Transcript OE-MM-FAQs

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Pre-activity Survey
• Please take out the Pre-activity Survey from your packet
• It is important that you fill out the demographic information
at the top of the form
• Your answers are important to us and will be used to help
shape future CME activities
Polling Question
Pre-activity Survey
Please rate your level of confidence in your ability to treat
and manage patients with multiple myeloma (MM):
1
Not at all confident
2
3
4
5
Expert
Polling Question
Pre-activity Survey
A 55-year-old patient presents with a progressive mild decrease in
hemoglobin, but is asymptomatic for MM. His workup revealed a
hemoglobin of 11, calcium of 9.2, paraprotein peak of 2.6 with a beta-2
microglobulin of 3.7, and 30% plasma cells with diploid cytogenetics
and no high-risk FISH. What further workup would you recommend at
this time?
A. No further work-up recommended
B. MRI and/or PET/CT
C. Gene expression profiling
D. Immune spectrotyping
Polling Question
Pre-activity Survey
Over a 4-month period, a patient receives 5 cycles of
lenalidomide/dexamethasone and bortezomib and achieves a partial
response. What is your treatment recommendation for this patient?
A. Continue on RVD
B. Change to other treatment
C. Proceed to stem-cell harvest and autograft consolidation
Polling Question
Pre-activity Survey
A patient relapses after an 18-month complete response following
consolidation with melphalan, autologous stem-cell rescue, and
lenalidomide daily maintenance. She is treated with 6 cycles of
bortezomib/dexamethasone; however, a month later, kappa-light
chains and FDG avid bone lesions on PET/CT increase. Which
treatment is most suitable for this patient?
A. Cyclophosphamide/bortezomib/dexamethasone
B. Salvage melphalan 200 mg/m2 with autologous stem-cell rescue
C. Bortezomib/lenalidomide/dexamethasone
D. Carfilzomib-based combinations OR pomalidomide/low-dose
dexamethasone
E. Lenalidomide/dexamethasone
Polling Question
Pre-activity Survey
Which of the following factors would NOT impact treatment
selection for relapsed/refractory MM:
A. Prior lines of therapy
B. Myeloma genomics
C. Comorbidities
D. Personal lifestyle
E. Clinical trial option
F. None of the above, since all these factors would impact
treatment selection
Educational Objectives
• Discuss the role of cytogenetic and molecular analyses in
personalizing care in MM
• Review the treatment course for patients with smoldering
MM
• Assess the optimal use of induction therapy and transplant
to improve patient survival in MM
• Evaluate the use of high-dose chemotherapy vs novel
agents for relapsed/refractory MM
Smoldering Multiple
Myeloma
FAQs Regarding Smoldering Myeloma
• How do I treat a patient who presents with none of the
common symptoms for myeloma (bone marrow clonal
plasma cells just greater than 10, monoclonal peak barely
at 3, mild anemia and no other symptoms related to the
disease)?
• Do I really have to wait for a patient to have a calcium level
of 11, creatinine level of 2, or less than 12 grams of
hemoglobin or to get infected before I initiate treatment?
Case Presentation
54-year-old male
2/11 progressive mild decrease in hemoglobin. No symptoms
and normal exam. W/up reveals Hb 11; Ca 9.2; IgG 3786;
albumin 4.2; mpeak 2.6; B2M 3.7
BMA 30% plasma cells
Diploid cytogenetic no high-risk FISH
Case Question
What further work-up is recommended?
1. No further work-up recommended
2. MRI and PET CT
3. Gene expression profiling
4. Immune spectrotyping
Specific Diagnostic Tests
• Laboratory analysis
– Complete blood count and complete metabolic panel
•
β2M, LDH
– M proteins
• Radiologic imaging
– Skeletal survey, MRI/CT, PET
• Bone marrow biopsy
• Specific tests to rule out other
• Causes of anemia, renal insufficiency,
• Hypercalcemia, etc.
National Comprehensive Cancer Network (NCCN) Guidelines for Diagnosis of Multiple Myeloma.
Differential Diagnosis
Premalignant condition
Plasma cell malignancy
MGUS1-4
(Monoclonal Gammopathy of
Undetermined Significance)
Smoldering
Multiple
Myeloma1-5
Multiple
Myeloma6-7
Asymptomatic
Asymptomatic
Symptomatic (~89%)
Active treatment
No
No or clinical trial
Yes
M-protein (per dL)
<3 g
>3 g
M-spike or
plasmacytoma
Clonal plasma cells
in bone marrow
<10%
>10%
>10%
End-organ damage
None
None
1 or more CRAB criteria
1% per year
10% per year for
first 5 years;
73% by 15 years
Not Applicable
Symptoms
Likelihood of
progression
1. Kyle RA et al. N Engl J Med. 2007;356:2582-2590.
2. International Myeloma Working Group. Br J Haematol. 2003;121:749-757.
3. Jagannath S et al. Clin Lymphoma Myeloma Leuk. 2010;10:28-43.
4. Kyle RA et al. Curr Hematol Malig Rep. 2010;5:62-69.
5. Mateos M-V et al. Blood. 2009;114:Abstract 614.
6. Durie BG Salmon SE. Cancer. 1975;36:842-854.
7. Durie BG et al. Leukemia. 2006;20:1467-1473.
CRAB CRITERIA
HyperCalcemia
Renal dysfunction
Anemia
Bone lesions
Increased Infections
Case Presentation
MRI no lesions
PET CT negative
Marrow 30% plasma cells diploid cytogenetics
Dxd with asymptomatic myeloma
What is the risk of this patient to progress to symptomatic
myeloma?
Risk Factors For Progression
Reference
Wisloff
Factor
% BM/PC
>20
Lytic Lesions
+
M peak
Dimop
Preoteinuria
>50
mg/24h
Witzig
>3 gm
Circulating
PC
Hb
FLC ratio
FISH Low
risk
Int risk
High risk
Facon
Dipenz
>20
>10%
>3gm
>2gm (IgA)
>3 gm
Rajkumar
Kastritis
>60%
+
<12
>8
>100
Normal
Others
T4,14 or
Del17
TTP 0 Risk
39 m
61 m
9m
>50 m
> 60 m
>60 m
73 m
TTP All Risk
10m
10 m
30 m
6m
24 m
24 m
8m
Disease Progression in SMM and
MGUS Patients
Smoldering Multiple Myeloma
10% risk of progression per year*
• Screen every 4-6 weeks
*For first 5 years, ~3% per year for
next 5 years, ~1% per year thereafter
MGUS
1% risk of progression per year
• First year: screen every 3 to 6 months
• After first year: screen at least
every 1 to 2 years
• 3% of people older than 50 years
• 5% of people older than 70 years
Kyle RA et al. N Engl J Med. 2007;356:2582-2590.
Jagannath S et al. Clin Lymphoma Myeloma Leuk. 2010;10:28-43.
Kyle RA et al. Curr Hematol Malig Rep. 2010;5:62-69.
Algorithm for Reclassifying SMM
and Active MM
*Consider including patients with the following FISH: deletion 17p, t(4;14), and 1q21 gains as active MM; this
population could account for as many as 30% of SMM patients. §Consider using more than 1 fluorodeox.
ARajkumar et al, 2014, Lancet Oncology, 15(12), e538-e548; Dispenzieri A et al. Blood. 2013;122:4172-4181.
Proposed Guidelines on Follow-up and Management of SMM
Patients suspected to have MM should first be defined as having MGUS,
SMM, or myeloma requiring therapy.
Ghobrial IM, Landgren O. Blood. 2014;124:3380-3388. © 2014 American Society of Hematology.
Evidence for Early Treatment of High-risk SMM
with Lenalidomide plus Dexamethasone
Survival Outcomes in the Per-Protocol Population
A
B
• Major Pitfalls of Mateos Study
C
– Control group DID NOT receive lenalidomide
– Control group did not receive uniform treatment
(some actually may have received MP)
• Notwithstanding
• Magnitude of benefit dramatic
Mateos et al. N Engl J Med. 2013;369:438-447.
Main Limitation of the Mateos Study
“…One limitation of the study was that patients received treatment off-protocol at the
time of disease progression to symptomatic myeloma. It would have been informative
to examine early treatment with lenalidomide and dexamethasone versus treatment
with lenalidomide and dexamethasone that was deferred until the time of
progression. However, the combination of lenalidomide and dexamethasone is not an
approved first-line regimen for newly diagnosed multiple myeloma, and most patients
in this study (81%) were treated with either bortezomib-based regimens (53% of
patients) or induction therapy followed by autologous stem-cell transplantation (28%)
at the time of progression…”
Summary
• Asymptomatic myeloma is an entity that needs to be better
defined
– All patients with newly diagnosed asymptomatic myeloma
need to be followed closely for the first 2-3 years (every
6-12 week visits)
– All patients should be encouraged to participate in clinical
trials
– Patients with high-risk disease should be treated as
symptomatic myeloma
Case Presentation
Over the next 6 months develops progressive anemia to a
Hb of 10gm/dL
Bone marrow now shows 60% plasma cells
15% show deletion 17 by FISH
Karyotype normal
No lytic lesions
Is there an optimal induction regimen?
FAQs for Induction
• Have we fully defined the role of molecular and cytogenetic
classifications in myeloma?
• What is the optimal induction regimen?
• How much induction treatment should a transplant-eligible
patient receive?
• Should I recommend SCT for a patient who has failed to
achieve a PR or CR after receiving 5 cycles of induction
therapy?
• Is allogeneic transplant a reasonable option for a patient
with standard-risk disease?
Multiple Myeloma Treatment Linesa
Front-line treatment
Induction
IMiD: Thal-Len
Proteasome Inhibitor: Bor-Car
Steroids: Dex-Pred
Alkylator: Cyclo-Mel
Anthracycline: LipoDnr-Adr
Consolidation
SCT
Maintenance
Relapsed
Maintenance
Rescue
Observation
IMiD: Thal-Len
Proteasome Inh-Bor
Steroids: Dex-Pred
IMiD: Thal-Len-Pom
Proteasome Inh: Bor-Car
Steroids: Dex-Pred
Alkylators: Mel-Cy-Benda
Investigational
aTransplant-eligible patients.
Bor/Dex = bortezomib, dexamethasone;
Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin;
Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone;
Len/Dex = lenalidomide, dexamethasone;
SCT = stem-cell transplant; Thal/pred = thalidomide, prednisone;
Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin.
NCCN, 2009.
Impact of Chromosomal Abnormalities on
Survival Outcomes in MM (cont.)
IMWG Analysis
Genetic Abnormalities
4-year Estimated OS
Minus vs Plus Abnormality
Log Rank
P Value
Any
73% vs 57%
<0.0001
t(4;14)
ISSI
ISS2
ISS3
64% vs 36%
81% vs 52%
63% vs 30%
44% vs 22%
<0.0001
<0.0001
<0.0001
<0.007
Del(17)
ISSI
ISS2
ISS3
68% vs 44%
81% vs 64%
68% vs 42%
48% vs 28%
<0.0001
<0.020
<0.0001
<0.020
a. ISSI or ISS2, normal FISH
193/610 deaths (76%)
b. ISSI + abnormal FISH/ISS3 +
normal FISH
140/252 deaths (52%)
c. ISS2 or ISS3 + abnormal FISH
146/196 deaths (32%)
ISS = International Staging System
Avet-Loisseau H et al. J Clin Oncol. 2009;27:4585-4590.
a vs b <0.0001
a vs c <0.0001
b vs c <0.0001
Goals of Therapy
Longest life with best quality of life with
minimal burden of treatment
A Meta-analysis of Phase III Studies Comparing
Bortezomib-based vs Non-bortezomib-based
Induction Treatment Before ASCT
A
B
100
100
80
80
Overall Survival (%)
Progression-Free Survival (%)
Bortezomib based
Bortezomib based
60
40
Non-bortezomib based
40
20
20
Non-bortezomib based
Bortezomib based
No. at risk
Non-bortezomib based
Bortezomib based
Non-bortezomib based
60
0
6
785
787
671
722
Non-bortezomib based
Bortezomib based
P=0.0001
0
12 18 24 30 36 42 48 54 60
Time (months)
604
675
527
609
429
491
306
360
178
212
98
101
54
58
25
31
10
10
Michele Cavo, MD. Presented at: ASH2013, Abstract #767.
No. at risk
Non-bortezomib based
Bortezomib based
6
P=0.0402
12 18 24 30 36 42 48 54 60
Time (months)
785
787
727
746
694
722
662
698
614
641
486
515
309
338
174
191
100
117
52
60
Sonneveld P. J Clin Oncol. 2013;31:3279-3287.
18
20
Case Presentation
Over the next 3 months receives 4 cycles of
lenalidomide / dexamethasone and bortezomib
and achieves a PR
Stem cells are collected
Case Question
What would you recommend for this patient?
• Continue on RVD?
• Change to other treatment?
• Proceed to autograft consolidation?
Autologous Bone Marrow Transplant –
Long-term Results
Barlogie B et al. Bone Marrow Transplant. 1998;21:1101-1107.
Role of High-dose
Melphalan in Myeloma in
the Era of IMiDs and
Proteasome Inhibitors
Benefit of Autografting for Myeloma
Figure 2
Koreth J et al. Biol Blood Marrow Transplant. 2007;13:183-196. (DOI:10.1016/j.bbmt.2006.09.010).
Copyright © 2007 American Society for Blood and Marrow Transplantation. Terms and Conditions.
IFM/DFCI 2009 Study
Newly Diagnosed MM Patients (SCT Candidates)
Randomize, stratification ISS & FISH
VRD x 3
CY (3g/m2)
MOBILIZATION
Induction
VRD x 3
Collection
CY (3g/m2)
MOBILIZATION
Goal: 5 x106 cells/kg
Goal: 5 x106 cells/kg
Melphalan 200mg/m2*
+ ASCT
VRD x 5
Consolidation
Lenalidomide 12 mos
VRD x 2
Lenalidomide 12 mos
Maintenance
http://www.clinicaltrials.gov/ct2/show/NCT01208662?term=nct01208662&rank=1.
SCT at relapse
MEL 200 mg/m2 if <65 yrs,
≥65 yrs 140mg/m2
Mel200-ASCT vs CC+R: PFS1
Median Follow-up from Randomization: 4 Years
Gay et al, Blood, 2014 124(21). Abstract 198.
Mel200-ASCT vs CC+R: Second-line Therapy
Gay et al, Blood, 2014 124(21). Abstract 198.
Mel200-ASCT vs CC+R: OS
Median Follow-up from Randomization: 4 Years
Gay et al, Blood, 2014 124(21). Abstract 198.
Mel200-ASCT vs CC+R
Mel200-ASCT
vs
CC+R
OS Subgroup analysis
HR (95% CI)
P value
Age <60
0.67 (0.41-1.11)
0.117
Age ≥60
0.44 (0.23-0.86)
0.015
KPS 60-70%
0.76 (0.33-1.72)
0.506
KPS 80-100%
0.54 (0.34-0.85)
0.008
ISS I/II
0.55 (0.34-0.89)
0.016
ISS III
0.75 (0.38-1.45)
0.376
No del17, t(4;14), t(14;16)
0.57 (0.34-0.94)
0.029
Del17, t(4;14), t(14,16)
0.60 (0.31-1.14)
0.118
LDH < ULN
0.62 (0.41-0.95)
0.027
LDH ≥ ULN
0.23 (0.03-1.92)
0.177
Favors Mel200-ASCT
Favors CC+R
OS, overall survival; KPS, Karnofsky Performance Status; ISS, International Staging System; LDH, lactate dehydrogenase; ULN, upper limit of normal; Mel200-ASCT,
melphalan 200 mg/m2 followed by autologous stem cell transplantation; CC+R, conventional chemotherapy + lenalidomide
Gay et al, Blood, 2014 124(21). Abstract 198.
1st Autologous
Transplant
n=710
No Sibling Donor
Auto-Auto
n=484
High
Risk
n=48
Sibling Donor
Auto-Allo
n=226
Standard
Risk
Standard
Risk
n=436
n=189
Main groups compared
High
Risk
n=37
Survival Outcomes after the First Transplant
Auto-Auto vs Auto-Allo: Intent-to-treat analysis
Progression-free Survival
100
Overall Survival
Auto/Auto, 80% @ 3yr
Auto/Auto, 46% @ 3yr
90
100
90
80
80
Probability, %
70
70
Auto/Allo, 77% @ 3yr
60
60
50
50
Auto/Allo, 43% @ 3yr
40
40
30
30
20
20
10
10
P-value = 0.67
0
Months
# at risk:
0
Auto/Auto 436
Auto/Allo 189
P-value = 0.19
0
6
12
18
24
30
36
42 48
0
6
12
18
24
30
36
42
48
395
165
348
138
292
117
242
105
213
89
178
71
54 42
23 16
436
189
424
183
406
167
395
160
370
156
348
143
305
124
107
43
79
27
CALGB 100104 Schema
Registration
D-S Stage 1-3, ≤70 years
≥2 cycles of induction
Attained SD or better
≤1 yr from start of therapy
≥2 x 106 CD34 cells/kg
Restaging
Days 90–100
Randomization
Placebo
Mel 200
ASCT
CR
PR
SD
Stratification based on registration -2M level and prior
thalidomide and lenalidomide use during Induction. Primary
Endpoint: powered to determine a prolongation of TTP from
24 months to 33.6 months (9.6 months)
Lenalidomide*
10 mg/d with ↑↓
(5–15 mg)
* provided by Celgene
Corp, Summit, NJ
Time to Progression
CALGB 100104; N Engl J Med. 2012.
Multivariate Analysis of Prognostic
Factors for PFS
Variable
PFS
HR
95% CI
P
< CR at induction
1.80
1.29-2.51
0.001
Del(17p) and/or t(4;14)
1.56
1.18-2.05
0.002
ISS > 2
1.57
1.14-2.17
0.006
Plts <150 (109/L)
1.48
1.05-2.08
0.025
Hb <10.5 (g/dL)
1.32
1.03-1.70
0.028
Del(13q)
1.20
0.94-1.54
0.145
IgA isotype
1.13
0.85-1.50
0.393
Creat >1.2 (mg/dL)
0.87
0.64-1.19
0.391
Hazard Ratio
Michele Cavo, MD. Presented at: ASH2013, Abstract #767.
1
2
PFS According to Preplanned ASCT(s) for Patients with
del(17p) and/or t(4;14) and Who Failed CR after B-based
Induction Regimens
Score
2
ISS
Prognostic factors
Cytogenetic abnormalities
Response at induction
1-2
Del(17p) ± t(4;14)
< CR
70 (11.55%)
3
3
Del(17p) – t(4;14)Del(17p) ± t(4;14)
< CR
CR
65 (10.73%)
6 (0.99%)
N° of pts (%)
141 (23.27%)
Kaplan-Meier survival estimates
1.00
0.75
1 ASCT
0.50
2 ASCT
42 mo
21 mo
0.25
Log rank test:
P=0.004
0.00
0
HR 0.41 (0.22 - 0.77)
P=0.006
12
Michele Cavo, MD. Presented at: ASH2013, Abstract #767.
24
Months
36
48
OS According to Preplanned ASCT(s) for Pts With
del(17p) and/or t(4;14) and Who Failed CR After B-based
Induction Regimens
Score
2
ISS
Prognostic factors
Cytogenetic abnormalities
Response at induction
1-2
Del(17p) ± t(4;14)
< CR
70 (11.55%)
3
3
Del(17p) – t(4;14)Del(17p) ± t(4;14)
< CR
CR
65 (10.73%)
6 (0.99%)
N° of pts (%)
141 (23.27%)
Kaplan-Meier survival estimates
1.00
0.75
2 ASCT
76%
0.50
0.25
Log rank test:
P=0.0001
0.00
0
1 ASCT
HR 0.22 (0.10 - 0.50)
P<0.001
12
Michele Cavo, MD. Presented at: ASH2013, Abstract #767.
33%
24
Months
36
48
BMT CTN 0702: SCHEMA
Lenalidomide*
Maintenance
Register and
Randomize
MEL 200mg/m2
* Bortezomib 1.3mg /m2 days 1, 4, 8,11
Lenalidomide 15mg days 1-15
Dexamethasone 40mg days 1, 8, 15
**Lenalidomide 15 mg daily x 3years
VRD x 4*
Lenalidomide
Maintenance**
MEL
200mg/m2
Lenalidomide
Maintenance**
Relapsed/Refractory
Multiple Myeloma
FAQs Regarding Relapsed/Refractory
Multiple Myeloma
• Is there a role for high-dose chemotherapy consolidation in
the era of novel, more effective agents and strategies? Do
we know the optimal timing for HD chemotherapy?
• What are the pros and cons of emerging therapies and
novel treatment strategies based on recent clinical data?
Case Presentation
• 54-year-old male with progressive anemia to Hb of
10gm/dL; Ca 9.2; IgG 6800; albumin 4.2; mpeak 4.5; B2M
5.5. No lytic lesions, but bone marrow 60% plasma cells,
normal karyotype with 15% deletion 17 by FISH
• Receives 4 cycles of lenalidomide/dexamethasone and
bortezomib and achieves a PR, followed by consolidation
with melphalan 200 mg/m2 with autologous stem cell
rescue and len 10 mg po daily maintenance (along with
monthly zoledronic acid) with a CR for 1.5 years and then
relapses by free light chains with a kappa of 150 mg/L and
KLR of 162
Case Presentation
• Treated with bortezomib/dexamethasone for 6 cycles
with a PR and then was off therapy for a preplanned trip.
The kappa light chains increased again 35 days later to
205 and a KLR of 232 along with asymptomatic but new
FDG avid bone lesions on PET-CT.
Case Question
Which treatment would you choose for this patient at this time?
1. Cyclophosphamide/bortezomib/dexamethasone
2. Salvage melphalan 200 mg/m2 with autologous stem cell
rescue
3. Bortezomib/lenalidomide/dexamethasone
4. Carfilzomib-based combinations
5. Pomalidomide/low-dose dexamethasone
6. Lenalidomide/dexamethasone
7. Unsure
Factors to Consider in Treatment Selection
• CRAB symptoms, disease burden, and rate of progression
• Prior therapies
– Depth and duration of prior response
– Side effects
– Time since therapy
• Myeloma genomics
• General health – diabetes, CBC, cardiac/hepatic/renal function,
neuropathy, VTE
• Personal lifestyle and preferences
• Option for clinical trial
MM-003 Final Analysis: Pomalidomide/LoDex vs
HiDex in Relapsed/Refractory MM: Efficacy Data
PFS*
1.0
Median PFS, Mos
0.8
Pom + LoDex (n = 302)
4.0
HiDex† (n = 153)
1.9
Proportion of Patients
Proportion of Patients
1.0
OS
0.6
HR: 0.50
P <0.001
0.4
0.2
0
Median OS, Mos
0.8
4
8
12
16
20
24
13.1
HiDex† (n = 153)
8.1
0.6
0.4
0.2
HR: 0.72
P =0.009
0
0
Pom + LoDex (n = 302)
0
4
PFS (Mos)
8
12
16
OS (Mos)
• ORR (overall): 31% (26% PR) Pom/LoDex vs 10% (9% PR) HiDex
*Primary endpoint.
†85 pts (56%) on the HiDex arm received subsequent Pom.
San Miguel J et al. Lancet Oncol. 2013;14:1055-1066.
Dimopoulos MA et al. Presented at: ASH 2013, Abstract #408. Reproduced with permission.
20
24
28
Pomalidomide/LoDex vs HiDex: Safety
• AEs generally similar between arms and across subgroups
– Most common grade 3/4 AEs: neutropenia, anemia, thrombocytopenia
– ≥ grade 3 PN in 15% with Pom plus LoDex vs 11% with HiDex
Pom + LoDex
(n = 300)
AE, %
HiDex
(n = 150)
Grade 3
Grade 4
Grade 5
Grade 3
Grade 4
Grade 5
Infections and infestations
24
6
4
19
5
9
Anemia
31
2
--
32
5
--
Neutropenia
26
22
--
9
7
--
Fatigue
5
--
--
6
--
--
Thrombocytopenia
9
13
--
9
17
--
Pyrexia
3
<1
--
3
1
--
Diarrhea
1
--
--
1
--
--
Constipation
2
--
--
--
--
--
<1
<1
--
<1
--
--
Back pain
4
1
--
3
<1
--
Dyspnea
4
1
--
5
--
--
Febrile neutropenia
8
2
--
--
--
--
Cough
San Miguel J et al. Lancet Oncol. 2013;14:1055-1066.
Carfilzomib, an Irreversible Proteasome
Inhibitor, in Relapsed/Refractory MM
– Approval based on
single-arm phase II
PX-171-003 study
(n = 266): ORR of 23.7%
and median DOR of
7.8 mos[1]
Pts Alive and Without Progression (%)
• Carfilzomib FDA approved in 2012 for treatment of MM after
≥2 previous therapies, including bortezomib and an IMiD, and with
progression on or within 60 days of treatment
PFS
100
Median PFS: 3.7 mos (95% Cl: 2.8-4.6)
75
50
25
Censored observations
Confidence band
0
0
1. Siegel DS et al. Blood. 2012;120:2817-2825.
2. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2014.
2.5
5.0
7.5 10.0 12.5 15.0
Mos From Start of Treatment
17.5
Integrated Safety Profile of Single-agent
Carfilzomib: Experience from 526 Patients
• 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005)
Select AEs, %
All Grades
Related
Grade 3/4
Serious AE
Fatigue
Anemia
Nausea
Any cardiac event
Cardiac failure
Any respiratory event
 Dyspnea
Any renal impairment
 Serum creatinine
 Acute renal failure
55.5
46.8
44.9
22.1
7.2
69.0
42.2
33.1
24.1
5.3
41.4
26.8
35.2
NR
7.6
22.4
1.3
9.5
5.7
10.3
4.9
7.2
2.7
4.4
0
1.3
0
7.8
4.9
6.5
2.1
6.1
1.3
4.2
Peripheral neuropathy
13.9
NR
1.3
NR
NR
NR
• Tolerable safety profile allows for administration of full-dose carfilzomib with low
discontinuation rates
Siegel D et al. Hematologica. 2013;98:1753-1761.
Single Agent and Doublet Efficacy
ORR
PFS
(months)
OS
(months)
0%
30%
2y : 20%
2y : 48%
49%
0%
38%
6.22
30
646
41%
0%
43%
9
33
3
177
41%
10%
61%
11.1
29.6
Len Dex MM010
3
349
30%
4.5%
60%
11.3
38
CFZ (+dex 8)
2
266
100%
99%
23.7%
3.7
15.6
Pom D vs Dex
3
302
100%
95%
31%
4.2
13.1
Trial
IMiD
PI
exposed exposed
Phase
n
Thalidomide
2
169
0%
BTZ vs DEX
3
669
BTZ + doxil vs
BTZ
3
Len Dex MM009
Barlogie B. Blood. 2001;98:492-494.
Richardson P. N Engl J Med. 2005;352:2487-2498.
Orlowski RZ. J Clin Oncol. 2007;25:3892-3901.
Weber D. N Engl J Med. 2007;357:2133-2142.
Dimopoulos M. N Engl J Med. 2007;357:2123-2132.
Siegel DS. Blood. 2012;120:2817-2825.
San Miguel J. Lancet Oncol. 2013;14:1055-1066.
Phase III CarRd vs Rd (ASPIRE) Study Design
28-day cycles
CarRd
Key inclusion criteria:
• 1–3 prior treatments
• Relapsed or PD
• ≥PR to at least 1 prior
regimen
Key exclusion criteria:
Carfilzomib 27 mg/m2 IV (10 min)
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)
Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
Randomization
n=792
After C12, carfilzomib given D 1, 2, 15, 16
After C18, carfilzomib discontinued
• CrCl <50 mL/min
• PD on BTZ
• PD on Rd
• Len or dex intolerance
Rd
Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
Primary Endpoint: Progression-free Survival
ITT Population (n=792)
Primary Endpoint: Progression-free Survival
by Subgroup
23.1 vs 13.9 mos (P 0.083)
29.6 vs 19.5 mos (P 0.004)
Kaplan-Meier 24-Month Overall
Survival Rates
Percentage of Patients
80
70
60
CarRd
50
40
30
73.3%
Rd
65.0%
20
10
0
• Unadjusted P value from the stratified log-rank test comparing the
overall survival curves up to 24 months was 0.0046
Adverse Events in the Safety Population
Stewart AK et al. N Engl J Med. 2014. DOI: 10.1056/NEJMoa1411321.
PI + IMiD + Dex (Triplet) Efficacy
Trial
Phase
n
IMiD
exposed
IMiD
PI
PI
refractory exposed refractory
ORR PFS OS
(mos) (mos)
Bort Thal
Dex
1-2
85
74%
most
0%
0%
65%
6
22
Bort Len
Dex
2
64
73%T
6% L
3%
53%
8%
64%
9.5
30
Bort Pom
Dex
1
28
100%
100%
100%
NA
71%
NA
NA
Car-LenDex
2
52
73%
44%
80%
25%
77% 15.4 NA
Car-PomDex
1/2
79
100%
100%
89%
91% in
ph 1
Pineda-Roman M. Leukemia. 2008;22:1419-1427.
Richardson PG et al. Blood. 2014;123:1461-1469.
Richardson PG et al. Presented at: ASCO 2014.
70%
Wang M et al. Blood. 2013;122:3122-3128.
Shah JJ et al. Presented at: ASH 2013. Abstract 690.
9.7
NR
PANORAMA 1: Phase III Study of Panobinostat +
Bortezomib + Dexamethasone in Relapsed or
Relapsed and Refractory MM
Panobinostat significantly extended progression-free survival
PBD
n = 387
Pbo-BD
n = 381
P
Median PFS, mo
11.99
8.08
<0.0001
Median OS, mo
33.64
30.39
0.26
ORR, %
60.7
54.6
0.09
CR/nCR, %
27.6
15.7
0.00006
Median DOR, mo
(range)
13.14
(11.76-14.92)
10.87
(9.23-11.76)
Median TTR, mo
(range)
1.51
(1.41-1.64)
2.00
(1.61-2.79)
Panobinostat, bortezomib, and dexamethasone
Placebo, bortezomib, and dexamethasone
Progression-free survival (%)
HR 0.63, 95% CI 0.52-0.76; P<0.0001
Time (months)
• Median PFS was significantly longer in the panobinostat group
• There is also a trend toward better OS in the panobinostat group
• ORRs were similar for the two groups; however, the CR/nCR rate was significantly higher for
panobinostat
• Common grade 3-4 laboratory abnormalities and adverse events included thrombocytopenia (67% vs
31%), lymphopenia (53% vs 40%), diarrhea (26% vs 8%), asthenia or fatigue (24% vs 12%), and
peripheral neuropathy (18% vs 15%)
San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206.
Pan + Btz + Dex Relapsed or Refractory MM
Efficacy in Patients with High-risk Cytogenetics
Hazard Ratio (95% CI)
Overall (n=768)
Cytogenetic risk group
- Normal risk (n=167)
- Poor risk (n=37)
0.63 (0.52-0.76)
0.88 (0.60-1.29)
0.47 (0.18-1.25)
0.25
0.5
PAN-BTZ-Dex
San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206.
0.75
1
1.25
1.5 1.75
2 2.25
Pbo-BTZ-Dex
Summary of Combo Therapy with HDACIs
Regimen
Panobinostat or placebo + VD
Phase (N)
III
(768)
Outcomes
ORR: 60.7% vs 54.6%
PFS: 12.0 vs 8.1 mos (P <0.0001) (9.9 vs 7.7)
OS: 33.6 vs 30.4 mos
Panobinostat + VD
II (55 BTZ ref)
Panobinostat + RD
II
(19)
ORR of 31%, CBR of 52 %
n=14 Len Ref: ORR 21%, CBR 42%
Panobinostat + Carfilzomib
I/II
(26)
ORR of 46%, CBR of 52 %
n=16 Btz Ref: ORR 44%
Vorinostat or placebo + V
(no dex)
III
(637)
ORR: 54% vs 41% (P <0.0001)
PFS: 7.6 vs 6.8 mos (P <0.01); OS no diff
Ricolinostat ± VD
I (20)
ORR: 25% (heavily pretreated); CBR: 60%
Ricolinostat + RD
I (22)
ORR: 64%, CBR: 100%
San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206.
Richardson PG et al. Blood. 2013;122:2331-2337.
Chari A. Presented at: ASH 2014.
Kaufman. Presented at: ASH Abstract #32.
ORR 34.5%, CBR 52.7%
Dimopoulos M et al. Lancet Oncol. 2013;14:1129-1140.
Raje N et al. Presented at: ASH 2013. Abstract #759.
Raje N et al. Presented at: EHA 2014. Abstract #P358.
CD38 Monoclonal Antibodies
• CD38 - transmembrane glycoprotein & ectoenzyme with high-receptor density on
MM cells1 (80%-100%) vs NHL2,3 (30%-80%) vs AML4 58% vs B-CLL5 20%-25%
• Also expressed on precursor B-cells
• Daratumumab and SAR650984 : humanized IgG1 monoclonal antibodies
1. Lin et al. Am J Clin Pathol. 2004;121:482-488.
2. Angelopoulou et al. Eur J Haematol. 2002;68:12-21.
3. Schwonzen et al. Brit J Haematol. 1993;83:232-239.
4. Keyhani et al. Leukemia Res. 1999;24:153-159.
5. Domingo-Domènech et al. Haematologica. 2002;87:1021-1027.
Daratumumab
• Part 1 (n=32): phase I, first in human
– Main toxicity grade 1 or 2 infusional toxicity
– 5 of 12 (42%) of patients dosed at 4-24 mg/mg achieved
PR as best response
• Part 2 (n= 50): expansion cohort
Patient Characteristics
All AEs Grade 3/4 and SAEs per Dose Group
Infusion Related Reactions (IRR)
Response
Daratumumab Status
• Breakthrough designation by FDA: May 2013 for >3 lines of therapy
or PI and IMiD refractory
• Newly Diagnosed
– Phase III (SCT eligible): DVTD vs VTD
– Phase III (non-SCT eligible): DRd vs Rd
– Phase III (non-SCT eligible): DVMP vs VMP
• Relapse (1+ lines of therapy)
– Phase III: DRd vs Rd
– Phase III: DVD vs VD
• Relapsed/Refractory
– Phase II: Dara
– Phase II: Dara + [VD, VMP, VTD, PomD]
Indatuximab Ravtansine (BT062): Antibodydrug Conjugate vs CD138
• An anti-CD138 chimerized monoclonal IgG4, covalently linked to the
cytotoxic agent maytansinoid (DM4)
• CD138 is highly expressed on MM cells but not other hematopoietic and marrow stromal cell
• To a lesser extent CD138 can also be found on epithelial cells
• BT062 is stable and non-toxic in circulation
1. Binding to CD138
2. Receptor (CD138)-mediated internalization
3. Lysosomal processing of SPDB linker leads
to lipophilic DM4 metabolites
(DM4 + S-methyl-DM4)
4. Inhibition of tubulin polymerization
5. Cell cycle arrest and apoptosis
6. Bystander killing of neighboring cells
Jagannath et al. Abstract #305.
Best Response in Study 969
Number of patients
Total
Percentage
treated with BT062
32
evaluable for response
28
100%
- PD
14
50%
- SD
11
39%
- Minor response
2
7%
- Partial response
1
4%
Objective
Clinical
Stable
Response
Benefit
Disease
*Stabilized
for
at
least
11
weeks
(C4D15)
Rate
Response
or better
50%
4%
11%
• Median # cycles for patients with ≥SD: 5 (105 days), range 4-25
• Patient with MR ongoing, progression free >18 months
• Related SAEs and DLTs in highest dose levels and CD138+ tissues; resolved after 10-52 days
- DLTs: elevated ggt, mucositis, HFS
- SAE: as above + GIB, blurred vision/dry eyes/photophobia due to corneal epithelial damage,
acneiform rash
Jagannath et al. Abstract #305.
Summary of Efficacy of Monoclonal
Antibodies (@ R2P2/Ph3 Doses)
Treatment
n
Eligibility
(% Refractory)
Response
Rate
PFS
DOR
(mos)
OS
(mos)
Elotuzumab Rd
36
NA -R sens
92%
33 mos
17.8
NR
Daratumumab
20
50/75/38
(% Ref: B/L/BL
35% (n=20)
NR
NR
NR
Sar650984
13
69% C&P exposed
30.8%
NA
5+
NA
Dara RD
30
6.7% L ref
87%
NA
NA
NS
Sar RD
24
80%L/20%P
~60 B/~50%Car
(48% L ref, n25)
63%
5.8 mos
NA
NA
BT062 RD
21
100%Bort, 87%L
73%
NA
NA
NA
(75% L ref, n8)
Dara Breakthrough designation May 2013 for >3 lines of therapy or PI and IMiD refractory
Elo Breakthrough designation by FDA: May 19 2014 for >1 line of therapy given with Rd
1. Lonial S et al. ASCO 2013. Abstract 8542.
3. Martin T et al. ASCO 2014. Abstract 8532.
5. Martin T et al. ASH 2014. Abstract 83.
2. Lokhorst HM et al. ASCO 2014. Abstract 8513.
4. Plesner T et al. ASH 2014. Abstract 84.
6. Kelly K et al. ASH 2013. Abstract 758.
Kinesin Spindle Protein – A New Drug Target
in Multiple Myeloma (MM)
• Kinesin Spindle Protein (KSP, eg5) is a
microtubule motor protein required for
mitosis and separation of spindle pole
– KSP inhibition prevents formation of
bipolar spindle, leading to cell death
• Rapid onset of apoptosis occurs in Mcl-1
Dependent MM
• Expected Differentiated AE profile
– No expected neuropathy
– Minimal non-hematological toxicity
Tunquist BJ et al. Mol Cancer Ther. 2010;9:2046-2056.
Hematologic Toxicity
Worst Grade On-Study
Filanesib Single-agent
Filanesib + Dex
N=55
N=32
Neutrophils
Platelets
Hemoglobin
Bleeding
Febrile
Neutropenia
0
25
50
75
100
0
25
Grade 3
Grade 4
Hematological toxicity predicted based on mechanism of action
• Managed with supportive care
• Low incidence of febrile neutropenia or bleeding events
50
75
100
Filanesib Activity
Filanesib granted orphan drug approval by FDA in May 2014.
Summary of Novel Agents with
Single-agent Activity
Treatment
n
Eligibility
ixazomib + dex
33
filanesib
in low AAG
filanesib + dex
in low AAG
ORR
PFS
DOR OS (mos)
(mos)
88% Lexp; B sens
34%
12.4
32
21
75% IMiD Ref
53% PI ref
16%
24%
3.7
5.3
8.6
8.6
55
36
100% IMiD Ref
98% PI ref
15%
19%
3.4
5.1
5.1
5.1
10.5
10.8
afuresertib
34
97% I; 88% PI
8.8%
selinexor + dex
8
Ref to all classes
50%
NR
NR
NR
LGH 447
59
NR
10.5%
NR
5.8
NR
Filanesib granted orphan drug approval by FDA in May 2014.
Kumar S et al. ASH 2013.
Lonial S. ASH 2013.
Voorhees et al. ASH 2013.
Chen C et al. EHA 2014.
Spencer A et al. Blood. 2014.
Raab et al. ASH 2014. Abstract 301.
96% @ 6 mo
19
23.3
Participant CME Evaluation
• Please take out the Participant CME Post-survey and
Evaluation Form from the back of your packet.
• If you are not seeking credit, we ask that you fill out the
information pertaining to your degree and specialty, as well
as the few post-activity survey questions measuring the
knowledge and competence you have garnered from this
program. The post-survey begins on page 1 of the
evaluation form.
• Your participation will help shape future CME activities.
Polling Question
Post-activity Survey
A 55-year-old patient presents with a progressive mild decrease in
hemoglobin, but is asymptomatic for MM. His workup revealed a
hemoglobin of 11, calcium of 9.2, paraprotein peak of 2.6 with a beta-2
microglobulin of 3.7, and 30% plasma cells with diploid cytogenetics
and no high-risk FISH. What further workup would you recommend at
this time?
A. No further work-up recommended
B. MRI and/or PET/CT
C. Gene expression profiling
D. Immune spectrotyping
Polling Question
Post-activity Survey
Over a 4-month period, a patient receives 5 cycles of
lenalidomide/dexamethasone and bortezomib and achieves a partial
response. What is your treatment recommendation for this patient?
A. Continue on RVD
B. Change to other treatment
C. Proceed to stem-cell harvest and autograft consolidation
Polling Question
Post-activity Survey
A patient relapses after an 18-month complete response following
consolidation with melphalan, autologous stem-cell rescue, and
lenalidomide daily maintenance. She is treated with 6 cycles of
bortezomib/dexamethasone; however, a month later, kappa-light
chains and FDG avid bone lesions on PET/CT increase. Which
treatment is most suitable for this patient?
A. Cyclophosphamide/bortezomib/dexamethasone
B. Salvage melphalan 200 mg/m2 with autologous stem-cell rescue
C. Bortezomib/lenalidomide/dexamethasone
D. Carfilzomib-based combinations OR pomalidomide/low-dose
dexamethasone
E. Lenalidomide/dexamethasone
Polling Question
Post-activity Survey
Which of the following factors would NOT impact treatment
selection for relapsed/refractory MM:
A. Prior lines of therapy
B. Myeloma genomics
C. Comorbidities
D. Personal lifestyle
E. Clinical trial option
F. None of the above, since all these factors would impact
treatment selection
Thank you for joining us today!