Transcript High Risk - Arizona Center for Cancer Care

Multiple Myeloma in 2014:
What Advanced Practice Providers Should Know
November 2014
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Joseph Mikhael, MD, MEd, FRCPC
Staff Hematologist, Mayo Clinic Arizona
Objectives
1. Provide an overview of the types and
spectrum of multiple myeloma
2. Discuss the “significance” of MGUS and its
practical management
3. Review the diagnosis and staging of
myeloma
4. Discuss the approach to therapy, including
stem cell transplantation
5. Highlight the improvement in prognosis for
patients with myeloma
Myeloma case
68 yo male
• 9 month history of low back pain
• Treated by FP, PT, Chiropractor – no
improvement
• FP did plain x-rays, revealed multiple
lytic lesions
• Gradual increasing fatigue, SOBOE
Case cont.
• Hb 7.8, WBC 5.6, Plts 132
• Ca 10.8, Creat 1.6
• IgG Level 5800 (A and M depressed)
• No Bence Jones proteinuria
• Bone Marrow: 60% plasmacytosis
• CRP normal, Albumin 3.4
• B2M elevated
Case contd.
• Does he have Myeloma?
• What is your first step?
• What to do about his hypercalcemia?
• What to do about his anemia?
• What to do about his bony disease?
Epidemiology
• 1% of malignancies
• 10% of Heme cancers
• 21000 Americans annually
Epidemiology
• Men > Women
• Blacks > Whites
• Median age of diagnosis is 66
• 10% < 50, 2% <40
Normal
+
-
M-protein
+
-
Pathophysiology
• Malignant plasma cell dyscrasia
• Accumulation of plasma cells in the bone
marrow
• These produce a single immunoglobulin
(Ig) – monoclonal protein
• Sequelae relate to presence of plasma
cells or interactions they induce via
cytokines in microenvironment
The Plasma Cell
Carr and Rodak: Clin Hematol Atlas
The malignant clone
IgM
Lymph node
Plasma cell
somatic
hypermutation
lymphoblast
plasmablast
IgG,A,D,E
plasma cell
Bone
Marrow
pre-B cell
How do plasma cells become “evil”?
Immunoglobulins
Mechanisms of Disease Progression in the
Monoclonal Gammopathies
Kyle, R. A. et al. N Engl J Med 2004;351:1860-1873
Molecular progression
Normal
plasma
cell
MGUS
Translocations
Infection
Inflammation
Asymptomatic
Myeloma
Active
Myeloma
ras & p53 mutation
c-myc dysregulation
Bone resorption
Angiogenesis
Aggressive
Myeloma
Del 13
Secondary
translocations
The Spectrum of Myeloma
MGUS
Organ
damage
none
Marrow
Disease
<10%
plasma
cells
Asymptomatic “True” MM PC
MM
Leukemia
(smouldering)
none
yes
yes
≥ 10% plasma ≥ 10%
cells
Management Monitor Close follow
1-2
up (q 3 mts)
times/yr
Transforma- 1% /yr
10-20%/yr
tion rate
plasma
cells
therapy
n/a
Plasma
cells in
blood
Highdose
combo
chemo
n/a
MGUS
Monoclonal Gammopathy of Unknown
Significance
• Presence of a serum monoclonal protein
(concentration ≤ 3g/dL)
• Less than 10% plasmacytosis in marrow
• No evidence of End-Organ damage (CRAB)
• Calcium elevation, Renal Insufficiency,
Anemia, Bony disease
• Asymptomatic
• No co-existing plasma cell dyscrasia or
lymphoproliferative disease (table)
Diseases associated with a monoclonal
gammopathy
• Plasma cell disorders
• Monoclonal gammopathy of undetermined significance
•
•
•
•
•
•
•
•
•
•
•
(MGUS)
Biclonal gammopathy of undetermined significance
Idiopathic Bence Jones proteinuria
POEMS syndrome, Osteosclerotic myeloma
Castleman's disease
AL (light chain) amyloidosis
Solitary plasmacytoma
Multiple myeloma, Smoldering multiple myeloma
B-cell lymphoproliferative disorders
Non-Hodgkin's lymphoma
Chronic lymphocytic leukemia
Lymphoplasmacytic lymphoma (Waldenstrom
macroglobulinemia)
• Post-transplant monoclonal gammopathies
Epidemiology
• Prevalence is approximately 1-3% in adults in
the USA, Sweden, France and Japan1
• Higher as we age:
• ≥ 50: 3.2%
• ≥ 70: 5.3%
• ≥ 85: 7.5%2
• 2-3 fold higher incidence in Africans and
African American population3
• Annual risk of transformation to MM or
related diseases of 1%4
1 Kyle Blood 1972, Axelsson Acta Med Scan 1986, Saleun J Clin Path 1982, Iwanaga Mayo Clin Proc 2007; 2 Kyle NEJM
2006; 3 Singh J Lab Clin Med 1990, Cohen AM J Med 1998, Landgren Blood 2006; 4 Kyle et al NEJM 2002
Risk of Progression among 1384 Residents of Southeastern Minnesota in Whom Monoclonal
Gammopathy of Undetermined Significance was Diagnosed in 1960 through 1994
Kyle R et al. N Engl J Med 2002;346:564-569
MGUS Progression
• Potential Predictive Factors of
Progression
• M protein size1
• IG class: IgA>IgM>IgG2
• Bone marrow plasmacytosis3,4
• Presence of urinary Bence Jones
proteinuria3
• Free Light Chain Assay5
1 Kyle NEJM 2002, 2 Kyle Blood 2003, 3 Cesana JCO 2002, 4
Perez-Persona Blood 2007 5 Rajkumar BJH 2004
Figure 3. Risk of progression of MGUS to myeloma or related disorder using a riskstratification model that incorporates the FLC ratio and the size and type of the serum
monoclonal protein
20 year
58%
37%
21%
5%
Rajkumar, S. V. et al. Blood 2005;106:812-817
Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.
Monitoring
• No absolute consensus
• Algorithm:
• Make accurate diagnosis
• Obtain baseline bloodwork (incl total Igs
and FLC), 24 hr urine and skeletal survey
• Repeat testing (history, physical, blood
work only) at 6 months
• If lower risk, can be seen annually
(assuming asymptomatic)
• If higher risk, I prefer every 6 months
Bone Marrow
Diagnosis of Myeloma
The diagnosis of Myeloma is made as a result of
several tests:
1. Blood Counts (CBC – white, red, platelets)
2. Blood and urine tests for immune proteins
– IgG, IgA, IgM – total number
(combination of normal protein and
abnormal or “M” protein)
– May also be “light chains” which are
component of abnormal protein
– May require 24 hour urine collections
Diagnosis of Myeloma contd.
3. Bone Marrow tests (aspirate and biopsy)
– This looks for the % of plasma cells in the marrow
– Also looks for abnormal cytogenetics of the plasma cells
and FISH analysis
4. X-rays
looking for osteopenia, lytic lesions and
fractures (NOT a bone scan)
possibly MRI of the spine
5. Other blood tests
creatinine, calcium, albumin beta-2microglobulin
Multiple Myeloma - Types
• Subtypes of MM are determined
based on the kind of abnormal
protein
IgG – 55%
IgA – 25%
IgD – 1-2%
IgM – 1%
Light Chain Disease only – 20%
Non Secretors 1-2 %
M spike in gamma region
Multiple Myeloma
• Unfortunately, MM is not a curable disease
(yet!!)
• Historically most people did not live for much
more than 2 years…
• However, the average survival is now at least 8
years
• This has been a result of two key
developments:
1. Autologous Stem Cell Transplant
2. Novel Drugs (thalidomide, bortezomib,
lenalidomide, carfilzomib, pomalidomide)
Myeloma Staging
• Older system of Salmon-Durie staging
• Not as useful anymore
• Newer system of using 2 factors:
• Albumin and Beta-2-microglobulin
• It is “prognostic” for survival
• Practically, there are 2 stages
1. Can wait and watch
2. Requires treatment
Cytogenetics
• These are the genes of the plasma cells
(not the patient)
• May indicate more about the biology of the
disease
• Most can be found at diagnosis, but others
may be “acquired” later
• Could well be the most “prognostic” tool
in myeloma as it may separate “high risk”
myeloma from standard risk
Molecular Prognostic Model
Survival probability
1.0
All others including
t(11;14)
P<0.001
0.8
D13
Poor
Intermediate
Good
0.6
0.4
24.7 mos
42.3 mos
51.0 mos
t(4;14)
t(14;16)
-17p13
0.2
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Months
Fonseca et al Blood 101:4569, 2003
Myeloma Treatment
Principles of therapy
1. Stop the production of the abnormal
plasma cells (chemo)
2. Strengthen the bone and prevent fractures
3. Increase the hemoglobin count and reduce
fatigue
4. Reduce risk of infections
5. Promote well being and quality of life
Treatment with Chemotherapy
• Goal is to reduce the number of plasma
cells and the proteins they produce
• Timing is important as it may be possible
to wait & watch
• It is not “curative” but may put the disease
into remission
• Must be tailored to individual based on
disease factors (type, severity, organs
involved) and patient factors (age, general
health…)
Managing myeloma: the components
Transplant
Eligible
Patients
Consolidation
Maintenance
Initial
Therapy
Transplant
Ineligible
patients
Treatment
of Relapsed
disease
Consolidation/ Maintenance/
Continued therapy
Supportive Care
mSMART
Mayo Stratification for Myeloma And Risk-adapted Therapy
Newly Diagnosed Myeloma
Website: www.msmart.org
mSMART 2.0: Classification of Active MM
High-Risk
 FISH
 Del 17p
 t(14;16)
 t(14;20)
 GEP
High risk
signature
Intermediate-Risk*
 FISH
 t(4;14)‡
 Cytogenetic
Deletion 13 or
hypodiploidy
 PCLI >3%
Mikhael et al Mayo Clinic Proceedings April 2013
Standard-Risk*†
All others including:
 Hyperdiploid
 t(11;14)**
 t(6;14)
mSMART 2.0: Classification of Active MM
High-Risk 20%
 FISH
 Del 17p
 t(14;16)
 t(14;20)
 GEP
High risk
signature
3 years
Intermediate-Risk 20%
 FISH
 t(4;14)*
 Cytogenetic
Deletion 13 or
hypodiploidy
Standard-Risk 60%
All others including:
 Hyperdiploid
 t(11;14)
 t(6;14)
 PCLI >3%
4-5 years
8-10 years
mSMART – Off-Study
Transplant Eligible
High Risk
Intermediate Risk
Standard Risk
4 cycles of VRd
4 cycles of CyBorD
4 cycles of Rda or CyBorD
Collect Stem Cellsb
Autologous stem cell
transplant, especially if
not in CR
V or VCd for minimum of
1 year
Autologous stem cell
transplant
Autologous stem cell
transplant
Bortezomib based therapy for
minimum of 1 year
a Bortezomib containing regimens preferred in renal failure or if rapid response
b If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixafor
needed
2 cycles of Rd
consolidation;
Then Len
maintenance if not
in VGPR and Len
responsive*
Continue
c
Rd; or
CyBorD
for ~12
months
c
Continue Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year
* Consider risks and benefits; consider limited duration 12-24 months
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin
Proc 2013;88:360-376. v11 //last reviewed Dec 2013
mSMART – Off-Study
Transplant Ineligible
High Risk
Intermediate Risk
Standard Risk*
VRd* for ~12 months,
MP + weekly Bortezomib
or weekly CyBorD for
~12 months
Rda, b
Continue VRd as
maintenance for minimum
of 1 year
Bortezomib based therapy
for minimum of 1 year
a
Dex is usually discontinued after first year
Bortezomib containing regimens preferred in renal failure or if rapid response needed
*Clinical trials strongly recommended as the first option
b
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin
Proc 2013;88:360-376. v11 //last reviewed Dec 2013
Initial Response
• Please note that the ultimate goal is both
•
•
•
DEPTH and LENGTH of response
Deepest response is “Complete”
Remission (=CR) vs partial remission or
minimal remission
It appears that a deeper response (esp CR)
may predict a longer remission and even
survival
HOWEVER, trends do not predict any
individual patient
• We treat the patient not the disease
Treatment sequence
Front line treatment
Induction
VAD
DEX
Consolidation
SCT
Maintenance
Maintenance
Nothing
Prednisone
Thalidomide
Relapsed
Rescue
Few options
Treatment sequence
NEW
Thal/Dex
VD
Rev/Dex
CyBorD
VTD
VRD
SCT
VD/VRD
Front line treatment
Induction
OLD
VAD
DEX
Consolidation
SCT
Nothing
Thalidomide?
Bortezomib?
Lenalidomide?
Maintenance
Post
consolidation
Nothing
Prednisone
Thalidomide
Bortezomib
Lenalidomide
Thalidomide
Carfilzomib
Pomalidomide
Elotuzumab
HDAC
Bendamustine
Monoclonal Antibodies
Relapsed
Rescue
Few options
IMPACT OF NOVEL THERAPY 2012/2013
Median 7.3 years
5 YEAR SURVIVAL BY AGE
AGE
AGE
≤ 65 YRS > 65 YRS
2012 ASH Abstract #3972 Kumar et al
2006-2010
73%
56%
2001-2005
63%
31%
Long-Term Survival With CyBorD
Induction Therapy In Newly Diagnosed
Multiple Myeloma
Craig B. Reeder, MD, Donna E. Reece, MD, Vishal Kukreti, MD, FRCPC, Joseph Mikhael, MD, Christine I.
Chen, MD, Suzanne Trudel, MD, Kristina Laumann, Joseph Hentz, Giovani Piza, Rafael Fonseca, MD, P.
Leif Bergsagel, MD, Jose F Leis, MD, PhD, Rodger E. Tiedemann, MBChB, PhD, FRACP, FRCPA, Jacy
Spong, BS, RN, BSN, Angela Mayo, PA/NP and Keith Stewart, MD
Reeder C. et al.; ASH 2013: abstract 3192
Results - Response
ITT
ORR
CR / nCR
Cohort 1
88% (29/33)
36% (12/33)
Cohort 2
90% (27/30)
47% (14/30)
All (n=63)
89% (56/63)
41% (26/63)
>VGPR
61% (20/33)
63% (19/33)
62% (39/63)
Cohort 1
Cohort 2
All (n=55)
96% (27/28)
46% (13/28)
93% (24/27)
48% (13/27)
93% (51/55)
47% (26/55)
71% (20/28)
63% (17/27)
67% (37/55)
After 4
cycles
ORR
CR / nCR
>VGPR
Reeder C. et al.; ASH 2013: abstract 3192
Results - Survival
Progression Free
Survival (5 yr)
Overall Survival (5
yr)
ALL
(n=63)
42%
(95% CI:31-57)
70%
(95% CI: 59-82)
Standard
Risk (n=39)
48%
(95% CI: 33-69)
81%
(95% CI: 69-95)
High Risk
(n=24)
33%
(95% CI: 19-59)
54%
(95% CI: 37-78)
Most patients underwent auto stem cell transplant after completing the induction trial
and most did not utilize maintenance therapy post SCT.
Reeder C. et al.; ASH 2013: abstract 3192
LONG-TERM SURVIVAL WITH CYBORD:
ASH 20131
OS by Risk Status
OS: All Patients
1
ASH Abstract #3192 Reeder et al
OS 81% at 5 years for
standard risk
The “NEW” CyBorD
• All three drugs given weekly
• Cyclophosphamide 300mg/m2 PO
• Bortezomib 1.5 mg/m2 IV or SQ
• Dexamethasone 40mg PO
• We consider one cycle a 4 week course
• No “week off”
• Less neuropathy, more convenience, equal
efficacy
• Always give viral prophylaxis
Retrospective, observational study: VCD and
VRD as initial treatment for MM
VCD
(n= 101)
Median age
Mean treatment duration
Pts undergoing ASCT
VRD
(n= 75)
62.7 years 60.9 years
5.1
5.4 months
months
59%
50%
Best response after 4 cycles
2-year PFS
2-year OS
Common AEs reported in at least 3 treatment
cycles
Fatigue
Peripheral Neuropathy
Anemia
GI
89%
66.6%
90.8%
81%
63.2%
87.4%
18%
11%
11%
9%
9%
16%
16%
8%
Conclusion: Comparable outcomes with VCD and VRD in terms of response,
PFS, OS and similar safety profiles
Kumar et al. ASH 2013: Abstract 3178, poster presentation
ASH 2012-3: Induction Regimens
Response Rates (%) & Survival
1
Trial
N
nCR/sCR
>=VGPR
>=PR
PFS
OS
CarCyDex
58
68
76
95
1-yr 86%
1 yr 85%
CarLenDex
41
68
88
96
1 yr ≤ 83
NA
CarThalDex1
50
18
60
92
1 yr 88%
NA
MLN9708-LenDex
65
23
58
90
1 yr 93%
NA
MLN9708-LenDex
64
24
67
96
NA
NA
CyCarThalDex
54
18
76
91
1 yr 90%
1 yr 98%
R2V2
30
40
73
97
1 yr 97%
1 yr 100%
Induction portion of CTD x 4 followed by HDM and consolidation with CTD x 4
Blood 120(21) 2012:
Sonneveld Abs 333
Blood 122(21) 2013:
Bringhen, Abs 685
Kumar Abs 332
Kaufman Abs 336: Len, Bortezomib, Dex, and Vorinostat
Korde, Abs 538
Mikhael, Abs 3179
Richardson Abs 535
How Deep a Response
Required before ASCT?
Effect of Pre-transplant Salvage Therapy Prior to
Autologous Transplant (ASCT) in Patients Not
Responding to Initial Induction for MM
Salvage Cohort
Salvage
Chemotherapy
Diagnosis and Initial
Induction
Autologous
Transplant
< PR to induction
No Salvage Cohort
Autologous
Transplant
Diagnosis
12 months from diagnosis to ASCT
Vij Blood 120(21) 2012, abstract 597
ASCT
MM06-04-12_6.ppt
Outcomes with/without Pre-ASCT Salvage
PFS
100
OS
100
90
90
P = NS
80
P = NS
70
80
NO SALVAGE
(n=251)
60
50
70
60
50
40
30
40
SALVAGE
(n=324)
SALVAGE
(n=324)
30
20
20
NO SALVAGE
(n=251)
10
0
0
2
4
6
Years
Vij Blood 120(21) 2012, abstract 597
10
0
8
10 0
2
4
6
Years
8
10
Median follow-up Salvage
No Salvage
Months
61 (9-181)
68 (110-180)
(Source: Txz12_23 & _24) MM06-04-12_15.ppt
Stem Cell Transplant
• Concept: eliminate any remaining abnormal
plasma cells in the bone marrow with HIGH dose
chemotherapy (ie what may be left after initial
chemotherapy)
•
Process
1. Use initial chemotherapy to reduce plasma cells
2. Collect stem cells from bone marrow
a. Mobilization with neupogen (G-CSF) +/- chemo
b. Collection by pheresis in stem cell unit
c. Storage of stem cells (frozen)
3. Admit and give high dose treatment (wipe out current marrow)
4. Re-Infuse stem cells previously collected and wait for them to
“grow”
ASCT
Patient
Priming
Therapy
Collect PBSCs
High-dose
Chemotherapy
Reinfuse
PBSCs
+/- Post-ASCT
therapy
Freeze
Autologous Stem Cell
Transplantation: Timing
• Most trials incorporate SCT as consolidation
therapy after initial treatment
• Trials comparing timing of transplant, as
part of initial treatment or after relapse,
show better disease free survival with initial
SCT but equivalent overall survival
• Currently there is some debate about the
role of SCT when novel drugs are used for
initial treatment
Autologous Transplant Improves Responses
after Traditional or Novel Induction
Sonneveld
JCO 12
Harrouseau
JCO 10
Cavo
Lancet 10
VAD
BtzAD
VAD
BtzD
ThalD
BtzThalD
Induction
≥nCR
5%
11%
7%
15%
11%
31%
Transplant
≥nCR
15%
31%
18%
35%
31%
52%
Transplant Ineligible
FIRST Design: Lenalidomide and Low-dose
Dexamethasone (Rd/Rd18) vs. MPT
n=535
Arm B
Rd18
n=541
LEN + Lo-DEX: 18 Cycles (72 wks)
LENALIDOMIDE 25mg D1-21/28
Lo-DEX
40mg D1,8,15 & 22/28
MEL + PRED + THAL 12 Cycles1 (72 wks)
Arm C
MPT
n=547
MELPHALAN
PREDNISONE
THALIDOMIDE
0.25mg/kg D1-4/42
2mg/kg D1-4/42
200mg D1-42/42
Subsequent anti-MM Tx
ARM
Arm AA
LENALIDOMIDE 25mg D1-21/28
Rd
N = 535 Lo-DEX
40mg D1,8,15 & 22/28
PD or Unacceptable Toxicity
LEN + Lo-DEX until Progressive Disease
RANDOMIZATION 1:1:1
LT Follow-Up
Active Treatment + PFS Follow-up Phase
PD, OS and
Screening
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 100 mg D1-42/42, Melphalan2 0.2 mg/kg D1–4
n= 1,623 - 18 countries from North America, Asia-Pacific, and Europe represented from 246 Centers
• Stratification: age, country and ISS stage
International Staging System; LT, long-term; PD, progressive disease; OS, overall survival
1Facon
T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.
Facon T. et._ASH 2013: Abstract 2
FIRST Trial: Final PFS
Continuous Rd  the risk of PFS events (PD or death) by 28% vs. MPT
Median PFS
100
80
Rd (n= 535)
25.5 mos
Rd18 (n= 541)
20.7 mos
MPT (n= 547)
21.2 mos
Hazard ratio
Patients (%)
Rd vs. MPT: 0.72; P = 0.00006
60
Rd vs. Rd18: 0.70; P = 0.00001
Rd18 vs. MPT: 1.03; P = 0.70349
40
72 wks
20
0
0
6
12
18
24
30
36
42
48
54
60
Time (months)
Rd
535
400
319
265
218
168
105
55
19
2
0
Rd18
541
391
319
265
167
108
56
30
7
2
0
MPT
547
380
304
244
170
116
58
28
6
1
0
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone.
Facon T. et._ASH 2013: Abstract 2
FIRST Trial: Overall Survival Interim Analysis
574 deaths (35% of ITT)
4-year OS
100
Patients (%)
80
Rd (n= 535)
59.4%
Rd18 (n= 541)
55.7%
MPT (n= 547)
51.4%
60
Hazard ratio
40
Rd vs. MPT: 0.78; P = 0.0168 ( 22% risk of death with Rd)
Rd vs. Rd18: 0.90; P = 0.307
Rd18 vs. MPT: 0.88; P = 0.184
20
The pre-specified boundary (p<0.0096) was not crossed for
Rd_continuous vs MPT_18 months
0
Rd
Rd18
MPT
0
6
12
535
541
547
488
505
484
457
465
448
18 24 30 36 42 48
Overall survival (months)
433
425
418
403
393
375
338
324
312
224
209
205
121
124
106
43
44
30
54
60
5
6
3
0
0
0
Facon T. et._ASH 2013: Abstract 2
Relapsed Disease
Treatment sequence
NEW
Thal/Dex
VD
Rev/Dex
CyBorD
VTD
VRD
SCT
VD/VRD
Front line treatment
Induction
OLD
VAD
DEX
Consolidation
SCT
Nothing
Thalidomide?
Bortezomib?
Lenalidomide?
Maintenance
Post
consolidation
Nothing
Prednisone
Thalidomide
Bortezomib
Lenalidomide
Thalidomide
Carfilzomib
Pomalidomide
Elotuzumab
HDAC
Bendamustine
Monoclonal Antibodies
Relapsed
Rescue
Few options
Carfilzomib: A Novel Agent Designed to Promote
Selective and Sustained Proteasome Inhibition
• Carfilzomib is a next-generation, selective proteasome inhibitor
• Potent and sustained target suppression
• Improved antitumor activity
• Minimal off-target activity with low neurotoxicity
Tetrapeptide
H
N
N
O
O
O
Adapted from: Kuhn DJ, et al. Blood. 2007;110:3281-3290.
N
H
H
N
O
Epoxyketone
O
O
N
H
O
69
Neuropathy Was Infrequent and Not Dose Limiting
Pooled data from single-agent studies (003 / 004 / 005)
N=505
• Peripheral neuropathy
occurred infrequently across
all single-agent studies*
• Only 6 patients (1.2%)
experienced a Grade 3
PN event
• No Grade 4 PN events
Did not experience
peripheral neuropathy
• Only 1 patient had drug
discontinued for PN (study 004;
BTZ-treated arm)
Grade 1/2 PN
(13.4%)
Grade 3 PN
(1.2%)
*Includes the terms peripheral neuropathy, neuropathy, peripheral sensory neuropathy,
Adapted from: Singhal S, et al. ASH 2010. Abstract 1954 (poster presentation).
peripheral
motor neuropathy
70
Carfilzomib - Practical
• Highly effective and very well tolerated
• Beware of tumor lysis hence dosing
schedule
• Cardiac issue present but mostly
mitigated by fluid management
• Issues of weekly dosing being explored
• Lack of neuropathy very attractive
• Upfront uses increasing
Molecular Structure of Thalidomide,
Lenalidomide and Pomalidomide
Structurally similar, but functionally different both qualitatively and quantitatively
Myeloma Pomalidomide Summary
Lacy
Pom/Dex
1-3 reg
Lacy
Pom/Dex
Len ref
Richardson
Pom+/- dex
MM-002
 PR
63%
32%
28%
 MR
82%*
47%
52%
Median 3 prior
regimens
Median 4-6 prior
regimens
73
Pomalidomide - Practical
• Similar to lenalidomide with slightly
less myelotoxicity and fatigue
• Dosing range 2-4mg
• Thromboprophylaxis necessary
• Feasible in combination
NEWER THERAPIES: ASH 2013
TOP 8
 Anti-CD 38 monoclonal antibodies (MAb) daratumumab
(abstracts #227 and #1986) and SAR 650984 (#284)
 MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983)
 ARRY 520 (abstracts #285 and #1982)
 ACY-1215 (abstracts #759 and #3190)
 Selinexor (also known as KPT-330, abstract #279)
 Anti-CD 138 monoclonal antibody (BT062, indatuximab
ravatansine, abstract #758)
 Panabinostat (abstract #1970)
 Bendamustine (abstract #1971)
Conclusions
•
MGUS is a common condition that must be
appropriately managed, including risk stratifying
patients
•
Multiple Myeloma is an uncommon condition but has
improved survival with use of novel agents and stem
cell transplant
•
Newer agents are showing outstanding results with
the recent additions of carfilzomib and
pomalidomide
•
Although the mainstay of treatment is directed at the
cancer itself, considerations must be given to
supportive care and quality of life