Ohio State's 2016 ASH Review - BEST OF ASH 2015 MULTIPLE MYELOMA AND PLASMA CELL DYSCRASIAS

BEST OFASH 2015
MULTIPLE MYELOMAAND PLASMACELLDYSCRASIAS
Yvonne Efebera MD. MPH
Disclosure: Takeda: Speaker, adjudication Committee

Overall Survival from Time of Diagnosis in 6-yr Intervals
based on date of Diagnosis
3
Kumar SK et al, Blood 2008: 111: 2516
Corticosteroids,
Alkylating agents,
radiation, etc.
Thalidomide, lenalidomide, Bortezomib

4
Old regimen
(VAD regimen)
New regimen
incorporating Novel
agents
Overall response rate
(ORR)
50-60% 80-100%
Complete response (CR) 16-25% 40-60%
Very good partial
response (VGPR)
5-10% 20-30%
5 yr Overall survival (OS) ~30-40% 60-80%
Median time to disease
progression (PFS)
15 months 25-30 months. Improved
to 53 mos with
Maintenance
Palumbo A et al, 2006, Lancet p825; Mateos MV et al, Blood 2010, p 2259; Facon T et al, lancet
2007, p 1209; Sacchi s, Leuk lymphoma 2011, p 1942;

A GREAT YEAR for Multiple Myeloma
• 4 New drugs approved for relapsed/refractory MM
• Daratumumab: Nov 16, 2015: monoclonal ab, anti-CD38, single agent
• Elotuzumab: Nov 30,2015: monoclonal ab, SLAM-7 and NK cell activation, in
combination with lenalidomide and Dex
• Ixazomib: Nov 20, 2015: oral proteosome inhibitor, in combination with lenalidomide
and Dex
• Panobinostat: Feb 28, 2015: HDAC inhibitor, in combination with bortezomib and Dex
Approved Newly Dx MM Newly Diagnosed Regimen Approved Relapsed MM
Thalidomide (T)
Lenalidomide (R )
Bortezomib (V)
Dexamethasone (D)
Prednisone (P)
VRD
CVD (CyborD)
CRD
RD
VD
Melphalan based (transplant
ineligible)
Pomalidomide
Carlfizomib
Panobinostat
Daratumumab
Ixazomib
Elotuzumab
Cyclophosphamide (C )
Vincristine
Doxil
Melphalan

Newly diagnosed Myeloma-
Transplant eligible Patient
Induction treatment: to reduce burden
of disease and prevent complications
2-6 cycles
Autologous Stem cell Transplant
Maintenance treatment.
Supportive Management
Radiation
Bisphosphonate

Newly diagnosed Myeloma-
Not Transplant eligible Patient
Induction treatment: to reduce burden
of disease, prevent complications,
With goal towards complete response
8-12 cycles
Maintenance treatment.
Supportive Management
Radiation:
Bisphosphonate

Overview
• Newly diagnosed Multiple Myeloma
• Autologous stem cell transplant vs chemotherapy (early
vs delayed SCT)
• Relapse Multiple Myeloma
• Treatment of older Adults
• AL Amyloidosis

INDUCTION REGIMEN
FOR NEWLY DX MM

VTD x 4 versus VCD x 4 as induction therapy prior to ASCT
Symptomatic de novo MM less than 66 years
Primary end-point : VGPR rate after cycle 4
340 patients overall (170 per arm).
Abstract 393 Bortezomib, Thalidomide and Dexamethasone (VTD) Is Superior
to Bortezomib, Cyclophosphamide and Dexamethasone (VCD) Prior to
Autologous Stem Cell Transplantation for Patients with De Novo Multiple
Myeloma. Results of the Prospective IFM 2013-04 Trial. Philippe Moreau et al
ISS1 / 2 versus ISS 3
t(4;14) and / or del17p versus others

ArmA: Induction Therapy: 4 cycles VTD
Each cycle : 21 days
Thalidomide® 100 mg/d, PO D1 to D21
o Velcade® 1.3 mg/m²/d, SC D1, 4, 8 and 11
o Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12
ARM B: Induction Therapy : 4 cycles of VCD
Each cycle : 21 days
o Cyclophosphamide 500 mg/m²/d, PO D1, 8, 15
o Velcade® 1.3 mg/m²/d, SC D1, 4, 8 and 11
o Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12

VTD
169
VCD
169
Total
338
Male
Female
Median age
ISS1
ISS2
ISS3
No t(4;14), no17p
t(4;14) and/or 17p
103
66
59.4
38 (22%)
94 (56%)
37 (22%)
137 (81%)
32 (19%)
108
61
60.2
43 (25%)
90 (53%)
36 (21%)
140 (83%)
29 (17%)
211
127
59.9
81 (24%)
184 (54%)
73 (22%)
277 (82%)
61 (18%)
Patients Characteristics
Cytogenetics: centralized analysis (Pr Avet-Loiseau, Toulouse)

VTD
N = 169
VCD
N = 169
P value
≥ CR
≥ VGPR
≥ PR
13.0%
66.3%
92.3%
8.9%
56.2%
83.4%
0.22
0.05
0.01
Intent-to-treat analysis
Response: centralized assessment (Dr Dejoie, Nantes), IMWG criteria 2011
VTD
N = 157
VCD
N = 154
P value
> = CR
> = VGPR
> = PR
14.0%
70.7%
98.7%
9.1%
60.4%
90.3%
0.17
0.05
0.001
Per protocol analysis

VTD, n = 169
Grade 3-4 %
VCD, n= 169
Grade 3-4 %
p value
Any Aes
Anemia
Neutropenia
Infection
Thrombocytopenia
Thrombosis
Cardiac disorders
Cystitis
GI symptoms
Periph. Neuropathy
PN grade 2-4
63.9
4.1
18.9
7.7
4.7
1.8
1.2
0
5.3
7.7
21.9
68.2
9.5
33.1
10.1
10.6
1.8
0
0.6
3.5
2.9
12.9
0.40
0.05
0.003
0.45
0.04
0.99
0.16
0.32
0.42
0.05
0.008
Toxicity
Toxicities assessed according to NCI CTCAE, version 4.0.

Toxicity
Five patients died during induction therapy (1.5%),
2 in arm A from infections (1) and pulmonary embolism (1)
3 in arm B from progression to extramedullary myeloma (1) and infections (2).
VTD, n = 169 VCD, n = 169
Dexamethasone
100%
dose reduction
Discontinuation
DOSE-INTENSITY
Bortezomib
100%
dose reduction
Discontinuation
DOSE-INTENSITY
Thalidomide / Cyclophosphamide
100%
dose reduction
Discontinuation
DOSE-INTENSITY
76.3%
14.2%
9.5%
92.4%
76.9%
16.0%
7.1%
94.9%
62.7%
21.3%
16%
81.9%
84.6%
10.9%
8.6%
96.1%
78.1%
13.6%
8.3%
96.4%
71.3%
16.6%
12.1%
94.5%

VTD
N = 157
VCD
N = 154
p value
CD34+ (106 / kg) 10.68 9.17 0.05
Stem cell harvest

Conclusions
- First prospective randomised trial : VTD vs VCD
- VGPR and PR rates are significantly superior in the VTD arm:
synergistic activity of PI + IMiD
- Hematologic toxicity increased in the VCD arm, while
Peripheral Neuropathy rate was higher in the VTD arm
- Median number CD34+ stem cells higher in the VTD
- Our data support the preferential use of VTD rather than VCD
in preparation for ASCT

Bortezomib-thalidomide-dexamethasone(VTD) is superior to bortezomib-cyclophosphamide-
dexamethasone(VCD)as induction therapy prior to autologous stem cell transplantation in
multiple myeloma. Cavo et al leukemia:2015,2429-2431
All patients VTD (n=236) VCD (n=236) P
Complete response 44 (19%; 14–24) 13 (6%; 3–8) <0.001
Very good partial
response or better
151 (64%; 58–70) 87 (37%; 31–43) <0.001
Partial response or better 220 (93%; 90–96) 192 (81%; 76–86) <0.001
Stable disease 16 (7%; 4–10) 38 (16%; 11–21) 0.001
Progressive disease 0 (0%) 6 (3%; 1–5) 0.015
Patients with ISS 2-3 VTD (n=129) VCD (n=129)
Complete response 26 (20%; 13–27) 5 (4%; 1–7) <0.001
Very good partial
response or better
86 (67%; 59–75) 45 (35%; 27–43) <0.001
Patients with t(4;14)
and/or del(17p)
VTD (n=53) VCD (n=53)
Complete response 12 (23%; 11–34) 4 (8%; 0–15) 0.030
Very good partial
response or better
44 (83%; 73–93) 25 (47%; 34–61) <0.001
Dose and schedule same as Moreau et al. except- V and C given IV, 3
cycles each before SCT

Toxicity
VTD (n=236) VCD (n=236) P
Any grade 3 or 4
adverse event
64 (27%) 61 (26%) 0.754
Any grade 3 or 4 non-hematological adverse event
Skin rash 19 (8%) 2 (1%) <0.001
Peripheral
neuropathy
17 (7%) 5 (2%) 0.009
Gastrointestinal
events
15 (6%) 8 (3%) 0.135
Liver toxicity 5 (2%) 8 (3%) 0.399
Any grade 3 or 4 hematological adverse event
Neutropenia 5 (2%) 19 (8%) 0.003
Anemia 0 16 (7%) <0.001
Thrombocytopenia
1 (<1%) 10 (4%) 0.006
Study protocol discontinuation during induction therapy
Toxic effects 8 (3%) 4 (2%) 0.242
Disease
progression
0 3 (1%) 0.124
Early death 1 (<1%) 2 (1%) 0.500

Abstract 25 Bortezomib,Lenalidomideand Dexamethasone (Rd)Vs. Lenalidomide and
Dexamethasonein Patients(Pts)(VRd) withPreviously UntreatedMultiple Myeloma withoutan
Intent for ImmediateAutologous Stem Cell Transplant(ASCT): Resultsof the Randomized
PhaseIII TrialSWOG S0777Brian Durie, MD et al
• Randomized phase III: 2008-2012
• Stratified to ISS stage (I,II,III), Intent to transplant (Yes, NO)
• Lenalidomide/dex (Rd): 232 patients: R 25 mg days 1-21, dex 40 mg/d days 1
8, 15, 22, cycle q 28 days x 6 cycles
• Bortezomib/Rd (VRd): 242 patients: R 25 mg days 1-14, dex 20 mg/d days 1-
4, 8-12, velcade 1.3 mg/m2 IV push days 1,4,8,11. cycle q 21 days x 8 cycles
• Maintenance: Rd until progression
• DVT prophylaxis: ASA 325 mg/d; HSV prophylaxis with VRd
• Differences b/w gps :
• Fewer women VRd(37% vs 47% p=0.033)
• Fewer older pts VRd (≥ 65yrs 38% vs 48% p=0.042)
• Primary Endpoint: PFS

Abstract 25 . BrianDurie,MD et al
VRd Rd P-value
ORR 71.07% 63.79%
Median PFS 43 mos 31 mos 0.0066
Median OS NR 63 mos 0.0114
≥Grade 3 hem tox (%)
Anemia
Neutropenia
thrombocytopenia
13
19
18
16
21
14
≥Grade 3 non- hem tox (%)
Neuropathy
Thrombosis/embolism
24
8
5
9
<0.0001
Second primary malignancy 7 pts (3%) 9(4%)
VRd provides meaningful improvement in PFS and OS with acceptable toxicity

What did we Learn?
• The combination of A proteosome inhibitor (bortezomib) ,
and an immune modulator( thalidomide, lenalidomide) as
induction treatment is a preferable regimen
• 3-drug regimen with Novel agents is superior to 2-drug
regimen with Novel agent as Induction regimen

AUTOLOGOUS SCT AS CONSOLIDATION IN
NEWLY DX MM VS CONTINUATION OF
THERAPY (EARLY VS DELAYED SCT) IN THE
ERA OF NOVEL THERAPIES

389 patients (younger than 65 years) randomized from 59 centers

Patients: Symptomatic disease, organ damage (CRAB),
measurable disease
392: Autologous Transplantation versus cyclophosphamide-lenalidomide-prednisone followed by
lenalidomide-prednisone versus lenalidomide maintenance in multiple myeloma: long-term results of a phase
III trial. Gay et al- lancet oncology Dec 2015 p1617
Rd
four 28-day courses
R: 25 mg/d, days 1-21
d: 40 mg/d, days
1,8,15,22
CRD
six 28-day courses
C: 300 mg/sqm, days
1,8,15
R: 25 mg/d, days 1-21
D: 40 mg days 1,8,15,22
MEL200-ASCT
two courses
M: 200 mg/m2 day -2
Stem cell support day 0
RP MAINTENANCE
28-day courses until
relapse
R: 10 mg/day, days 1-21
P: 50 mg every other day
R MAINTENANCE
28-day courses until
relapse
R
A
N
D
O
M
I
Z
A
T
I
O
N
1°
R
A
N
D
O
M
I
Z
A
T
I
O
N
2°
R, lenalidomide; D, dexamethasone; C, cyclophosphamide; P, prednisone; Rd, lenalidomide-dexamethasone; CRD, cyclophosphamide-lenalidomide-
dexamethasone; MEL200-ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; RP lenalidomide-prednisone,

CRD vs MEL200-ASCT
CRD
six 28-day courses
C: 300 mg/m2/d, days 1,8,15
R: 25 mg/d, days 1-21
D: 40 mg/d days 1,8,15,22
MEL200-ASCT
two courses
M: 200 mg/m2 day -2
R
A
N
D
O
M
I
Z
A
T
I
O
N
1°
CRD, cyclophosphamide-lenalidomide-dexamethasone; C, cyclophosphamide; D, dexamethasone; R, lenalidomide; MEL200-ASCT, melphalan 200 mg/m2
followed by autologous stem-cell transplantation

CRD vs MEL200-ASCT
CRD, cyclophosphamide-lenalidomide-dexamethasone; MEL200-ASCT, melphalan 200 mg/m2 followed by autologous stem-cell transplantation;
ISS, International Staging System
MEL200-ASCT
(n=127)
CRD
(n=129)
Age
median
>60 years
57
34
56
31
ISS Stage
I
II
III
51%
36%
13%
45%
50%
16%
Chromosomal Abnormalities
t (4;14)
t (14;16)
del 17
High-risk [t (4;14) or t(14;16) or del17]
9%
5%
5%
18%
13%
5%
8%
23%

CRD vs MEL200-ASCT
Median follow-up from consolidation : 47 months
Median PFS
MEL200-ASCT 43.3 months
CRD 28.6 months
MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; PFS
progression-free survival
Progression-free survival
HR 2.51 95% CI 1.60-3.94 P< 0.00010.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
Months
Proportionofpatients

Overall
Maintenance
Lenalidomide
Lenalidomide-Prednisone
Age
≤ 60
> 60
ISS
I
II
III
Cytogenetic risk
Standard
High
Missing
2.51 (1.60, 3.94)
2.18 (1.23, 3.88)
2.66 (1.50, 4.71)
1.78 (1.07, 2.97)
3.92 (2.00, 7.71)
3.15 (1.62, 6.13)
1.97 (1.08, 3.60)
1.72 (0.76, 3.90)
2.01 (1.06, 3.80)
3.81 (1.83, 7.93)
2.12 (1.06, 4.24)
HR (95% CI) Interaction-
2.51 (1.60, 3.94)
2.18 (1.23, 3.88)
2.66 (1.50, 4.71)
1.78 (1.07, 2.97)
3.92 (2.00, 7.71)
3.15 (1.62, 6.13)
1.97 (1.08, 3.60)
1.72 (0.76, 3.90)
2.01 (1.06, 3.80)
3.81 (1.83, 7.93)
2.12 (1.06, 4.24)
HR (95% CI)
.58
.04
.38
.32
- p
1.126 7.93
CRD vs MEL200-ASCT
MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; PFS,
progression-free survival.
Subgroup Analysis of PFS

CRD vs MEL200-ASCT
Median follow-up from consolidation : 47 months
MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; OS:
overall survival
4-year OS
MEL200-ASCT 86%
CRD 73%
Overall survival
HR 2.40 95% CI 1.32-4.38 P= 0.0040.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
Months

Overall
Maintenance
Lenalidomide
Lenalidomide-Prednisone
Age
≤ 60
> 60
ISS
I
II
III
Cytogenetic risk
Standard
High
Missing
2.40 (1.32, 4.38)
1.46 (0.58, 3.65)
3.17 (1.41, 7.12)
0.89 (0.43, 1.86)
7.83 (2.60, 23.56)
4.59 (1.26, 16.75)
1.59 (0.66, 3.62)
1.42 (0.51, 3.93)
1.46 (0.54, 3.96)
1.79 (0.73, 4.37)
9.38 (1.21, 72.98)
HR (95% CI)
.21
.32
Interaction-
2.40 (1.32, 4.38)
1.46 (0.58, 3.65)
3.17 (1.41, 7.12)
0.89 (0.43, 1.86)
7.83 (2.60, 23.56)
4.59 (1.26, 16.75)
1.59 (0.66, 3.62)
1.42 (0.51, 3.93)
1.46 (0.54, 3.96)
1.79 (0.73, 4.37)
9.38 (1.21, 72.98)
HR (95% CI)
.001
.27
p
1.0137 1 73
CRD vs MEL200-ASCT
MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; OS,
overall survival.
Subgroup Analysis of OS

RP maintenance vs R maintenance
R, lenalidomide; P, prednisone
R
A
N
D
O
M
I
Z
A
T
I
O
N
2°
R maintenance
28-day courses until relapse
RP MAINTENANCE

RP, lenalidomide-prednisone; R, lenalidomide; ISS, International Staging System; Percentage may not total 100 because of rounding
RP
(n=117)
R
(n=106)
Age
median
>60 years
57 56
ISS Stage
I
II
III
51%
38%
11%
49%
39%
12%
Chromosomal Abnormalities
t (4;14)
t (14;16)
del 17
High-risk [t (4;14) or t(14;16) or del17]
13%
4%
3%
19%
5%
7%
8%
18%

Median PFS
RP 37.5 months
R 28.5 months
Median follow-up from maintenance 41 months
HR 0.84, 95% CI 0.59-1.20, P =.34
Months
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50
RP: lenalidomide-prednsone; R lenalidomide; PFS progression-free survival

3-year OS
RP 83%
R 88%
Overall survival
Median follow-up from maintenance 41 months
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50
Months
HR 1.53, 95% CI 0.79-2.98, P =.21
RP: lenalidomide-prednsone; R lenalidomide; OS overall survival

AE, adverse event; GI, gastrointestinal events; RP: lenalidomide prednisone; R lenalidomide.
% of patients
P=.193
P=1.000
P=.417
P=.174
P=.449
P=.301
P=.117
Grade 3-4 AEs
P=.349

AE, adverse event; GI, gastrointestinal events; RP: lenalidomide prednisone; R lenalidomide.
% of patients
P=.0.004
Dose reductions
• Main reasons for prednisone dose reduction:
psychiatric disorders, endocrinopathy, hyperglicemia
• Main reasons for lenalidomide dose reductions:
RP: gastrointestinal AEs;
R: hematological and dermatological AEs

Induction Consolidation Maintenance
Rd MEL200-ASCT CRD RP R
N° of SPM
- Hematologic
- Solid
- Skin cancer
0
3
1
0
0
0
0
0
0
0
4
4
0
3
3
Second Primary Malignancies
R, lenalidomide; D, dexamethasone; C, cyclophosphamide; P, prednisone; Rd, lenalidomide-dexamethasone; CRD, cyclophosphamide-lenalidomide-
dexamethasone; MEL200-ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; RP lenalidomide-prednisone; AEs adverse
events; SPM, second primary malignancies
Rd
four 28-day courses
R: 25 mg/d, days 1-21
d: 40 mg/d, days
1,8,15,22
CRD
six 28-day courses
C: 300 mg/sqm, days 1,8,15
R: 25 mg/d, days 1-21
D: 40 mg days 1,8,15,22
MEL200-ASCT
two courses
M: 200 mg/m2 day -2
RP MAINTENANCE
R MAINTENANCE
R
A
N
D
O
M
I
Z
A
T
I
O
N
1°
R
A
N
D
O
M
I
Z
A
T
I
O
N
2°
6 of 7 patients who developd skin cancer during maintenance received previous MEL200-ASCT
4 of 7 patients who developed a solid tumor during maintenance received previous CRD

CRD MEL200 P value
 Median PFS 28.6 months 43.3 months <0.001
 4-year OS 86% 73% 0.004
RP maint. R maint. P value
 Median PFS 37.5 months 28.5 months 0.34
 3-year OS 83% 88% 0.21
Conclusions
CRD, cyclophosphamide-lenalidomide-dexamethasone; MEL200, melphalan 200 mg/m2; R,
lenalidomide, P prednisone; PFS, progression-free survival; OS, overall survival
 CRD vs MEL200
 RP vs R maintenance

Abstract 391: IFM/DFCI2009 Study (US and France) Newly Diagnosed MM
(N=1,360 combined)
RVDx3
RVD x 2
RVD x 5
Lenalidomide*
Melphalan
200mg/m2* +
ASCT
Induction
Consolidation
Maintenance
CY (3g/m2)
MOBILIZATION
Goal: 5 x106 cells/kg
RVDx3
CY (3g/m2)
MOBILIZATION
Randomize
Collection
Lenalidomide*
SCT at relapse
Calibration
MRD
MRD
MRD
MRD@CR
MRD@CR
Richardson et al, ASH 2014 *IFM vs. US: 1yr vs. Continuous

Best Response
RVD arm
N=350
Transplant arm
N=350
p-value
CR 49% 59%
VGPR 29% 29% 0.02
PR 20% 11%
<PR 2% 1%
At least VGPR 78% 88% 0.001
Neg MRD by FCM ,
n (%)
228 (65%) 280 (80%) 0.001

ASH 2015 (Attal et al): IFM 2009: PFS (9/2015)
P< 0 .0 01
0
10
20
30
40
50
60
70
80
90
10 0
Patients(%)
35 0 296 2 28 12 8 24no H D T
35 0 309 2 61 15 3 27H D T
N at risk
0 12 24 36 48
M o n th s of follo w -u p
H D T
no H D T
3 yr PFS: 61% HDT
vs 48 % no HDT

P N S
0
10
20
30
40
50
60
70
80
90
10 0
Patients(%)
35 0 33 8 3 20 24 4 56no H D T
35 0 32 8 3 09 22 6 55H D T
N at risk
0 12 24 36 48
M o n th s of f ollo w -u p
H D T
no H D T
IFM 2009: OS (9/2015)
3 yr OS: 88% both arms

IFM 2009: PFS.
0.20
0.97
0.53
0.69
Overall 158 / 350 204 / 350
<60 years 84 / 185 123 / 196
>=60 years 74 / 165 81 / 154
Stage I 44 / 118 58 / 115
Stage II 81 / 171 103 / 170
Stage III 33 / 61 43 / 65
Standard 87 / 213 118 / 212
High Risk 28 / 46 31 / 44
At least VGPR 93 / 180 122 / 190
PR SD PD 60 / 164 77 / 154
Transplant better RVD better
1.4 .6 .8 1 1.2 1.4
Response after induction
Cytogenetics
ISS
Age
Nb of events / Nb of patients
Transplant RVD Arm Hazard Ratio for
Progression or death
p-value for
interaction

ASH 2015: IFM 2009: Causes of Death (9/2015)
RVD arm
N=48
Transplant
N=54
Myeloma, n (%) 40/48 (83%) 35/54 (65%)
Toxicity, n (%) 4/48 (8%) 9/54 (16%)
SPM (AML/MDS) 1/48 (2%) 6/54 (11%)
Others 3/48 (6%) 4/54 (7%)

IFM 2009: Conclusions
 This second interim analysis demonstrates that transplantation :
• Is feasible: 93%
• Is associated with an acceptable Transplant Related Mortality: 1.4%.
• Is associated with an increased rate of neg MRD (80% vs 65%, p<0.01).
• Is associated with an improved 4-year PFS (47% vs 35%, p<0.001).
• Is associated with an improved 4-year TTP (49% vs 35%, p<0.001).
 A longer follow up is required to draw any conclusion concerning OS,
• Since the 4-year survival is high in both arms (80% vs 83%).
• However, transplantation is already associated with a reduced risk of
death due to myeloma, but has a higher rate of toxicity (acute and long
term)
 in the era of new drugs, Transplantation is
“A Standard of Care” but key questions remain.

Results of the US Trial remain Crucial.
 To confirm or not the PFS benefit of transplant using
maintenance until progression.
 To define the best Lenalidomide duration (inter trial):
• 1 year, what can be regarded as a consolidation
strategy.
• Until progression, a real maintenance strategy.
 To answer the key question of OS (meta-analysis),
since none of the 2 trials has been powered for OS
(but for PFS).
 To better evaluate the benefit of transplant in
cytogenetic subgroups… (meta-analysis).
 The remaining US effort is crucial for the 2 trials !

What did we learn?
• In the era of novel agents, Autologous SCT remains
important in the management of newly diagnosed MM-
improved PFS and maybe OS
• HOWEVER
• Could this be affected by a longer maintenance
?(indefinite)- the importance of the US study.
• No benefit to adding steroid to lenalidomide maintenance-
higher toxicity and trend towards decrease OS

IMAJEM (NCT01309334), 134 patients
RVDx3
RVD x 2
RVD x 5
Revlimid 1 year
Melphalan
200mg/m2* +
ASCT
CY (3g/m2)
MOBILIZATION
RVDx3
CY (3g/m2)
MOBILIZATION
Randomize
Revlimid 1 year
ARM A ARM B
ASCT at relapse
PET-CT / MRI at diagnosis
PET-CT / MRI after 3 cycles
PET-CT / MRI before maintenance
Abstract 395: Prospective Evaluation of MRI and PET-CT at Diagnosis and before
Maintenance Therapy in Symptomatic Patients with Multiple Myeloma Included in
the IFM/DFCI 2009 Trial
Primary Endpoint: Compare MRI (spine and pelvis) vs PET-CT
regarding the number of bone lesions at diagnosis. Secondary
Endpoint: Prognostic Impact: PFS, OS

• At diagnosis
MRI was positive in 127/134 (94.7%),
and PET-CT in 122/134 (91%) patients,
(McNemar test = 0.94, p-value = 0.33).
• MRI of the spine and pelvis and whole-body PET-CT are
equally effective to detect bone involvement in
symptomatic patients at diagnosis.
• Blindly reviewed by independent Committee: 2 radiologist,
2 nuclear medicine Physicians

Following 3 cycles of RVD. Impact on PFS
p = 0.04
78.7%
54.8%
PET-CT normalisation following 3 cycles of
RVD. Impact on PFS (32% normalised)
61.6%
p = 0.29
MRI normalisation following 3 cycles of RVD
Impact on PFS (3% normalised)

Following 3 cycles of RVD Impact on OS
p = 0.12
92.8%
81.8%
PET-CT normalisation following 3 cycles of
RVD Impact on OS (32% normalised)
MRI normalisation following 3 cycles of RVD
Impact on OS (3% normalised)
86.1%
p = 0.61

Before maintenance: Impact on PFS
p < 0.001
69%
51.6%
PET-CT normalisation before maintenance
MRI normalisation before maintenance
83.9%
60.7%
p = 0.30

Before Maintenance: Impact on OS
p = 0.003
94.6%
69.9%
PET-CT normalisation before maintenance
85.1%
p = 0.30
MRI normalisation before maintenance

Adjusted on other prognostic factors p = 0.009
Univariate log-rank, p = 0.027
PET-CT pre-maintenance is a prognostic factor
for PFS in Arm A: RVD x 8 cycles

Univariate log-rank, p = 0.01
for PFS in Arm B: frontline ASCT

Univariate log-rank, p < 0.001
for OS in Arm B: frontline ASCT

86 / 134 patients had also MRD evaluation
pre-maintenance by CMF*
PET-CT
pos
PET-CT
neg
MRD
pos
11 20
MRD
neg
14 41
Fisher exact test: p = 0.33
McNemmar test: p = 0.39
* Avet-Loiseau et al. ASH 2015

p = 0.02
PFS for patients with
negative PET-CT and negative MRD by flow
(47.7% of patients)
pre-maintenance vs others
89.6%
54.5%

CONCLUSION
- 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

Older Adult Myeloma
• Upfront AHSCT is safe Elderly MM (#1989)
• Median 68 yo (64-74)
• Standard induction AHSCT  82% consolidation
• 2-year PFS 76% and OS 88%
• MRD negativity = survival advantage even in Older
adults (#4181)
• Real World Management of Older adults
• RVD-lite (#4217): ORR 90%, 1y PFS 95%, OS: NR
• VMP-lite (#3043): Melphalan use at 6mg/m2
• GEM2010: Sequential VMP/Rd for high risk MM (#4243)
60

Abstract 29 ClinicalEfficacy of Daratumumab Monotherapyin Patients withHeavily
Pretreated Relapsed or Refractory MultipleMyeloma. Usmani et al
• ≥18 years of age, ECOG status ≤21,2
• GEN5011
• Open-label, multicenter, phase 1/2, dose-
escalation and dose-expansion study
• Relapsed from or refractory to
≥2 prior lines of therapy including
PIs and IMiDs
• SIRIUS2
• Open-label, multicenter, phase 2 study
• Patients had received ≥3 prior lines of
therapy, including a PI and an IMiD, or
were double refractory to a PI and an
IMID
• DARA was approved by the FDA on
November 16, 2015, based on these
studies
16 mg/kg
(n = 16)
8 mg/kg
(n = 18)
16 mg/kg
(n = 106)
Response evaluated
Randomization
Additional
90 patients
enrolled at
DARA 16 mg/kg
SIRIUS
Safety and response
evaluated
Dose-escalation
Doses from
0.005-24 mg/kg
(n = 32)
Dose-expansion
GEN501
16 mg/kg
(n = 42)
8 mg/kg
(n = 30)
1. Lokhorst HM, et al. N Engl J Med. 2015;373(13):1207-1219.
2. Lonial S, et al. Lancet. 2015. In press.
16 mg/kg
N = 148
62

Baseline Characteristics
16 mg/kg
GEN501, Part 2
n = 42
SIRIUS
n = 106
Combined
N = 148
Median (range) age, y
≥65 years of age, n (%)
64.0 (44-76)
20 (48)
63.5 (31-84)
48 (45)
64 (31-84)
68 (46)
Female/male sex, % 36/64 51/49 53/47
ECOG score, n (%)
0
1
2
12 (29)
28 (67)
2 (5)
29 (27)
69 (65)
8 (8)
41 (28)
97 (66)
10 (7)
Median (range) time since diagnosis, y 5.8 (0.8-23.7) 4.8 (1.1-23.8) 5.1 (0.8-23.8)
Median (range) number of prior lines
>3 prior lines, n (%)
4 (2-12)
26 (62)
5 (2-14)
87 (82)
5 (2-14)
113 (76)
Prior ASCT, n (%) 31 (74) 85 (80) 116 (78)
Prior PI, n (%)
Bortezomib
Carfilzomib
42 (100)
42 (100)
8 (19)
106 (100)
105 (99)
53 (50)
148 (100)
147 (99)
61 (41)
Prior IMiD, n (%)
Lenalidomide
Pomalidomide
Thalidomide
40 (95)
40 (95)
15 (36)
19 (45)
106 (100)
105 (99)
67 (63)
47 (44)
146 (99)
145 (98)
82 (55)
66 (45)
63

Baseline Refractory Status
16 mg/kg
Refractory to,
n (%)
GEN501, Part 2
n = 42
SIRIUS
n = 106
Combined
N = 148
Last line of therapy 32 (76) 103 (97) 135 (91)
Both PI and IMiD
PI only
IMiD only
27 (64)
3 (7)
4 (10)
101 (95)
3 (3)
1 (1)
128 (86)
6 (4)
5 (3)
PI + IMiD + alkylating agent 21 (50) 79 (75) 100 (68)
Bortezomib 30 (71) 95 (90) 125 (84)
Carfilzomib 7 (17) 51 (48) 58 (39)
Lenalidomide 31 (74) 93 (88) 124 (84)
Pomalidomide 15 (36) 67 (63) 82 (55)
Thalidomide 12 (29) 29 (27) 41 (28)
Alkylating agent only 25 (60) 82 (77) 107 (72)
64

Summary of Clinical Safety
• AEs were consistent with the individual GEN501 and SIRIUS
studies; no new safety signals were identified
• 48% of patients had infusion-related reactions
• 46%, 4%, and 3% occurred during the first, second, and subsequent
infusions, respectively
Treatment-emergent adverse event, n (%)
Any grade
N = 148
Grade ≥3
N = 148
Fatigue 61 (41) 3 (2)
Nausea 42 (28) 0
Anemia 41 (28) 26 (18)
Back pain 36 (24) 3 (2)
Cough 33 (22) 0
Neutropenia 30 (20) 15 (10)
Thrombocytopenia 30 (20) 21 (14)
Upper respiratory tract infection 30 (20) 1 (<1)
65

Efficacy in Combined Analysis
18%
10%
1%
2%
0
5
10
15
20
25
30
35
16 mg/kg
ORR,%
PR VGPR CR sCR
ORR = 31%
16 mg/kg (N = 148)
n (%) 95% CI
(sCR+CR+VGPR+PR)
46 (31) 23.7-39.2
Best response
sCR
CR
VGPR
PR
MR
SD
PD
NE
3 (2)
2 (1)
14 (10)
27 (18)
9 (6)
68 (46)
18 (12)
7 (5)
0.4-5.8
0.2-4.8
5.3-15.4
12.4-25.4
2.8-11.2
37.7-54.3
7.4-18.5
1.9-9.5
VGPR or better (sCR+CR+VGPR) 19 (13) 7.9-19.3
CR or better (sCR+CR) 5 (3) 1.1-7.7
• ORR = 31%
• ORR was consistent in subgroups including age, number of prior lines of therapy,
refractory status, or renal function
66
3%
CR or
better
13%
VGPR or
better
N = 148

Progression-free Survival
Responders: NE (7.4, NE)
MR/SD: 3.2 (2.8-3.7) months
PD/NE: 0.9 (0.9-1.0) months
67
0
Patientsprogression-freeandalive,%
2 6 8 12 14 18 20
Time from first dose, months
Patients at risk
Responders
MR/SD
PD/NE
0
25
50
75
100
4 10 16
Responders
MR/SD
PD/NE
46
77
25
46
45
0
35
13
0
27
3
0
13
1
0
5
0
0
3
0
0
0
0
0
41
21
0
14
2
0
3
0
0

Overall Survival
• For the combined analysis, median OS = 19.9 (95% CI, 15.1-NE) months
• 1-year overall survival rate = 69% (95% CI, 60.4-75.6)
68
0
Patientsalive,%
2 6 8 12 14 18 22
Patients at risk
Responders
MR/SD
PD/NE
Responders
0
25
50
75
100
4 10 16
MR/SD
PD/NE
46
77
25
46
74
16
45
63
11
44
57
7
42
47
5
29
37
4
3
1
0
0
0
0
46
67
12
43
53
7
15
10
1
20
13
5
1
Responders: NE (19.9, NE)
MR/SD: 17.5 (15.1-NE) months
PD/NE: 3.7 (1.7-7.6) months

Conclusions
• As a single agent, DARA induced rapid, deep, and
durable responses in a heavily pretreated/highly refractory
population
• Remarkable depth of response observed in patients
refractory to newer agents, including pomalidomide and
carfilzomib
• DARA conferred an OS benefit even in patients who
achieved stable disease or minimal response
• Updated analysis of the combined dataset of GEN501 and
SIRIUS did not identify any new safety signals
• DARA has immune-mediated and immunomodulatory
mechanisms that may be contributing to a survival benefit
69

Daratumumabin Combination With Lenalidomide and Dexamethasonein PatientsWith
Relapsedor Relapsedand RefractoryMultiple Myeloma: UpdatedResultsof a Phase1/2Study
(GEN503). Plesneret al
DARA* IV 2-16 mg/kg +
LEN PO 25 mg (Days 1-21) +
DEX PO 40 mg QW
DARA* IV 16 mg/kg +
LEN PO 25 mg (Days 1-21) +
DEX PO 40 mg QW
Key eligibility
• Measurable disease by M-protein
• Patients refractory or intolerant to
LEN were excluded
Part 1
• Relapsed MM following 2 to
4 prior lines of therapy
Part 2
• Relapsed MM following ≥1 prior
line of therapy (no upper limit)
Endpoints
Primary endpoint
• Incidence of adverse events
Key secondary endpoints
• Rate of response
• Pharmacokinetics
• Time to progression
• Duration of response
• Progression-free survival
Part 1 - Dose escalation (N = 13)
Open-label, IV infusions (28-day cycle)
Dose escalation: 3 + 3 scheme
Part 2 - Expansion cohort (N = 32)
Open-label, single-arm IV infusion
at 16 mg/kg (28-day cycle)
*QW for Months 1-2, Q2W for Months 3-6, and Q4W beyond.
70

Baseline Characteristics
N = 32
Median (range) age, y
≥65 years of age, n (%)
60 (41-76)
9 (28)
Female/male sex, % 31/69
ECOG score, n (%)
0
1
2
19 (59)
12 (38)
1 (3)
Median (range) time since diagnosis, y 3.2 (0.9-12.7)
Median (range) number of lines of prior therapy
≥2 prior lines of therapy, n (%)
2 (1-3)
17 (53)
Refractory to last line of therapy 7 (22)
Prior autologous stem cell transplant, n (%) 25 (78)
Prior PI, n (%)
Bortezomib
29 (91)
28 (88)
Prior IMiD, n (%)
Lenalidomide
Thalidomide
23 (72)
11 (34)
14 (44)
Prior chemotherapy, n (%)
Alkylating agents
Anthracyclines
32 (100)
29 (91)
15 (47)
71

Overall Response Rate: DARA + LEN/DEX
N = 32
n (%) 95% CI
(sCR+CR+VGPR+PR)
26 (81) 63.6-92.8
Best response
sCR
CR
VGPR
PR
8 (25)
3 (9)
9 (28)
6 (19)
11.5-43.4
2.0-25.0
13.7-46.7
7.2-36.4
VGPR or better
(sCR+CR+VGPR)
20 (63) 43.7-78.9
19%
28%
9%
25%
0
10
20
30
40
50
60
70
80
90
100
16 mg/kg
ORR,%
sCR CR VGPR PR
ORR = 81%
34%
CR or
better
63%
VGPR or
better
• ORR = 81%
• Clinical benefit rate (ORR + minimal response) = 88%
N = 32
72

Progression-free Survival: DARA + LEN/DEX
0
3 6 9 12 15 18 21
32 28 26 24 21 13 2 0Patients at risk
0
20
40
60
80
100
18-month PFS rate = 72% (95% CI, 51.7-85.0)
73

Overall Survival:DARA+ LEN/DEX
0
Patientsalive,%
3 6 9 12 15 18 21
32 32 31 29 28 18 6 0Patients at risk
0
20
40
60
80
100
18-month OS rate = 90% (95% CI, 73.1-96.8)
74

Conclusions
• DARA + LEN/DEX induced rapid, deep, and durable
responses
• At a median follow-up time of 15.6 months, ORR was 81%
including 28% VGPR and 34% CR/sCR
• Median time to first response was 1 month
• PFS rate of 72% at 18 months
• OS rate of 90% at 18 months
• DARA can be safely combined with LEN/DEX with no
additional safety signals
• Randomized phase 3 studies of DARA are ongoing:
• DARA + LEN/DEX in relapsed/refractory patients (POLLUX)*
• DARA + LEN/DEX in newly diagnosed patients (MAIA)†
*ClinicalTrials.gov Identifier: NCT02076009
†ClinicalTrials.gov Identifier: NCT02252172
75

Open-label,Multicenter,Phase 1b Study of Daratumumab in CombinationWith
Pomalidomideand Dexamethasone in Patients With ≥2 Lines of Prior Therapyand
Refractory or Relapsed and Refractory MultipleMyeloma (MM). Ajai et al
Treat 6 patients with DARA + POM-D
If ≤1 patient has DLTs
Enroll 6 additional patients
Expand up to 88 patients
Eligibility criteria
• Refractory to last line of therapy
• ≥2 prior lines of therapy, including
2 consecutive cycles of
lenalidomide and bortezomib
• Pomalidomide naïve
• ECOG score ≤2
• Absolute neutrophil count
≥1.0×109/L, and platelet count
≥75×109/L for patients with <50%
plasma cells (>50×109/L,
otherwise)
• Calculated creatinine clearance
≥45 mL/min/1.73 m2
76
DARA* IV 16 mg/kg +
Pomalidomide 4 mg (Days 1-21) +
Dexamethasone 40 mg QW
Open-label, multicenter, six-arm, Phase 1b
study
(28-day cycles)
*QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W beyond.

Prior Therapy Status
• Patients were heavily pretreated and highly refractory per inclusion
criteria
DARA + POM-D
N = 98
Median (range) time since MM diagnosis, y 5.2 (0.4-16.0)
N = 97
Median (range) number of prior lines of therapy 4.0 (2-13)
Prior
Autologous stem cell transplant
PI
Carfilzomib
Bortezomib
IMiD
73 (75)
97 (100)
31 (32)
96 (98)
97 (100)
N = 98
Refractory to
PI
Bortezomib
Carfilzomib
Lenalidomide
PI and IMiD
74 (76)
65 (66)
29 (30)
87 (89)
66 (67)

Overall Response Rate:DARA + POM-D
• ORR = 71%
• ORR in double-refractory patients = 67%
• Clinical benefit rate (ORR + minimal response) = 73%
DARA + POM-D
(N = 75)
n (%) 95% CI
(sCR+CR+VGPR+PR)
53 (71) 59.0-80.6
Best response
sCR
CR
VGPR
PR
MR
SD
PD
4 (5)
3 (4)
25 (33)
21 (28)
2 (3)
17 (23)
3 (4)
1.5-13.1
0.8-11.2
22.9-45.2
18.2-39.6
0.3-9.3
13.8-33.8
0.8-11.2
VGPR or better (sCR+CR+VGPR) 32 (43) 31.3-54.6
ORR = 71%
78
43%
VGPR or
better
9%
CR or
better
28%
33%
4%
5%
0
10
20
30
40
50
60
70
80
16 mg/kg
ORR,%
PR VGPR CR sCR
N = 75

Progression-free Survival at 6 Months: DARA+ POM-D
79
0
2 6
0
20
60
80
100
4
40
Patients at risk 98 67 39 19
6-month PFS rate = 66% (95% CI, 52.3-75.9)
• Median follow-up of 4.2 months

Abstract 28 Eloquent-2 Update:APhase 3, Randomized, Open-Label Study of Elotuzumabin
Combination withLenalidomide/Dexamethasonein PatientswithRelapsed/RefractoryMultiple
Myeloma - 3-YearSafety andEfficacy Follow-upDimopouloset al
• ELOQUENT-2 is an open-label, randomized, multicenter, phase 3 trial
• Statistical analysis
• Threshold for interim OS significance was 0.014 based on 295/427 events required for final analysis
Patients
• RRMM
• 1–3 prior lines of
therapy
• Prior Len
permitted in 10%
of patients (if not
refractory)
Elotuzumab plus Len/Dex (E-Ld):
n=321
• Elo: Cycles 1 and 2 weekly, then
every other week, 10 mg/kg IV
• Len: D1–21, 25 mg PO
• Dex: weekly equivalent, 40 mg
Endpoints
Co-primary
• PFS
• ORR
Others
• OS
• Safety
• Duration of
response
• Quality of life
Database lock:
November 2014
(ASCO/EHA 2015)
Minimum follow-
up: 24 months
Database lock:
August 2015
(ASH 2015)
Minimum follow-up:
33 months
June 2011
start
Premedication administered prior to elotuzumab infusion to
mitigate infusion reactions
Len/Dex (Ld): n=325
• Len: D1–21, 25 mg PO
• Dex: weekly, 40 mg PO

ELOQUENT-2: 2-Year Follow-up
Co-primary endpoint:
ORR
E-Ld Ld
%
95% CI
79
74, 83
66
60, 71
1. Lonial S et al. N Engl J Med 2015;373:621–31.
ELOQUENT-2 demonstrated clinical benefits of E-Ld compared
with lenalidomide and dexamethasone (Ld) alone1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
380 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
No. of patients at risk:
E-Ld
Ld
321
325
303
295
279
249
259
216
232
192
215
173
195
158
178
141
157
123
143
106
128
89
117
72
85
48
59
36
42
21
32
13
12
7
7
2
57%
68%
27%
41%
1-year PFS 2-year PFS
PFS (months)
Probabilityprogressionfree
1
0
0
0
Hazard ratio, 0.7
(95% CI, 0.57-0.85)
P<0.001
Co-primary endpoint:
PFS
From N Engl J Med, Lonial S et al, Elotuzumab therapy for relapsed or refractory multiple myeloma, 373, 621–31.
Copyright © 2015, Massachusetts Medical Society. Reprinted with permission
E-Ld
Ld

Characteristic E-Ld (n=321) Ld (n=325)
International Staging System disease stage,* n (%)
I 141 (44) 138 (42)
II 102 (32) 105 (32)
III 66 (21) 68 (21)
Cytogenetics (FISH),*† n (%)
del(17p)
Yes 102 (32) 104 (32)
No 213 (66) 218 (67)
t(4;14)
Yes 30 (9) 31 (10)
No 285 (89) 290 (89)
Prior regimens, median (range) 2 (1–4) 2 (1–4)
Prior therapies, n (%)
Bortezomib 219 (68) 231 (71)
Melphalan (PO or IV) 220 (69) 197 (61)
Thalidomide 153 (48) 157 (48)
Lenalidomide 16 (5) 21 (6)
Response to most recent line of therapy,‡ n (%)
Refractory 113 (35) 114 (35)
Relapsed 207 (65) 211 (65)
Prior stem cell transplantation, n (%) 167 (52) 185 (57)
Baseline Demographics and Disease Characteristics
*‘Not reported’ not shown; †No minimum cut-off for del(17p) positivity; ‡Response for 1 E-Ld patient unknown. FISH=fluorescence in situ hybridization.
From N Engl J Med, Lonial S et al, 373, 621–31. Copyright © 2015, Massachusetts Medical Society. Reprinted with permission

Treatment Summary
E-Ld (n=318) Ld (n=317)
Number of treatment cycles, median (Q1–Q3) 19 (9–37) 14 (6–25)
Patients on treatment, n (%) 83 (26) 43 (14)
Reasons off treatment
Disease progression 153 (48) 161 (51)
Study drug toxicity 30 (9) 44 (14)
Adverse event unrelated to study drug 22 (7) 32 (10)
Other* 31 (10) 36 (11)
Patients receiving full dose (relative dose intensity ≥90%), %
Elotuzumab 83 –
Lenalidomide 51 51
Dexamethasone 46 47
*‘Other’ includes: patient request, patient withdrew consent, other, death, patient no longer met criteria, poor/non-compliance

Extended Progression-Free Survival
E-Ld Ld
HR 0.73 (95% CI 0.60, 0.89); p=0.0014
Median
PFS
(95% CI)
19.4 mo
(16.6,
22.2)
14.9 mo
(12.1, 17.2)
E-Ld-treated patients had a 27% reduction in the risk of disease progression
or death and a 44% relative improvement in PFS vs Ld-treated patients at 36
months
0.0
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
480 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
E-Ld
Ld
321
325
293
266
259
215
227
181
171
130
144
106
125
80
107
67
94
60
85
51
59
36
34
15
19
7
8
3
PFS (months)
Probabilityprogressionfree
3
0
195
157
E-Ld
Ld0.1
1-year PFS 2-year PFS
Extended
follow-up
0
0
68%
41%
26%
57%
27%
18%

Progression-Free Survival
Parameter
E-Ld Ld
Relative
difference
Median PFS (months) 19.4 14.9
1-year PFS (%) 68 57 19
2-year PFS (%) 41 27 52
3-year PFS (%) 26 18 44
2-year follow-up
Hazard ratio (95% CI) 0.70 (0.57–0.85)
p=0.0004
3-year follow-up
Hazard ratio (95% CI)
0.73 (0.6–0.89)

Overall Survival
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
510 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
E-Ld
Ld
321
325
314
305
303
287
291
269
283
255
266
241
250
228
239
218
224
208
217
200
196
184
190
171
152
134
95
88
48
41
15
17
1-year OS 2-year OS
OS (months)
Probabilityalive
5
3
0
0
E-Ld
Ld
3-year OS
E-Ld Ld
HR 0.77 (95% CI 0.61, 0.97;
98.6% CI 0.58; 1.03); p=0.0257
Median OS
(95% CI)
43.7 mo
(40.3, NE)
39.6 mo
(33.3, NE)
Interim survival analysis demonstrated sustained benefit of E-Ld vs Ld that
was maintained over time

Adverse Events Of Special Interest
• Most infusion reactions were Grade 1 or 2 and occurred during the first treatment cycle
• There were no Grade 4 or 5 infusion reactions
Adverse event, n
(%)
E-Ld (n=318) Ld (n=317)
Any
Grade
Grade
3–4
Grade
5
Any
Grade
Grade
3–4
Grade
5
Infusion reactions 33 (10) 4 (1) 0 - - -
Cardiac failure 3 (1) 1 (0.3) 0 5 (2) 2 (1) 0
GI disorders 256 (81) 33 (10) 0 214 (68) 30 (10) 1 (0.3)
Peripheral neuropathy 48 (15) 5 (2) 0 27 (9) 5 (2) 0
Respiratory disorders 201 (63) 34 (11) 2 (1) 169 (53) 25 (8) 1 (0.3)
Renal/urinary disorders 78 (25) 13 (4) 1 (0.3) 58 (18) 14 (4) 1 (0.3)
Deep vein thrombosis 26 (8) 20 (6) 0 13 (4) 8 (3) 0
Hypertension 33 (10) 4 (1) 0 22 (7) 7 (2) 0

Summary
• The addition of elotuzumab, an immunostimulatory monoclonal antibody, to
Ld demonstrated an overall clinically relevant benefit in PFS vs Ld alone that
was maintained over time
• Relative improvement in PFS at 3 years was 44% in the E-Ld vs Ld-treated
patients
• Time to next treatment was delayed in the E-Ld arm vs the Ld arm
• Interim 3 year overall survival analysis demonstrated a strong trend in the
long-term benefit of E-Ld vs Ld
• PFS benefit was associated with a reduction in deaths in the E-Ld arm vs
the Ld arm
• The updated safety and tolerability data are consistent with previous findings,
confirming that there are minimal incremental toxicities associated with the
addition of elotuzumab

Study Drugs # patients Median #
priors
ORR (%) Comments/ Toxicities
San Miguel
#505
Pembrolizumab
len/dex
50(26
evaluable)
4 (1-5) 65 (+23% SD) Hematologic (23-47%)
Badros #506 Pembrolizumab
Pomalidomide/dex
33 3(2-5) 60 (+30% SD) 4 pt dose reduction
*Efebera #
1838
MDV9300(Pidilizumab
, CT011/len
13 2(2-11) 61.5% Steroid free. No infusion reaction
*Sbarov #1835 Reolysin/carlfizomib/d
ex
12 (1 pt dialysis) 2(1-4) 75% clinical benefit
(includes SD)
Flu-like sx, 1 pt myocarditis
Shah #378 Oprozomib(oral)/pom/
dex
31 4(1-22) 71% clinical benefit
(includes SD)
Gr3 mucositis/rash
Vorhees et al Ixazomib/pom/dex 22 3(2-10) 55 (+30% SD) Dose reduction 50%. Hem tox
Ramasamy
#374
Pomalidomide/dex in
renal insuff +dialysis
39 4 This study focused on
tolerability
Max dose 4 mg pom can be safely
used in HD pts. GCSF in 53%
Shah #376 Filanesib(FIL) iv
(Arry520)/Carlfizomib
(CFZ)
45 eval. Carlf
naïve
5(1-15) 44 (+44% SD). No
response in 11 CFZ
refractory
Pts received scheduled GCSFx5
after each dosing.
Zonder #728 Filanesib/Carlfizomib
vs CFZ.
30 CFZ+FIL 20
CFZ. All CFZ
naive
4(2-11) 37% vs 20% (clinical
benefit)
Chari #4226 Panobinostat/len/dex 26 2 73% clinical
benefit(includes SD)
No doses held or reduced for GI Tox.
Martin #509 Isatuximab (anti
CD38)
96 5(2-140
Raab #3035 Mor201(anti-CD38) 44 4(2-11)
Relapse/Refractory Studies

Other Drugs in relapse/refractory MM
• Ibrutinib/len/dex: all Oral. will be in Phase II with Alliance this Yr
• AR42 (HDAC inhibitor)/Pom/dex: all Oral. Will be opening soon
• Cpi-0610: BET inhibitor
• Melflufen: peptidase Targeted Therapy
• TG02: oral CDK9 inhibitor
• Selinexor( (KPT-330): XP01 inhibitor
• Ricolinostat (ACY-1215): HDAC6 inhibitor
• CD-839: First in Class Glutaminate inhibitor
• Marizomib: proteosome inhibitor (IV)
• Linsitinib(OSI 906): IGF-1 receptor inhibitor
• Sotatercept(ACE-011): activin type IIa receptor fusion protein: improves Hgb
and bone mineral density

Toxicities
• Cytokine release storm:
• Fever, tachycardia, hypotension, elevated LFTs, elevated CK,
elevated IL-6
• Cytopenia

Smoldering Myeloma(SMM)
• #4246: PVX-410 multi-peptide vaccine alone (12 pts) or +len (10 pts)
• SMM at risk for progression, HLA-2+
• Vaccine q 2 wks x 6 doses (0.1mg/peptide or 0.2 mg)+ 3 cycles len 25 mg d1-21 q 28 days
• Followed x 12 mos
• Vaccine alone (12 pts): 5 progressed, 7 SD
• Vaccine +len (9 evaluable): 5 MR/PR, 3SD, 1 progressed
• Randomized Phase 2 Trial to Evaluate Three Daratumumab Dose Schedules
in Smoldering Multiple Myeloma- ongoing
• Alliance Proposals: lenalidomide alone, len/dex vs placebo

AL amyloid
• #732 Wechalekar: case control study of oral Doxycycline(possible cardio
protective effect) concurrent with chemo vs control +chemo
• Doxy 100 mg bid (30 pts) vs 73 matched control (matched to cardiac stage,
NT proBNP, age, dFLC).
• #188 Langer et al: Chimeric Fibril-Reactive Monoclonal Ab 11-1F4
• Relapsed pts, EF >40%, Ivsd <2.5 cm, CrCl >30 cc/min, bil <3.0mg/dl
• Given once ( dose 0.5 – 500 mg/m2): MTD was 500
• 8 pts median stage 2, median organs involved 2
• 4 organ response: 3 decreased NT-proBNP, 1 decreased diarrhea
Median fu 13
mos
Doxy
duration
median 6
(1-24 mos)
Control P-value
Heme CR 56% 35%
VGPR 10 8
PR 30 37
At 2.3 mos 16% died 72% died
12 and 24 mos
OS
82 and 82% 53 and
40%
<0.0001

What is the preferred regimen for newly Dx MM eligible
for autologous SCT
A. A: Bortezomib, lenalidomide,
dex (VRD)
B. B: Bortezomib,
cyclophosphamide, dex (VCD,
CyBord)
C. C: Bortezomib, melphalan, dex
(VMD)
D. D: Melphalan, dex,
Lenalidomide (MDR) A:Bortezom
ib,lenalidom
...
B:Bortezom
ib,cyclopho...
C:Bortezom
ib,m
elphalan...
D:M
elphalan,dex,Lenal...
0% 0%0%0%

What is the appropriate length of Maintenance?
A. A: 6 months
B. B: 1 year
C. C: minimum 3 years
D. D: Until progression/relapse
A:6
m
onths
B:1
yearC:m
inim
um
3
years
0% 0%0%0%

How Long is Lenalidomide Maintenance?
• Minimum – 3 years.
• Disease Relapse/progression – many ongoing studies
103
CALGB
100101
McCarthy
NEJM 2012
IFM Attal
NEJM 2012
MM0-15
Palumbo
NEJM MPR-
R vs MPR
(non SCT)
IFM
VRD chemo
vs auto SCT
DFCI
VRD chemo vs
auto SCT
BMT/CTN
0702
BMT/CTN
0702- LTFU
Length
maintenance
Until
relapse/prog
Median 2 yrs
(1-3)
Until
relapse/prog
1 year Until
relapse/prog
3 years Until
relapse/prog
Median F/U 48 mos 45 mos 30 mos 39 mos
PFS-median 53 mos vs 27
placebo
41 mos vs 23 31 mos vs
14
3-yr PFS 61%
auto arm
OS NR NR 45.2 mos
3 yr OS 88% 88% 70% 88%
SPM 7.8 % vs
2.6% placebo
8 vs 4 % 7 vs 3% 11%
Induction
regimen
any any MPR VRD VRD any any

BMT CTN 0702: SCHEMA
Lenalidomide *
Maintenance
Lenalidomide Maintenance**
Lenalidomide Maintenance**
N=750 pts (250 in each arm)
Register and
Randomize
MEL
200mg/m2
VRD x 4*
MEL
200mg/m2
Bortezomib 1.3mg/m2 days 1, 4,
8,11
Lenalidomide 15mg days 1-15
Dexamethasone 40mg
days 1, 8, 15
**Lenalidomide x 3years : 10mg /d
for 3 cycles , then 15 mg /d

MM patients on Hemodialysis are excluded from
autologous SCT
A. A: True
B. B: False
A:True
B:False
0%0%

Upfront Trials:
OSU-14069 Phase III Comparing Conventional Dose RVD to High-Dose w PSCT in Initial Management of
Myeloma
OSU-14298 Ph 3 Comparing DRd vs Rd in Sbjcts w/ Previously Untreated MM Ineligible for High Dose Therapy
OSU-15003 Randomized Phase 2 Trial to Evaluate Three Daratumumab Dose Schedules in Smoldering Multiple
Myeloma
Relapsed/Refractory Trials:
ALLIANCE-A061202 Ph I/II Pom, Dex & Ixazomib vs Pom + Dex for MM Refractory to Lenalidomide and PI-based
Therapy
OSU-13128 Ph I/II Lenalidomide in Combination w/ Anti-PD-1 mab CT-011 in Pts w/ Relapsed/Refractory MM
OSU-14049 Ph I Elotuzumab in Combination w/ either Lirilumab or Urelumab in Subjects with Multiple Myeloma
OSU-15004 (opening Feb) A phase 1b trial of AR-42 with Pomalidomide in Relapsed Multiple Myeloma
OSU-15196 (opening Feb) Ph1b Durvalumab Either As Monotherapy Or In Combination w Pom with or without Low Dose Dex
In Subjects with Relapsed / Refractory MM
BMT Trials:
OSU-15124 (opening Feb) Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies
Trials for all MM:
BMT-CTN1302 Ph II Placebo Controlled Maintenance Ixazomib after Allogeneic HSCT for High Risk Multiple Myeloma
OSU-15045
BMT/CTN 1401 (pending)
Ph II of IRD for Consolidation Therapy followed by Ixazomib or Lenalidomide for Multiple Myeloma
Phase II Multicenter Trial of Single Autologous Hematopoietic Cell Transplant Followed by
Lenalidomide Maintenance for Multiple Myeloma with or without Vaccination with Dendritic Cell
/Myeloma Fusions
Enrolling Studies at OSU

We Thank YOU for your Referrals
Don Benson MD ,PhD
Associate Professor of Medicine
Myeloma Program, 614-293-8605
Don.Benson@osumc.edu
Craig Hofmeister MD, MPH
Associate Professor of Medicine
Myeloma Program
614-293-3507
Craig.Hofmeister@osumc.edu
Yvonne Efebera MD, MPH
Associate Professor of Medicine.
Myeloma Program 614-293-2268
yvonne.efebera@osumc.edu
Ashley Rosko MD
Assistant professor of medicine
Myeloma Program
614-293-2268
Ashley.rosko@osumc.edu

Ohio State's 2016 ASH Review - BEST OF ASH 2015 MULTIPLE MYELOMA AND PLASMA CELL DYSCRASIAS

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