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

Joon Young Hur; Sang Eun Yoon; Darae Kim; Jin-oh Choi; Ju-Hong Min; Byung Jun Kim; Jung Sun Kim; Jung Eun Lee; Joon Young Choi; Eun-Seok Jeon; Seok Jin Kim; Kihyun Kim

doi:10.5045/br.2021.2021121

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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

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

Joon Young Hur^1#, Sang Eun Yoon^2#, 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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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

Article

Original Article

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

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

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

Joon Young Hur^1#, Sang Eun Yoon^2#, 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

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

Abstract

Keywords: Bortezomib, Light-chain amyloidosis, Transplant ineligible

Abstract

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..

Characteristics		N	%
Characteristics		63	100
Age (yr)	Median (range)	66 (42–82)
Age (yr)	>65	36	57.1
Sex	Male/female	32/31	50.8/49.2
Presenting symptom	Dyspnea	33	52.4
	Edema	9	14.3
	Proteinuria	5	7.9
	Dizziness or syncope	3	4.8
	Diarrhea	2	3.2
Performance	ECOG PS 2 or more	14	22.2
Performance	NYHA Fc G2 or more	37	58.7
Organ involvement	Cardiac+renal	20	31.7
	Cardiac	41	65.0
	Renal	20	31.7
	Hepatic	4	6.4
	Peripheral neuropathy	23	36.5
	Autonomic neuropathy	46	73.0
	Gastrointestinal	11	17.5
	Pulmonary	2	3.2
	Soft tissue	16	25.4
N of organ involvement	1 site	8	12.7
	2 sites	20	31.7
	3 or more sites	35	55.6
Systolic blood pressure	<100 mmHg	27	42.8
Systolic blood pressure	≥100 mmHg	36	57.1
Heavy chain	IgG	14	22.2
	IgA	6	9.5
	IgD	3	4.8
	Light chain disease	40	63.5
Light chain	Kappa	15	23.8
Light chain	Lambda	47	74.6
CRAB	Anemia	32	50.8
	Hypercalcemia	3	4.8
	Renal insufficiency	13	20.6
	Lytic bone lesion	1	1.6
Type (N=50)	MM-CRAB	16	25.3
	MM-PC	26	41.2
	AL	8	12.6
NT-proBNP (N=62)	Median	6,238 (285–35,000)
	≥332 ng/L	61	98.4
	≥1,800 ng/L	51	82.3
	≥8,500 ng/L	23	37.1
Troponin T (N=54)	Median	0.074 (0.018–0.356)
	≥0.025 ng/mL	51	94.4
	≥0.035 ng/mL	48	88.8
	≥0.06 ng/mL	38	70.4
Troponin I (N=50)	Median	0.231 (0.010–3.82)
Troponin I (N=50)	≥0.1 ng/mL	38	76.0
dFLC	Median	458 (8–11,633)
dFLC	≥180 mg/L	49	77.8
Beta-2 microglobulin	Median	3.415 (1.06–23.86)
Beta-2 microglobulin	>3.5	27	42.8
Serum albumin	Median	3.6 (1.70–4.50)
Serum albumin	<3.5 g/dL	30	47.7
24-h urine protein	Median	0.698 (0.059–17.104)
24-h urine protein	>5 g	11	17.4
eGFR	Median	64.4 (7.80–308.60)
eGFR	<50 mL/min per 1.73 m²	21	33.3
Stage 2012 (N=55)	2	2	3.6
	3	18	32.7
	4	35	63.6

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)..

Regimen	N (%)	Hematologic response (%)				Organ response (heart or kidney)
Regimen	N (%)	ORR	CR	VGPR	PR	Organ response (heart or kidney)
Total	63 (100)	41 (65.1)	21 (33.3)	12 (19.0)	8 (12.7)	17/60 (28.3)
VMP	37 (58.7)	28 (75.7)	14 (37.8)	8 (21.6)	6 (16.2)	11/37 (29.7)
VD	9 (14.2)	5 (55.6)	2 (22.2)	2 (22.2)	1 (11.1)	2/9 (22.2)
VCD	8 (12.7)	4 (50.0)	2 (25)	1 (12.5)	1 (12.5)	2/8 (25)
VMD	8 (12.7)	4 (50.0)	3 (37.5)	1 (12.5)	0 (0.0)	2/8 (25)
VTD	1 (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..

Variables	Total patients
Variables	Grade 1/2	≥Grade 3
Anorexia	26 (41.2)	0
Nausea	15 (23.8)	0
Vomiting	8 (12.6)	1 (1.6)
Diarrhea	8 (12.6)	4 (6.3)
Constipation	9 (14.3)	0
Mucositis	6 (9.5)	0
Neuropathy	31 (49.2)	0
Insomnia	5 (7.9)	0
Fatigue	29 (46.0)	1 (1.6)
Rash	8 (12.6)	0
Anemia	5 (11.1)	2 (3.2)
Thrombocytopenia	8 (12.6)	2 (3.2)
Neutropenia	2 (3.2)	2 (3.2)

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

Regimen	Study	Patients	Hematologic response (%)	Cardiac response (%)	Renal response (%)	Grade 3/4 adverse events	Early death	Ref
VMP vs. VD vs.VCD vs. VMD	Retrospective	63 Untreated	65.1%	28.3% (heart or kidney response)		Thrombocytopenia: 3.2%	35% (21)
						Anemia: 3.2%
						Diarrhea: 6.3%
VD	Retrospective	18 Untreated 11/pretreated 7	94%	20%	14%	Thrombocytopenia: 11%	11% (2)	[13]
VCD vs. VD	Retrospective	42 vs. 59 Untreated	78% vs. 68%	21% vs. 29%	41% vs. 43%	Cytopenia<10% in both groups	NA	[25]
VMD vs. MD	Phase III	53 vs. 56 Untreated	73% 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%
VRD	Retrospective	34 Untreated	89%	41%	22%	Thrombocytopenia: 6%	NA	[30]
						Neutropenia: 3%
						Anemia: 6%