Best of ASH 2010: What does it mean for patients?
January 13, 2011
Los Angeles
Brian GM Durie, MD
Cedars-Sinai, Los Angeles
Key Topics at ASH 2010
· Role of maintenance
· Velcade 1/week and subcutaneous with less neuropathy
· Impact of age and new combinations
· No benefit with mini-allo in frontline therapy
· Does Zometa improve survival?
· Baseline testing: Hevylite
· Follow up on smoldering myeloma
· Role of PET/CT
· New drug updates
Carfilzomib
Pomalidomide
Elotuzimab
Targeting the myeloma stem cell
New Paradigm for 2011
Continuous therapy
Prolongs PFS
burden
umorT
Combination therapy
Increases CR rate
Time
Details of New Paradigm
· Induce best response with novel
combinations
Rd, MPR, RCD, VRD, BiRD, ...
VD, VTD, VCD, VRD, VMPT, ...
· Consider auto-transplant
· Maintain response
Revlimid; Thalidomide; Steroids;
Velcade/Carfilzomib...
Benefit with Continuous Treatment
Lenalidomide maintenance
001.
Revlimid
750.
500.
25
Placebo
0.
00
P < 10-7
0.
0
6
12
18
24
30
36
Placebo
Revlimid
McCarthy et al. ASCO 2010
Attal et al. ASCO 2010
Palumbo et al. EHA 2010
Bortezomib maintenance
1.00
1,0
PFS
0.75
0,8
VT
0,6
VMPT VT
0.50
0,4
VP
0.25
VT: median not reached
0,2
VMP
VP: 23 months
HR: 1.7; p=0.05
P = 0.006
0.00
0,0
0
5
10
15
20
25
30
35
010
20
30
40
50
60
Palumbo et al. ASH 2009
Mateos et al. ASH 2009
Bortezomib Maintenance vs. Thalidomide Maintenance
HOVON65/GMMG-HD4 study
Randomization, n=833
vincristine + AD 3X
bor 1.3 mg/m2 d
1,4,8,11+ AD 3X
Induction
CAD + GCSF
CAD + GCSF
Stem cell mobilization
HDM
HDM
ASCT
200mg/m2
200mg/m2
thalidomide
bortezomib 1.3
mg/m2 2x/month
Maintenance
50 mg/daily
HOVON-65/GMMG HD64: Bortezomib vs.
Thalidomide Maintenance*
· 613 patients: PAD vs. VAD with HDM
· Higher CR/nCR with PAD (Bortezomib) induction
· Bortezomib maintenance (vs. Thalidomide maintenance)
Bortezomib 1.3mg/m2 q2weeks
Well tolerated: only 9% (vs. 31%) OFF for toxicity
Additional response on maintenance
Superior PFS and OS vs. Thalidomide
* Abstract #40 ASH 2010, Peter Sonneveld et al.
GENETIC ANALYSES
Based on Myeloma GEP
Based on Patient Genetics
Purified myeloma
DNA from
plasma cells at
peripheral blood at
diagnosis
diagnosis
IMF: BOAC Chip
Panel of 3404 SNPs in 964
329 Gene Chips,
367 BOAC SNP
genes spanning 67 molecular
U133 2.0
chips
pathways in the biology of
MM, treatment response and
drug effects to conventional
and novel agents
SNPs/genes associated with early BiPN/ViPN after
one cycle of PAD/VAD grade 24
SNPs/genes associated with later BiPN/ ViPN grade
24 (following induction treatment)
BiPN/ViPN = Bortezomib/Velcade-Induced Peripheral Neuropathy
Surprise with Subcutaneous (SQ) Velcade
· Philippe Moreau: IFM: MY-3021*
· 222 patients at relapse
· ORR at 12 wks: SQ vs. IV
· ORR 52% in both arms
· Less neuropathy with SQ
SQ 38%; IV 53%
Gd 3: SQ 6%; IV 16%
· Discontinuation: SQ 22%; IV 27%
* Abstract #312 ASH 2010
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%
Peripheral Neuropathy
Total planned dose
67.6 mg/m2
67.6 mg/m2
46.8 mg/m2
Total delivered dose
na
40.1 mg/m2
39.4 mg/m2
Bringhen S, et al. Blood; 2010 Aug 31. [Epub ahead of print]
Sorting Through Treatment Choices
· Elderly (>75) / fragile patients
· Aggressive disease
· Poor risk FISH
· Neuropathy
· Renal insufficiency
·DVTs
Are all the elderly the same?
Age-Adjusted Doses
Further Dose
65-75 Years
>75 Years
Redcution
Dexamethasone
40 mg
20 mg
10 mg
weekly
Melphalan
0.25 mg/kg
0.18 mg/kg
0.13 mg/kg
days 1-4
Thalidomide
200 mg
100 mg
50 mg
per day
Lenalidomide*
25 mg
15 mg
10 mg
days 1-21
1.3 mg/m2
1.3 mg/m2
1.0 mg/m2
Bortezomib
biweekly
weekly
weekly
If a grade 3-4 AE occurs: 1. discontinue therapy; 2. wait for grade 1 AE; 3.
restart at a lower dose
*Lenalidomide plus melphalan starting dose 10 mg/d
Recommendations by A. Palumbo.
Clinical Impact of VTD Consolidation
in VGPR Patients After ASCT
Responses after ASCT
Responses after VTD
VGPR 85%
VGPR 49%
CR 15%
CR 49%
15%
49%
49%
85%
VGPR
CR
Ladetto M, et al. J Clin Oncol. 2010;28:2077-2084.
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(12):2077-84
Novel 3 and 4-drug Regimens
· Shaji Kumar et al: Abstract #621
· Evaluation of VCDR: Evolution study
· Compared VCDR, VRD, and VCD (high:CYBORD) and
VCD low
VCD "low" performed very well with lesser toxicity
VCDR not clearly superior to VRD
Role of Mini-Allo Transplant*
· BMT-CTN 0102 trial results
· 710 patients; 43 US centers
Double Auto
Auto Mini-Allo
ORR
65%
66%
PFS (3yr)
46%
43%
TRM
4%
11% (p=0.04)
OS (3yr)
80%
77%
No clear benefit of mini-allo in frontline therapy.
* 2010 ASH Abstract #41, Krishnan et al.
Zometa and Survival*
· Gareth Morgan et al: MRC Myeloma IX
· 1970 patients: Zometa vs. Clodronate
· Included "intensive" vs. "non-intensive"
Survival improved 5.5 months with Zometa
* ASH 2010 and The Lancet (Dec 2010) Vol 376:1989-1999
MRC Myeloma IX--ZOL OS
and PFS vs CLO
Risk
reduction
P value
0.842
OS (overall)
16%
.0118
0.850
(adjusted for SRE)a
15%
.0178
0.883
PFS (overall)
12%
.0179
00.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Hazard ratio (ZOL versus CLO)
In favour of ZOL
In favour of CLO
Abbreviations: CLO, clodronate; OS, overall survival; PFS, progression-free survival SRE, skeletal-related event; ZOL, zoledronic acid.
a Time to first SRE was included as a time-dependent covariate in an exploratory Cox model examining OS. 22
Caveats about Zometa*
· Nitrogen containing bisphosphonates inhibit farnesyl
pyrophosphate synthetase: maybe in myeloma cells
·BUT
What about versus Pamidronate?
What about 30% without bone disease?
Survival benefit occurred early (in first 4 mos)
Median Zometa Rx = only 1yr therefore what about need to
observe patients with longer Rx
* Editorial: Rajkumar, The Lancet, (Dec 2010) Vol 376:1965-1966
Using Hevylite for Staging
ISS for progression in 338 IFM patients (Prof Herve AvetLoiseau)
2m+albumin
2m+hevylite ratio
p=0.023
p=0.000013
0
1
2
Current Thinking About Smoldering
Myeloma
· Model of possible outcomes with Rx (e.g. Revlimid)
Recommendations
·Study carefully in trials
·Assess scenarios 1/2/3
Prognostic Relevance of PET/CT
· Zamagni et al (Bologna): Abstract #369
· 146 patients with upfront therapy
· Patient with 3 lesions and/or SUV >3.9 had shorter
overall survival
· At 3 months post-ASCT 65% NEG PET/CT
· With NEG PET/CT
VGPR 90% (P=0.0008)
PFS 50 months
OS 92% at 5 yrs
Myeloma Pomalidomide Summary
Pom/Dex1
Pom/Dex2
Pom+/- dex3
1-3 reg
Len ref
MM-002
Pom dose
2 mg x 28d
2 mg x 28d
MTD = 4 mg 21
of 28
>PR
63%
32%
28%
>MR
82%*
47%
52%
Median 3 prior regimens
Median 4-6 prior regimens
1) Lacy JCO 2009, 27:5008-5014
2) Lacy Leukemia 2010 Nov; 24(11):1934-9
3) Richardson P, et al. Blood. 2009;114(22):126-127
Does starting with higher Pom dose
lead to better response rates?
4mg vs 2 mg
We opened two sequential phase II trials using
the Pom/dex regimen at differing doses to
study the efficacy of this regimen in patients
who have failed both lenalidomide and
bortezomib.
Response Rates
2 mg
4 Mg
N=35
N=35
Confirmed Response
9 (26%)
9 (26%)
Rate (>PR)
CR
01
VGPR
53
49%
40%
PR
45
MR
85
SD
13
12
PD
28
NE
31
Long-term treatment and tolerability of the
novel proteasome inhibitor carfilzomib
in patients with relapsed and/or refractory
multiple myeloma
Sundar Jagannath,1 Ravi Vij,2 Jonathan L. Kaufman,3 Thomas Martin,4 Ruben
Niesvizky,5 Nashat Y. Gabrail,6 Melissa Alsina,7 Lori Kunkel, 8Alvin F. Wong, 9
Leanne McCulloch,9 Alison L. Hannah,9 Michael Kauffman,9 and David S. Siegel10
1Mount Sinai Medical Center, New York, NY; 2Washington University School of
Medicine, Saint Louis, MO; 3Emory University School of Medicine, Winship Cancer
Institute, Atlanta, GA; 4University of San Francisco, San Francisco, CA; 5Weill
Cornell Medical College, New York, NY; 6Gabrail Cancer Center Research, Canton,
OH; 7H. Lee Moffitt Cancer Center, Tampa, FL; 8Independent Consultant, San
Francisco, CA; 9Onyx Pharmaceuticals, Emeryville, CA; 10The John Theurer
Cancer Center Hackensack University Medical Center, Hackensack, NJ
Results
· · As of 9 November 2010, 32 of 46 patients (70%)
remain on treatment.
9 patients have completed 12 cycles of carfilzomib dosing on
protocol 010 in addition to the 12 cycles received in the original
protocol. All 9 patients remain active as of 9 November 2010.
· Longest duration of treatment is 30 cycles (28 months)
for the compassionate use patient.
Elotuzimab Studies
Humanized antibody against CS-1 on myeloma cells
· Abstract #1936: Lonial et al
ORR 82% with Elotuzimab + Rev/Lo Dex
· Abstract #986: Richardson et al
ORR 85% with Elotuzimab + Rev/Dex
· Abstract #3023: Jakubowiak et al
ORR 48% with Elotuzimab + Velcade/Dex
Targeting Myeloma Stem Cells
· Prior studies by Matsui et al showed benefit blocking
Hedgehog (Hh) pathway with Cyclopamine and related
inhibitors
· Tricot et al, Abstract #615
Blocking both Hh and Wnt pathways is particularly effective
Used Cyclopamine (Hh) + itraconazole (Hh) and CAY10404
(Wnt: Cox-2 inhibitor)- very effective combination in lab studies