1. Relapsed Refractory Myeloma: The Case for Single Agent Approach
Ruben Niesvizky MD Myeloma Center Myelomacenter.org

2. Time to Response Outcomes
Outcome of Pts Who Have Become Refractory to Bortezomib and at Least One IMiD (IMWG Study)
286 pts with relapsed MM; refractory to Bz and were relapsed following, refractory to, or ineligible to receive an IMiD (thal and/or len)
Time to Response Outcomes
Survival Outcomes
100
24-Month
Events/N Estimate
Minor response
Partial response
Very good partial response
Complete response
94/213
69/213
19/213
7/213
51%
38%
11% 4%
100
Median
Events/Nn Months
Overall survival
Event-free survival
170/286
217/286
9 (7,11)
5 (4,6) 80 80 60 60
Patients (%)
Patients (%) 40 40 20 20 4 8 12 16 20 24 28 32 36 40 44 48 12 24 36 48 60
Months
Months
IMiD, immunomodulatory drug
Kumar SK et al. Leukemia. 2012;26:149.

3. Clinical Factors When Choosing Therapy for Relapsed Disease
Comorbid conditions
Previous therapy
Time from previous therapy
Mode of drug administration
Genetic risk profile
Potential role of second ASCT
Laubach JP et al. Leukemia. 2009;23:2222. Blade J, Rosinol L. Haematologica. 2009;94:163.

4. Treatment of Relapsed/Refractory MM
Single agents vs combinations?
Duration of treatment: fixed cycles or until maximum response or until progression?
Stop and transplant a second time?

5. Management of Relapsed MM Available Choices
Cytotoxic agents Transplant options Thalidomide Bortezomib Lenalidomide Carfilzomib Pomalidomide/dex Research studies
Initial therapy
Salvage therapy

6. Combinations Appear More Active and Result in High ORRs and High CR/nCR Rates but 4 is not better than 3
3-Drug
4-Drug
100
≥PR
CR/nCR 80 60 40 20
RCD4
RCP5
MP-V6
RAD7
BPV8
VMD9
VDT10
VTD11
CyBorD1
CyBorD2
CyBorD3
DVd-T12
DVd-R13
RMPT14
VMPT15
VMDT16
1 novel agent
2 novel agents
1 novel agent
2 novel agents
1. Fu W et al. Am J Clin Oncol. 2012;35:562; 2. Kropff M et al. Br J Haematol. 2007;138:330; 3. Reece DE et al. J Clin Oncol. 2008;26:4777; 4. Schey SA et al. Br J Haematol. 2010;150:326; 5. Reece DM et al. Blood. 2008;112. Abstract 1723; 6. Romano A et al. Ann Oncol. 2012; Nov 7 [Epub ahead of print]; 7. Knop S et al. Blood. 2009;113:4137; 8. Ponisch W et al. J Cancer Res Clin Oncol. 2012;Nov 25 [Epub ahead of print]; 9. Popat R et al. Br J Haematol. 2009;144:887; 10. Chanan-Khan A et al. Leuk Lymphoma. 2009;50:1096; 11. Pineda-Roman N et al. Leukemia. 2008;22:1419; 12. Hussein MA et al. Mayo Clin Proc. 2006;81:889; 13. Baz R et al. Ann Oncol. 2006;17:1766; 14. Palumbo A et al. Leukemia. 2010;24:1037; 15. Palumbo A et al. Blood. 2007;109:2767; 16. Terpos E et al. Leukemia. 2008;22:2247.

7. Relapse Approaches EARLY AGGRESSIVE, RAPID, OR MULTIPLE RELAPSE
CONSIDER CLINICAL TRIAL WITH A NOVEL AGENT
EARLY
LENALIDOMIDE-BASED
Initial therapy with bz
Underlying PN
BORTEZOMIB-BASED
Initial therapy len / thal
Long DOR with prior bz
Renal dysfunction
TRANSPLANT
No previous SCT
Long remission post-SCT
AGGRESSIVE, RAPID, OR MULTIPLE RELAPSE
CT-BASED
DCEP vs DT-PACE
Oral vs IV CT
PS plays an important role
CT + NOVEL AGENT
Combinations of len
and / or bz with other agents
SCT-BASED
Likely to be short-lived Quick disease control Reconstitute marrow ?
Consider combination therapy. Don’t wait for symptomatic relapse.
Bz, bortezomib; PN, peripheral neuropathy; len, lenalidomide; thal, thalidomide; CT, chemotherapy; SCT, stem cell transplant; PS, performance status.
Lonial S, et al. Clin Cancer Res. 2011;17:

8. Petrucci et al, Br J Haem 2013,160,649-659

9. Petrucci et al, Br J Haem 2013,160,649-659

10. Vorinostat, Panobinostat
Novel Agents
Activity
2nd GENE R A T I ON
2nd Generation Agents
MONOT HERAP Y
Carfilzomib
Pomalidomide
+/- dexamethasone
N EW
C L A S S E S
Vorinostat, Panobinostat
Elotuzumab
Perifosine
Bendamustine
ENHANCER
+ bortezomib or lenalidomide
+/- dexamethasone

12. Carfilzomib Monotherapy in Heavily Pre-Treated MM Patients, Phase IIb
20 mg/m2 days 1, 2, 8, 9, 15, 16 every 28 days
N = 46
MM: Progressive disease
> 2 prior therapy lines
including bortezomib and thalidomide or lenalidomide
Carfilzomib
Dose escalation to 27 mg/m2 after cycle 1 up to 12 cycles
N = 266
Patient Baseline Characteristics
N = 266
Age
63 years (range, 37-87)
Median time since diagnosis
5.4 years (range, )
ECOG < 1
87%
Baseline grade 1/2 neuropathy
77%
Prior lines of therapy
> 4 prior lines
Median # anti-MM agents
PD at study entry
Refractory to last therapy
Refractory or intolerant to bortezomib
5 (range, 1-20)
82% 13
100%
95%
88%
Siegel DS, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8027.

13. Carfilzomib Monotherapy in Heavily Pre-Treated MM
DCR = 69%
CBR = 37%
ORR = 24%
Carfilzomib
N = 257
Median OS
15.6 months
Median OS for > PR
20.7 months
Median PFS
3.7 months
Median PFS for > MR
9.5 months
Median DOR
8 months
Median follow-up = 14.3 months
Unfavorable cytogenetics did not significantly impact response rates or DOR.
CR, complete response; VGPR, very good partial response; PR, partial response; MR, marginal response; SD, stable disease; PD, progressive disease; DCR, disease control rate; CBR, clinical benefit rate; ORR, overall response rate; OS, overall survival.
Siegel DS, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8027. Jakubowiak AJ, et al. ASH Annual Meeting Abstracts. 2011;118(21):1875.

14. Adverse Events With Carfilzomib in Heavily Pre-Treated MM Patients
> Grade 3
Hematologic: Anemia
(> 15%) Thrombocytopenia
Lymphopenia
Neutropenia
24%
29%
20%
11%
Non-hematologic: Fatigue
Dyspnea
Upper respiratory tract infection
Headache
7.5%
3.4%
4.5%
1.9%
Other: Febrile neutropenia
Peripheral neuropathy
0.8%
Siegel DS, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8027.

15. 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.

16. 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.

17. Carfilzomib: Toxicity
Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
Carfilzomib: Toxicity
004, Phase II, Bortezomib-Naïve Patients
> Grade 3 AE
Cohort 1 (20 mg/m2)
n = 59
Cohort 2 (20→27 mg/m2)
n = 70
Lymphopenia
14%
19%
Anemia
12%
17%
Thrombocytopenia
15%
11%
Neutropenia
Pneumonia
Fatigue 1%
Dyspnea 5% 6%
Peripheral Neuropathy
1 patient (grade 3)
No treatment discontinuations due to PN
Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813. Abstract 1099. 17

25. Current Phase III StudiesUS
Europe
Multiple Myeloma
1-3 Prior Therapies
Relapsed / Refractory
Multiple Myeloma* R R
1:1
1:1
Carfilzomib
Lenalidomide
Dexamethasone
Lenalidomide
Dexamethasone
Carfilzomib
Best Supportive Care
Stratified by b2M levels
Prior bortezomib
Prior lenalidomide
*Prior treatment must have included:
Bortezomib
Lenalidomide or thalidomide
Alkylating agent
Corticosteroid
Anthracycline
Trial has met accrual goal.
National Institutes of Health. Available at: Accessed March 2011.

26. Median No. Prior Regimens Refractory to Recent Therapy (%)
Pomalidomide
Pts, n
Median No. Prior Regimens
Refractory to Recent Therapy (%)
ORR (%)
Pomalidomide ± dex1
191 5
100
2534
Pomalidomide, dex2 70 6 NR
2629
Pomalidomide, dex3 84 85
3435
Pomalidomide, cyclophosphamide, prednisone4 32
(1 to 3)
44* 59
Pomalidomide, dex, clarithromycin5 46
NR (at least 3) 60
*Len specifically
1. Vij R et al. J Clin Oncol. 2012;30. Abstract 8016.
2. Lacy MQ et al. Blood. 2011;118: Leleu X et al. Blood. 2011;118. Abstract 812.
4. Palumbo A et al. Blood. 2011;118. Abstract 632.
Mark TM et al. Blood. 2011;118. Abstract 635.

27. Pomalidomide in Relapsed/Refractory Multiple Myeloma
POM + LoDEX achieved responses in pts with prior LEN and/or BORT treatment, including those who are refractory1-4
Study
Phase N
Treatment
Population
Median Prior Tx (Range)
≥ PR
Lacy4 2 60
POM: 2 mg
(28/28-day cycle)
Dex: 40 mg/week
1-3 prior Tx, relapsed/refractory
2 (1-3)
65% 34
LEN-refractory
4 (1-14)
32% 35
DEX: 40 mg/week
LEN- and BORT- refractory
6 (3-9)
26%
POM: 4 mg
1-3 prior Tx, LEN-refractory
37%
6 (2-11)
29%
1. Lacy MQ et al. J Clin Oncol. 2009;27: Lacy MQ et al. Leukemia. 2010;24:1934.
3. Lacy MQ et al. Blood. 2011;118: Lacy MQ et al. Blood. 2011;118: Abstract 3963. 27

28. MM-003 POM + LoDEX in RRMM Phase 3 —Trial Design
Primary endpoint: PFS
Key secondary endpoints: OS, ORR (≥ PR), DOR, safety
(n = 302)
POM: 4 mg D1-21
LoDEX: 40 mg (≤ 75 years) mg (> 75 years) D1, 8, 15, 22
Follow-up for OS and SPM until 5 years post- enrollment
(n = 153)
HiDEX: 40 mg (≤ 75 years) mg (> 75 years) D1-4, 9-12, 17-20
28-day cycles
PDa or intolerable AE
PDa
Companion trial MM-003C
POM 21/28 days
Thromboprophylaxis was indicated for those receiving POM or with DVT history
aPD was independently adjudicated in real time.
Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

29. MM-003 POM + LoDEX in RRMM Phase 3 — Patient Characteristics and Disposition
POM + LoDEX arm: 45% ongoing; 55% discontinued (7% due to AEs)
HiDEX arm: 25% ongoing; 75% discontinued (6% due to AEs)
29% of pts on HiDEX received POM after PD
Baseline Characteristics
POM + LoDEX
(n = 302)
HiDEX
(n = 153)
Median age, years (range)
64 (35-84)
65 (35-87)
Median time from diagnosis, years
5.3
6.1
Median no. prior Tx, n (range)
5 (1-14)
5 (2-17)
Prior LEN, %
100
Prior BORT, %
Prior SCT, % 71 69
LEN-refractory, % 93 90
BORT-refractory, % 78 77
LEN- and BORT-refractory, % 73
Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

30. MM-003 POM + LoDEX in RRMM Phase 3 — Progression-Free Survival, ITT Populationa
a Based on adjudicated data; IMWG criteria.
Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

31. MM-003 POM + LoDEX in RRMM Phase 3 — Overall Survival, ITT Population
OS was significantly longer with POM + LoDEX vs. HiDEX, despite 29% of pts receiving POM after progression on HiDEX
Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

32. MM-003 POM + LoDEX in RRMM Phase 3 — Adverse Events
Discontinuation due to AEs: 7% POM + LoDEX; 6% HiDEX
VTE, all grades: 3% POM + LoDEX; 2% HiDEX
Peripheral neuropathy, all grades: 12% POM + LoDEX; 11% HiDEX
Grade 3-4 AEs, %
POM + LoDEX
(n = 300)
HiDEX
(n = 149)
Neutropenia 42 15
Febrile neutropenia 7
Anemia 27 29
Thrombocytopenia 21 24
Infections 23
Pneumonia 9
Hemorrhage 3 5
Glucose intolerance
Fatigue
Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

33. ClaPd: Study Design Day
A single-center, phase 2 study of Clarithromycin (Biaxin®) combined with Pomalidomide + Low Dose Dexamethasone in RRMM
Day
Dex
40mg PO
Pomalidomide 4 mg PO
Clarithromycin 500mg PO BID
p.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.

34. Patient Baseline Characteristics
Median (range)
N = 100
Age, years
63 (42–87)
Sex
46 male, 54 female
β2-Microglobulin, mg/L
3.4 (1.2–12.4)
Albumin, g/dL
3.5 (0.7–4.5)
Lactate dehydrogenase, U/L
171 (110–1353)
Hemoglobin, g/dL
10.4 (6.4–14.6)
Creatinine, mg/dL
0.9 (0.44–2.5)
Calcium, mg/dL
9.1 (7.8–12.3)
Number of prior therapies
5 (3–15)

35. Baseline MM Stage and Cytogenetic Abnormalities
Durie-Salmon stage, N = 100 Ia 42
IIa 43
IIb 3
IIIa 11
IIIb 1
International Staging System stage, N = 84 I
32 (38) II
29 (35)
III
23 (27)
Cytogenetics*, N = 96
Standard risk
41 (43)
High risk
55 (57)
*Standard risk, n (%), defined by the presence of one or more of the following: t(11;14): 4(16); hyperdiploidy, 12(46); FISH del 13q14, 12(46);
no abnormality: 5(19).
High risk, n (%), defined by the presence of one or more of the following: del 17p: 5(19); karyotype del 13q: 3(12); amp 1q/ del 1p: 5(19); t(14;20): 1 (6); t(14;16): 1(6); t(4;14): 1(6); or other complex cytogenetic abnormalities.

36. Results Best Response (IMWG Criteria) n (%) Overall (N = 98)
ORR (≥ PR)
56 (57)
CBR (≥ MR)
65 (66)
sCR
6 (6)
VGPR
17 (17) PR
33 (34) MR
9 (9) SD
23 (23) PD
10 (10)
98 patients completed at least 1 cycle of ClaPD.
median number of cycles received was 6 (range 1–25)
median study follow-up was months (range 1.0–25.6)
In responding patients, median time to PR was 1 cycle (range 1–7).
Median time to best response was 2 cycles (range 1-14).
IMWG, International Myeloma Working Group; CBR, clinical benefit rate; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.

37. Treatment History With Len/Bort Did Not Influence Response to ClaPD
Best Response (IMWG Criteria)
n (%)
Overall
(N = 98)
Lenalidomide
refractory
(N = 83)
Bortezomib
Refractory
(N = 82)
Lenalidomide and
bortezomib refractory
(N = 72)
ORR (≥ PR)
56 (57)
47 (63)
46 (56)
39 (54)
CBR (≥ MR)
65 (66)
56 (67)
54 (65)
(65)
sCR
6 (6)
6 (7)
5 (6)
5 (7)
VGPR
17 (17)
13 (16)
9 (13) PR
33 (34)
28 (34)
25 (35) MR
9 (9)
8 (10)
8 (11) SD
23 (23)
18 (22)
19 (23)
16 (22) PD
10 (10)
8 (12)
9 (11)
IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.

38. PFS by cytogenetic risk
Results
PFS by cytogenetic risk
1.00
Standard risk
High risk
At latest analysis, adverse cytogenetics did not appear to influence the risk of progression:
HR = 1.23, 95% CI (0.73,2.07),
P = 0.448
0.75
No progression (%)
0.50
0.25
Time (days)
Number of patients at risk Standard risk
High risk

39. Results PFS by Lenalidomide AND Bortezomib history 1.00
Not double-refractory
Double-refractory
0.75
No progression (%)
0.50
0.25
Time (days)
Number of patients at risk Relapsed
D-Refractory
There was no difference seen in PFS in double-refractory patients.
HR 1.35, 95% CI (0.75,2.43), P = 0.307
Bort, bortezomib; Len, lenalidomide.

40. Results OS Median survival has not been reached.
1.00
Median survival has not been reached.
After median follow-up time for survival of 9.6 months, 72% of patients are alive
0.75
Survival (%)
0.50
0.25
Time (days)
Number of patients at risk

41. OS by double-refractory state
Results
OS by cytogenetic risk
OS by double-refractory state
1.00
1.00
0.75
0.75
Survival (%)
0.50
Survival (%)
0.50
Standard risk
High risk
Not double-refractory
Double-refractory
0.25
0.25
Time (days)
Time (days)
Number of patients at risk Relapsed
Refractory
Number of patients at risk Relapsed
Refractory
Adverse cytogenetics did not appear to influence risk of death as of last study follow-up.
HR 1.05, 95%CI (0.49,2.26), P = 0.888
A history of being double-refractory, however, approached a significant effect on survival time.
HR 2.67, 95%CI (0.93,7.69), P = 0.068

42. Grade 3/4 Adverse Events*
Anemia 21 4
Thrombocytopenia 17 16
Neutropenia 33 14
Lymphopenia 31 6
Hyperglycemia 7 3
Febrile neutropenia 2 1
Pulmonary embolism
DVT
Three patients withdrew from study due to adverse events:
1 grade 3 fatigue
1 grade 4 muscular weakness
1 grade 4 neutropenic sepsis
There was no treatment-related mortality
*Occurring in ≥ 10% of patients.

43. Conclusions
ClaPD has proven to be a highly effective regimen for a large cohort of heavily treated relapsed or refractory MM patients.
The addition of clarithromycin to pomalidomide + low dose dexamethasone appears to enhance expected efficacy.
ClaPD demonstrates clinical activity in patients with advanced MM who have received multiple prior therapies, including many who are refractory to both lenalidomide and bortezomib.
PFS in patients treated with ClaPD is sustained for > 8 months in the majority of patients.

44. Conclusions (2)
High-risk cytogenetics did adversely impact PFS or OS in patients treated with ClaPD.
A history of being refractory to prior lenalidomide, bortezomib, or double-refractory to both agents did not adversely influence PFS in patients treated with ClaPD; however, there is a trend towards shorter survival in double-refractory patients.
Incidence of venous thrombosis while on low-dose aspirin prophylaxis was 5%
Discontinuation rate due to adverse events was low at 3%.

46. MyelomaCenter. org Morton Coleman Roger N Pearse Tomer Mark
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