Key Points

  • Daratumumab monotherapy elicited deep and rapid hematological responses in previously treated AL patients, with a good safety profile.

  • Patients with a very good partial response or better can experience long-lasting responses after 6 months of daratumumab monotherapy.

Abstract

Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC <40 mg/L) or better. Median time to hematological response was 1 week. Patients with no response after 4 doses were unlikely to respond further. Renal and cardiac responses occurred in 8 and 7 patients, respectively. Daratumumab was well tolerated, with no unexpected adverse events. With a median follow-up of 26 months, the 2-year overall survival rate was 74% (95% confidence interval, 62-81). Daratumumab monotherapy is associated with deep and rapid hematological responses in previously treated AL patients, with a good safety profile. Further studies of daratumumab in combination regimens are warranted.

REFERENCES

REFERENCES
1.
Merlini
G
,
Dispenzieri
A
,
Sanchorawala
V
, et al
.
Systemic immunoglobulin light chain amyloidosis
.
Nat Rev Dis Primers
.
2018
;
4
(
1
):
38
.
2.
Duhamel
S
,
Mohty
D
,
Magne
J
, et al
.
Incidence and prevalence of light chain amyloidosis: a population-based study [abstract]
.
Blood
.
2017
;
130
(
suppl 1
). Abstract
5577
.
3.
Bochtler
T
,
Hegenbart
U
,
Heiss
C
, et al
.
Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14)
.
Blood
.
2011
;
117
(
14
):
3809
-
3815
.
4.
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
.
5.
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
.
6.
de Weers
M
,
Tai
YT
,
van der Veer
MS
, et al
.
Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors
.
J Immunol
.
2011
;
186
(
3
):
1840
-
1848
.
7.
Lammerts van Buren
J
,
Jakobs
D
,
Kalendhoven
N
, et al
.
Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984, and Ab79
.
Blood
.
2014
;
124
(
21
):
3474
.
8.
Laubach
JP
,
Richardson
PG
.
CD38-targeted immunochemotherapy in refractory multiple myeloma: a new horizon
.
Clin Cancer Res
.
2015
;
21
(
12
):
2660
-
2662
.
9.
Overdijk
MB
,
Verploegen
S
,
Bögels
M
, et al
.
Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma
.
MAbs
.
2015
;
7
(
2
):
311
-
321
.
10.
Overdijk
MB
,
Jansen
JH
,
Nederend
M
, et al
.
The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcγ receptor-mediated cross-linking
.
J Immunol
.
2016
;
197
(
3
):
807
-
813
.
11.
Krejcik
J
,
Casneuf
T
,
Nijhof
IS
, et al
.
Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma
.
Blood
.
2016
;
128
(
3
):
384
-
394
.
12.
Sher
T
,
Fenton
B
,
Akhtar
A
,
Gertz
MA
.
First report of safety and efficacy of daratumumab in 2 cases of advanced immunoglobulin light chain amyloidosis
.
Blood
.
2016
;
128
(
15
):
1987
-
1989
.
13.
Kaufman
GP
,
Schrier
SL
,
Lafayette
RA
,
Arai
S
,
Witteles
RM
,
Liedtke
M
.
Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis
.
Blood
.
2017
;
130
(
7
):
900
-
902
.
14.
Van de Wyngaert
Z
,
Carpentier
B
,
Pascal
L
, et al
.
Daratumumab is effective in the relapsed or refractory systemic light-chain amyloidosis but associated with high infection burden in a frail real-life population
.
Br J Haematol
.
2020
;
188
(
3
):
e24
-
e27
.
15.
Fleming
TR
.
One-sample multiple testing procedure for phase II clinical trials
.
Biometrics
.
1982
;
38
(
1
):
143
-
151
.
16.
Manwani
R
,
Cohen
O
,
Sharpley
F
, et al
.
A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib
.
Blood
.
2019
;
134
(
25
):
2271
-
2280
.
17.
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
.
18.
Khouri
J
,
Kin
A
,
Thapa
B
, et al
.
Daratumumab proves safe and highly effective in AL amyloidosis
.
Br J Haematol
.
2019
;
185
(
2
):
342
-
344
.
19.
Schwotzer
R
,
Manz
MG
,
Pederiva
S
, et al
.
Daratumumab for relapsed or refractory AL amyloidosis with high plasma cell burden
.
Hematol Oncol
.
2019
;
37
(
5
):
595
-
600
.
20.
Abeykoon
JP
,
Zanwar
S
,
Dispenzieri
A
, et al
.
Daratumumab-based therapy in patients with heavily-pretreated AL amyloidosis
.
Leukemia
.
2019
;
33
(
2
):
531
-
536
.
21.
Lokhorst
HM
,
Plesner
T
,
Laubach
JP
, et al
.
Targeting CD38 with daratumumab monotherapy in multiple myeloma
.
N Engl J Med
.
2015
;
373
(
13
):
1207
-
1219
.
22.
Manwani
R
,
Foard
D
,
Mahmood
S
, et al
.
Rapid hematologic responses improve outcomes in patients with very advanced (stage IIIb) cardiac immunoglobulin light chain amyloidosis
.
Haematologica
.
2018
;
103
(
4
):
e165
-
e168
.
23.
Sanchorawala
V
,
Sarosiek
S
,
Sloan
JM
, et al
.
Safety, tolerability and response rates of Daratumumab in patients with relapsed light chain (AL) amyloidosis: results of a phase II study [abstract]
.
Blood
.
2018
;
132
(
suppl 1
). Abstract
2005
.
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