Key Points

  • Upfront bortezomib results in deep and durable hematologic responses in AL amyloidosis.

  • A stringent dFLC response (<10 mg/L) confers superior outcomes.

Abstract

Bortezomib is a standard therapy in light-chain amyloidosis (AL), but little is known about response duration. A difference in involved amyloidogenic and uninvolved serum-free light chains (dFLC) < 10 mg/L (low dFLC response) predicts survival in AL patients with low presenting dFLC (20-50 mg/L). We report outcomes in the largest AL cohort treated with upfront bortezomib and explore the impact of posttreatment dFLC < 10 mg/L (“stringent dFLC response”). A total of 915 newly diagnosed AL patients treated with bortezomib and assessed at our center were included. Hematologic responses, 6-month dFLC, organ responses, overall survival (OS), and time-to-next-treatment (TNT) (excluded patients who died without starting second-line treatment) were evaluated. Overall response rate (intent-to-treat) was 65%, with 49% complete response (CR)/very good partial response/low dFLC response and with a stringent dFLC response, dFLC 10-40 mg/L, and dFLC > 40 mg/L was 30%, 22%, and 48%, respectively. Median OS was 72 months. A total of 289 patients died without progressing to second-line treatment. Median TNT was not reached, and 55% had not progressed to further treatment at 7 years. Patients with stringent dFLC responses had significantly better OS and TNT than did those with lesser responses. A total of 72% of CR patients did not progress to further treatment at 3 years compared with 84% with stringent dFLC responses. Cardiac responses were better in those with stringent dFLC responses (61%) compared with lesser responses (45%; P = .005). Upfront bortezomib confers durable hematologic responses. A stringent dFLC response predicts prolonged TNT and impressive organ responses.

REFERENCES

REFERENCES
1.
Kastritis
E
,
Wechalekar
AD
,
Dimopoulos
MA
, et al
.
Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis
.
J Clin Oncol
.
2010
;
28
(
6
):
1031
-
1037
.
2.
Mikhael
JR
,
Schuster
SR
,
Jimenez-Zepeda
VH
, et al
.
Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis
.
Blood
.
2012
;
119
(
19
):
4391
-
4394
.
3.
Venner
CP
,
Lane
T
,
Foard
D
, et al
.
Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival
.
Blood
.
2012
;
119
(
19
):
4387
-
4390
.
4.
Palladini
G
,
Sachchithanantham
S
,
Milani
P
, et al
.
A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis
.
Blood
.
2015
;
126
(
5
):
612
-
615
.
5.
Jaccard
A
,
Comenzo
RL
,
Hari
P
, et al
.
Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III)
.
Haematologica
.
2014
;
99
(
9
):
1479
-
1485
.
6.
Palladini
G
,
Dispenzieri
A
,
Gertz
MA
, et al
.
New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes
.
J Clin Oncol
.
2012
;
30
(
36
):
4541
-
4549
.
7.
Kumar
SK
,
Dispenzieri
A
,
Lacy
MQ
, et al
.
Changes in serum-free light chain rather than intact monoclonal immunoglobulin levels predicts outcome following therapy in primary amyloidosis
.
Am J Hematol
.
2011
;
86
(
3
):
251
-
255
.
8.
Dittrich
T
,
Bochtler
T
,
Kimmich
C
, et al
.
AL amyloidosis patients with low amyloidogenic free light chain levels at first diagnosis have an excellent prognosis
.
Blood
.
2017
;
130
(
5
):
632
-
642
.
9.
Milani
P
,
Basset
M
,
Russo
F
,
Foli
A
,
Merlini
G
,
Palladini
G
.
Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome
.
Blood
.
2017
;
130
(
5
):
625
-
631
.
10.
Comenzo
RL
,
Reece
D
,
Palladini
G
, et al
.
Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis
.
Leukemia
.
2012
;
26
(
11
):
2317
-
2325
.
11.
Gertz
MA
,
Comenzo
R
,
Falk
RH
, et al
.
Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004
.
Am J Hematol
.
2005
;
79
(
4
):
319
-
328
.
12.
Wechalekar
AD
,
Schonland
SO
,
Kastritis
E
, et al
.
A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis
.
Blood
.
2013
;
121
(
17
):
3420
-
3427
.
13.
Palladini
G
,
Milani
P
,
Foli
A
, et al
.
Presentation and outcome with second-line treatment in AL amyloidosis previously sensitive to nontransplant therapies
.
Blood
.
2018
;
131
(
5
):
525
-
532
.
14.
Muchtar
E
,
Gertz
MA
,
Kumar
SK
, et al
.
Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death
.
Blood
.
2017
;
129
(
15
):
2111
-
2119
.
15.
Oliva
L
,
Orfanelli
U
,
Resnati
M
, et al
.
The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity
.
Blood
.
2017
;
129
(
15
):
2132
-
2142
.
16.
Bianchi
G
,
Oliva
L
,
Cascio
P
, et al
.
The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition
.
Blood
.
2009
;
113
(
13
):
3040
-
3049
.
17.
Sanchorawala
V
,
Sun
F
,
Quillen
K
,
Sloan
JM
,
Berk
JL
,
Seldin
DC
.
Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience
.
Blood
.
2015
;
126
(
20
):
2345
-
2347
.
18.
Venner
CP
,
Gillmore
JD
,
Sachchithanantham
S
, et al
.
A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis
.
Leukemia
.
2014
;
28
(
12
):
2304
-
2310
.
19.
Kastritis
E
,
Leleu
X
,
Arnulf
B
, et al
.
A randomised phase III trial of melphalan and dexamethasone (MDex) versus bortezomib, melphalan and dexamethasone (BMDex) for untreated patients with AL amyloidosis [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract
646
.
20.
Wechalekar
AD
,
Gillmore
JD
,
Hawkins
PN
.
Systemic amyloidosis
.
Lancet
.
2016
;
387
(
10038
):
2641
-
2654
.
21.
Landau
H
,
Smith
M
,
Landry
C
, et al
.
Long-term event-free and overall survival after risk-adapted melphalan and SCT for systemic light chain amyloidosis
.
Leukemia
.
2017
;
31
(
1
):
136
-
142
.
22.
Cibeira
MT
,
Sanchorawala
V
,
Seldin
DC
, et al
.
Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients
.
Blood
.
2011
;
118
(
16
):
4346
-
4352
.
23.
Muchtar
E
,
Dispenzieri
A
,
Leung
N
, et al
.
Optimizing deep response assessment for AL amyloidosis using involved free light chain level at end of therapy: failure of the serum free light chain ratio
.
Leukemia
.
2019
;
33
(
2
):
527
-
531
.
24.
Kastritis
E
,
Roussou
M
,
Gavriatopoulou
M
, et al
.
Long-term outcomes of primary systemic light chain (AL) amyloidosis in patients treated upfront with bortezomib or lenalidomide and the importance of risk adapted strategies
.
Am J Hematol
.
2015
;
90
(
4
):
E60
-
E65
.
You do not currently have access to this content.