AL amyloidosis

Dangerous, small cloneMedian BMPC infiltrate: 10%

Unstable LCs

ProteotoxicityOligomers

Amyloid deposits

SAP, GAGs

endoproteases, metal ionsshear forces

Mayo Clinic / European staging system

Staging is based on NT-proBNP (cutoff 332

ng/L) and troponin I (cutoff 0.1 ng/mL) with

stage I, II, and III patients having 0, 1, or 2

markers above the cutoffs.

Very high (>8500 ng/L) NT-proBNP

identifies patients with advanced cardiac

dysfunction (Stage IIIb)

Revised Mayo Clinic staging system Renal staging system

Staging is based on NT-proBNP (cutoff

1800 ng/L), troponin I (cutoff 0.07

ng/mL), and dFLC (cutoff 180 mg/L), with

stage I, II, III, and IV patients having 0, 1,

2, or 3 markers above the cutoffs.

• Stage I: both proteinuria 5g/24h and eGFR 50 mL/min per 1.73 m2

• Stage II: either proteinuria >5g/24h or eGFR <50 mL/min per 1.73 m2

• Stage III: both proteinuria >5g/24h and eGFR <50 mL/min per 1.73 m2

Dispenzieri, et al. JCO 2004

Wechalekar, et al. Blood 2013

Kumar, et al. JCO 2012

Palladini, et al. Haematologica 2014

Milani, et al. Blood 2017

Dittrich, et al. Blood 2017

Sidana, et al. Leukemia 2017

Nguyen, et al. Amyloid 2018

Palladini, et al. Blood 2014

Biomarkers to assess severity of organ

involvement and predict survival

Dexamethasone

Alkylators

Targeting the clone to improve organ

dysfunction and prolong survival

ASCTIMiDs

Anti-plasma cell treatment

Proteasome

inhibitors

Immunotherapy

Hematologic response

dFLC

Improve organ

dysfunction

Organ response

NT-proBNP, proteinuria, ALP

Prolong survival

Patients surviving 5 years (%)data from1065 patients at Pavia ARTC

Cardiac response

Response Definition

Hematologic

For dFLC 20-50 mg/L

CR: negative s&u IFE + normal FLCR

VGPR: dFLC <40 mg/L

PR: dFLC decrease >50%

Low-dFLC response: dFLC <10 mg/L

Cardiac NT-proBNP decrease >30% & >300 ng/L

Renal Proteinuria decrease >30%

Palladini, et al. JCO 2012

Palladini, et al. Blood 2014

Milani, et al. Blood 2017

Dittrich, et al. Blood 2017

Sidana, et al. Leukemia 2017

Nguyen, et al. Amyloid 2018

Renal response

Validated criteria of hematologic and

organ response

Patients with organ response (%)

CR, VGPR, and PR data from 1065 patients at Pavia ARTC

?MRD data by NGF on 69

patients at Pavia ARTC

Organ response strictly depends on the

quality of hematologic response

Sidiqi, et al. JCO 2018

also, Seldin, et al. Blood 2015

ASCT in AL amyloidosis

Median OS, 75 months

Median OS, 120 months

Median OS, NR

Center Criteria

Amyloidosis Center Boston >70 years, >NYHA II, PS>2, sBP<90 mmHg, symptomatic pleural effusions, EF<40%

Mayo Clinic >70 years, >NYHA II, PS >2, cTNT >0.06 ng/ml, Crea-cl <30 ml/min (unless on chronic dialysis), >2 organs

Amyloidosis Center Pavia >65y, >NYHA II, PS>2, NT-proBNP>5000 ng/L, cTnT>0.06 ng/mL, EF<45%, sBP<90 mmHg, eGFR<50 mL/min, DLCO <50%

Memorial Sloan Kettering, NY > 60 years, >3 organs involved, advanced cardiac disease

HOVON Study Group PS >2, >NYHA III, EF <45%, other severe diseases

French Study group Inadequate organ function, elevated NT-ProBNP and TNT

NAC, London >2 organs, PS >1, eGFR <50 ml/min, significant cardiac involvement, autonomic neuropathy or gastrointestinal involvement, TNT >0.06 ng/mL.

Amyloidosis Center Heidelberg >70 years, >NYHA II, PS>2, sBP <90 mmHg, symptomatic pleural effusions. Crea-cl < 30 ml/min (unless on chronic dialysis).

Gertz, et al. BMT 2013D’Souza, et al. JCO 2015

Selection of ASCT candidates is vital

“Induction” therapy in AL amyloidosis

Hwa, et al. Am J Hematol 2016

Patients with BMPC>10% benefit from induction therapy

Turn off the Tap! The Need for Induction Therapy for AL Amyloidosis Before Transplant

Mikhael. Biol Blood Marrow Transplant 2018

Afrough, et al. Biol Blood Marrow Transplant 2018

Deferred autologous stem cell transplantation

after bortezomib-based therapy in AL amyloidosis

• 22 transplant ineligible patients

• All received bortezomib-based therapy

upfront

• All responded, became transplant

eligible, and received ASCT for

hematologic progression or

consolidation

Manwani, et al. Blood Cancer Journal 2018

“Consolidation” therapy in AL amyloidosis

CR almost 60% with “adjuvant” BDex

Landau, et al. Leukemia 2017

Regimen Time period Patients number and staging HR OR Survival

MDexPalladini 2014

2004-2009119 intermediate-risk (IIIa 13%)

140 high-risk (IIIa 24%, IIIb 36%)

76%

(CR 31%, VGPR 29%)

51%

(CR 17%, VGPR 28%)

H 37%, K 24%

H 20%, K 17%

median 88 months

median 20 months

LMDexHegenbart 2017

2009-2012 50 (IIIa 24%, IIIb 12%)68%

(CR 18%, VGPR 32%)H 22%, K 22% median 68 months

BMDexPalladini 2014

2007-201223 intermediate-risk

64 high-risk (IIIb 30%)

74%

(CR 48%, VGPR 17%)

67%

(CR 41%, VGPR 11%)

H 16%, K 16% 66% at 12 months

CTDVenner 2014

2008-2012 69 (IIIa 36%, IIIb 22%)80%

(CR 25%, VGPR 20%)H 15%, K 39% 67% at 12 months

CLDCibeira 2015

2010-2012 28 (III 50%)46%

(CR 25%, VGPR 18%)H 26%, K 43% 64% at 12 months

CyBorDPalladini 2015

2006-2013158 low/intermediate-risk (IIIa 39%)

43 high-risk (IIIb 100%)

68%

(CR 23%, VGPR 26%)

42%

(CR 14%, VGPR 9%)

H 22%, K25%

H 4%

Stage I, median n. r.

Stage II, 52% at 3 y

Stage IIIa, 55% at 3 y

Stage IIIb, 19% at 3 y

Non-transplant chemotherapy in AL

amyloidosis

The amyloidogenic LC is an intrinsic

stressor for PC

parental line: non-Ig-producing NS0

(mouse plasmocytoma)

Oliva, et al. Blood 2017

A phase III trial of BMDex vs. MDex in

newly-diagnosed AL

Kastritis, et al. Manuscript in

preparation

Response MDex (56 pts) BMDex (53 pts) P

Overall Hem. 32 (57%) 43 (81%) 0.005

CR 11 (20%) 12 (23%) 0.440

VGPR 11 (20%) 22 (42%) 0.007

PR 10 (17%) 9 (17%) 0.454

Heart 10/36 (28%) 10/26 (38%) 0.195

Kidney 15/35 (43%) 16/36 (44%) 0.448

t(11;14) (50% of patients) is

associated with lower response rates

and shorter survival in patients treated

with CyBorD and BDex

≥VGPR 23% vs. 47%

Bochtler, et al. JCO 2015

gain(1q21) (20% of patients) is

associated with lower response rates

and shorter survival in patients treated

with MDex

≥VGPR 5% vs. 25%

Bochtler, et al. Amyloid 2014

iFISH results can be used in designing

the treatment strategy

BMDex can overcome the effect of both gain(1q21) and t(11;14)

Exposure to both melphalan and

bortezomib prolongs time to re-treatment

Palladini, et al. Blood 2017

Cox univariate and multivariate analyses of

baseline variables predicting TFS

Choice of upfront treatment in transplant

ineligible patients

• BMDex – overcomes the effects of both gain 1q21 and t(11;14)

• CyBorD – stem cell sparing is preferred in patients with renal failure but

has a poor outcome in patients with t(11;14)

• MDex – preferred in patients with neuropathy or fibrotic lung disease

High risk patients (stage IIIb, NYHA class III or IV) – Low dose combination

regimens or standard regimens with intensive care support

Merlini, et al. Nat Rev Dis Primers. 2018

Rapid and deep responses improve outcome of

patients with advanced heart involvement

Manwani, et al. Haematologica 2018

Newer chemotherapy approaches - Ixazomib in

relapsed refractory AL amyloidosis

MTD: 4 mg

Hematologic response 52%

Organ response 56%

Sanchoravala, et al. Blood 2017

Phase III study of ixazomib vs. physician’s best choice in rel / ref AL amyloidosis ongoing

Lenalidomide can overcome resistance to

alkylating agents and proteasome inhibitors

Regimen Time periodPreviously treated patients

(prior therapies)HR OR Survival

L(Dex)Dispenzieri 2007

2004-2005 13 (ASCT 46%) 38% 15% -

L(Dex)Sanchorawala 2007

2004-2006 31 (ASCT 61%, T 23%) 52% 51% (kidney) -

CLDKumar 2012

2007-2008 11 (ASCT 64%, T 9%)60%

Including newly-diagnosed

32%

Including newly-diagnosed

Median

38 months

CLDKastritis 2012

2008-2011 13 (ASCT 31%, T 31%, B 39%) 58% (CR 8%) 42%Median

29 months

LDexPalladini 2012

2007-200924 (ASCT 29%, MDex 71%,

T 37%, B 100%)41% 6% (heart)

Median

14 months

CLDPalladini 2013

2008-200921 (ASCT 24%, MDex 81%,

T 29%, B 19%)62% (CR 5%, VGPR 24%) 19% (kidney)

Median

36 months

LDexMahmood 2014

2007- 2013 84 (ASCT 15%, T 76%, B 68%) 61% (CR 20%) 55% (kidney) 84% @ 2y

Newer chemotherapy approaches - Pomalidomide in

patients exposed to alkylators and bortezomib

Palladini, et al. Blood 2017.

Dispenzieri , et al. Blood 2012 and

Sanchorawala, et al. Blood 2016

Overall HR 68%

CR 4%

VGPR 25%

PR 39%

Newer (and older) chemotherapy approaches -

Bendamustine

Hematologic response

35% (CR 2%, VGPR 8%)

55-59% in patients with IgM-AL (CR 8-11%, VGPR 25-37%)

1. Milani, et al. Blood 2018 2. Manwani, et al. Blood 2018

Conclusion

• Biomarker-based staging and better understanding of the amyloid clone

allow tailoring the therapeutic strategy in patients with AL amyloidosis

• Therapy should be aimed at obtaining deep hematologic response and

organ response

• Sequential and combination use of available and new agents will further

improve the outcome of patients with AL amyloidosis

Acknowledgements

Giampaolo MerliniLaura Obici Andrea Foli Paolo Milani Mario NuvoloneFrancesca Lavatelli Roberta Mussinelli

Marco BassetStefano PerliniGiuseppina PalladiniMargherita MassaPaola Rognoni Tasaki MasayoshiGiovanni Ferraro

Pasquale Cascino Margherita BozzolaClaudia Cagnoni Simona CasariniJessica RipepiAlice NevoneAnna Carnevale Baraglia

Caludia SforziniElona Luka Eleonora Di BuduoAlberto BoveraArianna Pasi