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Original Article

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Blood Res 2021; 56(4):

Published online December 31, 2021

https://doi.org/10.5045/br.2021.2021121

© The Korean Society of Hematology

Outcomes of bortezomib combination chemotherapies in autologous stem cell transplantation-ineligible patients with AL amyloidosis

Joon Young Hur1#, Sang Eun Yoon2#, Darae Kim3, Jin-oh Choi3, Ju-Hong Min4, Byung Jun Kim4, Jung Sun Kim5, Jung Eun Lee6, Joon Young Choi7, Eun-Seok Jeon3, Seok Jin Kim2, Kihyun Kim2

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1Division of Hematology and Oncology, Department of Internal Medicine, Hanyang University Guri Hospital, Guri, 2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 3Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Departments of 4Neurology and 5Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 6Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 7Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to : Kihyun Kim, M.D., Ph.D.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
E-mail: kihyunk@skku.edu

#These authors contributed equally to this work.

Received: June 24, 2021; Revised: October 1, 2021; Accepted: October 6, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
Treatment protocols for light chain (AL) amyloidosis have been derived from myeloma treatment. Bortezomib is a key drug used for the treatment of myeloma and AL amyloidosis. We retrospectively investigated the efficacy and toxicity of bortezomib- based chemotherapy in patients with newly diagnosed AL amyloidosis.
Methods
We reviewed the outcomes of newly diagnosed autologous stem cell transplantation (auto-SCT)-ineligible AL amyloidosis patients who received bortezomib-based chemotherapy at a referral center between 2011 and 2017.
Results
Of 63 patients who received bortezomib-based chemotherapy, 32 were male, and the median age was 66 years (range, 42‒82 yr). The hematologic overall response rate (ORR) was 65.1%, and the chemotherapy regimen with the best hematologic response was VMP (75.7%, 28/37). Sixty patients had significant organ (heart or kidney) involvement; 28.3% of patients (N=17) had major organ responses after chemotherapy. With a median follow- up of 34 months, there was no significant difference in progression-free survival (P=0.49) or overall survival (P =0.67) according to regimen. Most hematologic and non-hematologic problems were manageable.
Conclusion
Various chemotherapy combinations based on bortezomib are currently employed in the clinical setting, but no difference was found in terms of efficacy or toxicity.

Keywords Bortezomib, Light-chain amyloidosis, Transplant ineligible

Article

Original Article

Blood Res 2021; 56(4): 266-278

Published online December 31, 2021 https://doi.org/10.5045/br.2021.2021121

Copyright © The Korean Society of Hematology.

Outcomes of bortezomib combination chemotherapies in autologous stem cell transplantation-ineligible patients with AL amyloidosis

Joon Young Hur1#, Sang Eun Yoon2#, Darae Kim3, Jin-oh Choi3, Ju-Hong Min4, Byung Jun Kim4, Jung Sun Kim5, Jung Eun Lee6, Joon Young Choi7, Eun-Seok Jeon3, Seok Jin Kim2, Kihyun Kim2

1Division of Hematology and Oncology, Department of Internal Medicine, Hanyang University Guri Hospital, Guri, 2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 3Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Departments of 4Neurology and 5Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 6Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 7Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to:Kihyun Kim, M.D., Ph.D.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
E-mail: kihyunk@skku.edu

#These authors contributed equally to this work.

Received: June 24, 2021; Revised: October 1, 2021; Accepted: October 6, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
Treatment protocols for light chain (AL) amyloidosis have been derived from myeloma treatment. Bortezomib is a key drug used for the treatment of myeloma and AL amyloidosis. We retrospectively investigated the efficacy and toxicity of bortezomib- based chemotherapy in patients with newly diagnosed AL amyloidosis.
Methods
We reviewed the outcomes of newly diagnosed autologous stem cell transplantation (auto-SCT)-ineligible AL amyloidosis patients who received bortezomib-based chemotherapy at a referral center between 2011 and 2017.
Results
Of 63 patients who received bortezomib-based chemotherapy, 32 were male, and the median age was 66 years (range, 42‒82 yr). The hematologic overall response rate (ORR) was 65.1%, and the chemotherapy regimen with the best hematologic response was VMP (75.7%, 28/37). Sixty patients had significant organ (heart or kidney) involvement; 28.3% of patients (N=17) had major organ responses after chemotherapy. With a median follow- up of 34 months, there was no significant difference in progression-free survival (P=0.49) or overall survival (P =0.67) according to regimen. Most hematologic and non-hematologic problems were manageable.
Conclusion
Various chemotherapy combinations based on bortezomib are currently employed in the clinical setting, but no difference was found in terms of efficacy or toxicity.

Keywords: Bortezomib, Light-chain amyloidosis, Transplant ineligible

Fig 1.

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Figure 1.Progression-free survival (PFS) of all patients (A), PFS according to MAYO 2012 stage (B), PFS of patients with organ involvement (C), PFS of patients who achieved an organ response (D), PFS of patients who achieved a hematologic response (E), comparison of PFS according to chemotherapy (F).
Blood Research 2021; 56: 266-278https://doi.org/10.5045/br.2021.2021121

Fig 2.

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Figure 2.Overall survival (OS) of all patients (A), OS according to MAYO 2012 stage (B), OS of patients with organ involvement (C), OS of patients who achieved an organ response (D), OS of patients who achieved a hematologic response (E), comparison of OS according to chemotherapy (F).
Blood Research 2021; 56: 266-278https://doi.org/10.5045/br.2021.2021121

Table 1 . Patient characteristics and clinical presentation factors in primary amyloidosis patients..

CharacteristicsN%
63100
Age (yr)Median (range)66 (42–82)
>653657.1
SexMale/female32/3150.8/49.2
Presenting symptomDyspnea3352.4
Edema914.3
Proteinuria57.9
Dizziness or syncope34.8
Diarrhea23.2
PerformanceECOG PS 2 or more1422.2
NYHA Fc G2 or more3758.7
Organ involvementCardiac+renal2031.7
Cardiac4165.0
Renal2031.7
Hepatic46.4
Peripheral neuropathy2336.5
Autonomic neuropathy4673.0
Gastrointestinal1117.5
Pulmonary23.2
Soft tissue1625.4
N of organ involvement1 site812.7
2 sites2031.7
3 or more sites3555.6
Systolic blood pressure<100 mmHg2742.8
≥100 mmHg3657.1
Heavy chainIgG1422.2
IgA69.5
IgD34.8
Light chain disease4063.5
Light chainKappa1523.8
Lambda4774.6
CRABAnemia3250.8
Hypercalcemia34.8
Renal insufficiency1320.6
Lytic bone lesion11.6
Type (N=50)MM-CRAB1625.3
MM-PC2641.2
AL812.6
NT-proBNP (N=62)Median6,238 (285–35,000)
≥332 ng/L6198.4
≥1,800 ng/L5182.3
≥8,500 ng/L2337.1
Troponin T (N=54)Median0.074 (0.018–0.356)
≥0.025 ng/mL5194.4
≥0.035 ng/mL4888.8
≥0.06 ng/mL3870.4
Troponin I (N=50)Median0.231 (0.010–3.82)
≥0.1 ng/mL3876.0
dFLCMedian458 (8–11,633)
≥180 mg/L4977.8
Beta-2 microglobulinMedian3.415 (1.06–23.86)
>3.52742.8
Serum albuminMedian3.6 (1.70–4.50)
<3.5 g/dL3047.7
24-h urine proteinMedian0.698 (0.059–17.104)
>5 g1117.4
eGFRMedian64.4 (7.80–308.60)
<50 mL/min per 1.73 m22133.3
Stage 2012 (N=55)223.6
31832.7
43563.6

Abbreviations: dFLC, difference between involved and uninvolved free light chain; ECOG, Eastern Cooperative Oncology Group; eGFR, estimated glomerular filtration rate; NT-proBNP, NT-proB-type natriuretic peptide; NYHA, New York Heart Association..

Table 2 . Hematologic and organ response analysis (N=63 patients)..

RegimenN (%)Hematologic response (%)Organ response
(heart or kidney)
ORRCRVGPRPR
Total63 (100)41 (65.1)21 (33.3)12 (19.0)8 (12.7)17/60 (28.3)
VMP37 (58.7)28 (75.7)14 (37.8)8 (21.6)6 (16.2)11/37 (29.7)
VD9 (14.2)5 (55.6)2 (22.2)2 (22.2)1 (11.1)2/9 (22.2)
VCD8 (12.7)4 (50.0)2 (25)1 (12.5)1 (12.5)2/8 (25)
VMD8 (12.7)4 (50.0)3 (37.5)1 (12.5)0 (0.0)2/8 (25)
VTD1 (1.6)0 (0)0 (0)0 (0)0 (0)0/1 (0.0)

Abbreviations: C, cyclophosphamide; CR, complete response; D, dexamethasone; M, melphalan; ORR, overall response rate; P, prednisolone; PR, partial response; T, thalidomide; V, bortezomib; VGPR, very good partial response..

Table 3 . Chemotherapy toxicity..

VariablesTotal patients
Grade 1/2≥Grade 3
Anorexia26 (41.2)0
Nausea15 (23.8)0
Vomiting8 (12.6)1 (1.6)
Diarrhea8 (12.6)4 (6.3)
Constipation9 (14.3)0
Mucositis6 (9.5)0
Neuropathy31 (49.2)0
Insomnia5 (7.9)0
Fatigue29 (46.0)1 (1.6)
Rash8 (12.6)0
Anemia5 (11.1)2 (3.2)
Thrombocytopenia8 (12.6)2 (3.2)
Neutropenia2 (3.2)2 (3.2)

Table 4 . Overview of bortezomib-based chemotherapy studies in untreated AL amyloidosis..

RegimenStudyPatientsHematologic response
(%)		Cardiac response
(%)		Renal response
(%)		Grade 3/4
adverse events		Early deathRef
VMP vs. VD vs.VCD vs. VMDRetrospective63 Untreated65.1%28.3% (heart or kidney response)Thrombocytopenia: 3.2%35% (21)
Anemia: 3.2%
Diarrhea: 6.3%
VDRetrospective18 Untreated 11/pretreated 794%20%14%Thrombocytopenia: 11%11% (2)[13]
VCD vs. VDRetrospective42 vs. 59 Untreated78% vs. 68%21% vs. 29%41% vs. 43%Cytopenia<10% in both groupsNA[25]
VMD vs. MDPhase III53 vs. 56 Untreated73% vs. 52% (after 3 cycles)38% vs. 28% (after 9 mo)33% vs. 26% (after 9 mo)Thrombocytopenia 5% vs. 10%4 vs. 2[16]
Neutropenia4% vs. 8%
Anemia2% vs. 4%
VRDRetrospective34 Untreated89%41%22%Thrombocytopenia: 6%NA[30]
Neutropenia: 3%
Anemia: 6%

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