MYELOMA 2012
BEST OF ASH 2011
WHAT PATIENTS NEED TO KNOW
January 25, 2012
Brian G M Durie, MD
ASH Overview 2011
· Myeloma Abstracts
712 Total
· Selected for Discussion
88 Abstracts
· Program Includes:
· Corporate "SUPERFRIDAY" Session
· Education Session
· Posters/Oral Presentations
· Major Oral Sessions on Monday
"TOP" Abstracts: 2011 ASH
· Approved Novel Agents
Thalidomide
8
VELCADE
12
34
REVLIMID
14
· Novel Agents @ Phase II/III
Pomalidomide
7
Carfilzomib
6
Bendamustine (TREANDA®)
4
Elotuzimab
2
MLN 9708
2
Vorinostat
2
Panobinostat
2
"TOP" Abstracts- 2011 ASH
Non-Therapy Topics
General Categories
Biology and Toxicities
· Smoldering
1
· Molecular Testing
9
· Young Patients
1
Cytogenetics
4
· Elderly
1
GEP
2
SNPs
2
·Race
1
Methylation
1
· Hevylite
2
23
16
PCR
2
· Prelixafor
2
· Occurrence of
· Neuropathy
4
· Renal
2
2o Malignancies
10
· Early Death
1
· Imaging (MRI;PET/CT) 4
·DVTS
1
2
Themes for ASH 2011
· Comparisons and longer follow-up of novel
combinations: not a lot new
· New Agent Data: Phase I/II / Phase II-III
· Some "Hot" Topics
·
2o Malignancies
·
Molecular Testing
·
Imaging
·
Prognostic Factors/Subgroups
·
Quality of Life/Toxicities
1. Know what you're dealing with. Get the correct diagnosis.
2. Tests you really need.
3. Initial treatment options.
4. Supportive care and how to get it.
5. Transplant: Do you need one?
6. Response Assessment.
7. Consolidation and/or Maintenance.
8. Monitoring without mystery
9. Relapse: Do you need a change in treatment?
10. New Trials: How to find them.
3
Knowledge of bone disease is crucial
Remstein E, Jevremovic D. 2010
Step 1. Know what you're dealing with. Get the correct
diagnosis.
Step 2. Tests you really need.
4
Indications for PET/CT or MRI
·SMM
· Solitary plasmacytoma
· Any MM with:
Suspected bone involvement but negative
skeletal survey
Bone disease on x-ray that needs
additional definition
Doubt about extent of tumor burden
Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple
myeloma patients treated with up-front autologous transplantation
Zamagni, BLOOD, Dec 2011,v.118, p 5989
5
MRI & FDG-PET in MM
Sagittal
Sagittal FDG Ant MIP
STIR MRI
PET
FDG PET
-- At diagnosis: > 3 focal lesions or SUV > 3,9.......
Shorter OS
-- 3m post-ASCT: Complete FDG suppression of
PET/CT ......Longer PFS & OS
Zamagni Blood 2011
Prognostic significance of the Number of Focal Lesions in MRI
before & after ASCT
Hillengass abs 1812 poster
· Post Transplant MRI N=100 p=0.02
6
Step 3. Initial treatment options.
Step 4. Supportive care and how to get it.
Current Controversial Issues
ANSWER
What is the value of an optimal
UNCLEAR!
response?
What is the best induction treatment?
UNCLEAR!
Is there still a role for HDT/ASCT?
YES...
WHICH PATIENTS?
What is the value of Consolidation
& Maintenance?
UNCLEAR!
Can novel drugs overcome high risk
NOT YET
cytogentics?
7
Do we have something better than VAD or TD?:
Response obtained with Novel Induction Regimens
100
90
80
70
60
esponse
ORR
R
50
CR
ercent
40
P
30
20
10
0
VAD
TD
TAD
LD
BzD
BzTD
BzLD BzCD
BzLCD
1.
Induction Regimen
Kumar ASH 2008 ( Blood 112, 91a)
VRD VCD
VRDC
2. Stewart EHA 2008 (Abs
A
tr 205)
- Kumar ASH 2010 (Abs
A
t 621): VRD, VCD, VRCD
3. Richardson ASCO 2008 (Abs
A
tr 8520)
- Ei
E nsel
i
e
nsel AS
A H
S
2009( Ab
A st
b
131): VCD
V
x 3 cycles
cycl
4. Kumar ASH 2008 (Blood
B
112, 93a).
- Jakubowiak ASH 2009 (Abs
A
t 132): VRDoxD
Bortezomib, Cyclo, Dex ± Thalidomide for Rel/Ref
Myeloma Ahn abs 1868 Poster
3 drugs as good as 4 in RR MM with less toxicity
· Retrospective review 67 VCD, 86 VCDT
· B 1.3 mg, Cy 150 po d 1-4, dex 20,thal 50mg
VCD
VCDT
p
No cycles
6 (2-18)
8 (2-24)
RR/CR
88%/48%
90%/49%
Gr3 PN
3%
14%
.02
zoster
3%
20%
.002
8
Velcade SQ
Just approved by FDA: Jan 2012!
Equal efficacy with reduced neuropathy in relapse
setting
Bortezomib: Once Weekly
VMP
VMP
VMP
(VISTA)
twice-weekly
once-weekly
CR
30%
27%
23%
2-year PFS
48%
56%
58%
Sensory PN
Any grade
44%
44%
22%
Grade 3/4
13%
14%
2%
Discontinuation due to
na
16%
4%
PN
Total planned dose
67.6 mg/m2
67.6 mg/m2
46.8 mg/m2
Total delivered dose
38.6 mg/m2
40.1 mg/m2
39.4 mg/m2
Bringhen S, et al. Blood. 2010;116:4745-53
9
Treatment algorithm
DOSE LEVEL 0
DOSE LEVEL -1
DOSE LEVEL -2
Lenalidomide 25 mg/d
15 mg/d
10 mg/d
d 1-21 / 4 wks
dd 1-21 / 4 wks
d 1-21 / 4 wks
Thalidomide 100 mg/d
50 mg/d
50 mg/every other day
Bortezomib 1.3 mg/m2
1.0 mg/m2
1.3 mg/m2
d 1,8,15,22 / 5 wks
d 1,8,15,22 / 5 wks
d 1,15 / 4 wks
Melphalan 0.2 mg/kg/d
0.15 mg/kg
0.10 mg/kg
d 1-4 / 5 wks
d 1-4 / 5 wks
d 1-4 / 5 wks
Prednisone 2 mg/kg/d
1.5 mg/kg/d
1 mg/kg/d
d 1-4 / 5 wks
d 1-4 / 5 wks
d 1-4 / 5 wks
Palumbo et al N Engl J Med. 2011;364:1046-60
Second Malignancies in Total Therapy Trials for
Newly Diagnosed Multiple Myeloma: Influence of
Lenalidomide Versus Thalidomide in
Maintenance Phases
Saad Z Usmani1, Rachael Sexton2,Antje Hoering2,
Christoph J. Heuck1,Bijay Nair1, Sarah Waheed1, Yazan
AlSayed1, Nathan Petty1, John Crowley2, Bart Barlogie1
10
Background
Study
Treatment
Overall
% SPM
(Median follow-up)
Schedule
SPM
IFM 2005-021
Len
17/299
5.5%
(24 months)
Placebo
3/292
1%
CALGB 1001042
Len
15/231
6.5%
(28 months)
Placebo
6/229
2.6%
MM-0153
MPL-L/MPL
11/335
3.1%
(30 months)
Placebo
2/154
1.3%
HISTORIC DATA
NSEER 1973-2000 (Within 20 years)
-
1219/23838
5.1%
ASCT 1983-20004 ( Within 15 years)
-
29/800
3.6%
Australian Cancer Registry 1982-20005
-
134/2174
6.1%
European Myeloma Network6
-
30/1798
1.6%
(1)Attal M et al ASH 2010, (2) McCarthy et al ASH 2010,(3) Palumbo A et al ASH 2010, (4)Forrest DL et al. BMT 2003, (5) Youlden et al BMC Cancer 2011,
(6) Palumbo A et al ASCO 2011
Total Therapy Trials Schema
TT21
TT3A2,3
TT3B4
DT-PACE
VTD-PACE
INDUCTION
VTD-PACE
X 4 Cycles
x 2 Cycles
x 2 Cycles
TRANSPLANT
MEL200 x 2
MEL200 x 2
MEL200 x 2
DT-PACE
VTD-PACE
VTD-PACE
CONSOLIDATION
X 4 Cycles
x 2 Cycles
x 2 Cycles
VTD x 1 year
MAINTENANCE
T vs. Control
VRD x 3 years
TD x 2 years
MEDIAN FOLLOW-UP
110 months
70 months
40 months
(1) Barlogie et al, NEJM 2003
(2) Barlogie et al, Br J Haematol 2007
(3) van Rhee F et al, Blood 2010
(4) Nair et al, Blood 2010
11
Types of SPM
SPM Type
TT2-Placebo
TT2-Thalidomide
TT3A (n/%)
TT3B(n/%)
All Cancers
24 (6.9%)
28 (8.7%)
18 (5.9%)
3 (1.7%)
Hematologic Malignancies
13 (3.8%)
11 (3.4%)
11 (3.6%)
2 (1.1%)
Solid Tumors
11 (3.1%)
17 (5.3%)
7 (2.3%)
1 (0.6%)
Hematologic Malignancies
Solid Tumors
·ALL
·AML
·MDS
·NHL
·Bladder
·Breast
·Colorectal
10
·Non-Melanoma Skin
·Prostate
·Renal Cell
9
·Thyroid
5
5
4
3
3
3
2
2
2
2
2 22
2
22
2
11
1
111 1
1
1
0
0
0
0 0
0
0
0
0
0 0
0 0 0
00
Cumulative Incidence of SPM-
Solid Cancer
ENROLLMENT
MAINTENANCE
Cumulative Incidence of Second Primary Malignancies from Enrollment
Cumulative Incidence of Second Primary Malignancies from Maintenance
By Protocol Status
By Protocol Status
Solid malignancies only
Solid malignancies only
25%
4-Year
25%
3-Year
Events / N
Estimate
Events / N
Estimate
TT2-Placebo
11 / 344
1.2% (1.1, 1.2)
TT2-Placebo
8 / 161
1.9% (1.8, 1.9)
20%
TT2-Thal
18 / 323
1.9% (1.8, 1.9) 20%
TT2-Thal
15 / 180
2.8% (2.7, 2.9)
TT3A
7 / 303
1.3% (1.3, 1.3)
TT3A
4 / 218
1.4% (1.4, 1.4)
TT3B
1 / 177
0.6% (0.6, 0.6)
TT3B
1 / 123
0.8% (0.8, 0.8)
P = .57
P = .33
15%
15%
10%
10%
5%
5%
0%
0%
0
5
10
15
0
3
6
9
12
Years from Enrollment
Years from Maintenance
12
Conclusions
· Total Therapy 2/3 shows CA2 in the treatment arms that are
comparable to the CALGB-100104, IFM 2005-02 and MM-015
trials.
· The data suggest that there are no discernable differences in
CA-2 when combining different IMiDs with BZ/D as maintenance
strategy.
· There is, however, an increased incidence of solid tumors in
TT2-Thal compared with TT2-Control signifying that CA2 may
be a class effect when combined with genotoxic therapy.
· We are currently exploring predictive models for SPM and MDS-
CA both with plasma cell GEP and BM-GEP, SNPs, etc.
Step 5. Transplant: Do you need one?
Step 6. Response Assessment.
Step 7. Consolidation and/or Maintenance.
Step 8. Monitoring without mystery
13
The debate..... ASCT:
ASCT upfront or at relapse?
Bz-Len-Dex x3
Bz-Len-Dex x3
Stem Collection
Stem Collection
ASCT
Bz-Len-Dex x5
Bz-Len-Dex
x2
Lenalid x12m
Lenalid x12m
ASCT at relapse
IFM-DFCI 2009
How to Improve the Efficacy of Conditioning
Regimens??
Melphalan 200 mg/m2
mg/m ............ the gold standard
Melphalan + Bortezomib
B
........ 70% VGPR (35% CR)1
CR)
(1 mg/m2
mg/m D -6,
-
-3, +1 +4)
Melphalan + Bortezomib.........
B
51% VGPR2
VGPR
(1.3 mg/m2
mg/m D-1 or +1)
Melphalan + Busulphan.........
B
may
m
be superior3
uperior
1. Roussel M, et al (IFM) Blood. 2010;115:32-37: superior CR vs matched patients conditioned with MEL only (35% vs
11%).
2. Lonial S, et al. Clin Cancer Res. 2010;16:5079-5086.
3. Lahuerta JJ, et al. Hematologica. 2010;Jul 27:[E-pub ahead of print].
14
Step 7. Consolidation and/or Maintenance.
BMT/CTN 0702 SCHEMA: Role of Consolidation
Unsolved Issue!
Lenalidomide
No Consolidation
Maintenance
Register
MEL
VRD x 4
Lenalidomide
and Randomize
200 mg/m2
Maintenance
MEL
Lenalidomide
200 mg/m2
Maintenance
Active myeloma within 12 mos of initial treatment
Age 70 yrs
Pts with progressive disease will be excluded
All pts will have enough PBPC collected for 2 transplants
Stratify by B2M, response to initial therapy, and cytogenetics
Intent-to-treat analysis. Randomization prior to first ASCT
New IWG criteria will be used for response assessment
ClinicalTrials.gov. NCT01109004.
15
Outcome and Continuous Treatment
Lenalidomide maintenance
001.
75
Lenalidomide
0.
500.
25
Placebo
0.
000.
P < 10-7
0
6
12
18
24
30
36
Placebo
Revlimid
Attal M, et al. ASCO 2010.
McCarthy PL, et al. ASCO 2010.
Palumbo A, et al. EHA 2010.
Abstract 8018.
Abstract 8017.
Abstract 566.
Bortezomib maintenance
1.00
1,0
PFS
0.75
0,8
0,6
VMPT VT
VT
0.50
0,4
0.25
0,2
VT: median not
VMP
reached
VP
P = .006
VP: 23 months
0.00
0,0
HR: 1.7; p=0.05
0
5
10
15
20
25
30
35
0
10
20
3040
5060
Palumbo A, et al. ASH 2009. Abstract 128.
Mateos MV, et al. ASH 2009. Abstract 3.
Complete Response
are all the same?
Tumor gene
Response Criteria
copy number
Diagnosis
25,000 - 500,000
PR
5,000 100,000
VGPR
1,500 20,000
Immunofixation-negative CR 1,000 10,000
Immunophenotypic CR*
10 100
Molecular CR^
5 20
*Paiva et al Blood 2009;114;4369-72; ^Ladetto et al. J Clin Oncol 2010;28:2077-84
16
Lenalidomide vs Placebo Maintenance: CALGB
Time to Progression
Median TTP: 39.6 mos
Median TTP: 21.9 mos
ITT analysis with a median follow-up from transplant of 18 months (P < .0001)
McCarthy PW, et al. IMW 2011.
Lenalidomide vs Placebo Maintenance: CALGB
Overall Survival
13 deaths in the lenalidomide arm
and 24 deaths in the placebo arm
Median follow-up: 18 months (P = .05)
McCarthy PW, et al. IMW 2011.
17
Step 9. Relapse: Do you need a change in treatment?
Step 10. New Trials: How to find them.
2011 NCCN Guidelines in Relapse
· Bortezomib (Category 1)
· Bortezomib/liposomal doxorubicin (1)
· Lenalidomide/dex (1)
· Bendamustine (2B)
· Repeat primary therapy (if relapse at > 6 mos.)
· Bortezomib/dex
· Bortezomib/lenalidomide/dex (2B)
· Lenalidomide
· Cyclophosphamide, Cy-VAD, or +VD or Rd
· Thalidomide, or thalidomide/dex
· Dex, or DCEP, or DT-PACE
18
Main New Drugs
· New small molecules
Second generation proteasome inhibitors
Second & third generation immunomodulators
Histone deacetylase & novel signal transduction inhibitors
· Monoclonal antibodies
Elotuzumab
Lorvotuzumab mertansine
Phase 2 randomised open label study of 2
modalities of Pomalidomide plus low-dose
Dexamethasone in patients with Multiple
Myeloma, refractory to both lenalidomide and
bortezomib. IFM 2009-02.
Xavier Leleu, Michel Attal, Philippe Moreau, Bertrand Arnulf, Catherine Traulle, Mauricette
Michalet, Gerald Marit, Claire Mathiot, Marie Odile Petillon, Margaret Macro, Murielle
Roussel, Brigitte Pegourie, Brigitte Kolb, Anne Marie Stoppa, Sabine Brechignac, Laurent
Garderet, Bruno Royer, Cyrille Hulin, Lotfi Benboubker, Olivier Decaux, Martine Escoffre-
Barbe, Denis Caillot, Jean Paul Fermand, Herve Avet-Loiseau, Thierry Facon
Service des Maladies du Sang
Hôpital Huriez, CHRU, Lille, France
19
Study Design
Arm A Cycle 21 days
Arm B Cycle 28 days
·Pomalidomide 4mg oral/d, 121
· Pomalidomide 4mg oral/d, d 128
Dexamethasone 40mg oral/w, 1, 8, 15, 22
Dexamethasone 40mg oral/w, 1, 8, 15, 22
· Aspirin/LMWH continue
· Aspirin/LMWH continue
- N=84 randomized
6 pts per arm
Key inclusion criteria
Primary objective
DMC TOLERANCE
· Relapsed MM
Rule: no difference
Response rate (PR and
· Resistant or Refractory to both
better) according to
17 pts per arm
lenalidomide and bortezomib
IMWG in either arm
· Measurable disease (central lab)
DMC - EFFICACY
Rule: 4 PR /arm
·ANC > 1 x109/L; Platelets 75
x109/L; Hb 8 g/dL
40 pts per arm
· Creatinine clearance 50 mL/min
Until Progression
(relapse or refractory)
Prior Therapy
21/28
28/28
(N=43)
(N=41)
Median number of lines
5
5
(min-max)
(1-13)
(2-10)
Patients > 6 lines of therapy, %
42
46
Refractory to*, %
Lenalidomide
84
95
Bortezomib
79
83
Both, lenalidomide and bortezomib
74
78
Last prior therapy
70
68
*refractory to as per IMWG criteria
20
Response on ITT as per IRC
· The median follow-up was 11.3 months, (similar in the 2 arms)
· Central lab
21/28
28/28
Response rate
Total
N=43
N=41
ORR (PR), n (%)
15 (35)
14 (34)
29 (34.5)
CR, n
12
3
VGPR, n
11
2
PR, n
13
11
24
Stable disease, n (%)
19 (44)
21 (51)
40 (48)
Progressive disease, n (%)
5 (12)
3 (7)
8 (9.5)
Not evaluable, n
43
7
Median time to First response (95%CI), months
2.7 (0.9 - 6.5)
1.1 (1.0 - 1.8)
1.8 (1.0 - 5.1)
Median Duration of response (95%CI), months
10.5 (3.5;12.6)
7.2 (3.6;12.6)
8.1 (5.6;12.6)
one year in responders, %
47.5
36
37.5
Conclusions
The combination of Pomalidomide and Dexamethasone is safe and effective
in MM patients resistant and refractory to bortezomib and lenalidomide
The combination of Pomalidomide and Dexamethasone is effective
regardless of subgroups and refractoriness to prior therapy
Pomalidomide 4mg 21/28 days +Dexamethasone appeared superior to
pomalidomide 4mg 28/28 +Dexamethasone considering DOR and treatment
duration, in view of a similar safety profile
21
Bortezomib + Vorinostat: Response Data
· ORR of 42%
· 33% in bortez
refractory
2011 ASH: Vorinostat + Bortezomib/Dex, 480 (12/12/11, 11:45)
Phase III of Vorinostat ± Bortezomib/Dex, 811 (12/12/11, 4:30)
Panobinostat + Bortezomib/Dex, 814 (12/12/11, 5:15)
Badros, A et al. Clin. Cancer Res. 15:5250, 2009.
Impact of Novel Agents at Relapse
1.0
Relapsed before 1998
Relapsed 19981999
0.8
Relapsed 20002001
Relapsed 20022003
Relapsed 20042005
0.6
0.4
Survival
0.2
P<0.001
0.0
0
20
40
60
80
100 Time (months)
Kumar, S et al. Blood 111:2516, 2008.
22
Combination of Bendamustine, Lenalidomide, and Dexamethasone
(BLD) in Patients with Refractory or Relapsed MM is Safe and Highly
Effective: Results of Phase I/II Open-Label, Dose Escalation Study
Publication Number: 304
Suzanne Lentzsch, MD, PhD,1 Amy O'Sullivan, RN, BSN,1
Ryan C. Kennedy, BS,1 Mohammad Abbas, MD1, Navkiranjit K. Gill, DO,1
Carrie Andreas, PA-C,1 Diane Gardner, MSN, CRNP, BC,1 Silvana Lalo Pregja,
MBA,2 Steve Burt, NP,2 Robert Redner, MD,1 Robert L. Volkin, MD,3
G. David Roodman, MD, PhD,1 Markus Y. Mapara, MD, PhD,1
Frank Viverette, MD,3 Mounzer Agha, MD,3 John Waas, MD3,
·
Daniel Normolle, PhD4, Jeffrey A. Zonder, MD2
·
1Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine
and Cancer Institute, Pittsburgh, PA, USA;
·
2Myeloma Program, Karmanos Cancer Institute, Detroit, MI, USA;
3UPMC Cancer Center Upper St. Clair, Pittsburgh, PA, USA
·
4Biostatistics Facility, University of Pittsburgh School of Medicine and
·
Cancer Institute, Pittsburgh, PA, USA
Objective and Treatment Schedule
Primary objective: Determine the MTD and safety of bendamustine and lenalidomide when
combined with dexamethasone in patients with relapsed or refractory MM
MTD
23
Best Response After 2 or More Treatment Cycles
(N = 25 patients evaluable)
ORR = 52%
CBR = 92%
30
25
20
15
Patients 10
of% 5
0
VGPR
PR
MR
SD
PD
(n = 6)
(n = 7)
(n = 6)
(n = 4)
(n = 2)
Time to VGPR+PR - median in months 1.6 (1.6, 3.5); 95% CI
ORR, objective response rate; CBR, clinical benefit rate; VGPR, very good partial response; PR, partial response; MR, minor response; SD, stable
disease; PD, progressive disease;
Relapsed/Refractory Therapy
· Revlimid/Dex and Velcade/Dex remain the
standards of care in this setting
· Novel single agents, such as carfilzomib and
pomalidomide are on the cusp of approval
Combine well with other agents
· New combinations, such as with perifosine,
elotuzumab, vorinostat, panobinostat showing
encouraging activity
24
Other Options
· "Novel-er" agents on the way as well
ARRY520
· Add old agents that are new again to prior
active regimens
Cyclophosphamide
· Mix and match agents that had been used in
different combinations
If had RD, VD RVD
If had RD, TD RTD
25