Updates in AL Amyloidosis and Light Chain Deposition Disease

Andrew J. Cowan, M.D.University of Washington / Fred Hutch / Seattle Cancer Care AllianceEmail: acowan@uw.edu

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

Disclosures

• 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

Objectives

• 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?

• 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)

Clinical Presentations That Should Raise Concern For Amyloidosis

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

• 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

How does a pathologist find amyloidosis?

Specimen from abdominal fat aspirate; note intense congophilic staining

Characteristic “apple green birefringence” under polarized light microscopy

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

• Monoclonal immunoglobulin light chains are deposited (not as amyloid fibrils)

• Most common site of involvement – kidney nephrotic range proteinuria

• Hepatic, cardiac, neural deposits also possible

What is Light Chain Deposition Disease (LCDD)?

Classic Physical Examination Findings in AL Amyloidosis

Diagnostic Algorithm for AmyloidosisSuspicion 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?

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

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

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

• 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

Clinical Pearls for Treating Patients with AL Amyloidosis

• 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

Eligibility Criteria for ASCT – Key Concerns

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

Autologous Stem Cell Transplantation (ASCT) for AL Amyloidosis

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

Upfront Bortezomib-based Therapy for AL Amyloidosis

Daratumumab and CyBorD for Newly Diagnosed AL: The ANDROMEDA Trial

Comenzo RL et al. EHA Annual Meeting, 2019

• 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

NEOD001 + CyBorD: The Phase 3 VITAL Study

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

• 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 analyses

HR (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

Sanchorawala V, et al. Blood. 2020 Jan 24

Daratumumab for Relapsed AL Amyloidosis

Immunomodulatory Agents for Relapsed AL Amyloidosis

1Dispenzieri A et al. Blood 2007 Jan 15;109(2):465-70; 2Sanchorawala V et al. Blood. 2007 Jan 15;109(2):492-6; 3Sanchorawala 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

• 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, fatigue

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

• 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

• 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

Conclusions