J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://www.thejh.org

Review

Volume 10, Number 4, August 2021, pages 147-161

Current Updates on the Management of AL Amyloidosis

**Table 1.** Diagnostic Workup for AL Amyloidosis
NT-proBNP: N-terminal prohormone of brain natriuretic peptide; FISH: fluorescence in situ hybridization; EMG: electromyography.
1) Serum and urine electrophoresis with immunofixation
2) Serum free light chain assay
3) Complete blood count
4) Comprehensive metabolic panel including liver and renal function
5) Troponin T level
6) NT-proBNP level, BNP level
7) 24-h urinary protein with immunofixation
8) Creatinine clearance
9) Factor X level
10) Bone marrow aspirate and biopsy with FISH studies
11) Bone imaging (if multiple myeloma is suspected)
12) Cardiac involvement assessment: echocardiogram, magnetic resonance imaging
13) Abdominal ultrasonography
14) EMG/nerve conduction study if suspected neuropathy
15) Fat pad biopsy, Congo red stain, mass spectrometry
16) Endoscopy and colonoscopy if AL amyloidosis involving gastrointestinal tract is suspected

Table 1. Diagnostic Workup for AL Amyloidosis

NT-proBNP: N-terminal prohormone of brain natriuretic peptide; FISH: fluorescence in situ hybridization; EMG: electromyography.

1) Serum and urine electrophoresis with immunofixation

2) Serum free light chain assay

3) Complete blood count

4) Comprehensive metabolic panel including liver and renal function

5) Troponin T level

6) NT-proBNP level, BNP level

7) 24-h urinary protein with immunofixation

8) Creatinine clearance

9) Factor X level

10) Bone marrow aspirate and biopsy with FISH studies

11) Bone imaging (if multiple myeloma is suspected)

12) Cardiac involvement assessment: echocardiogram, magnetic resonance imaging

13) Abdominal ultrasonography

14) EMG/nerve conduction study if suspected neuropathy

15) Fat pad biopsy, Congo red stain, mass spectrometry

16) Endoscopy and colonoscopy if AL amyloidosis involving gastrointestinal tract is suspected

**Table 2.** Therapeutic Combinations in the Management of AL Amyloidosis
Treatment	Line of therapy	Description
Autologous stem cell transplant (ASCT)	1) Upfront transplant (in selected cases); 2) Consolidation after induction [16]	1) High-dose melphalan 200 mg/m² followed by ASCT is considered as first-line treatment for patients who fit eligibility criteria and have minimum plasma cell percentage (< 10%) in the bone marrow [9, 17, 18]; 2) Criteria for HD-ASCT include patients up to 65 - 70 years of age with estimated glomerular filtration rate (eGFR) > 50 mL/min, low cardiac biomarkers (NT-pBNP < 590 pmol/L and/or troponin T < 0.06 ng/mL), plasma cell infiltration (< 10%) in the bone marrow at the time of transplant; 3) ASCT should be avoided in patients with severe autonomic neuropathy, significant gastrointestinal bleeding, advanced renal failure over 70 years (case by case basis), amyloid-related symptomatic pleural effusions or poor Eastern Cooperative Oncology Group performance status (> 2) [41]; 4) Bortezomib-based induction therapy is considered prior to ASCT if plasma cells > 10% in the bone marrow.
Alkylating agent (melphalan) and dexamethasone
Melphalan and Dex (M-Dex)	First-line therapy in selected transplant ineligible patients	Melphalan-dexamethasone can be considered as first line in elderly patients, neuropathy, poor performance status. Complete response (CR) rate 33%, overall response rate (ORR) 67% [19].
Proteasome inhibitior therapy
Bortezomib	Backbone therapy for various combinations
Bortezomib, cyclophosphamide, dexamethasone (CyBorD)	First line or relapse AL amyloidosis (can be considered for both transplant eligible and ineligible	CyBorD as upfront or second-line therapy is very effective regimen with overall hematologic response up to 94%. The regimen can be used in both transplant eligible and ineligible patients [20, 21].
Bortezomib, melphalan, dexamethasone (BMDex)	First line or relapse AL amyloidosis (transplant ineligible patients)	Treatment with BMDex compared with MDex resulted in improved hematologic responses at 3 months (79% vs. 52%; P = 0.002), Very good partial response (VGPR) and CR (64% vs. 39%; hazard ratio, 2.47; 95% confidence interval (CI), 1.30 to 4.71). Overall survival (OS) with 50% decrease in mortality rate [22].
Bortezomib, lenalidomide, dexamethasone (VRd)	Use is limited to selected patients with t11:14, no cardiac involvement, no history solid organ transplant	1) The regimen has high rate of VGPR at 6 months compared to CyBorD regimen (92% vs. 61%) [23]. Consider weekly bortezomib, low-dose lenalidomide (5 mg), and weekly dexamethasone; 2) The regimen is not used as upfront due to its non-hematologic toxicity; 3) Combination should be avoided in patients with cardiac involvement.
Carfilzomib	Not recommended outside of clinical trial	Patients have high grade 3 and grade 4 cardiac, renal, pulmonary and hematologic toxicities.
Ixazomib
Ixazomib + dexamethasone	Relapse/refractory AL amyloidosis after one or more prior lines of therapy	1) Hematologic response are 52%, 1-year OS 85% [42]; 2) Phase 3 ongoing, NCT01659658
Ixazomib + cyclophosphamide + dexamethasone	Investigational	Phase 1/2 ongoing in patients with relapse AL amyloidosis (NCT01864018, NCT03236792)
Immunomodulatory drugs
Thalidomide
Thalidomide, dexamethasone	1) Rarely used due to toxicity; 2) Not commonly prescribe in USA	1) Hematologic response 48%, CR 15%; 2) Increase risk of symptomatic bradycardia [24]
Thalidomide, cyclophosphamide, dexamethasone	1) Use in relapse AL amyloidosis (case by case basis); 2) Not commonly prescribe in the USA	1) Hematologic response 74%, CR 21% [25]; 2) Increase risk of cardiotoxicity
Lenalidomide
Lenalidomide-dexamethasone	Limited to selected cases for both first line and relapse AL amyloidosis	1) Hematologic response 61%, CR 20% [26]; 2) Serious cardiac and renal toxicity are reported [27, 28].
Lenalidomide, cyclophosphamide, dexamethasone	Limited to selected cases for both first line and relapse AL amyloidosis	1) Hematologic response 60%, VGPR 40% in upfront treatment; 2) Higher rate of hematologic toxicity [43]
Pomalidomide
Pomalidomide-Dexamethasone	1) Preferred over lenalidomide and dexamethasone; 2) Use is limited to relapse AL amyloidosis	Overall hematologic response varies 48-68% in relapse AL amyloidosis. Rapid response can be seen after starting treatment [29, 30].
Monoclonal antibodies targeting CD38
Daratumumab (IV)	Heavily pretreated AL amyloidosis	1) Hematologic response is 76%, CR 36%, VGPR 24%; 2) Median hematologic response reported at 1 month [31]
Daratumumab (SQ), bortezomib, cyclophosphamide, dexamethasone	Recommended as first line induction therapy both in transplant eligible and transplant ineligible patients (preferred)	1) Overall hematologic response reported 92%, CR 53% compared to CyBorD alone (77%, CR 18%) [32, 33]; 2) Six-month cardiac response 42% versus 22%; 3) Six-month renal response 54% versus 27%
Ixazomib + daratumumab + dexamethasone	Investigational	Combination is currently investigated in heavily pretreated AL amyloidosis (NCT03283917).
Daratumumab, pomalidomide	Investigational	Combination is currently investigated in heavily pretreated AL amyloidosis (NCT04895917).
Isatuximab	Investigational	Preliminary phase 2 results showed hematologic response 77%, VGPR 54% (NCT 08399808) [44].
Targeting amyloid component therapy
NEOD001	Investigational	Clinical trial failed to prove significant improvement in outcomes. Subgroup analysis of VITAL suggests benefit in Mayo stage IV patients with severe cardiac involvement and confirmatory trial is planned [34].
CAEL-101	Investigational	1) 63% patients have organ response [35, 36]; 2) A double-blind, randomized, multicenter international phase 3 study of CAEL-101 combined with the SoC treatment for plasma cell dyscrasia (PCD) versus placebo in patients with treatment naive Mayo stage IIIb AL amyloidosis (NCT045004825); 3) A phase 3, double-blind, multicenter study to evaluate the efficacy and safety of CAEL-101 and plasma cell dyscrasia treatment versus placebo and plasma cell dyscrasia treatment in plasma cell dyscrasia treatment naive patients with Mayo stage IIIa AL amyloidosis (NCT04512235).
Anti-metabolite and alkylating agent
Bendamustine	Investigational	Has better hematologic response in relapse IgM AL amyloidosis compared to non-IgM AL amyloidosis (58% versus 28%) particularly in combination with rituximab [37]
Small molecules
Doxycycline	Consider doxycycline as an adjuvant to standard chemotherapy	Doxycycline is associated with better hematologic response and survival rates at 12 and 24 months compared to matched historical controls (82% versus 53%), and (82% versus 40%) [38]
Venetoclax (BCL-2 inhibitor)	Investigational	Drug is evaluated as single agent and in combinations. Venetoclax has shown promising results with t11:14 translocation. Despite biochemical response, safety concerns and increase risk of death is a concern which require further investigation before its use to patients.
Epigallocatechin-3-gallate (ECGC)	Investigational	Use as an adjuvant treatment is not well established [39, 40].
Ibrutunib (bruton tyrosine kinase (BTK) inhibitor)	Investigational	Ibrutinib with or without bortezomib and dexamethasone in treating patients with relapsed or refractory immunoglobulin light chain amyloidosis (NCT03130348)
Oncopeptides
Melflufen + dexamethasone	Investigational	A phase 1/2 open label study of melphalan flufenamide (melflufen) in combination with dexamethasone for participants with Al amyloidosis following at least one prior line of therapy (NCT04115956)

Table 2. Therapeutic Combinations in the Management of AL Amyloidosis

Treatment

Line of therapy

Description

Autologous stem cell transplant (ASCT)

1) Upfront transplant (in selected cases); 2) Consolidation after induction [16]

1) High-dose melphalan 200 mg/m² followed by ASCT is considered as first-line treatment for patients who fit eligibility criteria and have minimum plasma cell percentage (< 10%) in the bone marrow [9, 17, 18]; 2) Criteria for HD-ASCT include patients up to 65 - 70 years of age with estimated glomerular filtration rate (eGFR) > 50 mL/min, low cardiac biomarkers (NT-pBNP < 590 pmol/L and/or troponin T < 0.06 ng/mL), plasma cell infiltration (< 10%) in the bone marrow at the time of transplant; 3) ASCT should be avoided in patients with severe autonomic neuropathy, significant gastrointestinal bleeding, advanced renal failure over 70 years (case by case basis), amyloid-related symptomatic pleural effusions or poor Eastern Cooperative Oncology Group performance status (> 2) [41]; 4) Bortezomib-based induction therapy is considered prior to ASCT if plasma cells > 10% in the bone marrow.

Alkylating agent (melphalan) and dexamethasone

Melphalan and Dex (M-Dex)

First-line therapy in selected transplant ineligible patients

Melphalan-dexamethasone can be considered as first line in elderly patients, neuropathy, poor performance status. Complete response (CR) rate 33%, overall response rate (ORR) 67% [19].

Proteasome inhibitior therapy

Bortezomib

Backbone therapy for various combinations

Bortezomib, cyclophosphamide, dexamethasone (CyBorD)

First line or relapse AL amyloidosis (can be considered for both transplant eligible and ineligible

CyBorD as upfront or second-line therapy is very effective regimen with overall hematologic response up to 94%. The regimen can be used in both transplant eligible and ineligible patients [20, 21].

Bortezomib, melphalan, dexamethasone (BMDex)

First line or relapse AL amyloidosis (transplant ineligible patients)

Treatment with BMDex compared with MDex resulted in improved hematologic responses at 3 months (79% vs. 52%; P = 0.002), Very good partial response (VGPR) and CR (64% vs. 39%; hazard ratio, 2.47; 95% confidence interval (CI), 1.30 to 4.71). Overall survival (OS) with 50% decrease in mortality rate [22].

Bortezomib, lenalidomide, dexamethasone (VRd)

Use is limited to selected patients with t11:14, no cardiac involvement, no history solid organ transplant

1) The regimen has high rate of VGPR at 6 months compared to CyBorD regimen (92% vs. 61%) [23]. Consider weekly bortezomib, low-dose lenalidomide (5 mg), and weekly dexamethasone; 2) The regimen is not used as upfront due to its non-hematologic toxicity; 3) Combination should be avoided in patients with cardiac involvement.

Carfilzomib

Not recommended outside of clinical trial

Patients have high grade 3 and grade 4 cardiac, renal, pulmonary and hematologic toxicities.

Ixazomib

Ixazomib + dexamethasone

Relapse/refractory AL amyloidosis after one or more prior lines of therapy

1) Hematologic response are 52%, 1-year OS 85% [42]; 2) Phase 3 ongoing, NCT01659658

Ixazomib + cyclophosphamide + dexamethasone

Investigational

Phase 1/2 ongoing in patients with relapse AL amyloidosis (NCT01864018, NCT03236792)

Immunomodulatory drugs

Thalidomide

Thalidomide, dexamethasone

1) Rarely used due to toxicity; 2) Not commonly prescribe in USA

1) Hematologic response 48%, CR 15%; 2) Increase risk of symptomatic bradycardia [24]

Thalidomide, cyclophosphamide, dexamethasone

1) Use in relapse AL amyloidosis (case by case basis); 2) Not commonly prescribe in the USA

1) Hematologic response 74%, CR 21% [25]; 2) Increase risk of cardiotoxicity

Lenalidomide

Lenalidomide-dexamethasone

Limited to selected cases for both first line and relapse AL amyloidosis

1) Hematologic response 61%, CR 20% [26]; 2) Serious cardiac and renal toxicity are reported [27, 28].

Lenalidomide, cyclophosphamide, dexamethasone

Limited to selected cases for both first line and relapse AL amyloidosis

1) Hematologic response 60%, VGPR 40% in upfront treatment; 2) Higher rate of hematologic toxicity [43]

Pomalidomide

Pomalidomide-Dexamethasone

1) Preferred over lenalidomide and dexamethasone; 2) Use is limited to relapse AL amyloidosis

Overall hematologic response varies 48-68% in relapse AL amyloidosis. Rapid response can be seen after starting treatment [29, 30].

Monoclonal antibodies targeting CD38

Daratumumab (IV)

Heavily pretreated AL amyloidosis

1) Hematologic response is 76%, CR 36%, VGPR 24%; 2) Median hematologic response reported at 1 month [31]

Daratumumab (SQ), bortezomib, cyclophosphamide, dexamethasone

Recommended as first line induction therapy both in transplant eligible and transplant ineligible patients (preferred)

1) Overall hematologic response reported 92%, CR 53% compared to CyBorD alone (77%, CR 18%) [32, 33]; 2) Six-month cardiac response 42% versus 22%; 3) Six-month renal response 54% versus 27%

Ixazomib + daratumumab + dexamethasone

Investigational

Combination is currently investigated in heavily pretreated AL amyloidosis (NCT03283917).

Daratumumab, pomalidomide

Investigational

Combination is currently investigated in heavily pretreated AL amyloidosis (NCT04895917).

Isatuximab

Investigational

Preliminary phase 2 results showed hematologic response 77%, VGPR 54% (NCT 08399808) [44].

Targeting amyloid component therapy

NEOD001

Investigational

Clinical trial failed to prove significant improvement in outcomes. Subgroup analysis of VITAL suggests benefit in Mayo stage IV patients with severe cardiac involvement and confirmatory trial is planned [34].

CAEL-101

Investigational

1) 63% patients have organ response [35, 36]; 2) A double-blind, randomized, multicenter international phase 3 study of CAEL-101 combined with the SoC treatment for plasma cell dyscrasia (PCD) versus placebo in patients with treatment naive Mayo stage IIIb AL amyloidosis (NCT045004825); 3) A phase 3, double-blind, multicenter study to evaluate the efficacy and safety of CAEL-101 and plasma cell dyscrasia treatment versus placebo and plasma cell dyscrasia treatment in plasma cell dyscrasia treatment naive patients with Mayo stage IIIa AL amyloidosis (NCT04512235).

Anti-metabolite and alkylating agent

Bendamustine

Investigational

Has better hematologic response in relapse IgM AL amyloidosis compared to non-IgM AL amyloidosis (58% versus 28%) particularly in combination with rituximab [37]

Small molecules

Doxycycline

Consider doxycycline as an adjuvant to standard chemotherapy

Doxycycline is associated with better hematologic response and survival rates at 12 and 24 months compared to matched historical controls (82% versus 53%), and (82% versus 40%) [38]

Venetoclax (BCL-2 inhibitor)

Investigational

Drug is evaluated as single agent and in combinations. Venetoclax has shown promising results with t11:14 translocation. Despite biochemical response, safety concerns and increase risk of death is a concern which require further investigation before its use to patients.

Epigallocatechin-3-gallate (ECGC)

Investigational

Use as an adjuvant treatment is not well established [39, 40].

Ibrutunib (bruton tyrosine kinase (BTK) inhibitor)

Investigational

Ibrutinib with or without bortezomib and dexamethasone in treating patients with relapsed or refractory immunoglobulin light chain amyloidosis (NCT03130348)

Oncopeptides

Melflufen + dexamethasone

Investigational

A phase 1/2 open label study of melphalan flufenamide (melflufen) in combination with dexamethasone for participants with Al amyloidosis following at least one prior line of therapy (NCT04115956)

**Table 3.** Prognostic Mayo Staging System for AL Amyloidosis 2012
Stage	No. of factors	OS in patients who received ASCT	OS in patients who did not receive ASCT
Factors related to risk stratification: 1) NT-proBNP ≥ 1,800 ng/L; 2) cTnT ≥ 0.025 µg/L; 3) FLC-diff ≥ 18 mg/dL. Mayo staging system has three different models, including 2004 and 2004-European staging systems, which do not include FLC-difference as a prognostic factor (they include only NT-proBNP ≥ 332 ng/L and cTnT ≥ 0.035 µg/L). Mayo staging system 2004-European model further classified stage III based on the NT-proBNP of 8,500 ng/L (stage IIIa has the two factors higher than the cutoff point with NT-proBNP < 8,500 ng/L, and stage IIIb has the two factors higher than the cutoff point with NT-proBNP > 8,500 ng/L), which found to be more useful in predicting early death within 6 months from diagnosis compared to other staging systems. Thus, it has been used more in determining patient eligibility for participation in clinical trials and to further stratify patients into intermediate vs. high-risk groups [111]. NT-proBNP: N-terminal prohormone of brain natriuretic peptide; FLC-diff: the difference between involved and uninvolved free light chains; OS: overall survival; ASCT: autologous stem cell transplantation; cTnT: cardiac troponin T.
Stage I	0	Not reached	87	55	50
Stage II	1	97	72	19	35
Stage III	2	58	56	12	20
Stage VI	3	22	46	5	15

Table 3. Prognostic Mayo Staging System for AL Amyloidosis 2012

Stage

No. of factors

OS in patients who received ASCT

OS in patients who did not receive ASCT

No. of months

% of 4-year survival rate

No. of months

% of 5-year survival rate

Factors related to risk stratification: 1) NT-proBNP ≥ 1,800 ng/L; 2) cTnT ≥ 0.025 µg/L; 3) FLC-diff ≥ 18 mg/dL. Mayo staging system has three different models, including 2004 and 2004-European staging systems, which do not include FLC-difference as a prognostic factor (they include only NT-proBNP ≥ 332 ng/L and cTnT ≥ 0.035 µg/L). Mayo staging system 2004-European model further classified stage III based on the NT-proBNP of 8,500 ng/L (stage IIIa has the two factors higher than the cutoff point with NT-proBNP < 8,500 ng/L, and stage IIIb has the two factors higher than the cutoff point with NT-proBNP > 8,500 ng/L), which found to be more useful in predicting early death within 6 months from diagnosis compared to other staging systems. Thus, it has been used more in determining patient eligibility for participation in clinical trials and to further stratify patients into intermediate vs. high-risk groups [111]. NT-proBNP: N-terminal prohormone of brain natriuretic peptide; FLC-diff: the difference between involved and uninvolved free light chains; OS: overall survival; ASCT: autologous stem cell transplantation; cTnT: cardiac troponin T.

Stage I

Not reached

Stage II

Stage III

Stage VI