Updates in AL Amyloidosis: The Moffitt ExperienceMoffitt Grand RoundsJanuary, 22, 2021

Dr. Brandon Blue, MD

Conflict of Interest

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I have no conflicts to disclose

Learning Objectives

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• 1) Understand approach to diagnosis and evaluation of AL Amyloidosis

• 2) Review current standard of care in management of AL Amyloidosis

• 3) Discuss outcomes of AL Amyloidosis patients within Moffitt catchment area

Amyloidosisextracellular tissue deposition of fibrils composed of low molecular weight subunits of a variety of proteins

Amyloidosis

Robbins & Cotran, Pathologic Basis of Disease, 2015

• Presence of amyloid-related systemic syndrome (organ involvement)• Positive Congo red staining of tissue deposits• Evidence the amyloid is light-chain related• Evidence of monoclonal plasma cell proliferative disorder

Primary Systemic (AL) AmyloidosisDiagnostic Criteria

• Demonstrate amyloid tissue deposition• BMBX• Abdominal fat pad biopsy• Salivary gland biopsy• Nerve biopsy• Rectal biopsy• Renal biopsy• Endomyocardial biopsy• Liver biopsy• Skin biopsy

• Typing of amyloid deposits• Gold standard-mass spectrometry• Immunostaining with electron microscopy• Immunohistochemistry

Diagnosis

• Amyloid Panel• CBC with Diff/CMP• SPEP/Immunofixation• Free Light Chains• 24 hour urine protein/UPEP/UFIX• LDH, Uric Acid• PT/PTT• Beta-2 microglobulin• Troponin T• NT-ProBNP

• Other labs• Factor X if indicated• BNP for patients with renal failure

Diagnostic Workup

• Skeletal Survey• Orthostatic Vital Signs• Assessment of Cardiac Involvement

• EKG• Echo with Strain• Cardiac MRI –preferred

• Consider depending on organ involvement:• Endocrine Testing• EMG/NCS• PFTs• Abdominal imaging• Endoscopy

Diagnostic Workup

Organ Involvement with AL Amyloidosis in 1065 Patients

Milani, et al. Medit J Hematol Infect Dis 2018;10:e2018022.

Organ Involvement Criteria for Amyloidosis

STAGESurvival in patients not undergoing stem cell transplantation Survival in patients undergoing stem cell transplantation

Median (mos) 5-yr survival % Median (mos) 4-yr survival %

I (0 Points) 55 50 Not Reached 87

II (1 Point) 19 35 97 72

III (2 Points) 12 20 58 56

IV (3 Points) 5 15 22 46

Revised Mayo Prognostic Staging

• NT-Pro-BNP ≥ 1800 ng/L• Troponin T ≥ 0.025 mcg/L• Difference between involved/uninvolved serum free light chains

≥ 18 mg/dl1 point for each factor

Hematologic Response Criteria for Primary Amyloidosis

Organ Response Criteria for Primary Amyloidosis

• Good Risk patients (Excellent performance status, good renal function, troponin T < 0.06 ng/ml, NT-Pro BNP < 5000 ng/L)• Autologous Transplant

• Intermediate Risk (NT-Pro BNP < 8500): • Combination chemotherapy• Chemo then transplant if organ improvement• Select patients may proceed straight to transplant

• High Risk (NT-Pro BNP > 8500):• Chemotherapy (dose attenuated)

Therapy of Primary AmyloidosisRisk Adapted Therapy

Merlini, et al. Blood 2013;121:5124.

Therapy of Primary AmyloidosisStem Cell Transplantation-OS by hematologic CR

Sanchorawala. Hem Onc Clin NA, 2014; 28:1131.

Therapy of Primary AmyloidosisStem Cell Transplantation-OS by cardiac involvement

Sanchorawala. Hem Onc Clin NA, 2014; 28:1131.

Therapy of Primary AmyloidosisStem Cell Transplantation-OS by ≤2 versus >2 organs

Sanchorawala. Hem Onc Clin NA, 2014; 28:1131.

Therapy of Primary AmyloidosisChemotherapy

Mikhael, et al. Blood 2012;119:4391 ; Venner, et al. Blood 2012;119:4387.

• CyBorD regimen: high response rate• Short median follow-up (21 and 14 months)• Good patient tolerance• UK trial

• 66.5% 2-year PFS

Therapy of Primary AmyloidosisChemotherapy

Palladini et al. Blood 2015;126:612 .

• Upfront CyBorD-230 patients• Hematologic response rate 60% with 43% ≥ VGPR• Cardiac response 17% ; Renal response 25%• Lower response rate in stage III cardiac patients [NT-ProBNP >

8500] (42%, ≥ VGPR 23%)• Worse median OS 7 months for stage III cardiac patients• 55% survival at 3 years

Therapy of Primary AmyloidosisOverall Survival with CyBorD in 230 Untreated Patients

Palladini et al. Blood 2015;126:612 .

Therapy of Primary AmyloidosisHigh Risk Cardiac Patients

Wechalekar, et al. Blood 2013;121:3420.

• Consider retreatment with bortezomib-based regimen (or ixazomib) If not refractory to bortezomib

• Consider Mel/Dex if not refractory Alkylating agents• If refractory to bortezomib—options include:

• Daratumumab• Lenalidomide/Dex• Pomalidomide/Dex• Carfilzomib• Len/Cy/Dex or Thal/Cy/Dex• Bendamustine

Treatment of Recurrent Disease

• AL amyloid fibril deposition causes cardiac dysfunction• Amyloidogenic light chains:

• Cardiotoxic• Reduce contractility in cardiac myocytes• Cause early death in zebra fish• Reduces pharyngeal contractility in C. elegans

• Doxycycline• Interferes with amyloid fibril formation• Abrogates light chain toxicity• Improved OS in patients getting doxycycline ABX prophylaxis post-auto-transplant

compared with PCN

Doxycyline for Cardiac AL Amyloidosis

Kumar et al. Blood 120, 3138 (2012)

• Retrospective case control of chemo + doxycycline• 30 patients with cardiac AL matched with 73 controls (cardiac stage, NT-ProBNP, age,

dFLC)• Doxycycline 100 mg PO BID• Improved ORR and CR rate• Improved median OS

Doxycyline for Cardiac AL Amyloidosis

Wechalekar Blood Cancer Journal 7, e546 (2017)

Doxycyline(OS by Mayo Stage)

Wechalekar Blood Cancer Journal 7, e546 (2017)

Doxycycline(Subgroup treated with upfront bortezomib combinations)

Wechalekar Blood Cancer Journal 7, e546 (2017)

Is There A Role For Allogeneic Transplant?

Schonland et al. Blood. 2006;107(6):

mOS 42 monthsPFS 19 monthsCR 26%

TRM 40%4 patients died <100 days

Recent Updates in AL Amyloidosis

ANDROMEDA trial

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Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA

Giovanni Palladini,Efstathios Kastritis,Mathew S. Maurer,Jeffrey Zonder,Monique C. Minnema,Ashutosh D. Wechalekar,Arnaud Jaccard,Hans C. Lee,Naresh Bumma,Jonathan L. Kaufman,Eva Medvedova,Tibor Kovacsovics,Michael Rosenzweig,Vaishali Sanchorawala,Xiang Qin,Sandra Y. Vasey,Brendan M. Weiss,Jessica Vermeulen,Giampaolo Merlini,Raymond L. Comenzo, Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA, Blood, 2020,

Copyright © 2021 American Society of Hematology

Importance of Alkylating Agent and Proteasome

Inhibitor in AL Amyloidosis

Overall Survival Progression Free Survival

The Moffitt Experience

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• Racial Disparities• Upfront Treatment• Doxycycline Use

Racial Disparities

Presented ASCO 2020

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Racial Disparities in AL Amyloidosis

Upfront Treatment in AL Amyloidosis

Upfront Treatment in AL Amyloidosis

Doxycycline Use in AL Amyloidosis

Factor No Doxycycline usen=189

Doxycycline usen=20 P value

Clinical DateMale 10 (50%) 116 (61.4%) 0.345Age at diagnosis 64 (0.76) 62 (2.2) 0.256Date of diagnosis before 1/2014 83 (43.9%) 6 (30 %) 0.342Concurrent Multiple Myeloma 38 (20.3%) 6 (31.6%) 0.250African American 18 (10.7%) 2 (10.5%) 1.0Stage

Stage I 38 (27.5%) 2 (12.5%)

0.337Stage II 33 (23.9%) 3 (18.8%)

Stage III 40 (29.0%) 5 (31.3%)Stage IV 27 (19.6%) 6 (37.5%)

Biomarkers at time of diagnosiseGFR 54 (2.3) 53 (6.6) 0.887NT-pro-BNP 5699 (964) 5562 (1477) 0.962cTnT 0.09 (0.01) 0.14 (0.03) 0.19224 hr urine protein 64 (55) 644 (539) 0.017sFLC 799 (179) 776 (298) 0.968Bone Marrow Plasma Cell % 18 (1.4) 24 (5.2) 0.239FISH t(11;14) 25 (19.4%) 4 (36.4%) 0.239

First line Treatment data No treatment 17(9.0%) 2 (10.5%)

0.296

HD Mel + ASCT 16 (8.5%) 2(10.5%)AA based therapy 14 (7.4%) 1 (5.3%)PI based therapy 60 (31.7%) 2 (10.5%)

PI+AA based therapy 67 (35.4%) 9 (47.4%)Others 15 (7.9%) 3 (15.8%)

Hematologic responseNo response 26 (20%) 0 (0%)

0.145Partial response 51 (39.2%) 3 (30%)

Very good response 20 (15.4%) 4 (40%)Complete response 33 (25.4%) 3 (30%)

Organ responseNo response 65 (57%) 1 (33.3%)

0.579Response 49 (43%) 2 (66.7%)

ToxicityNo Toxicity 69 (57%) 5 (50%)

0.554Grade I 23 (19%) 2 (20%)

Grade II 16 (13.2%) 3 (30%)Grade III 12 (9.9%) 0 (0%)Grade IV 1 (0.8%) 0 (0%)

Doxycycline Use in AL Amyloidosis

Biochemical vs. organ R/PMedian (IQR) or percentage All (n = 69) Biochemical R/P (n = 29) Organ R/P (n = 40) P valueAt diagnosisAge (years) 62 (57-70) 62 (57-72) 64 (58-69) 0.892Male (%) 42 (60.9) 19 (65.5) 23 (57.5) 0.501Lambda light chain (%) 50 (72.5) 17 (58.6) 33 (82.5) 0.028Cardiac stage 2/3 (%) 37 (66.1) (n = 56) 16 (64.0) (n = 25) 21 (67.7) (n = 31) 0.769Cardiac stage 3 (%) 12 (21.4) (n = 56) 7 (28.0) (n = 25) 5 (16.1) (n = 31) 0.282Renal stage 2/3 (%) 43 (68.3) (n = 63) 15 (60.0) (n = 25) 28 (73.7) (n = 38) 0.254Renal stage 3 (%) 11 (17.5) (n = 63) 4 (16.0) (n = 25) 7 (18.4) (n = 38) 0.804Organ number >= 3 (%) 20 (29.0) 9 (31.0) 11 (27.5) 0.749Elevated LDH (%) 39 (67.2) (n = 58) 16 (66.7) (n = 24) 23 (67.6) (n = 34) 0.938Elevated B2MG (%) 42 (72.4) (n = 58) 16 (69.6) (n = 23) 26 (74.3) (n = 35) 0.694BMPC >= 20% (%) 18 (26.9) (n = 67) 5 (17.2) 13 (34.2) (n = 38) 0.121T (11;14) (%) 9 (17.0) (n = 53) 6 (25) (n = 24) 3 (10.3) (n = 29) 0.157dFLC (mg/L) 121.1 (26.8-751.3) (n = 64) 312.5 (88.1-1189.0) (n = 25) 73.0 (16.3-327.1) (n = 39) 0.028Low dFLC (< 50 mg/L) (%) 19 (29.7) (n = 64) 2 (8.0) (n = 25) 17 (43.6) (n = 39) 0.002Upfront therapyHDM/ASCT (%) 25 (36.2) 10 (34.5) 15 (37.5) 0.797PI-based regimen (%) 36 (52.2) 16 (55.2) 20 (50.0) 0.671Adequate hematological response (>= VGPR or R) (%) 41 (60.3) (n = 68) 16 (55.2) 25 (64.1) (n = 39) 0.457Organ response (%) 41 (60.3) (n = 68) 16 (55.2) 25 (64.1) (n = 39) 0.457At relapseTime from upfront to salvage (months) 22 (7-42) 22 (5-28) 21 (8-48) 0.211dFLC (mg/L) 90.3 (34.4-256.3) (n = 58) 150.9 (56.8-277.7) (n = 22) 80.7 (25.5-229.8) (n = 36) 0.288High risk dFLC progression (%) 30 (54.5) (n = 55) 10 (50) (n = 20) 20 (57.1) (n = 35) 0.609Salvage therapyPI-based regimen (%) 38 (55.1) 16 (55.2) 22 (55.0) 0.989Daratumumab-based regimen (%) 9 (13.0) 5 (17.2) 4 (10.0) 0.378

Factors predicting post-relapse survivalVariables OS2

Univariate Multivariate 1 (Organ) ** Multivariate 2 (Cardiac) **HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value

At diagnosisAge (years) 0.987 (0.937-1.040) 0.635Male 0.500 (0.208-1.202) 0.121Lambda light chain 2.529 (0.744-8.602) 0.137Cardiac stage 2/3 2.934 (0.656-13.119) 0.159Renal stage 2/3 1.394 (0.501-3.876) 0.525Organ >= 3 0.770 (0.282-2.103) 0.61Elevated LDH 0.825 (0.288-2.364) 0.721Elevated B2MG 2.238 (0.664-7.850) 0.19BMPC >= 20% 5.800 (2.384-14.112) < 0.001 3.206 (1.283-8.012) 0.013 4.327 (1.713-10.925) 0.002T (11;14) 0.778 (0.174-3.469) 0.742Low dFLC (< 50 mg/L) 1.005 (0.404-2.502) 0.992Upfront therapyAdequate hematological response (>= VGPR or R) 0.628 (0.247-1.593) 0.327Organ response 0.581 (0.240-1.404) 0.227At relapseTime from upfront to salvage >= 24 (months) 0.409 (0.158-1.056) 0.065High risk dFLC progression 1.760 (0.667-4.647) 0.254Organ R/P * 7.581 (1.761-36.624) 0.007 5.506 (1.222-24.811) 0.026Cardiac R/P * 3.532 (1.453-8.585) 0.005 3.754 (1.461-9.642) 0.006Treatment sequencePI -> IMiD 1 1 1Others 0.129 (0.038-0.437) 0.001 0.234 (0.067-0.822) 0.023 0.149 (0.040-0.551) 0.004ASCT -> CyBorD/Dara, or PI -> Dara 0.025 (0.003-0.235) 0.001 0.051 (0.005-0.504) 0.011 0.034 (0.003-0.351) 0.005

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OS2: from salvage therapy to last follow up or death

OS1: from upfront therapy to last follow up or death

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Next Steps

Moffitt Cancer Center Amyloid Center

• Cardiology• Neurology• Nephrology• Gastroenterology• Hepatology

• Heme/Onc/BMT• Pulmonology• Radiology• Pathology

• Multidisciplinary Approach

Thank you

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