzomib 20 mg/m2 days 1,2 of cycle 1; 27 mg/m2 days 8,9,15,16 cycle 1, all days of following cycles
Dexamethasone
40 mg days 1, 8, 15, 22
N = 79
Pomalidomide
4 mg days 1–21
Maintenance cycles: cycles 7+, 28-day cycle, carfilzomib 27 mg/m2 days 1,2,15,16; dexamethasone and pomalidomide dosing remain unchanged
Coagulation prophylaxis with aspirin 81 mg QD or LMWH in aspirin-intolerant patients
Antiviral therapy administered with treatment
All patients refractory to previous lenalidomide treatment
LMWH, low molecular weight heparin; RRMM, relapsed/refractory multiple myeloma
Shah JJ, et al. ASH Abstract 690

44. Car-Pom-Dexa outcomes: ORR, DOR, PFS, and OS
Patient response
≥VGPR, % 27
ORR, % 70
CBR, % 83
DOR (median), mos
17.7
PFS (median), mos
9.7
OS (median), mos
>18
Median number prior patient therapy lines: 5
In patients with high-risk FISH/cytogenetic status (n = 18), the ORR was 78% (n = 14)
49% of patients had high- or intermediate-risk status at baseline
PFS and OS were sustained independent of risk status
Car, carfilzomib; CBR, clinical benefit rate; d, dexamethasone; pom, pomalidomide
Shah JJ, et al. ASH Abstract 690

45. Car-Pom-Dexa treatment-related AEs
AEs,* n
Grade 1
Grade 2
Grade 3
Grade 4
All, n (%)
Haematologic
Neutropenia 4 17 6
27 (34)
Anaemia 1 10 13
25 (32)
Thrombocytopenia 7 5
22 (28)
Febrile neutropenia 3
3 (4)
Non-haematologic
Fatigue 20
33 (42)
Dyspnea 12 9
Muscle spasms 11
14 (18)
Diarrhoea 2
13 (16)
Skin rash, pruritus
10 (13)
*2 treatment-related grade 5 events: 1 pneumonia, 1 pulmonary embolism
Shah JJ, et al. ASH Abstract 690

46. Ricolinostat in rel/ref myeloma
Phase 1b studies:
1Ricolinostat Btz + Dex
2Ricolinostat + Len + Dex
n=42
ORR 44% (2 VGPR, 9 PR)
Grade 3-4 AEs: thrombocytopenia , anemia, diarrhea, asymptomatic laboratory abnormalities
n=25
ORR 63% (1 sCR), 5 VGPR, 9 PR)
Grade 3/4 AEs: neutropenia, thrombocytopenia, anemia, fatigue, syncope
1. Vogl et al. ASH 2014 (Abstract 4764), poster presentation
2. Yee et al. ASH 2014 (Abstract 4772), poster presentation

47. Filanesib (ARRY-520): Mechanism of action
Cancer cell
Normal spindle:
proliferation
Monopolar spindle:
arrest & apoptosis
KSP
ARRY-520
ARRY-520 is a kinesin spindle protein (KSP) inhibitor
KSP inhibition prevents formation of bipolar spindle
Inducing rapid apoptosis leading to cell death
Shah JJ, et al. Blood. 2012;120:[Abstract 449].

48. Filanesib single-agent, n = 32
Filanesib  dexamethasone in relapsed/refractory multiple myeloma: Phase 2 study data
Cohort 1: Filanesib single agent, n=32, median of 6 prior TXs
Cohort 2: Filanesib + dexamethasone, n=55, median of 8 prior TXs
BORT-refractory: 53% (cohort 1) and 98% (cohort 2),
LEN-refractory: 75% (cohort 1) and 100% (cohort 2)
Triple-refractory: 41% (cohort 1) and 96% (cohort 2)
Outcome
Filanesib single-agent, n = 32
Filanesib + DEX n = 55
ORR (≥ PR), % 16 15
Median duration of response (≥ PR), months
8.6
5.1
TTNT, months
3.7
3.4
OS, months
19.0
10.5
Lonial S, et al. Blood. 2013;122:abstract 285.

49. Summary/Conclusions
Treatment at relapse influenced by patient, disease and treatment factors; distinction between biochemical and clinical relapse necessary
Bor, Thal and Len have improved outlook for patients with RR MM
Range of effective combinations available: KRD another “standard of care” in this setting
Retreatment with novel agents feasible
Pomalidomide and carfilzomib produces high response rates and increases survival in patients who are refractory to both len and bor. Their combination is more effective but also more expensive!
New classes of agents are of considerable interest and have antimyeloma activity (more promising: mAbs, panobinostat, ricolinostat, filanesib), mainly in combination with known anti-myeloma agents.

50. Thank you