Download MLN9708 in Relapsed and/or Refractory MM

New Paradigms, New Treatments in
Relapsed/Refractory Disease: An Update
Kenneth C. Anderson, M.D.
Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Harvard Medical School
Conflict of Interest: Kenneth C. Anderson, M.D.
Consultancy: Celgene, Onyx, Sanofi Aventis, and
Gilead
Scientific Founder: Acetylon, Oncopep
Integration of Novel Therapy
Into Myeloma Management
Bortezomib, Lenalidomide, Thalidomide, Doxil,
Carfilzomib, Pomalidamide
Target MM in the BM microenvironment to overcome
conventional drug resistance in vitro and in vivo
Effective in relapsed/refractory, relapsed,
induction, consolidation, and
maintenance therapy
Eight FDA approvals and median survival prolonged
from 3-4 to 6-7 years, with additional prolongation
from maintenance
New approaches needed to treat and ultimately
prevent relapse
There is a well defined and recognized
unmet need in multiple myeloma treatment
Unmet Need
Frontline
Treatment
Relapsed
Relapsed or
Intolerant
Expected
survival (m)
20-50
14-16
6-10
Sensitivity to
therapy
Sensitive
Less Sensitive/Resistant
Resistant
Peripheral
neuropathy
(~15% at diagnosis)
>80% incidence of
peripheral neuropathy
Compromised marrow
reserve
Cytopenia
Intolerant to or
ineligible for available
therapy
Treatment limitations/
comorbidities
Elderly population ( risk for heart, lung, renal, liver dysfunction, diabetes)
Adapted from: Durie BGM. Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition.
Jagannath S. Clin Lymphoma Myeloma. 2008;8 Suppl 4:S149-S156.
Overview of Phase III Trials with Len and
Bortezomib in Relapsed/Refractory MM
ORR, CR or ≥ VGPR,
%
nCR, %
%
Regimen
Trial
Len + dex
MM-009[1]
Len + dex
[2]
61
24
NE
DOR,
Mos
16
TTP or
PFS,
Mos
11
Median
OS,
Mos
35[5]
MM-010
60
25
NE
17
11
Bortezomib
APEX[3]
43
16
NE
8
6
30
Vdox
MMY3001[4]
44
13
27
10
9
NE
1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132.
3. Richardson PG, et al. Blood. 2007;110:3557-3560. 4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-3901. 5. Weber
D, et al. Blood. 2007;110:Abstract 412.
Efficacy and Toxicity by Bortezomib
schedule
VMP*
(VISTA)
VMP
twice weekly N=63
VMP
once weekly N=190
CR
30%
27%
23%
PFS @ 3 years
NA
32%
35%
Any grade
44%
43%
21%
Grade 3-4
13%
14%
2%
PN discontinuation
NA
16%
4%
Total planned dose
67.6
67.6 mg/m2
46.8 mg/m2
Total delivered dose
NA
41 mg/m2
40 mg/m2
Sensory PN
*Mateos et al. J Clin Oncol 2010; PN: peripheral neuropathy
Palumbo et al. ASH 2010 abstr 620.
SC vs IV Bortezomib for Relapsed/Refractory
Myeloma
Moreau et al, ASH 2010 abstr 312
EQUIVALENT EFFICACY
Bortezomib IV
(N=74)
Bortezomib SC
(N=148)
Pvalue*
Any PN event, %
53
38
0.04
Grade 2, %
41
24
0.01
Grade 3, %
16
6
0.03
Grade 1 PN at baseline
28
23
Diabetes at baseline
11
13
Exposure to prior neurotoxic agents
85
86
Peripheral Neuropathy
Risk factors for PN, %
*P-values are based on 2-sided Fisher’s exact test
Bortezomib, Lenalidomide and Dex Therapy
• Lenalidomide induces caspase 8 mediated apoptosis of MM
cells in BM in vitro and in vivo; Dex (caspase 9) enhances
response
• Synergistic MM cell toxicity of lenalidomide (caspase 8) with
Bortezomib (caspase 9>8) in vitro and in vivo (dual apoptotic
signaling)
• Phase I-II trials show that majority (58%) of patients
refractory to either agent alone respond to the combination
• Phase I-II trials show 100% response with 74% CR/VGPR
and 52% CR/nCR when used as initial therapy, including
molecular responses.
Richardson et al. JCO 2009; 27:5713-19.
Richardson et al. Blood 2010; 116:679-86.
Carfilzomib: A Novel Proteasome
(Chymotryptic) Inhibitor
• Novel chemical class with highly selective
and irreversible proteasome binding
• Improved antitumor activity with
consecutive day dosing
• No neurotoxicity in animals
H
N
N
O
O
Tetrapeptide
O
N
H
H
N
O
O
O
N
H
O
Epoxyketone
• Durable responses in relapsed and relapsed/ refractory
MM w/o neuropathy
• Carfilzomib lenalidomide Dex versus lenalidomide Dex
phase III trial for new drug approval
Demo et al. Cancer Res 2007; 67:6383
Kirk et al., Blood 2008, 112: 2765 Siegal et al. Blood 2012:120:2817.
Benefit of Carfilzomib in Relapsed/Refractory MM:
Meaningful ORR, DOR and OS
Response Category
Total
N = 266, n (%)
1 (0.4)
VGPR
PR
MR
SD
PD
13 (4.9)
47 (17.7)
CR
81 (30.5)
69 (25.9)
Not evaluable
Duration of response
21 (7.9)
Median DOR = 7.8 months (95% CI: 5.6, 9.2)
Overall Survival
Median OS = 15.4 months (95% CI: 12.5, 19.0)
ORR = 22.9%
(95% CI: 18.0, 28.5)
CBR = 35.7%
(95% CI: 30.0, 41.8)
CRd in Relapsed and Upfront MM
Wang et al ASCO 2011; Jakubowiak et al ASH 2011
• Response to CRd therapy was high, with an ORR of 78%
– 41% VGPR or better
• CRd well-tolerated with durable responses
• ASPIRE phase 3 open-label, international, multicenter trial
comparing CRd to Rd in R/R MM fully enrolled.
• Remarkable extent and frequency of response to CRd upfront
(100% ORR, 80% CR,nCR after 12 cycles)
Jakubowiak A. et al., Blood, 2012; 120: 1801-8.
Carfilzomib in
Relapsed/Refractory MM
Study
Ph
PX-171003-A11
II
PX-1710072
I/II
BTZ status
n
Relapsed and 266
refractory
Relapsed
and/or
refractory
20
Median
prior tx
lines
CFZ dose
5
20/27 mg/m2
2-10 min IV
infusion
24%
4.5
20/56 mg/m2
30-min IV
infusion
60%
Mode of
admin
ORR
1. Siegel et al. Blood. 2012;120(14):2817-2825
2. Papadopoulos KP, et al. Blood. 2011;118(21):Abstract and poster 2930.
Phase II Study of Infusional Carfilzomib in
Patients with Relapsed or Refractory MM
• CFZ dose of 20/56 mg/m2 administered as a 30-minute
IV infusion resulted in high response rates in our BTZ
treated/refractory population.
• Response rates were comparable to those seen in PX171-0071
• CFZ dose of 20/56 mg/m2 was associated with more
frequent cardiac and pulmonary toxicities, particularly
HTN and pulmonary edema/CHF.
– Possible contribution from “supportive” measures?
• CFZ dose of 20/56 mg/m2 continues to be explored in
Lendvai et al, ASH 2012 Abstr 947
ongoing Phase II/III studies.
Pomalidomide in Myeloma
C
MM cells
IL-6
TNF
B
IL-1
A
ICAM-1
Bone Marrow
Vessels
NFAT
PKC
IL-2
Bone Marrow
Stromal Cells
IL-2
IFN 
VEGF
bFGF
D
Hideshima et al. Blood 96: 2943, 2000
Davies et al. Blood 98: 210, 2001
Gupta et al. Leukemia 15: 1950, 2001
PI3K
Dendritic
Cells
CD28
CD8+ T
Cells
NK Cells
NK-T
Cells
E
Mitsiades et al. Blood 99: 4525, 2002
Lentzsch et al Cancer Res 62: 2300, 2002
LeBlanc R et al. Blood 103: 1787, 2004
Hayashi T et al. Brit J Hematol 128: 192, 2005
Pomalidomide With Low-Dose Dexamethasone
Relapsed and Refractory Multiple Myeloma
• POM was effective in heavily pretreated patients who had already received
LEN and bortezomib and who progressed on their last line of therapy
• The combination of POM with LoDEX improves the ORR due to synergy
between immunomodulatory agents and glucocorticoids
– POM + LoDEX, 34%; POM alone, 15%
• Response was durable with POM regardless of the addition of LoDEX
– POM + LoDEX, 8.3 months ; POM alone, 8.8 months
• POM is generally well tolerated, with low rates of discontinuations due to
AEs
• Age had no impact on ORR, DoR, or safety
Jagannath S, et al. ASH 2012 abstract 450.
Pomalidomide Plus Low-Dose Dexamethasone
(Pom/Dex) in Relapsed Myeloma (345 patients)
• Pom/Dex has high response rates even in heavily pretreated
relapsed myeloma
• Pom/Dex is well tolerated
• Toxicity and efficacy are similar between the 2mg and 4mg
dose levels
• The strongest predictors of response include the number
and type of prior regimens.
• The strongest predictors of TTP and survival include the
number and type of prior regimens, LDH, and B2M.
Lacy et al. ASH 2013 Abstr 201.
A Phase III Clinical Trial of Pomalidomide with
Low-dose Dex vs. High-dose Dex in
Relapsed/Refractory MM
• POM + LoDEX significantly improved PFS and OS
– Median PFS: 3.6 vs 1.8 months
• HR = 0.45; P < .001
– Median OS: not reached vs 7.8 months
• HR = 0.53; P < .001
• Equal benefit in pts refractory to both LEN and BORT
• POM + LoDEX was generally well tolerated
• POM + LoDEX should be considered as a new treatment option for these
pts
Dimopoulos et al. ASH 2013 LBA6
MM-005: A Phase 1 Trial of Pomalidomide,
Bortezomib, and Low-dose Dexamethasone in
Relapsed or Relapsed/Refractory MM
• POM + BORT + LoDEX (PVD) well tolerated
– cohort 5 as the MTD/MPD
• POM 4 mg; BORT 1.3 mg/m2; DEX 10/20 mg
• Responses in RR MM across all cohorts
– ORR: 73%, VGPR: 27%, SD: 27%
– Responses were rapid; majority are ongoing
– Efficacy even with adverse cytogenetics
• Phase III Trial Pom Bort Dex vs Bort Dex for full approval
Richardson et al. ASH 2013 Abstr 727.
Carfilzomib Pomalidomide Dexamethasone
(Car-Pom-d) in Relapsed/Refractory MM
• MTD was Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg, and
dexamethasone 40 mg
• There are limited G 3 and 4 non hematologic toxicities; the regimen was
tolerated well with no unexpected toxicity
• The combination of Car-Pom–d is highly active in this heavily pretreated,
refractory patient population
 ≥ VGPR
≥ ORR
≥ CBR
 PFS (median)
 OS
13%
50%
67%
7.4 months
90% @ 1 year
Shah et al. ASH 2012 Abstr 74.
Current and Future Directions
1. Development of immune therapies
2. Development of novel agents targeting the MM cell in the
BM microenvironment
3. Development of rationally-based combination therapies
4. Utilization of genomics for improved classification and
personalized therapy
Myeloma will be a chronic illness, with sustained CR in a
significant fraction of patients.
MAb-Based Therapeutic Targeting of Myeloma
Antibody-dependent
Cellular cytotoxicity
(ADCC)
Complement-dependent
Cytotoxicity (CDC)
Apoptosis/growth
arrest
via targeting
signaling pathways
C1q
C1q
Effector cells:
CDC
MM
ADCC
MM
FcR
MM
Daratumumab
(CD38)
huN901-DM1 (CD56)
nBT062-maytansinoid
(CD138)
1339 (IL-6)
BHQ880 (DKK1)
RAP-011 (activin A)
Daratumumab (CD38)
Lucatumumab or Dacetuzumab (CD40)
Elotuzumab (CS1)
Daratumumab (CD38)
XmAb 5592 (HM1.24)
Tai & Anderson Bone Marrow Research 2011
Phase 2 Elotuzumab Lenalidomide Low-dose Dex in
Relapsed/ Refractory MM
• Elotuzumab plus lenalidomide and low-dose dexamethasone has a high ORR
in relapsed and relapsed/refractory MM
– 82% for all pts (91% in pts who had received only 1 prior therapy)
– 92% for pts treated with elotuzumab 10 mg/kg
Median PFS was 33 mos for patients receiving elotuzumab
10 mg/kg
• The combination was generally well tolerated
– Most common Grade 3/4 treatment-emergent AEs were neutropenia (16%),
thrombocytopenia (16%), and lymphopenia (16%)
– Premedication regimen decreased incidence and mitigated severity of
infusion reactions*
Richardson et al. ASH 2012, Lonial et al. ASCO 2013
PHASE I/II STUDY OF DARATUMUMAB CD38
MONOCLONAL ANTIBODY IN
RELAPSED/REFRACTORY MM
• Favorable safety profile as monotherapy
• In 15 of 32 (47%) showed benefit
– 4 patients achieving PR (13%)
– 6 patients achieving MR (19%)
– 5 patients achieving SD (16%)
• At doses 4mg/kg and above, 8 of the 12 patients had at least MR
(66%)
• To be combined with lenalidomide dexamethasone
Plesner et al. ASH 2012 Abstr 73.
Phase I Trial of Vaccination with DC/MM
Fusions in Relapsed Refractory MM
• Well tolerated, no
autoimmunity
• Induced tumor reactive
lymphocytes in a majority of
patients
•
•
DC/MM fusions induce anti-MM
immunity in vitro and inhibit MM
cell growth in vivo in xenograft
models
Vasir et al. Brit J Hematol 2005;
129: 687-700
• Induced humoral responses
to novel antigens (SEREX
analysis)
• Disease stabilization in 70%
of patients
Rosenblatt et al. Blood 2011; 117:393-402
Background: MM/DC Vaccination following
Autologous PBSCT for Myeloma
100%
90%
80%
13%
33%
% Participants
70%
25%
60%
50%
38%
40%
30%
54%
20%
29%
10%
0%
100 Day Post-Transplant
CR/nCR
Post 100 Day (Best Response)
VGPR
PR
Rosenblatt et al., CCR 2013
PD-L1 Plays an Important Role in Dampening
the Anti-tumor Immune Response
PD-L1
IFNmediated
up-regulation
of tumor PDL1
lymphocyte
PD-L1/PD-1-mediated
Inhibition of
tumor cell killing
cancer cell
receptor
Priming and
Activation of T cells
Presence of intratumoral T-cells may lead
to adaptive immune resistance
PD-L1 expression in the tumor
microenvironment can inhibit
anti-tumor T cell activity:
Immune cell modulation of
T cells
Stromal PD-L1 modulation of T
cells
Chen DS, Irving BA, Hodi FS.
Clin Cancer Res. 2012;18:6580.
PD-L2 mediated inhibition of
TH-2 T cells
1. PD-L1 expression by tumor
infiltrating immune cells
2. PD-L1 expression by
cancer cells
Combination Immunotherapy Posttransplant
• Anti PD-1 Ab administration in the early post-autologous
transplant period is well tolerated
• Anti-PD1 results in the expansion of tumor reactive
lymphocytes in the post-transplant period that persist at
6 months
• This provides a promising platform for combination with
a tumor vaccine
• We have inititated enrollment into cohort 2, in which
patients receive an autologous DC/myeloma fusion
vaccine 1 week prior to each dose of Anti-PD-1Ab
Avigan et al.
Proteasome: Present and Future Therapies
Potential
Therapeutic Targets
UB enzymes E1, E2 and
E3-UB-Ligases
Deubiquitylating
Enzymes (DUBs)
Ub
Ub
ATPases/
Cdc48
Ub
P5091 target USP-7
ATP
Poly-ubiquitinated proteins
(proteasome substrates)
Immunoproteasome
ADP
PR-924
19S
Six Protease
activities
20S
 
20S
5, 5i
1, 1i
2, 2i
19S
Free
5
NPI-0052: 5, 1, 2
Ub
for re-cycling
Bortezomib,
Carfilzomib,
CEP-18770
ONYX-0912
MLN 2238
Degraded protein
26S PROTEASOME
P5091 Specifically Target USP-7 and
does not Alter Proteasome Activity
Proteasome Activity Assay
USP-7 Knockout
P5091 (µM)
Velcade (nM)
2.5
1
5
3
7.5
5
10
7
12.5
9
Chauhan et al. Cancer Cell 2012;22: 345-58
P5091 Overcomes Bortezomib-Resistance
in MM Cells
Chauhan et al. Cancer Cell 2012; 22: 345-58
MLN2238/9708 Decreases Cell Viability in
MM Cells and Overcomes BortezomibResistance
24h
48h
Chauhan et al.,
Clin Cancer Res,
2011; 17: 5311-21.
Weekly MLN9708 in Relapsed/Refractory
Multiple Myeloma: Phase I Study
• Single-agent oral MLN9708 MTD 2.97 mg/m2 on a weekly
(days 1, 8, and 15 every 28 days) schedule
• Oral MLN9708 generally well tolerated
– hematologic and gastrointestinal events generally
manageable, low rate of discontinuations
– Infrequent PN, only 1 grade 3 PN
• Pharmacokinetic profile supports weekly oral dosing
• Relapsed and/or refractory MM patients (median 4 prior
lines of therapy)
– ORR (≥PR) of 18%, plus 2% MR and 30% SD, including
relapse post Bortezomib
Kumar ASCO 2013
MLN9708 in Relapsed and/or Refractory MM:
Expansion Cohorts of a Phase 1 DoseEscalation study
•
46 pts evaluable for response
– 21 in dose-escalation cohorts
– 30 in expansion cohorts (including 6 from dose-escalation cohorts)
•
6 pts have achieved ≥PR
– 1 CR, confirmed by bone marrow (PI-naïve expansion cohort)
– 5 PRs (1 each at 1.2 and 2.23 mg/m2 in dose-escalation cohorts; 1 in RRMM and 2 in
bortezomib-relapsed expansion cohorts)
•
1 pt achieved MR (bortezomib-relapsed expansion cohort; 40% M-protein reduction)
•
All 7 pts remain in response, with duration of disease control of up to 15.9 months
•
28 pts have achieved SD
– 14 in dose-escalation cohorts
– 9, 5, and 2 in RRMM, bortezomib-relapsed, and PI-naïve expansion cohorts
– Durable, with disease stabilization for up to 12.9 months
Richardson et al. ASH 2011
In Vitro Anti-MM Activity of Oral
Chymotryptic Inhibitor ONX 0912 (Opromazib)
Myeloma Cell Lines
Patient Tumor Cells
• Phase I clinical trials ongoing
Chauhan et al. Blood. 2010;116:490614
Marizomib: A Non-Peptide Proteasome Inhibitor
Induces Rapid, Broad and Prolonged Inhibition
Marizomib (NPI-0052)
H
H
H
N
O
OH
O
O
H
CH3
•
Exhibits high levels of proteasome inhibition
without toxicities associated with bortezomib
•
Active in bortezomib and IMiD resistant
myeloma preclinically
Cl
Chauhan et al., Cancer Cell 2005; 8: 407-19
Responses to Marizomib +/- Dexamethasone in Evaluable Pts
at Full Dose [ >0.4 mg/m2 ]* Twice Weekly (n=21**)
Pts Refractory to Bortezomib
All Pts
EBMT
≥ SD
MR + PR
Uniform Criteria
≥ SD
PR + VGPR
11/20
3/20
12/21
4/21
55%
15%
EBMT
≥ SD
MR + PR
8/12
2/12
67%
17%
57%
19%
Uniform Criteria
≥ SD
PR + VGPR
8/12
2/12
67%
17%
Median Duration of Response (all Pts) = 133 days (~ 5 mos)
Pts Exposed to Bortezomib
EBMT
≥ SD
MR + PR
Uniform Criteria
≥ SD
PR + VGPR
11/19
3/19
11/19
3/19
Pts Refractory to Lenalidomide
58%
16%
EBMT
≥ SD
MR + PR
8/13
3/13
62%
23%
58%
16%
Uniform Criteria
≥ SD
PR + VGPR
9/14
4/14
64%
29%
• Response criteria defined with baseline SPEP ≥ 0.5 g/dL or UPEP ≥ 200 mg/24h with
at least 2 assessments after treatment Day 1 for EBMT ; also by free lite for UC**.
*As of
05 Dec 11
• Refractory defined as having PD during or within 60 days of last regimen.
Richardson et al. ASH 2011
Functional Sequelae of Btk Inhibition by PCI-32765
in the MM BM milieu
PCI32765
MM
Stem Cell
MM
Colony formation
Btk activation by
IL-6, SDF-1
Tumor
microenvironment
IL-6
SDF-1
MIP-1
MIP-1
M-CSF
MCP-1
PCI32765
Adhesion
Migration
Homing
MIP-1, MIP-1, IL-8, TGF1
RANTES, BAFF, TRAF2, CXCR4,
LAT, PLC2, MYD88, NFATc1
TRAP5b
SDF-1
IL-8
Activin A
APRIL
MIP-1
MIP-1
TGF1
RANTES
BAFF
PCI-32765
M-CSF, IL-6, MCP-1
M-CSF
Stromal cells
Bone
resorption
RANK
fms
Osteoclast precursors
Osteoclast
Tai et al. Blood2012; 120: 1877-87.
BET Bromodomain Inhibition Suppresses c-myc
Expression and Function and Triggers Anti-MM
Activity
Delmore JE., Issa GC, et al. Cell 2011; 146:904.
Additional Targeted Therapies in Development
 KSP inhibitors (Array 520)
 AKT inhibitor (GSK agent)
 Nuclear transport inhibitors (KPT)
 CDK inhibitors
Development of Rationally-based Combination
Therapies (HDAC and Proteasome Inhibitors)
Protein
Ub
Ub
Ub
protein aggregates
(toxic)
Ub
Ub
26S proteasome
Ub
HDAC6
Ub
Panibinostat,
Vorinostat, ACY1215
Ub
Bortezomib, Carfilzomib, NPI0052,
MLN9708, ONX 0912
HDAC6
dynein
Ub
HDAC6
dynein
Microtubule
Ub
Aggresome
Ub Ub
Lysosome
Ub Ub
Ub
Ub
Autophagy
Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:3441-9.
VANTAGE 088: An International, Multicenter,
Randomized, Double-Blind Study of Vorinostat
or Placebo with Bortezomib in Relapsed MM
• The combination of vorinostat + bortezomib is active in patients with
relapsed and refractory MM
– Significant improvement in response rate
– ORR 54% vs 41% (P<0.0001); CBR 71% vs 53% (P<0.0001)
• PFS and TTP were prolonged in the combination arm compared with
bortezomib alone
PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4)
versus 6.83 months (5.7–7.7)
• Diarrhea, fatigue, and thrombocytopenia limited tolerability
Dimopoulos et al. ASH 2011, Lancet Oncology, in press
Bench to Bedside Translation
of HDAC 6 Selective Inhibitor ACY 1215
• Orally bioavailable, highly potent, selective
• inhibitor of HDAC 6 synthesized in fall 2009
• Synergistic MM cytotoxicity with Bortezomib
• in vitro and in vivo
• Favorable PK/PD, toxicity profile
• Phase Ia/Ib/II clinical trials of ACY1215, alone and with
Bortezomib
and
with
lenalidomide/dexamethasone,
ongoing; trials with pomalidomide and carfilzomib this year.
Santo et al. Blood 2012;119:2579-89
Mutations in Myeloma
19 Patients Each With
Newly Diagnosed and Relapsed MM
•
Protein homeostasis: 42% including FAM46C, RPL10, RPS6KA1,
EIF3B, XBP1, LRRK2
•
NF-kB signaling: 10 point mutations, 4 additional structural rearrangements affecting coding
Confers bortezomib sensitivity
•
Histone methylating enzymes: WHSC1, UTX, MLL
•
BRAF: 4% activating : Single patient MM response
Andrulis et al Cancer Discovery 2013; 3: 862-9.
•
PSMB5 b5 proteasome subunit mutation confers proteasome
inhibitor resistance in laboratory, not identified in clinic
Lichter et al Blood 2012: 120: 4513-16.
Chapman et al. Nature 2011; 471: 467-72.
Whole Genome Sequencing Identifies Acquisition of New
Changes in MM: 71 Patient Study
(Munshi et al, ASH 2011 Abstract 276)
New mutations
in late sample
1.2
1
PD4301
Early
mutation
not in
late
sample
0.8
0.6
%MutLate
0.4
%MutEarly
0.2
Early Tumor
Late Tumor
EARLY
LATE
TRPM3
LRRC69
TIAM2
COL9A1
CDKAL1
PCDHB6
ACOT12
PLS1
NCKAP5
ASXL2
USH2A
NRAS
PRAMEF12
0
Early Tumor Late Tumor
Relapsed Refractory Myeloma
1. Lenalidomide dexamethasone, bortezomib, and pegylated
doxorubicin are approved regimens for relapsed MM.
1. Pomalidomide/dex and carfilzomib are newly FDA approved
options.
3. There are many promising protocols of novel immune and
targeted agents which show promise, alone and in
combination.
4. Genomic analyses are both defining the basis for evolution
underlying relapse and identifying new targets.
United Nations Against Myeloma:
Bench to Bedside Research Team
USA
UK
India
Italy
Israel
Kenneth Anderson
Nikhil Munshi
Paul Richardson
Robert Schlossman
Irene Ghobrial
Steven Treon
Jacob Laubach
Deborah Doss
Kathleen Colson
Mary McKenney
Kim Noonan
Tina Flaherty
Kathleen Finn
Muriel Gannon
Stacey Chuma
Janet Kunsman
Diane Warren
Carolyn Revta
Andrea Freeman
Alexis Fields
Andrea Kolligian
John Feather
Farzana Masood
Nora Loughney
Heather Goddard
Tiffany Poon
Nicole Stavitzski
Ranjit Banwait
Shawna Corman
Heather Goddard
Meghan Marie Leahy
Caitlin O’Gallagher
Christina Tripsas
Karin Anderson
Shannon Viera
Katherine Redman
Amber Walsh
Samir Amin
Wanling Xie
Parantu Shah
Holly Bartel
Lisa Popitz
Jeffrey Sorrell
Japan
Canada
Germany
Austria
China
Teru Hideshima
Constantine Mitsiades
Dharminder Chauhan
Noopur Raje
Yu-Tzu Tai
Ruben Carrasco
James Bradner
Gullu Gorgun
Jooeun Bae
Francesca Cottini
Michele Cea
Antonia Cagnetta
Teresa Calimeri
Edie Weller
Ajita Singh
Ze Tian
Diana Cirstea
Yiguo Hu
Naoya Mimura
Jiro Minami
Sun-Yung Kong
Weihua Song
Douglas McMillin
Catriona Hayes
Steffen Klippel
Jana Jakubikova
Panisinee Lawasut
Niels van de Donk
Eugen Dhimolea
Jake Delmore
Hannah Jacobs
Masood Shammas
Mariateresa Fulciniti
Jianhong Lin
Jagannath Pal
Samantha Pozzi
Loredana Santo
Claire Fabre
Anuj Mahindra
Rao Prabhala
Jake Delmore
Puru Nanjappa
Michael Sellito
Avani Vaishnav
Greece
Taiwan
Turkey
Australia
Ireland