Updates in AL Amyloidosis and Light Chain Deposition Disease

Andrew J. Cowan, M.D.University of Washington / Fred Hutch / Seattle Cancer Care Alliance

Disclosures• Advisory Board: Sanofi; Cellectar• Consulting: Bristol Myers Squibb; Janssen• Research support: Bristol Myers Squibb; Janssen; Abbvie; Sanofi

Objectives• Review basic pathophysiology, diagnosis of AL amyloidosis and light

chain deposition disease

• Distinguish between different treatment options for newly diagnosed patients with AL amyloidosis and LCDD

• Understand new/emerging treatment options for patients with relapsed or refractory AL amyloidosis

• Definition: a group of diseases characterized by:– Normally soluble proteins deposit, leading to formation of

insoluble extracellular amyloid fibrils• Classification:

– Systemic: amyloidogenic protein produced at site distant from site of deposition

– Localized: amyloid deposition at same site as production of amyloidogenic protein

What is Amyloidosis?

Clinical presentations that should raise concern for amyloidosis

• Heart failure with preserved ejection fraction (HFPEF)

• Nephrotic range proteinuria

• Gastroparesis, isolated hepatomegaly

• Peripheral neuropathy with autonomic features, carpal tunnel syndrome

• Any patient with MGUS (esp λ clonality), or Multiple Myeloma (12-20% of patients)

How does a pathologist find amyloidosis?• Congo Red: stain used in histology for documenting the presence of

amyloidosis in tissue• Congo red initially began as a textile dye; in 1922, was found to bind avidly

to amyloid protein1

• “Amyloid” initially termed by German botanist Matthias Schleiden to describe starch material in plants that stained blue with iodine1

Specimen from abdominal fat aspirate; note intense congophilicstaining

Characteristic “apple green birefringence” under polarized light microscopy

1David P. Steensma (2001) “Congo” Red. Archives of Pathology & Laboratory Medicine: February 2001, Vol. 125, No. 2, pp. 250-252.

What is light chain deposition disease (LCDD)?• Monoclonal immunoglobulin light chains are deposited (not as

amyloid fibrils)• Most common site of involvement – kidney à nephrotic range

proteinuria• Hepatic, cardiac, neural deposits also possible

Sayed RH et al. Blood. 2015 Dec 24;126(26):2805-10

Classic Physical Examination Findings in AL Amyloidosis

Diagnostic Algorithm for Amyloidosis

Suspicion for Amyloidosis

Biopsy of surrogate site:• Fat pad aspirate• Minor labial salivary gland biopsy

Typing:• Gold standard: Laser capture / Mass

spectrometry• Also: IHC; Immunogold electron microscopy

Plasma cell dyscrasia work-up:• Serum free light chain

assay• Bone marrow aspirate and

biopsy with flow cytometry, FISH, and conventional cytogenetics

• SPEP with immunofixation• 24 hour urine protein with

UPEP

Other testing for assessment of vital organ involvement:• Orthostatic vital

signs• nt-pro BNP,

troponin T (or BNP, Tn-I)

• LFTs• Transthoracic

echocardiogram• Cardiac MRI

PYP/DPD scan (for ATTR-CM) *

If negative:• Biopsy of involved organ

Concern for ATTR?

Revised Prognostic Staging System for AL Amyloidosis

Factors

dFLC ≥ 18 mg/dL

Cardiac troponin-T ≥ 0.025 ng/ml

NT-ProBNP ≥ 1,800 pg/mL

Each gets 1 point; score from 0, 1, 2, and 3 points denoting stages I, II, III and IV

Kumar S et al. J Clin Oncol. 2012 Mar 20;30(9):989-95

Treatment of Newly Diagnosed AL Amyloidosis and LCDD

Newly Diagnosed Patient with AL Amyloidosis

Autologous Stem Cell Transplantation

Conditioning:Melphalan 200 mg/m2

Bortezomib-based regimens (e.g., CyBorD, Vd, VMP)

ORClinical Trial

Transplant Eligible Not Transplant Eligible

Clinical Pearls for Treating Patients with AL Amyloidosis

• Watch the dexamethasone dose… 10-20 mg is usually enough

• Manage fluid retention carefully

• Bortezomib can unmask neuropathy (peripheral and autonomic)

• Spironolactone can be helpful for amyloid cardiomyopathy

• Midodrine very useful for orthostatic hypotension

• Key Point: Treating this like Multiple Myeloma (same doses, regimens, etc) is often too much for these frail patients

Eligibility Criteria for ASCT – Key Concerns• Due to risks of transplant-related mortality (TRM), eligibility

criteria have evolved over time to select optimal patients• Typical Criteria:

• Cardiac ejection fraction > 40%• DLCO > 50% predicted• Supine systolic blood pressure > 90 mmHg• NT pro BNP < 5,000 / Troponin T < 0.06

• Common challenges:• Cardiac involvement – increased TRM (16%) seen in cardiac

involvement with ASCT• Determining extent of organ involvement

Autologous Stem Cell Transplantation (ASCT) for AL Amyloidosis

Sanchorawala V, et al. Blood (2015) 126 (20): 2345-2347

Upfront Bortezomib-based therapy for AL Amyloidosis

Manwani R et al. Blood 2019 Dec 19;134(25):2271-2280

Daratumumab and CyBorD for Newly Diagnosed AL: The ANDROMEDA Trial• Phase 3 study of daratumumab SC

plus CyBorD vs CyBorD alone

• Newly diagnosed AL Amyloidosis

• Primary endpoint: Overall complete hematologic response rate

• Eligibility:• AL with ≥ 1 organ involved• Cardiac Stage I-IIIA

Comenzo RL et al. EHA Annual Meeting, 2019

NEOD001 + CyBorD: The Phase 3 VITAL Study

• NEOD001: Investigational humanized IgG1 monoclonal antibody

• Preclinical evidence of promotion of phagocytic clearance of amyloid deposits

• Phase 3 study of CyBorD +/- NEOD001 in newly diagnosed, untreated AL was conducted

• No significance difference between study arm and control for the PE

• Post hoc analysis suggest potential survival benefit for Stage IV AL patients

ITT and mITT (Initial 12-Month Study Period) Results:

Mayo Stage(N) Endpoint

ITT analysesHR (95%CI)

p-value

mITT analyses

HR (95%CI)p-value

All(N=260)

Composite primary

endpoint

0.835 (0.5799, 1.2011)

p=0.3300

0.784 (0.5341, 1.1507)

p=0.2129

Stage I-III(n=183)

All-cause mortality

1.334 (0.7386, 2.4107)

p=0.3375

1.244 (0.6435, 2.4035)

p=0.5159

Stage IV(n=77)

All-cause mortality

0.544 (0.2738, 1.0826)

p=0.0787

0.498 (0.2404, 1.0304)

p=0.0556

Gertz MA et al. Blood (2019) 134 (Supplement_1): 3166.

Sanchorawala V, et al. Blood. 2020 Jan 24

Daratumumab for Relapsed AL Amyloidosis

Immunomodulatory agents for Relapsed AL Amyloidosis • Lenalidomide and

dexamethasone:• Overall Response Rates: 41-67%,

median time to response ~6 months1,2

• Tox profile: Myelosuppression, dermatologic, fatigue

• Pomalidomide:• Overall Response Rates: 48-50 %,

median time to response, 1.9 months3,4

• Tox: Myelosuppression, fatigue1Dispenzieri A et al. Blood 2007 Jan 15;109(2):465-70; 2Sanchorawala V et al. Blood. Blood. 2007 Jan 15;109(2):492-63Sanchorawala V et al. Blood. 2016 Aug 25;128(8):1059-62; 4Dispenzieri A et al Blood 2012 Jun 7;119(23):5397-404 5Warsame R et al. Blood Cancer j. 2020 Jan 8;10(1):4

• Venetoclax – an oral, small molecule BCL2 inhibitor; most promising development in plasma cell neoplasms in patients harboring t(11;14)

• AL Amyloidosis – 50% prevalence of t(11;14)1

• Small case reports have suggested benefit in AL amyloidosis2-3; Clinical trials are enrolling

Venetoclax in AL Amyloidosis

1Hayman SR et al, Blood. 2001; 98(7):2266-2268; 2Premkumar V et al. Clin Lymphoma Myeloma Leuk. 2019; Oct;19(10):686-688; 3Leung N et al. Haematologica 2018; Mar;103(3):e135-e137

Conclusions• Think about the diagnosis in appropriate scenarios! Remember that

typing of the amyloid protein is critical

• Differentiate between LCDD and AL amyloidosis – different diseases, similar treatment modalities

• Upfront treatment – prefer autologous HSCT for eligible patients, bortezomib-based therapies for all others

• No FDA approved options for relapsed AL amyloidosis/LCDD – but MM therapies like daratumumab, IMiDs, all effective