Download Multiple Myeloma Patient Management: New Agents, New Challenges

Multiple Myeloma Patient Management:
New Agents, New Challenges
8:15 AM – 8:25 AM
8:25 AM – 8:40 AM
8:40 AM – 8:55 AM
8:55 AM – 9:05 AM
9:05 AM – 9:20 AM
9:20 AM – 9:35 AM
9:35 AM – 9:45 AM
9:45 AM – 10:00 AM
10:00 AM – 10:15 AM
10:15 AM – 10:30 AM
10:30 AM – 11:00 AM
Community Case 1
Robert M. Rifkin, MD
Advances in the Diagnostic Workup: Imaging and Genomics
A. Keith Stewart, MBChB
Making Sense of Frontline Options
Thierry Facon, MD
Community Case 2
Robert M. Rifkin, MD
Strategies to Prolong Response
Amrita Y. Krishnan, MD
Panel Discussion
Community Case 3
Robert M. Rifkin, MD
New Agents, Classes in the Relapsed Setting
Faith E. Davies MD
The Way Forward: Immunotherapy
Paul G. Richardson, MD
Panel Discussion
Question and Answer Session
1
Patient Case 1
Robert M. Rifkin, MD
Associate Chair – US Oncology Research
Disease Lead – Multiple Myeloma
Attending Physician
Rocky Mountain Cancer Centers
Denver, Colorado
Case Study 1
• 75-year-old man referred for workup of back pain
that radiated to ribs and chest.
• CT pulmonary Angiogram was negative for
pulmonary embolus (creatinine 1.5).
• This showed multifocal lytic bone disease. Felt
well except for pain in his back.
2
Case Study 1
75-year-old man referred for workup of back pain that radiated to ribs and
chest.
Past medical
history
• Hypertension
• T2DM
• Coronary
artery disease
with 2 stents
Past surgical
history
• Left rotator
cuff repair 7
years ago
Family
history
• Brother and
five sisters—
all healthy
• Four children
Social
history
Physical
exam
• Married,
bilingual
instructor for
OSHA
• Nonsmoker,
rare social
alcohol
• No substance
use
• Normal
• ROS: negative
except for
back pain
Case Study 1: Labs
Actual
Value
CBC with
differential
CMP
SPEP +
serum
immunofixation
Normal
Range
WBC (103/mL)
5.4
(4–11)
Hemoglobin (g/dL)
12.0
(13–16)
Hematocrit (%)
38
(34–45)
Platelets (103/mL)
210
(150–400)
Neutrophils (103/mL)
4.3
(1.9–7.5)
BUN (mg/dL)
34
(7–20)
Creatinine (mg/dL)
1.5
(0.7–1.2)
Calcium (mg/dL)
9.4
(8.4–10.2)
Total protein (g/dL)
8.7
(6.3–8.2)
Albumin (g/dL)
3.7
(3.5–5.0)
β2M
4.5
Actual
Value
IgG (mg/dL)
Quantitative
IgA (mg/dL)
Igs
IgM (mg/dL)
FLC
Normal
Range
2,425 (H) (700–1,600)
20 (L)
(70–400)
3 (L)
(40–230)
Kappa quant Free Lite Chain
(mg/L)
112 (H)
(3.30–19.40)
Lambda quant FLC (mg/L)
1.8 (L)
(5.71–26.30)
Kappa/lambda quant FLC
ratio
62.2 (H)
(0.26–1.65)
IF-IgG
M protein spike (g/dL)
1.7
3
Case Study 1: Imaging and BM Biopsy
Bone
imaging
Skeletal survey
• 1.6 cm lytic lesion
in the parietal bone;
severe loss of bone
mineralization—
osteoporosis
PET scan
• Expansile lytic
lesion in right
acromion. Multiple
areas of uptake in
bilateral ribs, and
increased uptake in
T5
MRI
• Multifocal lesions in
spine and ribs
Scottsdale, Arizona
BM
biopsy
• 70% cellular with
70%–80% plasma
cells
• Aspirate 66%
plasma cells
Rochester, Minnesota
Flow
cytometry
Cytogenetics
and FISH
• 25.6% events
positive for CD38,
CD56, CD138, and
kappa light chain
Cytogenetics
• 46, XY
FISH (CD138
selected plasma
cells)
• 74% with gain of
1q21
• 5.4% low-level gain
of 11q23
• 91% with loss of
13q14
• 12.0 % with lowlevel loss of TP53
• 92.5% positive for
IgH rearrangement
variant
Jacksonville, Florida
Advances in the Diagnostic
Workup: Imaging and Genomics
A. Keith Stewart, MBChB, MRCP, FRCPC, MBA
Carlson and Nelson Endowed Director
Center for Individualized Medicine
Vasek and Anna Maria Polak Professor of Cancer Research
Consultant, Division of Hematology/Oncology, Mayo Clinic
Rochester, Minnesota and Scottsdale, Arizona
4
Improving Survival in MM
1.0
0.9
0.8
Proportion Surviving
1960–1965
1965–1970
1970–1975
1975–1980
1980–1985
1985–1990
1990–1995
1995–2000
2000–2005
2005–2010
25% of patients live
less than 3 years
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
Follow Up From Diagnosis (Years)
16
18
20
Adapted from Kumar SK et al. Leukemia. 2014;28:1122.
Prognostic Systems
Combining Genetics and ISS Model
+
Risk
Criteria
Median OS
Standard
Lack of del(17p),
t(4;14), t(14;16)
50.5 mo
High
Table 2, page 3415:
Greipp PR et al.
J Clin Oncol. 2005;23:3412.
At least one of
24.5 mo
del(17p), t(4;14) or
(P<0.001)
t(14;16)
Fonseca R et al. Leukemia. 2009;23:2210.
Greipp PR et al. J Clin Oncol. 2005;23:3412.
5
Revised International Staging System
(R-ISS) for MM
• R-ISS I (n=871)
– Including ISS stage I (serum β2M level <3.5
mg/L and serum albumin level ≥3.5 g/dL)
– No high-risk CA [del(17p) and/or t(4;14)
and/or t(14;16)]
– Normal LDH level (less than the upper limit of
normal range)
• R-ISS III (n=295)
– Including ISS stage III (serum β2M level >5.5
mg/L)
– High-risk CA or high LDH level
5-Year OS*
(%)
5-Year PFS*
(%)
R-ISS I
82
55
R-ISS II
62
36
R-ISS III
40
24
*At a median follow-up of 46 months
• R-ISS II (n=1,894)
– Including all the other possible combinations
Palumbo A et al. J Clin Oncol. 2015;33:2863.
mSMART 2.0
Variable Outcomes in MM
High
20%
• FISH
‒ del 17p
‒ t(14;16)
‒ t(14;20)
• GEP
‒ High-risk signature
3–4 years
Intermediate
20%
Standard
60%
• FISH t(4;14)
• Amplification
chromosome 1q
• Others
‒ Hyperdiploid
‒ t(11;14)
‒ t(6;14)
5–6 years
8–10 years
Mikhael JR et al. Mayo Clin Proc. 2013;88:360.
6
Cytogenetics: Biologically
Defined Unique Subsets
Figure 2, page 2033
Garand R et al.
Leukemia.
2003;17:2032.
t(4;14)1
• Translocation upregulates MMSET + FGFR3
• Found in 15% of patients
• Associated with IgA myeloma
• Immature morphology
• Often associated with del17
• Tendency for less lytic bone disease, younger age
t(11:14)2
• Translocation upregulates cyclinD1
• Found in 20% of patients
• Associated with IgD, IgM, and nonsecretory MM
• Lymphoplasmacytoid morphology
• Often associated with B lineage–associated Ag
• Enriched for amyloid/plasma cell leukemia
1. Jaksic W et al. J Clin Oncol. 2005;23:7069.
2. An G et al. Leuk Res. 2013;37:1251.
Risk Stratification in Myeloma
How do we customize treatment?
• t(4;14) MM
– Inferior outcomes with traditional ASCT
– Results better with integration of novel agents, particularly BTZ
(consolidation or maintenance) and use of tandem transplant
• Del17p (p53 deletion) MM
– Improved outcome for low-risk del17p with aggressive multicombination and prolonged therapy
– New treatment approaches required (eg, immune-based
approaches, use of epigenetic modulators)
• Hyperdiploid
– Myc dependant
– Super responders to IMiDs
7
Venetoclax in t(11;14) MM
ORR by t(11;14) Status
sCR
CR
VGPR
PR
200
ORR 40%
3%
40
Kappa FLC
150
7%
mg/dL
Percentage of Patients
50
30
20
ORR 21%
3%
3%
10
9%
17%
100
50
Generalized normal high
13%
t(11;14)
(n=30)
Non-t(11;14) or
undetermined
(n=36)
6%
0
All Patients
(n=6)
0
ORR 6%
3%
3%
Generalized normal low
A.K. Stewart, unpublished
Kumar S et al. Blood. 2016;128: Abstract 488.
Imaging in Myeloma:
IMAJEM (NCT01309334)
ARM A
RVD × 3
CY (3g/m2)
MOBILIZATION
Randomize
PET-CT/MRI at diagnosis
PET-CT/MRI after 3 cycles
ARM B
RVD × 3
CY (3g/m2)
MOBILIZATION
Goal: 5 ×106 cells/kg
Goal: 5 ×106 cells/kg
RVD × 5
Melphalan 200
mg/m2 + ASCT
Lenalidomide 1 year
ASCT at relapse
PET-CT/MRI before maintenance
RVD × 2
Lenalidomide 1 year
N=134
Moreau P et al. Blood. 2015;126: Abstract 395.
8
Imaging in Myeloma:
IMAJEM (NCT01309334)
• At diagnosis
– MRI was positive in 127/134 (94.7%)
– PET-CT in 122/134 (91%) patients
(McNemar test = 0.94, P=0.33)
• MRI of the spine and pelvis and whole-body PETCT are equally effective to detect bone
involvement in symptomatic patients at diagnosis
Moreau P et al. Blood. 2015;126: Abstract 395.
Imaging in Myeloma:
IMAJEM (NCT01309334)
• Univariate analysis for PFS/134 patients
• Variables tested:
Gender, age, Ca, creatinine, ISS, response after 3 cycles
of induction, response pre-maintenance, cytogenetics,
MRI after 3 cycles, PET-CT after 3 cycles, MRI premaintenance, PET-CT pre-maintenance
• PET-CT after 3 cycles, P=0.04
• PET-CT pre-maintenance, P<0.001
• Response after 3 cycles (≥VGPR), P=0.04
Moreau P et al. Blood. 2015;126: Abstract 395.
9
PET-CT Normalization Before Maintenance
Impact on PFS (62% Normalized)
1.0
0.8
69%
0.6
51.6%
0.4
P< 0.001
0.2
0.0
0
10
20
30
Moreau P et al. Blood. 2015;126: Abstract 395.
PET-CT -ve correlates with OS
• Univariate analysis for OS/134 patients
• Variables tested:
Gender, age, Ca, creatinine, ISS, response after 3 cycles
of induction, response pre-maintenance, cytogenetics,
MRI after 3 cycles, PET-CT after 3 cycles, MRI premaintenance, PET-CT pre-maintenance
• PET-CT pre-maintenance, P=0.003
Moreau P et al. Blood. 2015;126: Abstract 395.
10
PET-CT Normalization Before Maintenance
Impact on OS (62% Normalized)
1.0
94.6%
69.9%
0.8
0.6
0.4
P=0.003
0.2
0.0
0
10
20
30
40
Moreau P et al. Blood. 2015;126: Abstract 395.
Conclusions
• PET-CT and MRI are equally effective to detect bone
involvement in symptomatic patients at diagnosis
• MRI is not a good imaging method during follow-up
• PET-CT after 3 cycles of RVD and pre-maintenance is a
powerful prognostic marker for PFS
• PET-CT pre-maintenance is a powerful prognostic marker
for OS
11
Genomic Landscape in MM
• >1000 whole-exome/genome sequences
• A limited set of genes is recurrently mutated in MM:
KRAS, NRAS, TP53, DIS3, FAM46C, BRAF, TRAF3
results are predominantly obtained from newly-diagnosed
MM
Figure 1, page 93
Lohr JG et al. Cancer Cell. 2014;25:91.
Chapman MA et al. Nature. 2011;471:467.
Bolli N et al. Nat Commun. 2014;5:2997.
Lohr JG et al. Cancer Cell. 2014;25:91.
Walker BA et al. J Clin Oncol. 2015;33:3911.
Lonial S et al. Blood. 2014;124: Abstract 722.
Keats JJ et al. Blood. 2012;120:1067.
Myeloma Mutation Panel (M3P)
•
•
•
•
•
•
•
Recurrently mutated putative MM genes: FAM46C, TP53, DIS3
Actionable genes: RAS, BRAF, IDH1
Pathways: MAPK, Cereblon, MYC
Drug resistance: IMiDs, proteasome inhibitors, glucocorticoid
Copy-number changes and common translocations
Biallelic deletions of tumor suppressors
Sample purity measurement: J regions IGH, IGL-K and IGL-L
 88 genes, 1,327 amplicons, 373 Kb
51% of genes shared with Foundation Heme
panel, 35% with Foundation ONE
Kortuem KM et al. Blood. 2015;126: Abstract 1795.
Hofste op Bruinink D et al. Blood. 2015;126: Abstract 2984.
Kortüm KM et al. Blood. 2016;128:1226.
12
Most Mutations Are Subclonal
Figure 1
Kortuem KM et al. Blood Cancer J. 2016;26:e397.
Myeloma-Specific Gene Mutation Panel
Tracks Clonal Changes Over Time
Patient One
26.1
26.2
Patient Two
44.2
77.1
77.2
FAM46C
24%
92%
88%
FAT1
73%
60%
53%
85%
23%
82%
94%
KRAS
SP140
44.1
Patient Three
28%
48%
37%
SPEN
18%
24%
TP53
92%
78%
88%
Kortuem KM et al. Ann Hematol. 2015;94:1205.
13
Impact of Mutation on Myeloma Survival
Figure 3, page 3913
Walker BA et al. J Clin Oncol. 2015;33:3911.
Figure 4, page 3916
Walker BA et al. J Clin Oncol. 2015;33:3911.
Mutations in the Cereblon Pathway in at Least
26% of Relapsed/Refractory Patients
CRBN
DDB1
CUL4
*
IMiDs
*
ROC1
IKZF1/3
IRF4
MYC
*
MM cytotoxicity
*gene found mutated in cohort
*
CRBN
CUL4B
IKZF3
IRF4
1
1 1
1 1 1
1
1
1 1 1
• In a patient refractory to Len/Dex
therapy we identified mutations in both
CRBN and IRF4
• One patient had 4 different CRBN
mutations
• Probably higher as we did not look for
structural change on chromosome 3
• 4 out of 5 IRF4-mutated patients shared
a K123R variant
Kortüm KM et al. Blood. 2016;128:1226.
14
CoMMpass Enrollment
• 1,000+ patients enrolled from >90 sites worldwide, with
over 850 samples molecularly profiled at baseline and
>100 sequentially
CoMMpass: Triplets versus Doublets
Early data suggests that patients on a triplet regimen (for ex. Bor-Len-Dex)
appear to be doing better than those on a doublet (ex. Bor-Dex or Len-Dex)
15
CoMMpass: High Risk Disease
Integrative analyses using CoMMpass data will help identify patients at
greater risk of progression upfront and optimize their treatment
Age
Ethnicity
ISS stage
Baseline treatment
Cytogenetics
Time to progression (mos)
p53 status
MM cells in blood (%)
Circulating MM cells
CoMMpass MMRF2172
CoMMpass MMRF2250
72
Caucasian
II
VRD
t(4;14), del13, del17p
1
mutated
1.7
36,648
71
Caucasian
II
VRD
t(4;14), del13, del17p
>18
WT
0
614
Finding New Treatment Options
By looking closely at the molecular changes happening at progression, one can
identify potential new therapeutic options (for ex. a BRAF inhibitor here)
16
Summary
• Revised ISS can assist therapeutic decision making
• PET-CT normalization is also predictive
• Clinical mutation panels now available
–
–
–
–
Clonal depth of mutation
Actionable mutation
Prognosis
Drug resistance
• CoMMpass study largest genomics cohort in cancer,
leading to precision therapy trials
– Additional CoMMpass data to be presented Saturday, 12/3 at
2:00PM
Making Sense of Frontline Options
for Transplant Ineligible Patients
Thierry Facon, MD
Professor of Haematology
Department of Haematology
Lille University Hospital
Lille, France
17
Patient Case
•
•
•
•
•
•
•
75-year-old patient
Significant previous medical history
No significant previous surgical history
Physical examination: normal
Lytic bone disease
Impaired renal function
Revised ISS stage II
The patient is an ELDERLY patient with
comorbidities, but good performance status.
He needs treatment.
The Transplant Eligibility Discussion (1)
• Patient is considered transplant candidate and so
needs induction-ASCT with or without
consolidation and maintenance
• Patient is (most likely) not a transplant candidate
and needs conventional treatment
18
The Transplant Eligibility Discussion (2)
• ASCT remains a standard of care for patients ≤65 years
of age in most countries
– IFM 2009 and EMN studies1,2
• No large phase 3 randomized study has established the
role of ASCT in elderly patients in the era of novel agents
• ASCT (single or even double) is routinely performed in
some countries/centers for elderly patients between 65
and 75 years of age
1. Attal M et al. Blood. 2015;126: Abstract 391.
2. Gay F et al. Blood. 2015;126: Abstract 392.
IFM 99-06 Study Protocol
Newly Diagnosed MM Patients 65–75 Years
Arm MP
Arm MP-T
Arm MEL100
MP 1
MP
VAD 1
Overall Survival According to Treatment
1
+
Thalidomide
VAD 2
 400 mg/d
MP 3
MP 12
Cyclophosphamide
3g/m2 + lenograstim
+ PBSC harvest
MEL 100 mg/m2
+ PBSC +
lenograstim
0.8
Proportion
MP 2
0.6
0.4
Survival time
Treatment O/N median ± se (month)
MP
97/196
32.2 ± 4.2
MP-T
43/125
53.6 ± 5.2
MEL100
66/126
38.6 ± 3.4
0.2
0
0
mg/m2
MEL 100
+ PBSC +
lenograstim
12
24
36
48
60
72
Time From Randomization (month)
Facon T et al. Lancet. 2007;370:1209.
19
IFM 2017 Study
A Phase III Trial Evaluating Conventional Dose Combination
Immunochemotherapy With Ixazomib-Lenalidomide-Dexamethasone
and Daratumumab (IRD2) to High-Dose Treatment With ASCT in the
Initial Management of Fit MM Patients Aged 65–75.
Arm A
IRD2
IRD2
IRD2
Collection
IRD2
IRD2
Collection
IRD2
IRD2
IRD2
IRD2
IRD2
DR maintenance
IRD2
IRD2
DR maintenance
Arm B
IRD2
ASCT
MPT and VMP Become Standards of Care
(2008)
Facon T et al. Lancet. 2007;370:1209.
Fayers PM et al. Blood. 2011;118:1239.
San Miguel JF et al. N Engl J Med. 2008;359: 906.
20
FIRST (IFM2007-01/MM-020):
Study Design
LT Follow-Up
Screening
LEN + LoDEX Continuously
LENALIDOMIDE 25 mg D1-21/28
LoDEX
40 mg D1, 8, 15 & 22/28
Arm B
Rd18
LEN + LoDEX 18 Cycles (72 wks)
LENALIDOMIDE
25 mg D1-21/28
LoDEX
40 mg D1, 8, 15 & 22/28
Arm C
MPT
MEL + PRED + THAL 12 Cycles2,3 (72 wks)
MELPHALAN
0.25 mg/kg D1-4/42
PREDNISONE
2 mg/kg D1-4/42
THALIDOMIDE
200 mg D1-42/42
PD, OS, and
Subsequent AMT
Arm A
Rd Continuous
PD or Unacceptable Toxicity
RANDOMIZATION 1:1:1
Active Treatment + PFS Follow-Up Phase
Pts aged >75 yrs: LoDEX 20 mg D1, 8, 15 & 22/28; MEL 0.2 mg/kg D1–4; THAL 100 mg D1–42/42.
All pts received thromboprophylaxis.
1. Benboubker L et al. N Engl J Med. 2014;371:906.
2. Facon T et al. Lancet. 2007;370:1209.
3. Hulin C et al. J Clin Oncol. 2009;27:3664.
Avet-Loiseau H et al. Blood. 2015;126: Abstract 730.
• Stratification: age, country, and ISS stage
IFM 2007-01 FIRST Trial: PFS and OS
PFS as per investigator assessment1
OS2
Data cut-off: 3 March 2014
Median follow-up: 45.5 mos
Data cut-off: 3 March 2014
Median follow-up: 45.5 mos
697 deaths (43% of ITT)
Median PFS
26.0 mos
Rd18 (n = 541)
21.0 mos
MPT (n = 547)
21.9 mos
1.0
Survival Probability
Survival Probability
1.0
Rd (n = 535)
0.8
0.6
33%
0.4
Hazard ratio
Rd vs MPT: 0.69; P<0.001
Rd vs Rd18: 0.71; P<0.001
Rd18 vs MPT: 0.99; P=0.866
0.2
0
0
6
12
18
24
30
14%
13%
36
42
PFS (months)
48
54
Median OS 4-year OS
Rd (n = 535)
58.9 mos
60%
Rd18 (n = 541)
56.7 mos
57%
MPT (n = 547)
48.5 mos
51%
0.8
0.6
0.4
Hazard ratio
Rd vs MPT: 0.75; P=0.002
Rd vs Rd18: 0.91; P=0.30
0.2
0
60
66
72
0
6
12
18
24
30
36
42
48
54
60
66 72
OS (months)
1. Lenalidomide European Public Assessment Report. March 2015.
2. Facon T et al. J Clin Oncol. 2015;33: Abstract 8524.
21
IFM 2007-01, FIRST Trial:
Age Analysis, OS
Median follow-up of 45.5 months as of 3 March 2014
Age ≤75 Years
Age >75 Years
Median, 4-yr,
months %
Rd continuous
60.9
64
Rd18
60.6
61
MPT
55.3
57
Patients (%)
80
100
80
Patients (%)
100
60
40
Hazard ratio (95% CI)
Rd vs MPT: 0.76 (0.60–0.96)
Rd vs Rd18: 0.90 (0.71–1.15)
Rd18 vs MPT: 0.84 (0.66–1.06)
20
0
0
6
12
18
24
30
36
Median, 4-yr,
months %
Rd continuous
52.3
52
Rd18
45.7
48
MPT
37.8
39
60
40
Hazard ratio (95% CI)
Rd vs MPT: 0.72 (0.54–0.96)
Rd vs Rd18: 0.91 (0.68–1.22)
Rd18 vs MPT: 0.79 (0.60–1.04
20
0
42
48
54
60
66
0
6
12
18
24
OS (months)
Rd
Rd18
MPT
349
348
359
329
328
330
311
309
306
295
287
291
272 249
265 246
262 244
231
229
223
171
164
161
30
36
42
48
54
60
66
4
4
3
0
0
0
OS (months)
110
99
88
55
49
41
12
13
8
0
0
0
Rd
Rd18
MPT
MPT, melphalan, prednisone, thalidomide;
Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles.
186
193
188
136
137
125
108
106
94
88
83
72
70
49
54
57
31
37
44
23
26
27
15
20
12
7
7
Hulin C et al. Haematologica. 2015;100: Abstract S429.
a National Cancer Institute program
SWOG S0777: Study Design
Eight 21-day cycles of VRd
Randomization
N = 525
Stratification:
• ISS (I, II, III)
• Intent to
transplant at
progression
(yes/no)
Bortezomib 1.3/mg2 IV
Days 1, 4, 8, and 11
Lenalidomide 25 mg/day PO
Days 1–14
Dexamethasone 20 mg/day PO
Days 1, 2, 4, 5, 8, 9, 11, 12
Six 28-day cycles of Rd
Rd maintenance
until PD, toxicity,
or withdrawal
After
induction
Lenalidomide 25 mg
PO days 1–21
Dexamethasone 40 mg
PO days 1, 8,15, 22
Lenalidomide 25 mg/day PO
Days 1-21
Dexamethasone 40 mg/day PO
Days 1, 8, 15, 22
• All patients received aspirin 325 mg/day
• VRd patients received HSV prophylaxis
Durie B et al. Blood. 2015;126: Abstract 25.
22
SWOG S0777: PFS and OS by
Assigned Treatment Arm
PFS by assigned treatment arm
Events/N
100
VRd
137/242
43 (39, 52)
90
Rd
166/229
30 (25, 39)
Patients (%)
80
70
60
50
40
VRd
30
20
10
80
Patients (%)
90
OS by assigned treatment arm
Median in
months
100
Rd
Median in
months
VRd
76/242
75 (66, -)
Rd
100/229
64 (56, -)
60
VRd
Rd
50
40
30
HR = 0.709 (0.516, 0.973)*
Log-rank P value = 0.0250
(two sided)*
10
0
Events/N
70
20
HR = 0.712 (0.560, 0.906)*
Log-rank P value = 0.0018
(one sided)*
a National Cancer Institute program
0
0
24
48
72
96
0
Months From Registration
24
48
72
96
Months From Registration
* Stratified
Durie B et al. Blood. 2015;126: Abstract 25.
Combination Study of Carfilzomib, Lenalidomide, and
Dexamethasone in Patients With NDMM: Study Design
Key inclusion
criteria
• Age ≥18 years
• NDMM with
measurable
disease
• Creatinine
clearance ≥60
mL/min
• ECOG PS 0–2
• ANC ≥1.0 × 109/L,
hemoglobin ≥8.0
g/dL, platelet
count ≥75 × 109/L
• Adequate hepatic
function
Eight 28-day cycles
Stem cell harvest after 4 cycles of KRd
for transplant-eligible patients
KRd
Extended dosing
24 cycles
Carfilzomib
20/36 mg/m2 IV, days 1, 2, 8, 9, 15, 16
Cycle 1, days 1, 2: carfilzomib dose 20 mg/m2
Lenalidomide
25 mg/day PO, days 1–21
Lenalidomide was administered on days 2–21
in cycle 1 alone and on days 1–21 of cycles 2–8
Dexamethasone
20/10 mg IV or PO, days 1, 2, 8, 9, 15, 16, 22, 23
Cycles 1–4: dexamethasone dose 20 mg;
cycles 5–8: dexamethasone dose 10 mg.
*Assessed at the following time points: baseline, achievement of a CR and/or at the
completion of cycles 8, 20, and 32, and at termination of protocol therapy.
If ≥SD
Lenalidomide
10 mg/day PO,
days 1–21
Primary
end point
• Rate of PN
grade ≥ 3
Secondary
end point
• MRD*
• Response
rates
• Progressionfree survival
• Duration of
response
• Safety
Korde N et al. JAMA Oncol. 2015;1:746.
23
Combination Study of Carfilzomib, Lenalidomide, and
Dexamethasone in Patients With NDMM: Efficacy
Table 3, page 50
Korde N et al. JAMA Oncol. 2015;1:746.
What about the evaluation of
frailty?
Do we need specific studies for frail patients?
24
FIRST (MM-020):
Frailty Analysis-Frailty Algorithm
• Patients were categorized into three severity groups (fit, intermediate, frail) as
described by a proxy algorithm based on the IMWG frailty scale1
IMWG Frailty Scale1
Proxy for MM-020 Analysis
Age
≤75 yrs
76−80 yrs
>80 yrs
Activity of Daily Living score
>4
≤4
Instrumental Activity of Daily Living score
5
≤5
Charlson Comorbidity Index score
≤1
≥2
Age
≤75 years
76−80 yrs
>80 yrs
EQ-5D: Self Care score
1 (no problem)
2−3 (moderate or severe problem)
EQ-5D: Usual Activities score
1 (no problem)
2−3 (moderate or severe problem)
Charlson Comorbidity Index score
≤1
≥2
Score
0
1
2
0
1
0
1
0
1
Total
0: Fit
1: Intermediate
≥2: Frail
1. Palumbo A et al. Blood. 2015;125:2068.
Facon T et al. Blood. 2015;126: Abstract 4239.
FIRST (MM-020): Frailty Analysis
PFS and OS by Severity Group With ISS Stage
• No treatment effects seen in these groups, likely due to small patient numbers
1.0
Survival Probability
Survival Probability
1.0
0.8
0.6
0.4
0.2
0
0
20
Severity
Fit + ISS I
Fit + ISS II/III
Int + ISS I/II
Int + ISS III
Frail + ISS I/II
Frail + ISS III
n
84
171
298
150
437
377
40
60
PFS By Investigator, mos
Median PFS, mos (95% CI)
34.1 (25.6-43.7)
23.3 (21.2-30.2)
27.7 (24.6-30.4)
19.2 (17.6-21.3)
23.0 (20.5-25.8)
17.1 (14.1-19.0)
80
HR (95% CI)
0.71 (0.50-0.99)
0.63 (0.49-0.80)
0.69 (0.58-0.82)
0.8
0.6
0.4
0.2
0
0
20
40
OS, mos
Severity
Fit + ISS I
Fit + ISS II/III
Int + ISS I/II
Int + ISS III
Frail + ISS I/II
Frail + ISS III
n
84
171
298
150
437
377
Median OS, mos (95% CI)
NR
NR
63.1 (58.2-NR)
44.3 (33.5-56.1)
58.9 (49.5-NR)
35.6 (32.5-40.6)
60
80
HR (95% CI)
0.57 (0.33-1.00)
0.43 (0.32-0.59)
0.57 (0.47-0.69)
Facon T et al. Blood. 2015;126: Abstract 4239.
25
UKMRA Myeloma XIV: FITNESS
Frailty-Adjusted Therapy In Transplant
Non-Eligible PatientS With
Symptomatic Myeloma
First-line therapy in the nonintensive setting for myeloma
CI: Prof Graham Jackson & Prof Gordon Cook
Trial design
1:1
1:2
C – 500 mg D1 & D8
R – 25 mg D1–21
D – 20 mg
I – 4 mg weekly
ADAPTIVE
Frailty index–adjusted therapy
Non-adjusted
MAINTENANCE
INDUCTION
REACTIVE
CRDa
Frailty indexing (FI) performed
in all patients at baseline
Transplant-ineligible NDMM
IRDa
CRDa
FIT
UNFIT
FRAIL
1:2
1:2
1:2
IRDa
CRDa
IRDa
CRDa
IRDa
FIT: C – 500 mg D1 & D8, R – 25 mg D1-21, D – 20 mg/wk, I – 4 mg/wk
UNFIT: C – 350 mg D1 & D8, R – 15 mg D1-21, D – 10 mg/wk, I – 3 mg/wk
FRAIL: C – 250 mg D1 & D8, R – 10 mg D1-21, D – 10 mg/wk, I – 3 mg/wk
TREAT TO MAXIMUM RESPONSE (6–8 cycles)
1:1
Lenalidomide
Ixazomib/Lenalidomide
26
Treatment of MM in Elderly Patients:
Landscape and Perspectives
VMP
# Vd
<
MP
<
<
Alternating
regimens8 ?
?
MPT
<
VMP – Daratumumab1
VRD2,3
Rd – Ixazomib4
Rd – Elotuzumab5
Rd – Daratumumab6
Rd
MPR-R
MPT-T
MP – Carfilzomib7
1. DaraVMP vs. VMP. Available at: https://clinicaltrials.gov/ct2/show/NCT02195479
2. Durie B et al. Blood. 2015;126: Abstract 25.
3. O’Donnell EK et al. Blood. 2015;126: Abstract 4217.
4. IRD vs RD (Tourmaline 2). Available at: https://clinicaltrials.gov/ct2/show/NCT01850524.
5. EloRD vs RD (Eloquent 1). Available at: https://clinicaltrials.gov/ct2/show/NCT01335399.
6. DaraRD vs. RD. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172.
7. KMP vs. VMP (Clarion). Available at: https://clinicaltrials.gov/ct2/show/NCT01818752.
8. Mateos MV et al. Blood. 2016;127:420.
Phase 3 Rd-Based Continuous
Studies for Elderly Patients
NCT01335399
Elotuzumab
NCT01850524
Ixazomib
Rd
ELO-Rd
Rd
R: 25 mg PO ; D1–21
DEX: 40 mg PO ; D1,
8, 15 & 22
28-d cycles until PD
ELO: 10 mg/kg; D1,
8, 15 & 22 (cycles 1–
2); D1 & 15 (cycles
3–18); 20 mg/kg on
D1 (cycles ≥ 19)
R: 25 mg PO ; D1–21
DEX: 40 mg PO ; D1,
8, 15 & 22
28-d cycles/18 mos
28-d cycles, until PD
DEX: 40 mg; D1, 8,
15 & 22
28-d cycles/18 mos
R: 25 mg, D1–21
DEX: 40 mg D1, 8, 15
& 22 (cycles 1–2);
D1 & 15 (cycles 3–
18); D1 (cycles ≥ 19)
Ixazomib-Rd
Ixazomib: 4 mg
R: 25 mg
DEX Discontinued
DEX Discontinued
Placebo + R
R 10 mg
Until PD
Ixazomib+ R
Ixazomib: 3 mg
R: 10 mg
Until PD
NCT02252172
Daratumumab
Rd
R: 25 mg PO ; D1–21
DEX: 40 mg PO ; D1,
8, 15 & 22
28-d cycles until PD
DARA-Rd
DARA: 16 mg/kg
q1wk for 8 wks; q2wk
for 16 wks; q4wk
thereafter
R: 25 mg PO d;
D1–21
DEX: 40 mg PO d;
D1, 8, 15 & 22
28-d cycles; Rd
for up to 2 years;
DARA until PD
• Primary end point for all studies is PFS
1. EloRD vs RD (Eloquent 1). Available at: https://clinicaltrials.gov/ct2/show/NCT01335399.
2. IRD vs RD (Tourmaline 2). Available at: https://clinicaltrials.gov/ct2/show/NCT01850524.
3. DaraRD vs. RD. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172.
27
Patient Case 2
Robert M. Rifkin, MD
Associate Chair – US Oncology Research
Disease Lead – Multiple Myeloma
Attending Physician
Rocky Mountain Cancer Centers
Denver, Colorado
Case Study 2
• 52-year-old woman referred for workup of
anemia that proved to be iron deficiency. This
was only partly corrected with oral iron
supplementation. Due to her incomplete
response to iron replacement, further workup
was undertaken.
28
Case Study 2
52-year-old woman referred for workup of anemia.
Past medical
history
Past surgical
history
• None
• Appendectomy
and varicose
vein stripping
Family
history
• Sister-in-law
has myeloma
and failed two
SCTs
Social
history
Physical
exam
• Married, works
at a uniform
supply firm
• Nonsmoker,
rare social
alcohol
• No substance
use
• Normal
• ROS: negative
except for mild
fatigue
Case Study 2: Labs
Actual
Value
CBC with
differential
CMP
SPEP
Normal
Range
WBC (103/mL)
3.7
(4–11)
Hemoglobin (g/dL)
9.8
(13–16)
Hematocrit (%)
30.1
(34–45)
Platelets (103/mL)*
278
(150–400)
Neutrophils (103/mL)
5.6
(1.9–7.5)
BUN (mg/dL)
16
(7–20)
Creatinine (mg/dL)
0.8
(0.7–1.2)
Calcium (mg/dL)
8.6
(8.4–10.2)
Total protein (g/dL)
8.0
(6.3–8.2)
Albumin (g/dL)
3.4
(3.5–5.0)
Quantitative IgG (mg/dL)
Igs + serum IgA (mg/dL)
immunoIgM (mg/dL)
fixation
FLC
Actual
Value
Normal
Range
3,431 (H)
(700–1,600)
158 (H)
(70–400)
40 (H)
(40–230)
Kappa quant FLC (mg/L)
437.6 (H) (3.30–19.40)
Lambda quant FLC (mg/L)
13.67 (H) (5.71–26.30)
Kappa/lambda quant FLC
ratio
31.9 (H)
(0.26–1.65)
IF- IgG
M protein spike (g/dL)
2.6
*With normal iron studies
29
Case Study 2: Imaging and BM Biopsy
Bone
imaging
BM
biopsy
Skeletal survey
• Indeterminate
lesions in right
intertrochanteric
area
DEXA scan
• Osteopenia
• 40% cellular with
30% plasma
cells
• Aspirate 24%
plasma cells
Flow
cytometry
• 2% events
positive for
CD38, CD56,
CD138, and
cytoplasmic
kappa light
chains
Cytogenetics
• 46, XX
FISH*
• Negative for gain
of 1q21
• Negative for loss
of chromosome
13q
• Negative for loss
of TP53 and
ATM
• Negative for IgH
(14q32) and
IGH/CCND1
[t(11;14)]
rearrangement
*CD138 selected plasma cells
Strategies to
Prolong Response
Amrita Y. Krishnan, MD
Professor, Department of Hematology & Hematopoietic Cell
Transplantation
Director, Judy and Bernard Briskin Center for Multiple Myeloma Research
City of Hope Medical Center
Duarte, California
30
Options to Prolong Remission
• Increase depth of response
– High dose chemotherapy (single versus tandem)
• EMN02,[1] BMT-CTN0702[2]
• Prolong therapy
– Consolidation
• RVD: EMN02/HO95,[3] BMTCTN0702 Stamina2
• Zimmerman (KRd)4 Roussel (KRd)5
– Maintenance
• Myeloma XI[6]
1. Cavo M et al. Blood. 2016;128: Abstract 991.
2. Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.
3. Sonneveld P et al. Blood. 2016;128: Abstract 242.
4. Zimmerman T et al. Blood. 2016;128: Abstract 675.
5. Roussel M et al. Blood. 2016;128: Abstract 1142.
6. Jackson GH et al. Blood. 2016;128: Abstract 1143.
IFM/DFCI 2009 Study Schema
Registration, newly diagnosed MM pts 65 years (ASCT candidates)
1 cycle RVD
ARM A: Late transplant arm
Randomize, stratification ISS & FISH
ARM B: Early transplant arm
RVD, cycles 2, 3
Induction
RVD, cycles 2, 3
CY (3g/m2) + G-CSF
MOBILIZATION
Goal: 5 ×106 cells/kg
PBSC collection
CY (3g/m2) + G-CSF
MOBILIZATION
Goal: 5 ×106 cells/kg
Melphalan
200 mg/m2 + ASCT
Consolidation
RVD × 5
RVD × 2
Maintenance
Lenalidomide (10–15 m/d)
12 mos
SCT at relapse
MEL 200 mg/m2 if <65 yrs,
≥65 yrs 140 mg/m2
US len maintenance till progression
Lenalidomide (10–15 mg/d)
12 mos
Attal M et al. Blood. 2015;126: Abstract 391.
31
IFM 2009: Best Response
RVD Arm
N=350
Transplant Arm
N=350
CR (%)
49
59
VGPR (%)
29
29
PR (%)
20
11
<PR (%)
2
1
At least VGPR (%)
78
88
0.001
228 (65%)
280 (80%)
0.001
Neg MRD by FCM, n (%)
P Value
0.02
Attal M et al. Blood. 2015;126: Abstract 391.
Patients (%)
IFM 2009: PFS (9/2015)
100
90
80
70
60
50
40
30
20
10
0
HDT
no HDT
P<0.001
0
12
24
36
48
153
128
27
24
Months of Follow-Up
N at risk
HDT 350
no HDT 350
309
296
261
228
Attal M et al. Blood. 2015;126: Abstract 391.
32
Patients (%)
IFM 2009: OS (9/2015)
100
90
80
70
60
50
40
30
20
10
0
P NS
HDT
no HDT
0
12
24
36
48
226
244
55
56
Months of Follow-Up
N at risk
HDT 350
no HDT 350
328
338
309
320
Attal M et al. Blood. 2015;126: Abstract 391.
IFM 2009: Cause of Death (9/2015)
RVD Arm
N=48
Transplant
N=54
40/48 (83)
35/54 (65)
Toxicity, n (%)
4/48 (8)
9*/54 (16)
SPM, n (%)
1/48 (2)
6/54 (11)
Others, n (%)
3/48 (6)
4/54 (7)
Myeloma, n (%)
*Including 5 transplant related deaths.
Attal M et al. Blood. 2015;126: Abstract 391.
33
Intensification Therapy with Bortezomib-Melphalan-Prednisone Versus Autologous
Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma:
An Intergroup, Multicenter, Phase III Study of the European Myeloma Network
(EMN02/HO95 MM Trial)
VMP
4, 42-day cycles
RVD
R2
R1
HDM + Single ASCT
CyBorD
3-4, 21-day cycles
HDM + Double ASCT
No
RVD
Len
Consolidation Maintenance
Induction
Median PFS (mos)
3-Yr PFS (%)
Probability of achieving ≥VGPR (%)
VMP
(n=497)
44
57.5
74
HDM
(n=695)
NR
66
85.5
HR/OD (95% CI)
─
HR 0.73 (0.59-0.90)
OD 1.90 (1.42-2.54)
P Value
─
0.003
<0.001
Upfront HDM and ASCT significantly improved PFS and
increased the rate of high quality responses.
Cavo M et al. Blood. 2016;128: Abstract 673.
High Dose Therapy: Single vs Tandem
EMN02/HO95
VMP
4, 42-day cycles
R1
CyBorD
3-4, 21-day cycles
HDM + Double ASCT
Median PFS (27-mos f/up):
• ASCT1, 45 mos
• ASCT2, NR
Lenalidomide
AM
Maintenance
Stamina
Register and
Randomize
HDM + Single ASCT
MEL
200mg/m2
VRD x 4
Lenalidomide ACM
Maintenance
MEL
200mg/m2
Lenalidomide
Maintenance TAM
Estimated PFS (38-mos):
• TAM, 56%
• ACM, 57%
• AM, 52%
Cavo M et al. Blood. 2016;128: Abstract 991.
Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.
34
Increase Depth of Response: MRD
100
90
80
70
60
50
40
30
20
10
0
N at risk
MRD pos
MRD neg
Transplant Arm
MRD pos
MRD neg
Patients (%)
Patients (%)
RVD Arm
P<0.001
0
12
89
140
75
135
24
36
Months of Follow-Up
54
113
22
72
100
90
80
70
60
50
40
30
20
10
0
48
2
14
N at risk
MRD pos
MRD neg
MRD pos
MRD neg
P<0.001
0
12
65
172
57
166
24
36
Months of Follow-Up
43
151
30
86
48
4
17
Attal M et al. Blood. 2015;126: Abstract 391.
Avet-Loiseau H et al. Blood. 2015;126: Abstract 191.
MRD: Still ??
Advantages
Disadvantages
Flow cytometry
• Feasible in 100% of patients
• Does not require diagnostic sample
• Widely available/low cost
Flow cytometry
• Fresh sample (<24–48 h)
• Sensitivity 10-4–10-5
• Lack of standardization (operator)
NGS (adaptive)
• Sensitivity <10-6
• Frozen samples
• Fully standardized
NGS (adaptive)
• Requires diagnostic sample (clone
ID)
• Feasibility
Paiva B et al. Clin Cancer Res. 2015;21:2001.
Nishihori T et al. Curr Hematol Malig Rep. 2016;11:118.
35
Sensitivity Matters
MRD at post-maintenance
1.0
Patients Without
Progression (%)
0.9
<10-6
0.8
0.7
0.6
0.5
0.4
[10-6; 10-5]
[10-5; 10-4]
≥10-4
P value (trend): P<0.0001
0.3
0.2
0
6
12
18
24
30
36
42
48
Months Since Randomization
N at risk (events)
<10-6
[10-6; 10-5]
-5
[10 ; 10-4]
[10-4; 10-3]
86
29
23
40
(0)
(0)
(0)
(0)
86
29
23
40
(0)
(0)
(0)
(0)
86
29
23
40
(0)
(0)
(0)
(0)
86
29
23
40
(0)
(0)
(1)
(6)
86
28
22
33
(5)
(5)
(3)
(9)
77
22
19
23
(3)
(3)
(2)
(6)
61
16
14
15
(5)
(4)
(5)
(4)
36
4
3
4
(0)
(1)
(0)
(1)
10
1
2
2
Avet-Loiseau H et al. Blood. 2015;126: Abstract 191.
Association of MRD With Superior
Survival Outcomes in Patients With Multiple Myeloma:
A Meta-Analysis
•
•
•
•
•
•
14 studies
MRD negativity correlated with PFS/OS
5 trials included ASCT
PCR > MFC (sensitivity)
Only 1 study showed predictive value in unfavorable cytogenetics
10 studies maintenance (2 post maintenance)
Munshi NC et al. JAMA Oncol. 2016. Sept 15 [Epub ahead of print].
36
IMWG Criteria for Response and
MRD Assessment in MM
Sustained MRD-negative
• MRD negativity in the marrow (NGF, NGS, or both) and by imaging as defined below, confirmed minimum of 1 year apart.
Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years)
Flow MRD-negative
• Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone marrow aspirates using the EuroFlow standard
operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of
1 in 105 nucleated cells or higher
Sequencing MRD-negative
• Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two
identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or
validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher
Imaging plus MRD-negative
• MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline
or a preceding PET/CT or decrease to less mediastinal blood pool SUV or decrease to less than that of surrounding
normal tissue
Kumar S et al. Lancet Oncol. 2016;17:e328.
Prolong Response: Consolidation
BMT CTN 0702
Register and
Randomize
Lenalidomide
Maintenance
N
38-mo PFS (%)
VRD x 4
Lenalidomide
Maintenance
ACM
MEL
200mg/m2
Lenalidomide
Maintenance
TAM
Consolidation with
Len Maintenance
(ACM)
254
57
Tandem ASCT with
Len Maintenance
(TAM)
247
56
MEL 200mg/m2
N=750 pts (250 in each arm)
ASCT with Len
Maintenance
(AM)
257
52
AM
Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.
37
Prolong Response: Consolidation
EMN02/HO95
VMP
4, 42-day cycles
RVD
R2
R1
CyBorD
3-4, 21-day cycles
Len
No
RVD
HDM + Single ASCT
HDM + Double ASCT
Consolidation Maintenance
Induction
Consolidation
No
Consolidation
P Value
65
60
0.045
3-year PFS (%)
Not retained in high risk cytogenetics (0.91)
Sonneveld P et al. Blood. 2016;128: Abstract 242.
Prolong Response: Consolidation
Phase 2 US Study1
Consolidation Maintenance
(Cycles 5–8) (Cycles 9–18)
Induction
(Cycles 1–4)
KRd
KRd
KRd
ASCT
Indefinite
Maintenance
Lenalidomide
Post
SCT
Post KRd
Consol
Post KRd
Maint
MRD (%)
MFC/NGS
--
82/66
90/71
sCR (%)
20
69
82
Phase 2 IFM Study2
Induction
(Cycles 1–4)
KRd
ASCT
Consolidation
(Cycles 5–8)
Maintenance
KRd
Lenalidomide,
1 Year
KRd is now being compared with
VRd in a randomized clinical trial.
Post
Induction Post ASCT
(n=46)
(n=42)
Post
Consol
(n=42)
MRD (%) by flow
63
81
89
CR + sCR (%)
26
45
69
ORR (%)
98
98
98
1. Zimmerman T et al. Blood. 2016;128: Abstract 675.
2. Roussel M et al. Blood. 2016;128: Abstract 1142.
38
Prolonging Response: Maintenance
• What is the optimal drug?
• What is the optimal duration of maintenance?
• What is the benefit of maintenance?
• Ultimate goal; prolonged survival
Maintenance Therapy Post SCT:
What Is Known
• Bortezomib maintenance; HOVON1
• Lenalidomide maintenance after ASCT reduces
the risk of progression or death by approximately
50%2-5
• All phase 3 studies had progression-free survival
as the primary end point
1. Sonneveld P et al. J Clin Oncol, 2012;30:2946.
2. Palumbo A et al. N Engl J Med. 2014;371:895.
3. McCarthy PL et al. N Engl J Med. 2012;366:1770.
4. Attal M et al. N Engl J Med. 2012;366:1782.
5. Palumbo A et al. N Engl J Med. 2012;366:1759.
39
HOVON Study Schema
MM Stage II or III, Age 18–65
Randomization
3 × VAD
3 × PAD
CAD + GCSF
CAD + GCSF
MEL 200 + PBSCT
MEL 200 + PBSCT
Allogeneic
transplant
In GMMG 2nd
MEL 200 + PBSCT
Thalidomide
maintenance
50 mg/day for
2 years
Bortezomib
1.3 mg/m2
i.v., 2x/w
Doxorubicin
9 mg/m2
Dexameth
40 mg
In GMMG 2nd
MEL 200 + PBSCT
Bortezomib
maintenance
1.3 mg/m2/2 weeks
for 2 years
Sonneveld P et al. J Clin Oncol, 2012;30:2946.
OS by Treatment Arm
100
Cumulative Percentage
• OS at 96 m: 48%
vs 45%
• HR: 0.87, 95% CI
0.71–1.04; P=0.22
Overall Survival
Randomization Arm
75
B: PAD
50
A: VAD
N
D
A: VAD
414
217
B: PAD
413
204
Cox LR Stratified P=0.22
25
0
0
24
48
Months
72
96
• RMST8y: 4.8
months (95% CI
0.2–9.5; P=0.04)
Sonneveld P et al. Blood. 2015;126: Abstract 27.
40
Studies Included in Meta-Analysis
CALGB 100104
IFM 2005-02
GIMEMA (RV-MM-PI-209)
(accrual 8/2005–11/2009)
(accrual 6/2006–8/2008)
(accrual 11/2007–7/2009)
INDUCTION
ASCT
1:1 RANDOMIZATION
“NO EVIDENCE OF PD”
INDUCTION
ASCT
1:1 RANDOMIZATION
“NO EVIDENCE OF PD”
2 × 2 DESIGN
LEN + DEX × 4
INDUCTION
MPR: 6 COURSES
ASCT
LEN: 2 COURSES
LEN MNTCa
(n=231)
PLACEBO
(n=229)
LEN MNTCa
(n=307)
PLACEBO
(n=307)
INTERIM ANALYSIS AND
INTERIM
UNBLINDING
ANALYSIS AND UNBLINDING
Dec 2009
CROSSOVER
BEFORE PD
ALLOWED
NO TREATMENT
LEN MNTCb
PRIMARY ANALYSIS
Jan 2010
NO
CROSSOVER
BEFORE PD
ALLOWED
CONTINUED
TREATMENT
LEN MNTCb
(n=67)
NO TREATMENT
(n=68)
CONTINUED
TREATMENT
CONTINUED
TREATMENT
CONTINUED
TREATMENT
ALL TREATMENT
DISCONTINUED
Jan 2011
Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT
a Starting
b Patients
dose of 10 mg/day on days 1–28/28 was increased to 15 mg/day if tolerated and continued until PD.
received maintenance 10 mg/day on days 1–21/28 until PD.
Attal M et al. J Clin Oncol. 2016;34: Abstract 8001.
Overall Survival: Median
Follow-Up of 80 Months
There is a 26% reduction in risk of death, representing an
estimated 2.5-year increase in median survival.a
1.0
7-yr OS
Survival
Probability
0.8
62%
0.6
0.4
0.2
N=1,209
Lenalidomide
NE
(NE–NE)
Median OS
(95% CI), mos
HR (95% CI)
P value
50%
Control
86.0
(79.8–96.0)
0.74 (0.62–0.89)
0.001
0.0
Patients at risk
a Median
0
10
20
30
40
605
604
578
569
555
542
509
505
474
458
50
60
70
Overall Survival, mos
431
425
385
350
for lenalidomide treatment arm was extrapolated to be 116 months based on
median of the control arm and HR (median, 86 months; HR = 0.74).
282
271
80
90
100
110
120
200
174
95
71
20
10
1
0
0
Attal M et al. J Clin Oncol. 2016;34: Abstract 8001.
41
Cumulative Incidence of
Second Primary Malignancies
Hematologic
Solid Tumor
1.00
Cumulative Incidence
Cumulative Incidence
1.00
0.80
Lenalidomide
Control
0.60
HR (95% CI): 2.03a (1.14–3.61)
P=0.015b
0.40
0.20
0.0
0
Patients 586
at risk 602
12
559
559
24
36
48
60
72
84
96
Time to Hematologic SPM Onset, mos
514
525
465
468
422
428
365
340
251
248
139
119
38
28
108
1
0
0.80
Lenalidomide
Control
0.60
HR (95% CI): 1.71a (1.04–2.79)
P=0.032b
0.40
0.20
0.0
0
Patients 586
at risk 602
12
24
36
48
60
72
84
96
Time to Solid Tumor SPM Onset, mos
554
559
508
520
458
461
415
417
360
328
251
241
136
117
35
28
108
0
0
a HR
b
based on Cox proportional hazards model.
P value is based on log-rank test.
Attal M et al. J Clin Oncol. 2016;34: Abstract 8001.
Lenalidomide is Highly Effective Maintenance
Therapy in MM: Phase 3 Myeloma XI study
• Lenalidomide continued to disease progression versus no
therapy in both newly diagnosed transplant eligible (TE)
and transplant non-eligible (TNE) populations
TE (n=828)
Median PFS (mos)
TNE (n=722)
Maint
No Maint
Maint
No Maint
P Value
60
28
26
12
<0.0001
• Hematologic second primary malignancy 0.9% with
maintenance vs 0.3% with no maintenance
Jackson G et al. Blood. 2016;128: Abstract 1143.
42
Ultimate Goal: Prolong Survival
• High dose therapy (IFM/DFCI, EMN02, BMTCTN)
• Consolidation (EMN02, BMTCTN)
• Maintenance
– Lenalidomide: Estimated 2.5-year improvement in median
overall survival
– Bortezomib: Estimated 5-month improvement in overall survival
Future: MRD-directed therapy
Panel Discussion
43
Patient Case 3
Robert M. Rifkin, MD
Associate Chair – US Oncology Research
Disease Lead – Multiple Myeloma
Attending Physician
Rocky Mountain Cancer Centers
Denver, Colorado
Case Study 3
• 73-year-old man with a 7-year history of IgG kappa MGUS
• Experiences evolution of disease to symptomatic myeloma:
– IgG has increased to 7,233 mg/dL
– Hgb has fallen to 8.5 gm/dL
– Bone marrow is 60% cellular with 50% plasma cells that are
CD138(+)
– Marrow cytogenetics shows 46,XY
– Myeloma FISH panel is negative
• The patient is placed on lenalidomide and dexamethasone
– Achieves VGPR after 2½ years of therapy
– Stops this due to diarrhea and asthenia
44
Case Study 3
• Patient becomes anemic again after being off of therapy
for 9 months
• He then moves to Colorado, where he reports dyspnea
that he feels is due to the altitude
– IgG is 8592 mg/dL
– Hgb is 8.0 gm/dL
– Bone marrow biopsy shows 75% cellularity with 80% plasma
cells, some in sheets
– Conventional cytogenetics are normal
– FISH panel shows new del17p
Case Study 3
• The patient elects to begin therapy with carfilzomib and
dexamethasone; refuses further lenalidomide
• After two cycles, the patient presents with dyspnea; a
cardiac echo shows a LVEF of 40%
• Patient also notes left tibial pain; a plain x-ray shows a
destructive lesion
• Patient undergoes surgery to place an IM rod in his left
femur following treatment of his presumed carfilzomib
cardiomyopathy
• Patient now returns to clinic to discuss his next therapy after
completion of five fractions of radiation to his tibia
45
Case Study 3: Labs
Actual
Value
WBC (103/mL)
CBC with
differential
3,400
(4–11)
Hemoglobin (g/dL)
9.9
(13–16)
Hematocrit (%)
31.6
(34–45)
Platelets (103/mL)
164
(150–400)
Neutrophils (103/mL)
2.1
(1.9–7.5)
BUN (mg/dL)
24
(7–20)
0.85
(0.7–1.2)
Calcium (mg/dL)
7.6
(8.4–10.2)
Total protein (g/dL)
10.6
(6.3–8.2)
Albumin (g/dL)
1.7
(3.5–5.0)
Creatinine (mg/dL)
CMP
SPEP
Normal
Range
Quantitative IgG (mg/dL)
Igs + serum IgA (mg/dL)
immunoIgM (mg/dL)
fixation
FLC
Actual
Value
Normal
Range
8,431 (H)
(700–1,600)
<30 (L)
(70–400)
<5 (L)
(40–230)
Kappa quant FLC (mg/L)
760.4 (H) (3.30–19.40)
Lambda quant FLC (mg/L)
13.67 (H) (5.71–26.30)
Kappa/lambda quant FLC
ratio
55.62 (H)
(0.26–1.65)
IF- IgG
M protein spike (g/dL)
4.5
New Agents, Classes in the
Relapsed Setting
Faith E. Davies, MBBCh, MRCP, MD, FRCPath
Professor of Medicine
Medical Director, Myeloma Institute
University of Arkansas for Medical Sciences
Little Rock, Arkansas
46
Factors Affecting Treatment
Decisions in RRMM
First-line
therapy
Class of prior
therapy*; degree
of response to
prior therapy;
PFS; tolerability
of prior therapy
(treatmentrelated AEs)
Salvage therapies
Patient-related
factors: age,
PS, counts,
PN, VTE, RI,
cytogenetic
profile,
extramedullary
involvement,
etc
Aggressiveness
of disease and
prognostic
features
Number and
degree of
relapses and
refractory
disease
Disease progression
*IMiD-based, proteasome-based, alkylators, dexamethasone.
Current Therapies for RRMM 1–3 Lines Can Be
Classified by the Drug’s Mechanism of Action
Proteasome inhibitors
Bortezomib
Carfilzomib
Ixazomib
Immunomodulators
Thalidomide
Lenalidomide
Pomalidomide
Critical to understand
treatment patterns
Panobinostat
specific to your own country/region as
Monoclonal antibodies
Daratumumab
Elotuzumab
drug approval variability exists
Histone deacetylase
Alkylators
High-dose melphalan
Bendamustine
Cyclophosphamide
Steroids
Dexamethasone
Prednisolone
Methyl prednisolone
47
Two Important Questions
• Which drugs do I use in the combination?
– Individualize the drug choice toward the specific
patient
– Take advantage of different mechanisms of action
• How many drugs should I use?
– Aim for a triplet
– Monitor closely and mange the side effects
– Staying on treatment is the key
Two Important Questions
• Which drugs do I use in the combination?
– Individualize the drug choice toward the specific
patient
– Take advantage of different mechanisms of action
• How many drugs should I use?
– Aim for a triplet
– Monitor closely and mange the side effects
– Staying on treatment is the key
48
Plethora of New Randomized Studies
to Help Guide Treatment Decisions
Control Arm
Comparator Arm
Trial Name
Carfilzomib, lenalidomide, and dexamethasone
ASPIRE
Elotuzumab, lenalidomide, and
dexamethasone
ELOQUENT 2
Ixazomib, lenalidomide, and dexamethasone
TOURMALINE 1
Bortezomib and
dexamethasone
Carfilzomib and dexamethasone
ENDEAVOR
Dexamethasone
Pomalidomide and dexamethasone
MM03 NIMBUS
No transplant
High-dose melphalan
Myeloma X
Lenalidomide and
dexamethasone
Panobinostat, bortezomib, and dexamethasone PANORAMA 1
Differences Between Studies
in Baseline Characteristics
Study
N
Treatment
ASPIRE1
792
Carfilzomib-lenalidomide-dexamethasone (KRd) vs
lenalidomide-dexamethasone (Rd)
ELOQUENT-22
646
Elotuzumab-lenalidomide-dexamethasone (Erd) vs
lenalidomide-dexamethasone (Rd)
TOURMALINE-MM13
722
Ixazomib-lenalidomide-dexamethasone (Ird)
vs placebo-lenalidomide-dexamethasone (Rd)
ENDEAVOR4
929
Carfilzomib-dexamethasone (Kd)
vs bortezomib-dexamethasone (Vd)
Proportion of patients with refractory disease, disease stage
ISS III, low creatinine clearance, high risk cytogenetics
1. Stewart AK et al. N Engl J Med. 2015;372:142.
2. Lonial S et al. N Engl J Med. 2015;373:621.
3. Moreau P et al. N Engl J Med. 2016;374:1621.
4. Dimopoulos MA et al. Lancet Oncol. 2016;17:27.
49
ASPIRE: Carfilzomib-Lenalidomide-Dexamethasone
(KRd) vs Lenalidomide-Dexamethasone (Rd)
• Phase 3, open-label, randomized, multicenter study
N=792
RRMM patients
• Prior treatment
with 1–3
regimens
• ≥ PR to ≥1 prior
regimen
•
•
•
•
KRd
CFZ: 20/27 mg/m2, d 1–2*, 8–9, 15–16
LEN: 25 mg, d 1–21
DEX: 40 mg, d 1, 8, 15, 22
Twelve 28-day cycles
KRd
CFZ: 27 mg/m2, d 1, 2, 15, 16
LEN: 25 mg, d 1–21
DEX: 40 mg, d 1, 8, 15, 22
Six 28-day cycles
Rd
LEN: 25 mg, d 1–21
DEX: 40 mg,
d 1, 8, 15, 22
Until PD
Rd
LEN: 25 mg, d 1–21
DEX: 40 mg, d 1, 8, 15, 22
28-day cycles until progression
Stratified for previous Bortezomib therapy
Patients received antiviral and antithrombotic prophylaxis
Primary end point: PFS
Secondary end points: OS, ORR, DoR, HRQoL, safety
*Carfilzomib is administered at 20 mg/m2 on Days 1 and 2
Stewart AK et al. N Engl J Med. 2015;372:142.
ASPIRE: KRd vs Rd
Efficacy
Rd
(n=396)
HR;
P value
Median PFS, months
26.3
17.6
HR = 0.69;
P=0.0001*
Median OS, months
2-year OS, %
NR
73.3
NR
65.0
HR = 0.79;
P=0.04†
Time to response, months
1.0
1.0
─
Median DOR, months
28.6
21.2
NR
• Median follow-up was 32.3 months for KRd and 31.5
months for Rd
• PFS benefit for KRd was observed across all
predefined subgroups ‡
Response rates
100
Patients, %
KRd
(n=396)
80
14.1
ORR: 66.7%
60
17.7
4.3
5.1
40
38.1
20
17.2
0
*Prespecified stopping boundary was met
† Interim analysis, prespecified stopping boundary was not met
‡ Predefined subgroups included sex, age, geographic region, β2M level, cytogenetics,
peripheral neuropathy at baseline, prior BORT, prior LEN, any prior IMiD,
nonresponsive to BORT in prior regimen, refractory to prior IMiD
ORR: 87.1%
KRd
(n=396)
31.1
sCR
CR
VGPR
PR
≥PR, ≥VGPR
and ≥CR:
P<0.001
26.3
Rd
(n=396)
Stewart AK et al. N Engl J Med. 2015;372:142.
50
ASPIRE: KRd vs Rd
Progression-Free Survival
Figure 1, page 148
Stewart AK et al. N Engl J Med.
2015;372:142.
ELOQUENT 2:
Elotuzumab-Rd (ERd) vs Rd
ERd (n = 321)
N=646
RRMM
1–3 prior lines
Not LEN-refractory
ELO: 10 mg/kg, d1, 8, 15, 22 IV
(cycles 1–2); d1, 15 (cycles ≥ 3);
LEN: 25 mg, d1–21
DEX: weekly equivalent, 40 mg
28-day cycles until progression
Rd (n = 325)
LEN: 25 mg, d1–21
DEX: 40 mg, d1, 8, 15, 22
28-day cycles until progression
• Primary end points: PFS, ORR
• Secondary end points: OS, DoR, QoL, safety
Lonial S et al. N Engl J Med. 2015;373:621.
51
ELOQUENT-2: ERd vs Rd
Efficacy
Responses1
Patients (%)
80
ORR 79%a
4
ORR 66%*
60
28
7
21
40
20
ERd
(n=321)
Rd
(n=325)
Median PFS,
months2
19.4
14.9
Median TTNT,
months2
33
21
43.7
39.6
20.7
16.7
P<0.001
100
46
CR
VGPR
PR
38
0
ERd
Rd
n=321
n=325
*Values may not sum due to rounding.
Median OS,
months2
Median DoR,
months1
HR;
P value
0.73;
0.0014
0.62
(95% CI
0.50–0.77)
0.77;
0.0257
NR
1. Lonial S et al. N Engl J Med. 2015;373:621-31.
2. Dimopoulos MA et al. Blood. 2015;126: Abstract 28.
ELOQUENT-2: ERd vs Rd
Progression-Free Survival
Figure 1, page 627
Lonial S et al. N Engl J
Med. 2015;373:621.
ERd
(n=321)
Median PFS,
mos (95% CI)
3-yr PFS, %
Rd
(n=325)
19.4 (16.6−22.2)
14.9 (12.1−17.2)
HR=0.73 (95% CI 0.60−0.89; P=0.0014)
26
18
Dimopoulos MA et al. Blood. 2015;126: Abstract 28.
52
TOURMALINE-MM1: Ixazomib-LenalidomideDexamethasone vs Lenalidomide-Dexamethasone
IRd
LEN: 25 mg* PO d1–21
DEX: 40 mg PO d1, 8, 15, 22
IXA: 4 mg PO d1, 8, 15
28-day cycles
N=722
Pts with RRMM
1–3 prior therapies
Not LEN- or PI-refractory
1:1
Rd + Placebo
LEN: 25 mg* PO d1–21
DEX: 40 mg PO d1, 8, 15, 22
Placebo: PO d1, 8, 15
28-day cycles
Stratification:
• Prior treatment
• ISS stage
• PI exposure
FOLLOW-UP
Every 4 weeks until
PD, then every 12
weeks for OS
• Primary end point: PFS by independent review committee using IMWG criteria
• Key secondary end points: OS, OS in high-risk patients† with del(17)
*10 mg for pts with CrCl ≤ 60 or ≤ 50 mL/min, depending on local practice/label.
†High-risk was defined as del(17p), t(4;14), or t(l4;16), including 10% del(17p).
Moreau P et al. N Engl J Med. 2016;374:1621.
TOURMALINE-MM1: IRd vs Rd
Efficacy Summary
Responses
P<0.001
100
Patients (%)
80
ORR 78%*
12
ORR 72%a
7
36
32
60
40
20
30
33
CR
VGPR
PR
CR: P=0.019;
CR + VGPR:
P=0.014
Table 2, page 1626
Moreau P et al. N Engl
J Med. 016;374:1621.
0
IRd
Rd
n=360
n=362
*Values may not sum due to rounding.
Moreau P et al. N Engl J Med. 2016;374:1621.
53
TOURMALINE-MM1: IRd vs Rd
PFS Analysis
Figure 1, page 1627
Moreau P et al. N Engl J Med.
2016;374:1621.
• Consistent PFS benefit across pre-specified patient subgroups
ENDEAVOR Study Design
Kd
Randomization 1:1
N=929
Stratification:
• Prior proteasome
inhibitor therapy
• Prior lines of
treatment
• ISS stage
• Route of
administration
• Primary end point: PFS
Carfilzomib 56 mg/m2 IV
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 Days 1, 2, cycle 1 only)
Infusion duration: 30 minutes for all doses
Dexamethasone 20 mg
Days 1, 2, 8, 9, 15, 16, 22, 23
28-day cycles until disease progression or unacceptable toxicity
Vd
Bortezomib 1.3 mg/m2 (3–5 second IV bolus or subcutaneous injection)
Days 1, 4, 8, 11
Dexamethasone 20 mg
Days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycles until disease progression or unacceptable toxicity
BOR NAÏVE OR BOR SENSITIVE
Dimopoulos MA et al. Lancet Oncol. 2016;17:27.
54
ENDEAVOR: Kd vs Vd in RRMM
Progression-Free Survival
• Median follow-up: 11.9 mos for Kd; 11.1 mos for Vd
100
Median PFS, months
(95% CI)
Hazard ratio
P value
80
PFS (%)
Kd
Vd
(n=464)
(n=465)
18.7
9.4
(15.6−NE)
(8.4−0.4)
0.53 (0.44−0.65)
<0.0001
60
40
Kd
Vd
20
0
0
6
12
18
Time (years)
24
30
• A consistent PFS benefit for Kd was observed across predefined subgroups
*Predefined subgroups included sex, age, geographic region, ECOG performance status
baseline creatinine clearance, previous peripheral neuropathy, disease stage, cytogenetics,
number of prior regimens, prior transplant, prior BORT, prior IMiD, prior LEN, prior THAL,
refractory to prior BORT, refractory to prior LEN.
Dimopoulos MA et al. Lancet Oncol. 2016;17:27.
PANORAMA 1: Panobinostat + Bortezomib and
Dexamethasone vs Bortezomib and Dexamethasone
• Multicenter, randomized, double-blind, placebo-controlled, phase 3 study
Study population
Treatment phase 1 (TP1)
• N = 768
• 1–3 lines prior
therapy
• Measurable
M protein
component in
serum or
urine at study
screening
• ECOG ≤2
Treatment phase 2 (TP2)
PanVD (21-day cycle)
Panobinostat
• 20 mg PO on d1, 3, 5, 8, 10, 12
Bortezomib
• 1.3 mg/m2 IV on d1, 4, 8, 11
Dexamethasone
• 20 mg PO on d1, 2, 4, 5, 8, 9, 11, 12
PanVD (42-day cycle)
Panobinostat
• 20 mg PO as TP1 + on d22, 24, 26, 29, 31, 33
Bortezomib
• 1.3 mg/m2 IV d1, 8, 22, 29
Dexamethasone
• 20 mg PO on d1, 2, 8, 9, 22, 23, 29, 30
Placebo + VD (21-day cycle)
Placebo
Bortezomib
• As above
Dexamethasone
• As above
Placebo + VD (42-day cycle)
Placebo
Bortezomib
• As above
Dexamethasone
• As above
R
• Primary end point: PFS
San Miguel JF et al. Lancet Oncol. 2014;15:1195.
55
PanoVD for RRMM Patients Who
Received Prior Bortezomib and IMiDs
• Subgroup analysis of patients who received ≥2 previous treatments,
including bortezomib and an IMiD indication based on subgroup analysis
Figure 1, page 716
Richardson PG et al. Blood. 2016;127:713.
San-Miguel JF et al. J Clin Oncol. 2015;33: Abstract 8526.
Richardson PG et al. Blood. 2016;127:713.
MM-003 NIMBUS: Pomalidomide
Dexamethasone vs Dexamethasone
RANDOMIZATION 2:1
(N=455)
28-day cycles
POM*:
LoDEX:
HiDEX:
(n=302)
4 mg/day Day 1–21 +
40 mg (≤75 years)
20 mg (>75 years)
Day 1, 8, 15, 22
(n=153)
40 mg (≤75 years)
20 mg (>75 years)
Day 1–4, 9–12, 17–20
PD
PD
Follow-up for
OS and SPM until
5 years postenrollment
Companion trial
MM-003C
POM 21/28 days
Stratification
• Age (≤75 vs >75 yrs)
• Number of prior treatments (2 vs >2)
• Disease population (primary refractory vs relapsed/refractory vs intolerance/failure)
• Primary end point: PFS
*Thromboprophylaxis was indicated for those receiving
POM or with deep vein thrombosis history.
San Miguel JF et al. Lancet Oncol 2013;14:1055.
56
MM-003 NIMBUS: POM + LoDEX vs HiDEX PFS
Median Follow-Up 15.4 months
Adapted from Figure 2, page 1059
San Miguel JF et al. Lancet Oncol
2013;14:1055.
Myeloma X: Autologous Transplantation
vs Ongoing Chemotherapy
N=297
Bortezomib, doxorubicin,
dexamethasone (PAD)
Response ≥SD
PBSC mobilization
PD
or
CD34+ cells <2×106/kg
R
Off study
Melphalan 200mg/m2 IV
ASCT
Cyclophosphamide
400 mg/m2 PO/week × 12
N=89
N=89
Follow-up
Cook G et al. Lancet Oncol. 2014;15:874.
57
Myeloma X: Autologous Transplantation
vs Ongoing Chemotherapy PFS
Figure 2, page 879
Cook G et al. Lancet Oncol. 2014;15:874.
ASPIRE: Carfilzomib (KRd vs Rd)
Safety Profile
Table 3, page 151
Stewart AK et al. N Engl J Med.
2015;372:142.
• 15% of patients in the KRd group and 18% in the Rd group discontinued treatment due to AEs
• 8% of patients in the KRd group and 9% in the Rd group died while on treatment or within 30 days of last dose
58
ENDEAVOR: Carfilzomib (Kd vs Vd)
Cardiac Substudy
Cardiac Substudy
Kd (N=74)
Vd (N=74)
n (%)
n (%)
All grades
Cardiac arrhythmias (SMQN)
Cardiac failure (SMQN)
Overall Safety Population
Kd (N=463)
Vd (N=456)
n (%)
n (%)
3 (4.1)
3 (4.1)
29 (6.2)
43 (9.4)
8 (10.8)
3 (4.1)
38 (8.2)
13 (2.9)
Decreased ejection fraction
4 (5.4)
2 (2.7)
10 (2.2)
4 (0.9)
Cardiac failure
3 (4.1)
1 (1.4)
15 (3.2)
4 (0.9)
Cardiac failure acute
1 (1.4)
0
4 (0.9)
1 (0.2)
Cardiac failure chronic
1 (1.4)
0
1 (0.2)
0
Right ventricular failure
0
1 (1.4)
1 (0.2)
1 (0.2)
0
2 (2.7)
13 (2.8)
9 (2.0)
31 (41.9)
25 (33.8)
264 (57.0)
161 (35.3)
15 (20.3)
6 (8.1)
115 (24.8)
40 (8.8)
Ischemic heart disease (SMQN)
Respiratory, thoracic, and mediastinal disorders
Hypertension
Dimopoulos MA et al. Lancet Oncol. 2016;17:27.
ELOQUENT-2: Elotuzumab (ERd vs Rd)
Safety Profile
Table 3, page 630
Lonial S et al. N Engl J Med.
2015;373:621.
Lonial S et al. N Engl J Med. 2015;373:621.
59
TOURMALINE-MM1: IRd vs Rd
Safety Profile
Table 4, page 1630
Moreau P et al. N Engl J Med.
2016;374:1621.
MM03 NIMBUS Pom Dex vs Dex
Safety Profile
Table 4, page 1630
San Miguel JF et al. Lancet Oncol
2013;14:1055.
60
Conclusions
• Many choices
– Good response, improved PFS, good safety profiles
• Individualize the choice toward the specific patient
–
–
–
–
Type of relapse
Previous therapy received
Previous side effects
Oral vs IV
• Aim for a triplet
• Monitor closely and manage side effects
– Staying on treatment is the key
The Way Forward: Immunotherapy
Paul G. Richardson, MD
R.J. Corman Professor of Medicine
Harvard Medical School
Clinical Program Leader and Director of Clinical Research
Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Boston, Massachusetts
61
Key Targets in MM
• Excess protein production
>> Target protein degradation
• Genomic abnormalities and acquired resistance
>> Target and overcome mutations
• Immune suppression
>> Restore anti-MM immunity
WGS at Diagnosis
Courtesy of Nikhil Munshi MD, DFCI
62
WGS at Relapse
Courtesy of Nikhil Munshi MD, DFCI
Restoring Immune Function
• Immunomodulatory drugs, other small
molecules (eg, HDACi’s)
• Monoclonal antibodies
• Checkpoint inhibitors
• Vaccines
• Cellular therapies
63
Lenalidomide and Pomalidomide in MM
C
MM cells
IL-6
B
TNFα
A
IL-1β
ICAM-1
Bone marrow
vessels
Hideshima T et al. Blood. 2000;96:2943.
Davies FE et al. Blood. 2001;98:210.
Gupta D et al. Leukemia. 2001;15:1950.
Mitsiades N et al. Blood. 2002;99:4525.
IL-2
IL-2
IFN 
VEGF
bFGF
D
NFAT
PKC
Bone marrow
stromal cells
PI3K
Dendritic
cells
CD28
CD8+ T
cells
NK cells
NK-T cells
E
Lentzsch S et al. Cancer Res. 2002;62:2300.
LeBlanc R et al. Blood. 2004;103:1787.
Hayashi T et al. Br J Haematol. 2005;128:192.
Immunomodulatory Agents
IMiDs: Mechanism of Action
Adapted from Figure, page 347
Stewart AK. Science. 2014;343:256.
Krönke J et al Science. 2014;343:301.
Lu G et al. Science 2014;343:305.
64
Model of Lenalidomide and Pomalidomide Costimulation
of T Cells via Degradation of Aiolos and Ikaros
Figure 9, page 819
Gandhi AK et al. Br J Haematol.
2014;164:811.
Efficacy Results of POMALIDOMIDE + LoDEX in
Advanced RRMM (Phase 2/3: MM002 & MM003)
MR
PR
VGPR
CR/sCR
Percentage
Response
50
40
12
8
30
20
10
30
ORR = 33%
3
1
0
MM-002
(n=113)1
7
MM-003 (n=302)2,3
MM 002
Median
follow-up,
months 1
MM-002
(n=113)
Median DoR, months
Median PFS, months
Median OS, months
ORR = 32%
24
MM 003
MM-0021
14.2
8.3
4.2
16.5
MM-0032,3
15.4
7.5
4.0
13.1
1. Richardson PG et al. Blood. 2014;123:1826.
2. San Miguel J et al. Lancet Oncology. 2013;14:1055.
3. San Miguel J et al. Blood. 2013;122; Abstract 686.
65
Monoclonal Antibodies Kill MM
Through Multiple Mechanisms
DIRECT EFFECTS
Interferes with
survival or
delivers myelomakilling substances
INDIRECT EFFECTS
Labels myeloma cells for
killing by complement
Monoclonal antibody
Labels myeloma cells for
killing by NK cells
Activates T cells by
taking the brakes off
NK cell toxins
Myeloma cell surface target
Checkpoint inhibitor
Complement
Fc receptor
Adapted from Richardson PG, ASH 2012
Elotuzumab: Immunostimulatory
Mechanism of Action
• Elotuzumab is an immunostimulatory monoclonal antibody that recognizes SLAMF7,
a protein highly expressed by myeloma and natural killer cells1
• Elotuzumab causes myeloma cell death via a dual mechanism of action2
Natural killer cell
Elotuzumab
Natural killer cell
A Directly
activating natural
killer cells
B Tagging for
recognition
(ADCC)
SLAMF7
EAT-2
EAT-2
Downstream
activating signaling
cascade
Granule synthesis
Polarization
SLAMF7
Myeloma
cell death
Degranulation
Perforin,
granzyme B
release
Myeloma
Myeloma
cell
cell
1. Hsi ED et al. Clin Cancer Res. 2008;14:2775.
2. Collins SM et al. Cancer Immunol Immunother. 2013;62:1841.
66
ELOQUENT-2: Primary Analysis
Figure 1, page 627
Lonial S et al. N Engl J Med.
2015;373:621.
From Table 2, page 629
ELOQUENT-2 demonstrated
clinical benefits of E-Ld
compared with lenalidomide
and dexamethasone (Ld)
alone1
Lonial S et al. N Engl J Med.
2015;373:621.
1. Lonial S et al. N Engl J Med. 2015;373:621.
Elotuzumab in High-Risk Patients
ELOQUENT-2 Study Results
Progression-Free Survival of Patients With del(17p) and t(4;14) Translocation
del(17p)+
0.8
0.7
0.6
0.5
E-Ld
0.4
Ld
0.3
0.2
0.1
t(4;14)+
1.0
0.9
Hazard ratio: 0.65
(95% CI, 0.450.94)
Probability Progression Free
Probability Progression Free
1.0
0.9
0.8
0.7
0.6
0.5
0.4
E-Ld
0.3
0.2
0.1
Hazard ratio: 0.53
(95% CI, 0.290.95)
Ld
0.0
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
PFS (months)
PFS (months)
Lonial S et al. J Clin Oncol. 2015;33. Abstract 8508.
67
Daratumumab: Mechanism of Action
• Human CD38 IgGκ
monoclonal antibody
• Direct and indirect antimyeloma activity1-5
• Depletes CD38+
immunosuppressive
regulatory cells5
• Promotes T-cell expansion
and activation5
1. Lammerts van Bueren J et al. Blood. 2014;124: Abstract 3474. 2. Jansen JHM et al. Blood. 2012;120: Abstract 2974.
3. de Weers M et al. J Immunol. 2011;186:1840. 4. Overdijk MB et al. MAbs. 2015;7:311.
5. Krejcik J et al. Blood. 2016;128:384.
Lokhorst HM et al. N Engl J Med. 2015;373:1207.
Lonial S et al. Lancet. 2016;387:1551.
68
Daratumumab Monotherapy:
Efficacy in Combined Analysis
Figure 4, page 42
Usmani SZ et al. Blood. 2016;128:37.
Usmani SZ et al. Blood. 2016;128:37.
Daratumumab Phase 2 Study
ORR, %
Single Agent in RRMM
40
35
30
25
20
15
10
5
0
ORR by Subgroup
33
33
30
30
21
29
28
28
26
21
20
Refractory to
Lonial S et al. Lancet. 2016;387:1551.
69
Daratumumab Phase 2 Study
Single Agent in RRMM
Progression-Free and Overall Survival
Patients
Progression-Free
and Alive (%)
100
Figure 4, page 1558
80
60
Median PFS = 3.7 months
(95% CI, 2.8–4.6)
40
Lonial S et al. Lancet.
2016;387:1551.
20
0
0 2 4 6 8 10 12 14 16
Months From Start of Treatment
• 29 of 31 responders are still alive
• 1-year survival rate 65% (95% CI, 51.2–75.5)
Lonial S et al. Lancet. 2016;387:1551.
Synergistic With Other Standard MM Therapies,
Including Bortezomib and Lenalidomide
Modified from Figure 1, page e42
van der Veer MS et al. Blood Cancer J.
2011;1:e41.
70
Palumbo A et al. N Engl J Med. 2016;375:754.
Phase 3 Randomized Controlled Study of DVd vs Vd
in Pts With Relapsed or Refractory MM: CASTOR
CASTOR Study Design
Multicenter, randomized, open-label, active-controlled phase 3 study
Key eligibility
criteria
• RRMM
• ≥1 prior line of
therapy
• Prior
bortezomib
exposure, but
not refractory
DVd (n=251)
R
Daratumumab (16 mg/kg IV)
A
Every week: cycles 1–3
N
Every 3 weeks: cycles 4–8
D
Every 4 weeks: cycles 9+
O 1:1 Vel: 1.3 mg/m2 SC, days 1, 4, 8, 11: cycles 1–8
Dex: 20 mg PO-IV, days 1, 2, 4, 5, 8, 9, 11, 12: cycles 1–8
M
I
Vd (n=247)
Z
Vel: 1.3 mg/m2 SC, days 1, 4, 8, 11: cycles 1–8
E
Primary end point
• PFS
Secondary end point
•
•
•
•
•
•
TTP
OS
ORR, VGPR, CR
MRD
Time to response
Duration of response
Dex: 20 mg PO-IV, days 1, 2, 4, 5, 8, 9, 11, 12: cycles 1–8
Statistical analyses
• Cycles 1–8: repeat every 21 days
• Cycles 9+: repeat every 28 days
Daratumumab IV administered in 1,000 mL to 500 mL;
gradual escalation from 50 mL to 200 mL/hour permitted
• 295 PFS events: 85%
power for 4.3 month PFS
• Interim analysis: ~177
PFS events
Palumbo A et al. N Engl J Med. 2016;375:754.
71
Phase 3 Randomized Controlled Study of DVd vs Vd
in Pts With Relapsed or Refractory MM: CASTOR
CASTOR Efficacy
DVd
Vd
HR
95% CI
P Value
N
251
247
─
─
─
PFS (mos)
NR
7.2
0.39
0.280.53
<0.0001
1-year PFS (%)
60.7
26.9
Median TTP (mos)
NR
7.3
0.30
0.210.43
<0.0001
ORR (%)
83
63
─
─
<0.0001
≥VGPR
59
29
─
─
<0.0001
≥CR
0.0012
19
9
─
─
MRD-negative (10-4) (%)
14
3
─
─
Median duration of response (mos)
NR
7.9
─
─
─
Palumbo A et al. N Engl J Med. 2016;375:754.
Phase 3 Randomized Controlled Study of DVd vs Vd
in Pts With Relapsed or Refractory MM: CASTOR
Proportion Surviving
Without Progression
CASTOR PFS
1.0
Median: not reached
1-year PFS*
0.8
60.7%
0.6
DVd
0.4
Median: 7.2 months
0.2
0
No. at risk
Vd
DVd
26.9%
Vd
HR: 0.39 (95% CI, 0.28-0.53); P<0.0001
0
3
6
9
12
15
247
251
182
215
106
145
25
56
5
11
0
0
61% reduction in the risk of disease progression or death for DVd vs Vd
Palumbo A et al. N Engl J Med. 2016;375:754.
72
Daratumumab + Lenalidomide +
Dexamethasone: Overall Response Rate
• ORR = 81%
• Clinical benefit rate (ORR + minimal response) = 88%
From Table 4, page 1825
Plesner T et al. Blood. 2016;128:1821.
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
73
Phase 3 Randomized Controlled Study of DRd vs Rd
in Pts With Relapsed or Refractory MM: POLLUX
POLLUX Study Design
Key eligibility
criteria
• RRMM
• ≥1 prior line of
therapy
• Prior lenalidomide
exposure, but not
refractory
• Patients with
creatinine clearance
≥30 mL/min
Stratification factors
• No prior lines of therapy
• ISS stage at study entry
• Prior lenalidomide
R
DRd (n=286)
A
Daratumumab 16 mg/kg V
• Qw in Cycles 1–2, q2w in Cycles 3–6, then q4w until
N
PD
D
R 25 mg PO
• Days 1–21 of each cycle until PD
O
1:1
d 40 mg PO
M
• 40 mg weekly until PD
I
Rd (n=283)
Z
R 25 mg PO
E
• Days 1–21 of each cycle until PD
Primary end point
• PFS
Secondary end point
•
•
•
•
•
•
d 40 mg PO
• 40 mg weekly until PD
Cycles: 28 days
Pre-medication for the DRd treatment group consisted of
dexamethasone 20 mga, paracetamol, and an antihistamine.
TTP
OS
ORR, VGPR, CR
MRD
Time to response
Duration of response
Statistical analyses
• 295 PFS events: 85%
power for 7.7 month
PFS improvement
• Interim analysis: ~177
PFS events
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
Phase 3 Randomized Controlled Study of DRd vs Rd
in Pts With Relapsed or Refractory MM: POLLUX
Proportion Surviving
Without Progression
POLLUX PFS
12-month PFS*
1.0
18-month PFS*
83%
78%
0.8
DRd
60%
0.6
52%
Rd
Median PFS: 18.4 months
0.4
0.2
HR: 0.37 (95% CI, 0.27–0.52); P<0.0001
0
No. at risk
Rd
DRd
0
3
6
9
12
15
18
283
286
249
266
206
248
179
232
139
189
36
55
5
8
24
0
0
63% reduction in the risk of disease progression or death for DRd vs Rd
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
74
Phase 3 Randomized Controlled Study of DRd vs Rd
in Pts With Relapsed or Refractory MM: POLLUX
POLLUX Efficacy
DRd
Rd
P Value
N
286
283
─
ORR (%)
93
76
<0.0001
≥VGPR
76
44
<0.0001
≥CR
43
19
<0.0001
NR
17.4
─
Median duration of response
(mos)
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
MRD-negative Rate (%)
Phase 3 Randomized Controlled Study of DRd vs Rd
in Pts With Relapsed or Refractory MM: POLLUX
50
45
40
35
30
25
20
15
10
5
0
POLLUX MRD-Negativity Rate
P<0.0001
DRd
Rd
P<0.0001
30%
23%
8%
MRD-neg (10-4)
P<0.0001
10%
5%
MRD-neg (10-5)
2%
MRD-neg (10-6)
Dimopoulos M et al. N Engl J Med. 2016;375:1319.
75
Daratumumab in High-Risk Patients
ORR, %
Daratumumab Phase 2 Study
Single Agent in RRMM ORR by Subgroup
40
35
30
25
20
15
10
5
0
33
33
30
30
21
29
28
28
26
21
20
Refractory to
Lonial S et al. J Clin Oncol. 2015;33. Abstract LBA 8512.
Isatuximab
CD38
Updated Data From a Dose Finding Phase II Trial
of Single Agent Isatuximab (Anti-CD38 mAb)
in Relapsed/Refractory Multiple Myeloma
[ASCO 2016]
Joshua Richter,1 Thomas Martin,2 Ravi Vij,3 Craig Cole,4 Djordje Atanackovic,5 Jeffrey Zonder,6
Jonathan Kaufman,7 Joseph Mikhael,8 William Bensinger,9 Meletios Dimopoulos,10 Todd
Zimmerman,11 Nikoletta Lendvai,12 Parameswaran Hari,13 Enrique Ocio,14 Cristina Gasparetto,15
Shaji Kumar,16 Corina Oprea,17 Eric Charpentier,17 Stephen Strickland,18 Jesús San Miguel19
1Hackensack University Medical Center, Hackensack, NJ, USA; 2University of California at San Francisco, San Francisco, CA, USA; 3Washington University, St. Louis,
MO, USA; 4University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA; 5Huntsman Cancer Institute, Salt Lake City, UT, USA; 6Karmanos Cancer Center,
Detroit, MI, USA; 7Winship Cancer Institute of Emory University, Atlanta, GA, USA; 8Mayo Clinic, Scottsdale, AZ, USA; 9Fred Hutchinson Cancer Research Center,
Seattle, WA, USA; 10National and Kapodistrian University of Athens, Athens, Greece; 11University of Chicago, Chicago, IL, USA; 12Memorial Sloan-Kettering Cancer
Center, New York, NY, USA; 13Medical College of Wisconsin, Milwaukee, WI, USA; 14University Hospital of Salamanca, Salamanca, Spain; 15Duke University Medical
Center, Durham, NC, USA; 16Mayo Clinic, Rochester, MN, USA; 17Sanofi-Genzyme Oncology, Cambridge, MA, USA; 18Vanderbilt-Ingram Cancer Center, Nashville,
TN,19University of Navarra, Pamplona, Spain
76
ASCO 2016: Summary
• Isatuximab was generally well tolerated at ≥10 mg/kg
– Most infusion reactions were grade 1/2, and occurred during the first
infusion
– Median infusion duration is shorter following the first infusion
• Isatuximab demonstrated single-agent activity in heavily pretreated patients
with RRMM
– Median 5 (2–14) prior lines of therapy
• The ORR was 20%–29% at isatuximab ≥10 mg/kg
– ORR was similar across subgroups, including high-risk cytogenetics
– Median duration of response was 8.75–12.9 (3.7–14.8) months
• At isatuximab ≥10 mg/kg, PFS was 3.65 months and OS was 18.63 months
– 11 patients remained on treatment at data cutoff
– Median OS has not been reached in the 20 mg/kg QW/Q2W and 10 mg/kg
Q2W/Q4W cohorts
Richter JR et al. J Clin Oncol. 2016;34: Abstract 8005.
Immune Suppressive
Microenvironment in MM
pDC
MDSC
PD-L1
TAM
PD-L1
IL-6, IL-10, TGFβ, PGE,
ARG1, NO, ROS, COX2
Depletion of cysteine
pDC, MDSC induced
immune suppression
PD1
PD1
PD-L1
Treg
MM
PD1
MM
MM
MM
PD-L1
PD1
PD1
CD8
CD4
NKT
NK
B
MM induced
immune
suppression
Tumor promotion and
induction of PD-L1
expression
Stroma
Görgün GT et al. Blood. 2013;121:2975.
77
Immune Checkpoint Inhibitors in MM
Target PD-1, PDL-1
Allow T cells to function
Current agents under investigation in MM:
nivolumab and pembrolizumab
Activity only in combination with other MM agents
Immune Checkpoint Inhibitors for
Relapsed/Refractory Multiple Myeloma
Keynote-023: Pembrolizumab +
Lenalidomide and
Dexamethasone1
Phase 2 of Pembrolizumab +
Pomalidomide and
Dexamethasone2
RRMM for whom ≥2 prior therapies,
including a proteasome inhibitor and
an IMiD, have failed
RRMM for whom ≥2 prior therapies,
including a proteasome inhibitor and
an IMiD, have failed
Pembrolizumab
200 mg fixed dose*
200 mg IV every 2 weeks
IMiD
Lenalidomide: 25 mg
Pomalidomide: 4 mg daily  21 days
Dexamethasone
40 mg (low-dose)
40 mg weekly
17 patients; 76% response rate
11 of 22 evaluable patients
(50% response rate)
Patient population
Dosing
Response
*Used in the phase 2 portion of study based on MTD/MAD
1. San Miguel J et al. Blood. 2015;126: Abstract 505.
2. Badros AZ et al. Blood. 2015;126: Abstract 506.
78
Durvalumab
Figure 1, page 475
Ibrahim R et al. Semin Oncol. 2015;42(3):474.
Harnessing the Immune
System to Fight Myeloma
Types of Immunotherapy, Immuno-Oncology
Passive
Active
Monoclonal
antibodies
Chimeric antigen
receptor (CAR) T cells
Direct effects
Monoclonal antibody
Vaccines (therapeutic
not preventive)
1. Extract WBCs
from patient
2. Modify and
expand cells
in lab
Antigen
CDC
C1q
Myeloma cell
MAC
Lysis
ADCC
Fc receptor
NK cell
3. Infuse MM-targeted
cells back to
patient
Cell death
79
Phase 1 Trial of Vaccination
With DC/MM Fusions in RRMM
Figure 1, page 396
Rosenblatt J et al. Blood.
2011;117:393.
• Well tolerated, no autoimmunity
• Induced tumor reactive
lymphocytes in a majority of
patients
• Induced humoral responses to
novel antigens (SEREX analysis)
• Disease stabilization in 70% of
patients
• DC/MM fusions induce anti-MM
immunity in vitro and inhibit MM
cell growth in vivo in xenograft
models
Rosenblatt J et al. Blood. 2011;117:393.
Vasir B et al. Br J Haematol. 2005;129:687.
Vaccines Targeting MM-Specific
Peptides in Smoldering MM
• Goal is to prevent evolution of smoldering to active
myeloma
• Cocktails of immunogenic HLA-A2-specific XBP1,
CD138, CS1 peptides to induce MM-specific and HLArestricted CTL responses
• Clinical trials:
–
–
–
–
Immune responses to vaccine in all patients
Lenalidomide with vaccine to augment immune response
Lenalidomide and PDL-1 with vaccine to induce memory
Immune response against myeloma
Bae J et al. Leukemia. 2011;25:1610.
Bae J et al. Br J Haematol. 2011;155:349.
Bae J et al. Br J Haematol. 2012;157:687.
Bae J et al. Clin Can Res. 2012;17:4850.
Bae J et al. Leukemia. 2015;29:218.
80
Therapeutic Vaccines in Development
MM Vaccine
Patient Types
Study
Phase
Sites
Dendritic cell fusion vaccine + CT-011
(monoclonal antibody)
Post-transplant*
2
Beth Israel Deaconess Medical Center/
Dana-Farber
Hiltonol (MAGE-A3 vaccine Poly-ICLC)
Post-transplant*
2
University of Pennsylvania
Oncolytic measles virus (MV-NIS)
RR
1
Mayo Clinic (Rochester, MN)
Oncolytic measles virus (MV-NIS)
RR
2
University of Arkansas
PVX-410
SMM
PVX-410
Post-transplant
1/2
2
Emory/Illinois Cancer Specialists/
Beth Israel Deaconess Medical
Center/Massachusetts General Hospital/
DFCI/ MD Anderson Cancer Center
Emory University
*Goal of eliminating any remaining cancer cells
Immune Cell Therapy in Development
Patient Types
Study
Phase
CART-19 for multiple myeloma
Relapsed/ refractory
1
University of Pennsylvania
Safety study of CAR-modified T cells targeting NKG2Dligands
Relapsed/ refractory
1
Dana-Farber Cancer Institute
Study of T cells targeting B-cell maturation antigen
(BCMA) for previously treated multiple myeloma
Relapsed/ refractory
1
National Cancer Institute
University of Pennsylvania
Tadalafil and lenalidomide maintenance with or without
activated marrow infiltrating lymphocytes (MILs) in highrisk myeloma
Newly diagnosed;
relapsed (without
prior ASCT)
2
Sidney Kimmel Comprehensive
Cancer Center
Adoptive immunotherapy with activated marrowinfiltrating lymphocytes and cyclophosphamide graftversus-host disease prophylaxis in patients with relapse
of hematologic malignancies after allogeneic
hematopoietic cell transplantation
Relapsed/ refractory
1
Sidney Kimmel Comprehensive
Cancer Center
Affinityenhanced
T cells
Engineered autologous T cells expressing an affinityenhanced TCR specific for NY-ESO-1 and LAGE-1
Relapsed/
refractory
DLI
CD3/CD28 activated Id-KLH primed autologous
lymphocytes
Post-transplant
Type
CAR T
MILs
Trial
1/2
2
Site(s)
City of Hope
University of Maryland
University of Pennsylvania
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Myeloma CAR Therapy
• Multiple promising targets:
– CD19, CD138, CD38, CD56, kappa, Lewis Y, CD44v6, CS1 (SLAMF7), BCMA
• Functional CAR T cells can be generated from MM patients
• CAR T and NK cells have in vitro and in vivo activity against MM
• Clinical trials under way
– Anecdotal prolonged responses but no robust efficacy data available yet
• Many questions remain about CAR design:
–
–
–
–
–
Optimal costimulatory domains
Optimal vector
Optimal dose and schedule
Need for chemotherapy
Perhaps “cocktails” of multiple CARs or CARs + chemotherapy will be
required for best outcomes
MM Pt #1:
Response to CD19 CAR Therapy
Figures 1 and 2, page 1042
Garfall AL et al. N Engl J Med. 2015;373:1040.
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CAR-BCMA T Cells in MM: Study Design
First-in-human phase 1 trial
Pts with advanced RRMM;
≥3 prior lines of therapy;
normal organ function;
clear, uniform BCMA
expression on MM cells
(N=12)
Cyclophosphamide 300 mg/m2
Fludarabine 30 mg/m2
QD for 3 days
CAR-BCMA T cells*
Single infusion
*Dose escalation of
CAR+ T cells/kg
0.3 × 106
1.0 × 106
3.0 × 106
9.0 × 106
• CAR-BCMA expression determined by flow cytometry
Ali SA et al. Blood. 2016;128:1688.
CAR-BCMA T Cells in MM: Response
Table 1, page 1690
Ali SA et al. Blood. 2016;128:1688.
83
Bi-Specific Antibody (bsAb) Constructs
Bivalent
Antibody
conjugates
Tetravalent
Small molecules
(eg, BiTEs)
~
Derived from Kontermann RE, Brinkmann U. Drug Discov Today. 2015;20:838.
Zonder J. Presented at: 15th International Myeloma Workshop . Rome, Italy. September 2015.
Integration and Impact of Novel Agents,
including Immune Therapies
• Innovations (PIs, IMiDs) to date have produced significant improvements in PFS
and OS: recent approvals (eg, carfilzomib, ixazomib) will augment this
• Next wave of therapies…crucially, agnostic to mutational thrust?
• Baseline immune function appears to also be a key barrier to success but may
be targetable (eg, use of PD1/PDL1 blockade)
• MoAbs (Elo, DARA, ISA) have activity in high-risk disease and represent true
new novel mechanisms, as well as other immuno-therapeutics (eg, checkpoint
inhibitors, vaccines)
• New insights to mechanisms of drug action (eg, AC 241) are further expanding
therapeutic opportunities with combinations
• Numerous other small molecule inhibitors show promise (eg, HDACis, CXCR4,
BCL, AKT, CDK, HSP 90, Nuclear Transport, KSP, BET bromodomain
proteins/Myc, DUBs, MEK)
• Further refinement of prognostics and MRD will guide therapy
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Continuing Evolution of MM Treatment:
Selected New Classes and Targets 2016
2nd-Generation Novel Therapies/
Immunotherapy
1st-Generation Novel Agents
Lenalidomide
Carfilzomib
Pomalidomide
Bortezomib
Bortezomib +
Doxil
Nivolumab*
Pembrolizumab*
Ixazomib
Thalidomide
Daratumumab
Panobinostat
Elotuzumab
Atezolizumab*
Durvalumab*
AC-241/1215*
Vaccines*
CAR-T*
Marizomib*
Isatuximab*
3rd Generation
IMiDs*
Melflufen*
2003
2006 2007
2016+
2012 2013 2015
IMiD
HDAC inhibitor
Monoclonal antibody
Vaccines
Proteasome inhibitor
Chemotherapy
Adoptive T cell therapy
Checkpoint inhibitors
*Not yet FDA-approved for MM; available in clinical trials
Ongoing MM Collaborative Model for
Rapid Translation From Bench to Bedside
Pharmaceuticals
Academia
NIH
NCI
Progress
and hope
Advocacy
MMRF/C;IMF
IMWG; IMS
FDA
EMEA
19 new FDA-approved drugs/combos/indications in last 13 yrs
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