amyloidosis: past and present · 2019-04-07 · amyloidosis: past and present ... sq) “there were...
TRANSCRIPT
![Page 1: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/1.jpg)
Amyloidosis:Past and Present
Raymond L Comenzo, MD
The John Conant Davis Myeloma and Amyloid Program
![Page 2: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/2.jpg)
Disclosures• Research Funding
– Prothena
– Takeda
– Janssen
– Karyopharm
– ARF
– Lymphoma Foundation
– Lloyd Foundation
• Consultant/Advisor
– Prothena
– Takeda
– Caelum
– Janssen
– Karyopharm
– Unum
– Sanofi
![Page 3: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/3.jpg)
![Page 4: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/4.jpg)
7/20/10: An 80 year-old man NYHA class 3 after AVR
• Increasingly symptomatic after AVR
• HFpEF
• HTN, atrial fibrillation
• IgG kappa MGUS
• Cardiac biopsy shows amyloid
![Page 5: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/5.jpg)
80 year-old man with cardiacamyloid and IgGκ MGUS
• Increasingly symptomatic after AVR• Stable MGUS – IgGκ with κ light chains• LMD/MS: ATTR, TTR gene sequence wildtype• No standard therapy
Blood 2009;114:4957
Blood 2012;119:1844
Amyloid 2018;25:62
![Page 6: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/6.jpg)
Microdissection
Trypsin digestion
Tandem MS/MS
NFLC
ESI
Data analysis
Typing with LMD Mass Spec
Courtesy of Ahmet Dogan, MDNFLC=nano flow liquid chromatographyESI=electrospray ionization
![Page 7: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/7.jpg)
ATTRwt and ATTRm
Dissociation of Tetramer
Exp Rev Mol Med 2007;9:1
Blood 2006:107:3489
ATTRm• Sporadic & inherited• > 120 mutant TTR• Autosomal dominant• High penetrance• PNS, ANS, CM
ATTRwt• HFpEF• Increasingly diagnosed• 25% in the very old• Male predominance• CM
TTR• 18q12.1• 7kb / 127aa• 20-40mg/dL
![Page 8: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/8.jpg)
ARC Guidelines
Organ Involvement in ATTR Amyloidosis
![Page 9: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/9.jpg)
Circulation 2012;126:1286
ATTRwt and ATTRm
![Page 10: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/10.jpg)
AkceaEur Heart J 2013;34:520Am J Pathol 1996;148:351
ATTRm: Genotype-Phenotype
![Page 11: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/11.jpg)
Ther Adv Neurol Disord 2013;6:129
Met30 TTR-FAP
![Page 12: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/12.jpg)
3/8/19: 76 year old man with HFpEF
• Born in the USA– Family is from Ragoli in Northern Italy
• CVA 2 years prior
• Bilateral carpal tunnel 7 years prior
• Dyspnea on exertion for 1 year
• Grade 2 sensory neuropathy
• No monoclonal gammopathy, fat pad negative x 2
• PYP = grade 3 uptake
• TTR gene = mutation, Ile68Leu
Brit Heart J 1993;70:111
![Page 13: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/13.jpg)
12
3I-
SAP
in p
lasm
a
123I-SAP in body
![Page 14: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/14.jpg)
PYP Scan
J Nucl Cardiol 2016;23: 1355
![Page 15: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/15.jpg)
Serum Total Protein, Protein Electrophoresis, Immunofixation, Free Light Chains
H
L
6 . 2 5
6 . 5 0
6 . 7 5
7 . 0 0
7 . 2 5
7 . 5 0
7 . 7 5
8 . 0 0
8 . 2 5
8 . 5 0
2 0 0 0 2 0 0 1 2 0 0 2 2 0 0 3 2 0 0 4
P r o t e i n , T o t a l
g/
dl
W I N O G R A D , A L F R E D A
P r o t e i n , T o t a l ( g / d l )
Patient AW
Nat Rev Nephrology 2009;5:621
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000
Se
rum
La
mb
da
FL
C (
mg
/L)
Serum Kappa FLC (mg/L)
Normal Sera
Kappa LCMM
AL Amyloid
Lambda LCMM
![Page 16: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/16.jpg)
ARC Guidelines
![Page 17: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/17.jpg)
Repurposing Diflunisal for FAPDissociation of Tetramer
JAMA 2013;310:2658
![Page 18: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/18.jpg)
Disease-modifying Targets in ATTR
Circulation 2017;135:1357
PRX004
Small peptides
![Page 19: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/19.jpg)
Inotersen (ASOSQ)
“There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia.”
N Engl J Med 2018; 379:22
![Page 20: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/20.jpg)
Patisiran (RNAiiv)
N Engl J Med 2018; 379:11
![Page 21: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/21.jpg)
76 year old man ATTRm on Patisiran
• On Apixaban for CVA prophylaxis
• Concern re thrombocytopenia
• Every 3 weeks IV
• Alnylam support
• NT-proBNP 2860pg/mL
• LVEF 25%– Not eligible for PRX004
• Add Doxycycline
![Page 22: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/22.jpg)
TafamidisDissociation of Tetramer
N Engl J Med 2018; 379:1007
![Page 23: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/23.jpg)
Open Questions
• Timing of therapy – ‘seeding’?
• Define the risk of disease
• Natural history of ATTR with multiple therapies
• Combination trials– Endpoints??
– Support??
• Surrogate markers: progression and Response– NIS+7
– NT-proBNP
– 6 minute walk
– QOL
– Imaging
![Page 24: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/24.jpg)
Open Questions
• ATTR disease
• Precursors
– Carpal tunnel
– Spinal stenosis
• Arc of time
– Relative risks
• Contributing factors
• Genetic links
• Proteostasis pathways
• HFpEF
• Gender bias
• Improved imaging
• TTR Monomer
– Biomarkers
– Assays
• Gene carriers
– Inhibit Seeding?
– Inhibit Aggregation?
![Page 25: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/25.jpg)
![Page 26: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/26.jpg)
Nature Reviews 2018;4:38
Organ Involvement in AL Amyloidosis
![Page 27: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/27.jpg)
Systemic AL AmyloidosisTimeline
?
?
![Page 28: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/28.jpg)
1994
Melphalan, Prednisone & Colchicine
Am J Med 1996;100:290-8Am J Med 1996;100:290 NEJM 1997;336:1202
![Page 29: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/29.jpg)
High-dose Melphalan and SCT: The Early Experience
0 5 10 15 20 25 30 35 40 45 50 55 600
25
50
75
100
PD (n=43)
CR (n=41)
p<<0.001
Months
OS
(%
)
0 5 10 15 20 25 30 35 40 45 50 55 600
25
50
75
100
PD (n=43)
CR (n=41)
p<<0.001
Months
OS
(%
)
0 5 10 15 20 25 30 35 40 45 50 55 600
25
50
75
100
PD (n=43)
CR (n=41)
p<<0.001
Months
OS
(%
)
Leukemia and Lymphoma 2000:37:245-58Leukemia and Lymphoma 2000;37:245Blood 2002;99:4276
Peri-transplant mortality
Advanced organ involvement
Age and melphalan dosing
Patient selection
Risk-adapted melphalan
200/140/100
Hematologic response
Survival and organ responses
![Page 30: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/30.jpg)
MEL 200 SCT on a Clinical Trial:Complete Hematologic Response
51 year old man, 8 years s/p SCT
Blood 1996;88:2301-6
1 year post-SCT
10 years post-SCT
1 year post-SCT
10 years post-SCT
Blood 1996;88:2801
43 year old man, AL with
profound polyneuropathy
51 year old man, 8 years s/p SCT
Blood 1996;88:2301-6
1 year post-SCT
10 years post-SCT
1 year post-SCT
10 years post-SCT
![Page 31: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/31.jpg)
CIBMTR AL SCT 1995-2012
J Clin Oncol 2015;33:3741
![Page 32: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/32.jpg)
RA-SCT and Consolidation
Leukemia 2017;31:136
![Page 33: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/33.jpg)
Clonal Plasma Cell Burden
“dominant cardiac involvement among patients with myeloma (10 of 23) versus those without myeloma (5 of 37) . . . achieve(d) significance (RR 3.22) (Blood 2001)”
![Page 34: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/34.jpg)
Complete Hematologic Response
aCR = normal FLC ratio, negative S-IFE and U-IFE
![Page 35: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/35.jpg)
Pre-SCT Post-SCT
CR and Resorption of Amyloid Post-SCT
With Loss of Hepatosplenic RBC Changes
![Page 36: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/36.jpg)
Bortezomib for Relapsed AL CAN2007
• Primary objectives: determine MTD (phase I) and safety (phase II)• Secondary objective: determine best hematologic response rate and
duration of response at MTD• Hematologic and organ responses assessed during rest period of each cycle
according to established consensus criteria• Stringent assessment of response and safety: central laboratory
measurements of efficacy parameters, central cardiology laboratory, regular IDMC review of safety and efficacy
Days 1 8 15 22 35
Days 1 4 8 11 21
QW dosingcycle
BIW dosingcycle
x 8 treatment cycles(prolonged treatment for patients showing clinical benefit)
0.7, 1.0, 1.3, 1.6 mg/m2
0.7, 1.0, 1.3 mg/m2
Blood 2011;118:865
![Page 37: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/37.jpg)
Best Hematologic Responses
31.3
42.4
27.8
37.524.2
11.1
0
10
20
30
40
50
60
70
80H
em
ato
log
ic r
es
po
ns
e r
ate
, % CR
PR
1.6 mg/m2 QW 1.3 mg/m2 BIW Lower doses
68.8 66.7
38.9
Among responding patients: 1.6 mg/m2
QW, N=111.3 mg/m2
BIW, N=22Lower doses,
N=7
Median time to first/best response, mo 2.1 / 3.2 0.7 / 1.2 1.2 / 1.2
Duration of response ≥1 year, % 79 76 83
![Page 38: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/38.jpg)
Blood 2014;124:2498
Bortezomib for Relapsed AL CAN2007
![Page 39: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/39.jpg)
Bortezomib for ConsolidationPost-SCT
Leukemia 2013;27:823
![Page 40: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/40.jpg)
![Page 41: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/41.jpg)
Test Results MM (%) AL (%)
+ S/U M-spike 97 51
+ S M-spike 80 30
+ S-IFE 93 69
+ U-IFE 75 62
Abn FLC ratio 88 90
PC Median 40 (8-99) 10 (2-66)
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000
Se
rum
La
mb
da
FL
C (
mg
/L)
Serum Kappa FLC (mg/L)
Normal Sera
Kappa LCMM
AL Amyloid
Lambda LCMM
Κ-to-λ Case Ratio 3:2 1:3.5
![Page 42: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/42.jpg)
AL: FISH
Abnormal Parameters
cIg(n = 401)
CD138-selected(n = 101)
t(11;14) 40 63
del 13 30 34
gain 1q ----- 28
del 17p 2 6
Br J Haematol 2003;122 :78
Blood 2007;109:3489
Blood 2008;111:4700
![Page 43: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/43.jpg)
2001
IGVL Gene Usage
Blood 2001 98: 714-720
MX B 1 2 3 4
![Page 44: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/44.jpg)
λ GermlineGene
AL(N / Total)
MM(N / Total)
Odds RatioFavoring AL
95% CI P-value
KV1-16 16/181κ 1/133κ 12.8 1.68 to 97.8 < 0.01
LV6-57 113/616λ 3/117λ 7.2 2.3 to 22.1 < 0.0001
LV1-44 80/616λ 6/117λ 2.53 1.13 to 5.67 0.01
KV4-1 41/181κ 17/133κ 2.00 1.08 to 3.7 0.03
LV3-21 21/616λ 9/117λ 2.36 1.05 to 5.29 0.04
LV3-1 177/616λ 41/117λ 1.22 0.93 to 1.61 0.19
LV2-14 59/616λ 7/117λ 1.7 0.75 to 3.4 0.29
AL-Base http://albase.bumc.bu.edu/aldb
![Page 45: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/45.jpg)
Impact on OutcomesCCND1hi & t(11;14)
Clin Lymphoma Myel Leuk 2012;12:49
Blood Cancer J 2015;5,e310
![Page 46: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/46.jpg)
Impact on Outcomes with MEL SCTt(11;14)
Blood 2016;128:594
![Page 47: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/47.jpg)
Amyloid 2014;21:9
Impact on Outcomest(11;14)
Mel Dex 103 Consecutive AL Patients
Bortez Dex101 Consecutive AL Patients
J Clin Oncol 2015;33:1371
![Page 48: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/48.jpg)
Impact on Outcomes with del 17p(N=44)
Clin Lymph Myel Leuk 2018;18:e483
![Page 49: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/49.jpg)
Cardiac AL AmyloidosisNot Eligible for SCT
Br J Haematol 2008;143:369Haematologica 2014;99:1479
MDex CyBorD
n=40
![Page 50: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/50.jpg)
Systemic AL: Staging
JCO 2012;30:989-995
![Page 51: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/51.jpg)
Nature Reviews 2018;4:38
NT-proBNP > 352ng/LTroponin I > 0.10ng/mL
Cardiac Staging
![Page 52: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/52.jpg)
Outcomes of Renal Patients in the Modern Era (N=77)
Clin Lymph Myel Leuk 2017;17:759
![Page 53: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/53.jpg)
Clin Lymph Myeloma Leuk 2015;15:635
CD38
![Page 54: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/54.jpg)
ANDROMEDA: Janssen
JCO 2018;36(15S):8011EHA 2019
Run-in N = 28> VGPR = 96%Normal iFLC = 54%
![Page 55: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/55.jpg)
Biomarker 1/18/19 2/19/19
NT-proBNP (pg/L) 5915 3089
UTP 24 (mg) 8010 3961
CyBorD + Dara SQ
![Page 56: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/56.jpg)
A VITAL[NEOD001] Patient
![Page 57: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/57.jpg)
Now a 74 year-old WomanVITAL Trial –NEOD001/Placebo + weekly CyBorD
Heart biopsy 9/6/16 - AL, λ-typeStage IV, FLC λ 877mg/L NT-proBNP 6120pg/mL
![Page 58: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/58.jpg)
FLC Response Predicts SurvivalLandmark Analysis
J Clin Onc 2012;30:4541
Leukemia 2012;30:1979
0 12 24 36 48
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ng/L and 30% increase), 169 patients
NT-proBNP stable, 108 patients
NT-proBNP response (at least 300 ng/L and 30% decrease), 100 patients
p<0.001
p<0.001
0 12 24 36 48
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0P
rop
ort
ion
su
rviv
ing
CR (97 patients, 3.6 deaths/100 py)
VGPR (233 patients, 9.6 deaths/100 py)
PR (140 patients, 23.7 deaths/100 py)
NR (179 patients, 47.2 deaths/100 py)
p=0.01
p<0.001
p<0.001
![Page 59: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/59.jpg)
Cardiac Progression
VITAL Trial –NEOD001/Placebo + weekly CyBorD
![Page 60: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/60.jpg)
0 12 24 36 48
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ng/L and 30% increase), 169 patients
NT-proBNP stable, 108 patients
NT-proBNP response (at least 300 ng/L and 30% decrease), 100 patients
p<0.001
p<0.001
NT-proBNP Response and Progression Predict Survival
J Clin Onc 2012;30:4541
Leukemia 2016;30:1979
HR = 0.23, 95% CI 0.14 to 0.38, P< 0.001
HR = 4.36, 95% CI 3.24 to 5.89, P < 0.001
![Page 61: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/61.jpg)
FLC responseVITAL Trial –NEOD001/Placebo + weekly CyBorD
Add Daratumumab
![Page 62: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/62.jpg)
Cardiac Responsewith Dual Antibody Therapy
Daratumumab
NEOD001 + CyBorD
![Page 63: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/63.jpg)
NT-proBNP
λ FLC
![Page 64: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/64.jpg)
Dual Monoclonal Antibody TherapyAnti-CD38
• Anti-CD38 Daratumumab (Isatuximab)
• Anti-Plasma cell
– CDC, ADCC, ADPC, Trogocytosis
• Daratumumab also
– Improves adaptive immune response
– Eliminates CD38-positive immune suppressor cells
– Shifts effector T-cells towards an antigen-experienced phenotype
![Page 65: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/65.jpg)
Dual Monoclonal Antibody TherapyAnti-Amyloid
• NEOD001
– Encouraging Phase I/II data.
– 23 April 2018: Trial design failure?
– Soluble aggregates of LV6-57 LC from ALMC-1 cells
Amyloid 2016;23:168-77
![Page 66: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/66.jpg)
Dual Monoclonal Antibody TherapyAnti-Amyloid
• CAEL-101
– Imaging activity
– In vivo activity
– Encouraging Phase I/II data Blood 2010;116:2241-44
https://ash.confex.com/ash/2018/webprogram/Paper118464.html
![Page 67: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/67.jpg)
Preliminary Data (ASCO 2019)
NEOD001+Dara(n=9)
Daratumumab(n=11)
Hematologic response(> VGPR)
8/9 (88%) 8/10 (80%)
Reduction in involved light chains (median)
83% 83%
Days to best hematologic response
33 (19-161) 75 (22-242)
Cardiac response 7/8 (88%) 4/6 (67%)
Reduction in NT-proBNP(median)
74% 50%
Days to cardiac response 86 115
Renal response 2/4 (50%) 4/5 (80%)Days to renal response 112 252
Additive? Synergistic?Coincidental?
![Page 68: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/68.jpg)
Open Questions & Emerging Approaches
• How can we achieve truly early diagnosis?
• What are the dimensions of FLC toxicity?
• What is organ involvement?
• Are anti-amyloid therapies relevant?
• What is the role of imaging?
• Is the aCR the last word on response?
• How is MRD testing relevant?
• Are there anti-light chain therapies?
![Page 69: Amyloidosis: Past and Present · 2019-04-07 · Amyloidosis: Past and Present ... SQ) “There were five deaths in the inotersen group and none in the placebo group. The most frequent](https://reader034.vdocuments.us/reader034/viewer/2022042307/5ed2e1434768b17a677423b0/html5/thumbnails/69.jpg)
Condition % positive
AL 84
ATTRm 45
ATTRwt 15
AL Precursor State
??
Abdominal Fat Pad Aspirate
Stained with Congo red
Eur Heart J 2017;38:1905