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
Conflict of Interest: Kenneth C. Anderson, M.D.
Consultancy: Celgene, Onyx, Sanofi Aventis, and
Gilead
Scientific Founder: Acetylon, Oncopep
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
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
Combinations in the Upfront Treatment of MM
Stewart AK, Richardson PG, San Miguel JF Blood 2009
Lenalidomide and Bortezomib/Lenalidomide-Based
Consolidation
Study details
IFM
Response data
n=572
2005-021
•Len consolidation (2 mos)
•Maintenance randomization:
Len vs placebo
1Attal
p
CR (IF–)
14%
20%
<0.0001
≥ VGPR
58%
67%
<0.0001
n=31
Postinduction
PostASCT
Postconsolidation
sCR
13%
26%
38%
CR
10%
10%
10%
≥ VGPR
62%
68%
84%
≥PR
94%
91%
94%
IFM 20082
•VRD induction
•ASCT
•VRD consolidation (2 cycles)
•Len maintenance
PrePostconsolidation consolidation
et al. Haematologica 2011; 96 (s1): S23; oral presentation at IMW 2011
2Roussel et al. ASH 2010 (Abstract 624), oral presentation
5
CALGB 100104: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;366:1770-1781.
Lenalidomide Maintenance Therapy MetaAnalysis
Oral Abstract #407 - Lenalidomide Maintenance Therapy In
Multiple Myeloma: A Meta-Analysis Of Randomized Trials
Monday, December 9, 2013: 11:30 AM 393-394
•
Singh M, et al. ASH 2013. Abstract 407.
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
Bortezomib induction and maintenance
in ASCT
NDMM, TE, sge 18–65 y
Randomization
3 x PAD
3 x VAD
CAD + GCSF
Thalidomide
maintenance
50 mg/day for
2 years
1.3 mg/m2
i.v.
Doxorubicin
9 mg/m2
Dexameth
40 mg
CAD + GCSF
MEL 200 + PBSCT
In GMMG 2nd
MEL 200 + PBSCT
Bortezomib
MEL 200 + PBSCT
Allogeneic
Tx
In GMMG 2nd
MEL 200 + PBSCT
Bortezomib
Maintenance
1.3 mg/m2 / 2 weeks
for 2 years
Sonneveld et al, ASH 2013
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
Carfilzomib With Thalidomide
and Dexamethasone in ASCT
Intensification* (1 cycle)
Induction
Consolidation
(4 28-day cycles)
(4 28-day cycles)
Phase II
open-label
doseescalation
trial (N=70)
Carfilzomib, 20/27 mg/m2
Days 1,2,8,9,15,16
Carfilzomib, 27 mg/m2
Days 1,2,8,9,15,16
Thalidomide, 200 mg
Days 1-28
Thalidomide, 50 mg
Days 1-28
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 2013. Abstract 688.
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
90
90
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 2013. Abstract 688.
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; 27:3664-70
4Waage et al. Blood 2010; 116:1405-12
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): 2259-2266
9Palumbo et al. ASH 2010 (Abstract 622)
10Mateos et al. Lancet Oncol 2010; 11(10): 934-941
11Palumbo et al. ASH 2010 (Abstract 620)
15
FIRST Trial: Study Design
Active Treatment + PFS Follow-up Phase
Arm B
Rd18
LEN + Lo-DEX: 18 Cycles (72 wks)
Arm C
MPT
LENALIDOMIDE
Lo-DEX
LENALIDOMIDE
Lo-DEX
25mg D1-21/28
40mg D1,8,15 & 22/28
25mg D1-21/28
40mg D1,8,15 & 22/28
MEL + PRED + THAL 12 Cycles1 (72 wks)
MELPHALAN
PREDNISONE
THALIDOMIDE
0.25mg/kg D1-4/42
2mg/kg D1-4/42
200mg D1-42/42
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 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;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.
Facon T, et al. Blood. 2013;122:abstract 2.
Subsequent anti-MM Tx
LEN + Lo-DEX Continuously
PD, OS and
Arm A
Continuous Rd
LT Follow-Up
PD or Unacceptable Toxicity
RANDOMIZATION 1:1:1
Screening
16
FIRST Trial: Final Progression-free Survival
Median PFS
100
Rd
Patients (%)
80
(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 = 0.00006
Rd vs. Rd18: 0.70; P = 0.00001
Rd18 vs. MPT: 1.03; P = 0.70349
60
42% (Rd)
40
20
23% (Rd18)
23% (MPT)
0
0
6
12
18
24
30
36
42
48
54
60
Time (months)
Rd
535
400
319
265
218
168
105
55
19
2
0
Rd18
541
391
319
265
167
108
56
30
7
2
0
MPT
547
380
304
244
170
116
58
28
6
1
0
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.
FIRST Trial: Consistent PFS Benefit Across Subgroups
Subgroup
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
0.81 (0.62 - 1.05)
0.68 (0.56 - 0.83)
0.73 (0.58 - 0.93)
0.71 (0.57 -0.88)
0.61 (0.33 - 1.14)
0.77 (0.63 - 0.93)
0.64 (0.46 - 0.89)
0.70 (0.57 - 0.87)
0.75 (0.59 - 0.95)
0.76 (0.44 - 1.30)
0.66 (0.48 - 0.91)
0.74 (0.58 - 0.95)
0.71 (0.51 - 1.01)
0.54 (0.39 - 0.74)
0.81 (0.65 - 1.01)
0.80 (0.57 - 1.12)
0.69 (0.58 - 0.83)
0.96 (0.66 - 1.39)
1.23 (0.78 - 1.93)
0.69 (0.53 - 0.90)
ITT patients
0.72 (0.61 - 0.85)
0.125
0. 25
0.5
Favoring Rd
1
2
4
17
8
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)
FIRST Trial: TTP and Time to
2nd
Anti-myeloma Therapy
Time to Progression
Time to 2nd AMT
Median Time to
2nd AMT
Median TTP
100
Rd
(n=535)
32.5 mos
Rd18
(n=541)
21.9 mos
MPT
(n=547)
23.9 mos
100
Rd
(n=535)
39.1 mos
Rd18
(n=541)
28.5 mos
MPT
(n=547)
26.7 mos
80
Patients (%)
Patients (%)
80
60
40
Hazard ratio
Rd vs. MPT: 0.68; P=0.00001
Rd vs. Rd18: 0.62; P≤0.00001
Rd18 vs. MPT: 1.11; P=0.21718
20
60
40
0
535
541
547
6
398
389
379
12 18 24 30 36 42
TTP (months)
318
317
303
263
265
242
218
167
169
167
108
115
Facon T, et al. Blood. 2013;122:abstract 2.
105
56
58
55
30
28
Hazard ratio
Rd vs. MPT: 0.66; P<0.00001
Rd vs. Rd18: 0.74; P=0.00067
Rd18 vs. MPT: 0.88; P=0.12333
20
0
0
Rd
Rd18
MPT
18
48
54 60
0
6
12
18
24
30
36
42
48
54
60
3
2
1
0
0
0
Time to 2nd AMT (months)
19
7
6
2
2
1
0
0
0
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
FIRST Trial: Conclusions
19
• Continuous Rd significantly extended PFS, with an OS benefit vs. MPT
– PFS:
•
•
•
•
HR= 0.72 (P= 0.00006)
Consistent benefit across most subgroups
Rd better than Rd18 (HR= 0.70, P= 0.00001)
3 yr PFS: 42% Rd vs. 23% Rd18 and MPT
– Planned interim OS: HR= 0.78 (P= 0.0168)
– 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
Facon T, et al. Blood. 2013;122:abstract 2.
20
Progression-Free and Overall Survival
All Patients
Median PFS
100
4-year OS
MPR-R
31 months
MPR-R
59%
MPR
14 months
MPR
58%
MP
13 months
MP
58%
100
HR 0.898
75
HR 0.395
50
P < .001
HR 0.796
25
P = .135
0
0
10
20
Time (Months)
30
40
Patients (%)
Patients (%)
75
P = .579
50
HR 1.089
P = .648
25
0
0
10
20
30
40
50
Time (Months)
• TTP HR advantages were similar: MPR-R vs MP = 0.337; MPR vs MP = 0.826
HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone,
lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression-free survival; TTP, time to progression.
60
21
Second Primary Malignancies
All Patients
Hematologic SPM
PD/Death
MPR-R
Patients (%)
100
Solid Tumor
MPR
100
75
75
75
50
50
50
25
25
25
0
0
0
20
40
60
Time (Months)
MP
100
0
0
20
40
60
0
20
40
Time (Months)
Time (Months)
SPM, n (IR per 100 per year)
MPR-R
(n = 150)
MPR
(n = 152)
MP
(n = 153)
Total Invasive SPMs
12 (3.04)
10 (2.57)
4 (0.98)
Hematologic
7 (1.75)
6 (1.54)
1 (0.24)
Solid tumors
5 (1.26)
5 (1.28)
3 (0.74)
2 (0.50)
5 (1.29)
6 (1.50)
Non-melanoma skin cancer
IR, incidence rate; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone,
lenalidomide with lenalidomide maintenance; PD, progressive disease; PY, person-year; SPM, second primary malignancy.
60
Treatment schema
 152 patients
 ≥ 75 years or younger with co-morbidities
 At baseline: geriatric assessment (ADL, IADL, Charlson)
VP
Nine 35-day courses
Vsc: 1.3 mg/sqm, d 1,8,15,22
P: 50 mg, 3 times wk
MAINTENANCE
28-day course until relapse
Vsc: 1.3 mg/sqm, d 1, 15
VMP
Nine 35-day courses
Vsc: 1.3 mg/sqm, d 1,8,15,22
M: 2 mg, 3 times wk
P: 50 mg, 3 times wk
VCP
Nine 35-day courses
Vsc: 1.3 mg/sqm, d 1,8,15,22
C: 50 mg, 3 times wk
P: 50 mg, 3 times wk
MAINTENANCE
28-day course until relapse
Vsc: 1.3 mg/sqm, d 1, 15
MAINTENANCE
28-day course until relapse
Vsc: 1.3 mg/sqm, d 1, 15
Vsc, subcutaneous bortezomib; C, cyclophosphamide; M, melphalan; P, prednisone
Larocca et al ASH 2013
Subgroup analysis: Age
Progression-free Survival
Overall Survival
100
75
75
Patients (%)
100
50
50
25
Age 75-80 years
Age <75 years
Age 80 years
25
0
Age 75-80 years
Age <75 years
Age  80 years
0
0
6
12
18
24
30
Time (months)
PFS, Age 75-80 vs Age<75, HR=0.96 p=0.865
PFS, Age  80 vs Age<75, HR=0.80 p=0.449
0
6
12
18
24
30
Time (months)
OS, Age 75-80 vs Age<75, HR=0.79 p=0.571
OS, Age  80 vs Age<75, HR=0.99 p=0.990
Conclusions
•
The global population is rapidly aging.
Aging is associated with an increased incidence of comorbidity, frailty, and disability.
•
PFS and OS appeared similar between the 2- drug
and the 3-drug combinations
•
Melphalan seemed more toxic than cyclophosphamide
•
Fit patients 
Full dose therapy
Unfit patients 
Reduced-dose therapy
Frail patients 
Further reduced-dose therapy
Larocca et al, ASH 2013
Study design
• Phase II
• Multicenter (10 centres)
CCd Induction
Cycles 1-9
C Maintenance
Until progression
Response Assessments
Cycle day 1 2 8 9 1516 22 1 2 8 9 1516 22 1 2 8 9 1516 22
Carfilzomib
Dose (mg/m2)
Dosing
20 36 36
CYCLE 11
CYCLE
36 36 36
CYCLE 22
CYCLE
36 36 36
12
36
CYCLE 39
CYCLE
15 16
12
15 16
36
36
36
12
36
CYCLE 5
MAINTENANCE
Cyphosphamide
300 mg/m2 orally
Dexamethasone
40 mg orally
Bringhen et al ASH 2013
15 16
36
Conclusions 1
CCd
MPT
VMP
Rd
≥ VGPR
77%
36%
41%
40%
nCR/CR/sCR
47%
27%
30%*
14%
2-yr PFS
76%
47%
~47%
~47%
2-yr OS
87%
76%
79%
87%
Response rates
Long-term outcomes
* CR only, nCR not reported
Palumbo at al, Lancet, 2006 ;367:825-31.Fayers et al, Blood 2011; 118:1239-47; San Miguel et al, N Eng J Med 2008;359:906-17;
Rajkumar et al, Lancet Oncol 2010; 11:29-37
Bringhen et al ASH 2013
Oral MLN 9708 Len Dex in Newly Diagnosed MM
Maintenance
Induction: up to 16 x 21-day treatment cycles
1
2
4
5
8 9
MLN9708
MLN9708
MLN9708
Dex*
Dex*
Dex*
11 12
15
21
MLN9708
Dex*
Lenalidomide 25 mg, days 1–14
MLN9708
maintenance
Days 1, 4, 8, 11
21-day cycles
*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
Ixazomib lenalidomide dexamethasone in newly
diagnosed multiple myeloma
Dose level (cohort):
Ph 1, 3.0 mg
Ph 2, 3.0 mg
% decreases in M-protein
0
–20
–25%
–40
–50%
–60
–80
–90%
–100
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
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
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.
MM-003 Design: POM + LoDEX vs. HiDEX
28-day cycles
RANDOMIZATION 2:1
(n = 302)
POM:
4 mg/day D1-21 +
LoDEX: 40 mg (≤ 75 yrs)
20 mg (> 75 yrs)
D1, 8, 15, 22
PDa or
Unacceptable AE
Follow-Up for OS
and SPM Until
5 Years Post
Enrollment
(n = 153)
HiDEX:
40 mg (≤ 75 yrs)
20 mg (> 75 yrs)
D1-4, 9-12, 17-20
PDa or
Companion trial
MM-003C
Unacceptable AE
POM 21/28 days
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].
PFS Based on Cytogenetic Profile
• POM + LoDEX significantly improved PFS vs. HiDEX regardless of the
presence of del17p or t(4;14)
Subgroup
POM +
LoDEXa
HiDEXa
ITT Population
253/302
138/153 0.49 (0.40-0.61)
del(17p)/t(4;14)
71/77
32/35
0.44 (0.28-0.68)
Standard-Risk
Cytogenetics
126/148
63/72
0.55 (0.40-0.75)
0.25
0.5
Favors POM + LoDEX
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].
1
2
Favors HiDEX
HR (95% CI)
Forest Plot of OS Based on Prior Treatment
POM + LoDEXa
HiDEXa
HR (95% CI)
176/302
101/153
0.72 (0.56-0.92)
≤ 3 Prior Tx
41/70
22/33
0.56 (0.33-0.96)
> 3 Prior Tx
135/232
79/120
0.76 (0.58-1.00)
Prior THAL
102/173
64/93
0.75 (0.55-1.03)
No Prior THAL
74/129
37/60
0.66 (0.45-0.99)
LEN Ref
168/286
94/141
0.70 (0.55-0.90)
BORT Ref
142/238
79/121
0.77 (0.58-1.01)
LEN and BORT Ref
135/225
74/113
0.77 (0.58-1.02)
LEN as Last Prior
47/85
32/49
0.56 (0.36-0.88)
BORT as Last Prior
76/134
39/66
0.92 (0.63-1.36)
Subgroup
ITT Population
0.25
0.5
Favoring POM-LoDex
a
Number of events/number of pts.
San Miguel JF, et al. ASH 2013 [abstract 686].
1
2
Favoring HiDEX
MM-003: PFS and OS by M-Protein Reduction
Patients Assigned to POM + LoDEX
Proportion of Patients
1.0
0.8
≥ 25 % (n = 163)
7.4 mos
≥ 25 % (n = 163)
17.2 mos
≥ 50 % (n = 113)
8.4 mos
≥ 50 % (n = 113)
19.9 mos
< 25% (n = 96)
2.3 mos
< 25% (n = 96)
7.5 mos
1.0
0.8
0.6
0.4
0.4
0.2
0.2
0.0
0.0
4
8
Median
OS
Median
PFS
0.6
0
M-Protein
Reduction
M-Protein
Reduction
12
PFS (mos)
16
20
24
0
4
8
12
16
20
24
28
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].
Pom low dose dex and bortezomib in
relapsed MM
Table 4. Summary of Best Response (IMWG) in Intravenous BORT
Cohorts
Cohort 1
(n = 3)
Cohort 2
(n = 3)
Cohort 3
(n = 3)
Cohort 4
(n = 3)
Cohort 5 +
Exp Cohort
(n = 9)a
2 (67)
1 (33)
3 (100)
3 (100)
6 (67)
0
0
0
0
1 (11)
VGPR
1 (33)
0
2 (67)
1 (33)
4 (44)
PR
1 (33)
1 (33)
1 (33)
2 (67)
1 (11)
1 (33)
2 (67)
0
0
3 (33)
5 (4-16)
6 (4-18)
16 (5-20)
10 (4-13)
11 (6-15)
Outcome
Overall response, n (%)
sCR/CR
SD
Median cycles received (range)
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
Carfilzomib: A Novel Proteasome
(Chymotryptic) Inhibitor
• Novel chemical class with highly selective
and irreversible proteasome binding
Tetrapeptide
• Improved antitumor activity with
consecutive day dosing
• No neurotoxicity in animals
H
N
N
O
O
O
N
H
H
N
O
O
O
N
H
O
Epoxyketone
• 23% Responses lasting 7.8 months with survival 15.4
months in relapsed and relapsed/ refractory MM w/o
Demo et al Cancer Res 2007; 67:6383
Kirk et al, Blood 2008, 112: 2765 ; Siegel et al Blood 2012:120:2817.
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
Carfilzomib Pomalidomide Low dose Dex
•
Median of 5 prior lines of therapy; 49% of patients had high/intermediate risk
cytogenetics at baseline
 ≥ VGPR
ORR
CBR
 DOR (median)
 PFS (median)
 OS (median)
27%
70%
83%
17.7 months
9.7 months
> 18 months
• Response rates, PFS, and OS were preserved independent of
FISH/cytogenetic risk status
• Well tolerated with no unexpected toxicities
Shah et al ASH 2013
MAb-Based Therapeutic Targeting of Myeloma
Antibody-dependent
Cellular cytotoxicity
(ADCC)
Complement-dependent
Cytotoxicity (CDC)
Apoptosis/growth
arrest
via targeting
signaling pathways
C1q
C1q
Effector cells:
CDC
MM
ADCC
MM
FcR
MM
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
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;14:2775-2784; Tai YT et al. Blood.
2008;112:1329-1337; Van Rhee F et al. Mol Cancer Ther. 2009;8:26162624; Lonial S et al. Blood. 2009;114:432; Richardson et al Blood
2010:864 Lonial et al, ASH 2012
Martin et al ASH 2013
Martin et al 2013
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
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
Plesner et al ASH 2013
44
Kelley et al ASH 2013
Kelly et al ASH 2013
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
Lonial et al ASH 2013
47
Lonial et al ASH 2013
Low AAG is Associated with Higher ORR
Filanesib Single-agent
All Pts1
n
AAG-High AAG-Low
Filanesib + Dex
All Pts2
AAG-High AAG-Low
32
6
21
55
15
36
ORR (≥ PR)
5 (16%)
0 (0%)
5 (24%)
8 (15%)
0 (0%)
7 (19%)
CBR (≥ MR)
7 (22%)
0 (0%)
7 (33%)
11 (20%)
0 (0%)
10 (28%)
Duration of Response
(months)
8.6
-
8.6
5.1
-
5.1
Time to Next
Treatment (months)
3.7
2.6
5.3
3.4
2.0
5.1
OS (months)
19.0
4.5
23.3
10.5
2.9
10.8
1
2
5 patients did not have a baseline AAG measurement
4 patients did not have a baseline AAG measurement, including 1 responder
48
Development of Rationally-Based Combination
Therapies (HDAC and Proteasome Inhibitors)
Protein
Ub
Ub
Ub
protein aggregates
(toxic)
Ub
Ub
26S proteasome
Ub
HDAC6
Ub
Panibinostat,
Vorinostat, ACY1215
Ub
Bortezomib, Carfilzomib, NPI0052,
MLN9708, ONX 0912
HDAC6
dynein
Ub
HDAC6
dynein
Microtubule
Ub
Aggresome
Ub Ub
Lysosome
Ub Ub
Ub
Ub
Autophagy
Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:3441-9.
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); 7.63 months (6.9–8.4)
versus 6.83 months (5.7–7.7)
• Diarrhea, fatigue, and thrombocytopenia limited tolerability.
Dimopoulos et al Lancet Oncol
2013; 14: 1129-40.
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
Monotherapy response data from Final CSR. Combination response data pulled from
live database Nov 8, 2013
1
51
One patient had a 26% decrease in M Protein after Cycle 2 and withdrew after two
subsequent cycles with SD
VGPR
2
PR
3
MR1
2
SD
5
Ricolinostat (HDAC 6 inhibitor) lenalidomide
dexamethasone in relapsed refractory MM
M protein % change
CR
1
VGPR
3
PR1
7
MR
2
SD
3
• 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
52
PKB115125 Akt Inhibitor: Dose Limiting Toxicities
Afur / Bor / Dex
dose (mg)
n
DLT
Comment
75- 1.0- 20
4
None
-
100 - 1.3- 20
6
1/6
LFT elevation G2
125 - 1.3- 20
6
1/6
Erythema Multiforme G3
150 - 1.3- 20
6
None
-
175 - 1.3- 20
6
2/6
Rash G3
Rash G3 / Diarrhea G3 /Thrombocytopenia G3
150 -1.3- 40
6
NA
-
All DLTs were reversible
MTD / RP2D:
Voorhees et al ASH 2013
Afuresertib
150 mg PO daily
Bortezomib
1.3 mg/m2 IV/SC on days: 1,4,8,11
Dexamethasone
40 mg PO on days: 1,4,8,11
Maximum % change in M-protein or FLC from baseline
Voorhees et al ASH 2013
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.
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 SAR650984 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