Amyloidosis:Past and Present

Raymond L Comenzo, MD

The John Conant Davis Myeloma and Amyloid Program

Disclosures• Research Funding

– Prothena

– Takeda

– Janssen

– Karyopharm

– ARF

– Lymphoma Foundation

– Lloyd Foundation

• Consultant/Advisor

– Prothena

– Takeda

– Caelum

– Janssen

– Karyopharm

– Unum

– Sanofi

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

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

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

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

ARC Guidelines

Organ Involvement in ATTR Amyloidosis

Circulation 2012;126:1286

ATTRwt and ATTRm

AkceaEur Heart J 2013;34:520Am J Pathol 1996;148:351

ATTRm: Genotype-Phenotype

Ther Adv Neurol Disord 2013;6:129

Met30 TTR-FAP

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

12

3I-

SAP

in p

lasm

a

123I-SAP in body

PYP Scan

J Nucl Cardiol 2016;23: 1355

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

ARC Guidelines

Repurposing Diflunisal for FAPDissociation of Tetramer

JAMA 2013;310:2658

Disease-modifying Targets in ATTR

Circulation 2017;135:1357

PRX004

Small peptides

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

Patisiran (RNAiiv)

N Engl J Med 2018; 379:11

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

TafamidisDissociation of Tetramer

N Engl J Med 2018; 379:1007

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

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?

Nature Reviews 2018;4:38

Organ Involvement in AL Amyloidosis

Systemic AL AmyloidosisTimeline

?

?

1994

Melphalan, Prednisone & Colchicine

Am J Med 1996;100:290-8Am J Med 1996;100:290 NEJM 1997;336:1202

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

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

CIBMTR AL SCT 1995-2012

J Clin Oncol 2015;33:3741

RA-SCT and Consolidation

Leukemia 2017;31:136

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)”

Complete Hematologic Response

aCR = normal FLC ratio, negative S-IFE and U-IFE

Pre-SCT Post-SCT

CR and Resorption of Amyloid Post-SCT

With Loss of Hepatosplenic RBC Changes

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

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

Blood 2014;124:2498

Bortezomib for Relapsed AL CAN2007

Bortezomib for ConsolidationPost-SCT

Leukemia 2013;27:823

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

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

2001

IGVL Gene Usage

Blood 2001 98: 714-720

MX B 1 2 3 4

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

Impact on OutcomesCCND1hi & t(11;14)

Clin Lymphoma Myel Leuk 2012;12:49

Blood Cancer J 2015;5,e310

Impact on Outcomes with MEL SCTt(11;14)

Blood 2016;128:594

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

Impact on Outcomes with del 17p(N=44)

Clin Lymph Myel Leuk 2018;18:e483

Cardiac AL AmyloidosisNot Eligible for SCT

Br J Haematol 2008;143:369Haematologica 2014;99:1479

MDex CyBorD

n=40

Systemic AL: Staging

JCO 2012;30:989-995

Nature Reviews 2018;4:38

NT-proBNP > 352ng/LTroponin I > 0.10ng/mL

Cardiac Staging

Outcomes of Renal Patients in the Modern Era (N=77)

Clin Lymph Myel Leuk 2017;17:759

Clin Lymph Myeloma Leuk 2015;15:635

CD38

ANDROMEDA: Janssen

JCO 2018;36(15S):8011EHA 2019

Run-in N = 28> VGPR = 96%Normal iFLC = 54%

Biomarker 1/18/19 2/19/19

NT-proBNP (pg/L) 5915 3089

UTP 24 (mg) 8010 3961

CyBorD + Dara SQ

A VITAL[NEOD001] Patient

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

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

Cardiac Progression

VITAL Trial –NEOD001/Placebo + weekly CyBorD

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

FLC responseVITAL Trial –NEOD001/Placebo + weekly CyBorD

Add Daratumumab

Cardiac Responsewith Dual Antibody Therapy

Daratumumab

NEOD001 + CyBorD

NT-proBNP

λ FLC

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

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

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

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?

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?

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