Abstract

The course of multiple myeloma (MM) from initial diagnosis to a relapsed/refractory state is characterized by acquisition of drug resistance as well as progressive immunologic dysfunction. Despite this, however, a number of novel therapies that work in part or solely via immune stimulation are in development for MM, with promising early clinical results. Several new whole-cell or multiepitope vaccine approaches are demonstrating immunologic efficacy in smoldering MM or as posttherapy consolidation, with trials ongoing to see whether this translates into delayed progression or elimination of minimal residual disease. Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibition in combination with immunomodulatory drugs demonstrated excessive toxicity in randomized trials; however, antibodies targeting PD-1/PD-L1 and other checkpoint molecules continue to be explored in combination with tumor-targeted antibodies and other T cell–directed therapies. B-cell maturation antigen (BCMA) has emerged as the next big antigen target, with multiple BCMA-specific antibody-drug conjugates (ADCs) and T cell–directed bispecific antibodies/bispecific therapeutic engagers (BiTEs) entering the clinic. In initial trials, the ADC GSK2857916 and the BiTE AMG 420 have demonstrated high response rates in relapsed/refractory patients, with depth and durability of responses that may end up rivaling chimeric antigen receptor T-cell therapies. These agents have unique toxicities that require close monitoring, but they are moving forward in larger registration studies and in combination with standard MM agents. Additional ADCs and bispecific antibodies targeting BCMA and other surface antigens (eg, CD38, CD46, CD48, FcRH5, and G protein–coupled receptor, class C group 5 member D) are moving forward in phase 1 trials and may provide even more options for MM patients.

References

References
1.
Tamura
H
.
Immunopathogenesis and immunotherapy of multiple myeloma
.
Int J Hematol
.
2018
;
107
(
3
):
278
-
285
.
2.
Rapoport
AP
,
Aqui
NA
,
Stadtmauer
EA
, et al
.
Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells
.
Clin Cancer Res
.
2014
;
20
(
5
):
1355
-
1365
.
3.
Rapoport
AP
,
Aqui
NA
,
Stadtmauer
EA
, et al
.
Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma
.
Blood
.
2011
;
117
(
3
):
788
-
797
.
4.
Qazilbash
MH
,
Stadtmauer
EA
,
Baladandayuthapani
V
, et al
.
Randomized phase II trial of combination idiotype vaccine and anti-CD3/anti-CD28 costimulated autologous T cells in patients with multiple myeloma post-autotransplantation
.
Blood
.
2016
;
128
(
22
). Abstract 4548.
5.
Cohen
AD
,
Lendvai
N
,
Nataraj
S
, et al
.
Autologous lymphocyte infusion supports tumor antigen vaccine-induced immunity in autologous stem cell transplant for multiple myeloma
.
Cancer Immunol Res
.
2019
;
7
(
4
):
658
-
669
.
6.
Rosenblatt
J
,
Avivi
I
,
Vasir
B
, et al
.
Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients
.
Clin Cancer Res
.
2013
;
19
(
13
):
3640
-
3648
.
7.
Borrello
IM
,
Noonan
K
,
Huff
CA
, et al
.
Allogeneic myeloma GVAX with lenalidomide enhances progression free survival through the generation of tumor specific immunity in patients in near complete remission
.
Blood
.
2015
;
126
(
23
).
Abstract 4238
.
8.
Nooka
AK
,
Wang
ML
,
Yee
AJ
, et al
.
Assessment of safety and immunogenicity of PVX-410 vaccine with or without lenalidomide in patients with smoldering multiple myeloma: a nonrandomized clinical trial
.
JAMA Oncol
.
2018
;
4
(
12
):
e183267
.
9.
Rosenblatt
J
,
Glotzbecker
B
,
Mills
H
, et al
.
PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine
.
J Immunother
.
2011
;
34
(
5
):
409
-
418
.
10.
Tamura
H
,
Ishibashi
M
,
Yamashita
T
, et al
.
Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma
.
Leukemia
.
2013
;
27
(
2
):
464
-
472
.
11.
Hallett
WH
,
Jing
W
,
Drobyski
WR
,
Johnson
BD
.
Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade
.
Biol Blood Marrow Transplant
.
2011
;
17
(
8
):
1133
-
1145
.
12.
Lesokhin
AM
,
Ansell
SM
,
Armand
P
, et al
.
Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study
.
J Clin Oncol
.
2016
;
34
(
23
):
2698
-
2704
.
13.
Mateos
M-V
,
Orlowski
RZ
,
Siegel
DSD
, et al
.
Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): final efficacy and safety analysis
.
J Clin Oncol
.
2016
;
34
(
15 suppl
):
8010
-
8010
.
14.
Badros
A
,
Hyjek
E
,
Ma
N
, et al
.
Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma
.
Blood
.
2017
;
130
(
10
):
1189
-
1197
.
15.
US FDA
. FDA Alerts Healthcare Professionals and Oncology Clinical Investigators About Two Clinical Trials on Hold Evaluating KEYTRUDA® (Pembrolizumab) in Patients with Multiple Myeloma. Silver Springs, MD: US FDA; 30 September 2017.
16.
Cherkassky
L
,
Morello
A
,
Villena-Vargas
J
, et al
.
Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition
.
J Clin Invest
.
2016
;
126
(
8
):
3130
-
3144
.
17.
Bezman
NA
,
Jhatakia
A
,
Kearney
AY
, et al
.
PD-1 blockade enhances elotuzumab efficacy in mouse tumor models
.
Blood Adv
.
2017
;
1
(
12
):
753
-
765
.
18.
Cho
HJ
,
Costa
LJ
,
Davies
FE
, et al
.
Atezolizumab in combination with daratumumab with or without lenalidomide or pomalidomide: a phase Ib study in patients with Multiple Myeloma
.
Blood
.
2018
;
132
(
suppl 1
).
Abstract 597
.
19.
Chung
DJ
,
Pronschinske
KB
,
Shyer
JA
, et al
.
T-cell exhaustion in multiple myeloma relapse after autotransplant: optimal timing of immunotherapy
.
Cancer Immunol Res
.
2016
;
4
(
1
):
61
-
71
.
20.
Guillerey
C
,
Harjunpää
H
,
Carrié
N
, et al
.
TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma
.
Blood
.
2018
;
132
(
16
):
1689
-
1694
.
21.
Jing
W
,
Gershan
JA
,
Weber
J
, et al
.
Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma
.
J Immunother Cancer
.
2015
;
3
(
1
):
2
.
22.
Bae
J
,
Samur
M
,
Richardson
P
,
Munshi
NC
,
Anderson
KC
.
Selective targeting of multiple myeloma by B cell maturation antigen (BCMA)-specific central memory CD8+ cytotoxic T lymphocytes: immunotherapeutic application in vaccination and adoptive immunotherapy [published online ahead of print March 12, 2019]
.
Leukemia
.
doi:10.1038/s41375-019-0414-z
.
23.
Laubach
JP
,
van de Donk
N
,
Davies
FE
,
Mikhael
J
.
Practical considerations for antibodies in myeloma
.
Am Soc Clin Oncol Educ Book
.
2018
;
38
(
38
):
667
-
674
.
24.
van de Donk
NWCJ
,
Usmani
SZ
.
CD38 antibodies in multiple myeloma: mechanisms of action and modes of resistance
.
Front Immunol
.
2018
;
9
(
2134
):
2134
.
25.
Campbell
KS
,
Cohen
AD
,
Pazina
T
.
Mechanisms of NK cell activation and clinical activity of the therapeutic SLAMF7 antibody, elotuzumab in multiple myeloma
.
Front Immunol
.
2018
;
9
:
2551
.
26.
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
.
27.
Rickert
RC
,
Jellusova
J
,
Miletic
AV
.
Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease
.
Immunol Rev
.
2011
;
244
(
1
):
115
-
133
.
28.
Frigyesi
I
,
Adolfsson
J
,
Ali
M
, et al
.
Robust isolation of malignant plasma cells in multiple myeloma
.
Blood
.
2014
;
123
(
9
):
1336
-
1340
.
29.
Tai
YT
,
Mayes
PA
,
Acharya
C
, et al
.
Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma
.
Blood
.
2014
;
123
(
20
):
3128
-
3138
.
30.
Seckinger
A
,
Delgado
JA
,
Moser
S
, et al
.
Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment
.
Cancer Cell
.
2017
;
31
(
3
):
396
-
410
.
31.
Moreaux
J
,
Legouffe
E
,
Jourdan
E
, et al
.
BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone
.
Blood
.
2004
;
103
(
8
):
3148
-
3157
.
32.
Tai
YT
,
Acharya
C
,
An
G
, et al
.
APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment
.
Blood
.
2016
;
127
(
25
):
3225
-
3236
.
33.
Sanchez
E
,
Li
M
,
Kitto
A
, et al
.
Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival
.
Br J Haematol
.
2012
;
158
(
6
):
727
-
738
.
34.
Lee
L
,
Bounds
D
,
Paterson
J
, et al
.
Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma
.
Br J Haematol
.
2016
;
174
(
6
):
911
-
922
.
35.
Trudel
S
,
Lendvai
N
,
Popat
R
, et al
.
Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial
.
Lancet Oncol
.
2018
;
19
(
12
):
1641
-
1653
.
36.
Trudel
S
,
Lendvai
N
,
Popat
R
, et al
.
Antibody-drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study
.
Blood Cancer J
.
2019
;
9
(
4
):
37
.
37.
Kinneer
K
,
Meekin
J
,
Varkey
R
, et al
.
Preclinical evaluation of MEDI2228, a BCMA-targeting pyrrolobenzodiazepine-linked antibody drug conjugate for the treatment of multiple myeloma
.
Blood
.
2017
;
130
(
suppl 1
).
Abstract 3153
.
38.
Singh
RK
,
Jones
RJ
,
Hong
S
, et al
.
HDP101, a novel B-cell maturation antigen (BCMA)-targeted antibody conjugated to α-amanitin, is active against myeloma with preferential efficacy against pre-clinical models of deletion 17p
.
Blood
.
2018
;
132
(
suppl 1
).
Abstract 593
.
39.
Cohen
AD
,
Garfall
AL
,
Stadtmauer
EA
, et al
.
B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma
.
J Clin Invest
.
2019
;
129
(
6
):
2210
-
2221
.
40.
Ailawadhi
S
,
Kelly
KR
,
Vescio
RA
, et al
.
A phase I study to assess the safety and pharmacokinetics of single-agent lorvotuzumab mertansine (IMGN901) in patients with relapsed and/or refractory CD-56-positive multiple myeloma
.
Clin Lymphoma Myeloma Leuk
.
2019
;
19
(
1
):
29
-
34
.
41.
Abrahams
CL
,
Li
X
,
Embry
M
, et al
.
Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001
.
Oncotarget
.
2018
;
9
(
102
):
37700
-
37714
.
42.
Sherbenou
DW
,
Aftab
BT
,
Su
Y
, et al
.
Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells
.
J Clin Invest
.
2016
;
126
(
12
):
4640
-
4653
.
43.
Lewis
TS
,
Olson
D
,
Gordon
K
, et al
.
SGN-CD48A: a novel humanized anti-CD48 antibody-drug conjugate for the treatment of multiple myeloma
.
Blood
.
2016
;
128
(
22
).
Abstract 4470
.
44.
Willert
E
,
Robinson
G
,
Higgins
J
, et al
. TAK-169, an exceptionally potent CD38 targeted engineered toxin body, as a novel direct cell kill approach for the treatment of multiple myeloma. In: Proceedings of the AACR Annual Meeting;
29 March-3 April 2019
; Atlanta, GA. Abstract 2384.
45.
Velasquez
MP
,
Bonifant
CL
,
Gottschalk
S
.
Redirecting T cells to hematological malignancies with bispecific antibodies
.
Blood
.
2018
;
131
(
1
):
30
-
38
.
46.
Hipp
S
,
Tai
YT
,
Blanset
D
, et al
.
A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo [published correction appears in Leukemia. 2017;31(10):2278]
.
Leukemia
.
2017
;
31
(
8
):
1743
-
1751
.
47.
Topp
MS
,
Duell
J
,
Zugmaier
G
, et al
. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: updated results of a first-in-human (FIH) phase I dose escalation study. In: Proceedings of the American Society of Clinical Oncology Annual Meeting;
31 May-4 June 2019
; Chicago, IL. Abstract 8007.
48.
Cho
S-F
,
Lin
L
,
Xing
L
, et al
.
Anti-BCMA BiTE® AMG 701 potently induces specific T cell lysis of human multiple myeloma (MM) cells and immunomodulation in the bone marrow microenvironment
.
Blood
.
2018
;
132
(
suppl 1
).
Abstract 592
.
49.
Panowski
SH
,
Kuo
T
,
Chen
A
, et al
.
Preclinical evaluation of a potent anti-Bcma CD3 bispecific molecule for the treatment of multiple myeloma
.
Blood
.
2016
;
128
(
22
).
Abstract 383
.
50.
Pillarisetti
K
,
Baldwin
E
,
Babich
A
, et al
.
Development of a new BCMAxCD3 Duobody® antibody for multiple myeloma
.
Blood
.
2016
;
128
(
22
).
Abstract 2116
.
51.
Dilillo
DJ
,
Olson
K
,
Mohrs
K
, et al
.
REGN5458, a bispecific BCMAxCD3 T cell engaging antibody, demonstrates robust in vitro and in vivo anti-tumor efficacy in multiple myeloma models, comparable to that of BCMA CAR T cells
.
Blood
.
2018
;
132
(
suppl 1
).
Abstract 1944
.
52.
Law
C-L
,
Aaron
W
,
Austin
R
, et al
.
Preclinical and nonclinical characterization of HPN217: a tri-specific t cell activating construct (TriTAC) targeting B cell maturation antigen (BCMA) for the treatment of multiple myeloma
.
Blood
.
2018
;
132
(
suppl 1
).
Abstract 3225
.
53.
Foureau
DM
,
Bhutani
M
,
Robinson
M
, et al
.
Ex vivo assessment of Tnb-383B, a Bcma-bispecific antibody, against primary tumor and endogenous T cells from relapsing multiple myeloma patients
.
Blood
.
2018
;
132
(
suppl 1
).
Abstract 1940
.
54.
Ross
T
,
Reusch
U
,
Wingert
S
, et al
.
Preclinical characterization of AFM26, a novel B cell maturation antigen (BCMA)-Directed tetravalent bispecific antibody for high affinity retargeting of NK cells against myeloma
.
Blood
.
2018
;
132
(
suppl 1
).
Abstract 1927
.
55.
Richter
JR
,
Landgren
CO
,
Kauh
JS
, et al
.
Phase 1, multicenter, open-label study of single-agent bispecific antibody t-cell engager GBR 1342 in relapsed/refractory multiple myeloma
.
J Clin Oncol
.
2018
;
36
(
15 suppl
):
TPS3132
.
56.
Zuch de Zafra
CL
,
Fajardo
F
,
Zhong
W
, et al
.
Targeting multiple myeloma with AMG 424, a novel anti-CD38/CD3 bispecific T-cell-recruiting antibody optimized for cytotoxicity and cytokine release
.
Clin Cancer Res
.
2019
;
25
(
13
):
3921
-
3933
.
57.
Nijhof
IS
,
Casneuf
T
,
van Velzen
J
, et al
.
CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma
.
Blood
.
2016
;
128
(
7
):
959
-
970
.
58.
Li
J
,
Stagg
NJ
,
Johnston
J
, et al
.
Membrane-proximal epitope facilitates efficient T cell synapse formation by anti-FcRH5/CD3 and is a requirement for myeloma cell killing
.
Cancer Cell
.
2017
;
31
(
3
):
383
-
395
.
59.
Smith
EL
,
Harrington
K
,
Staehr
M
, et al
.
GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells
.
Sci Transl Med
.
2019
;
11
(
485
):
eaau7746
.
60.
Cohen
AD
,
Garfall
AL
,
Dogan
A
, et al
.
Serial treatment of relapsed/refractory multiple myeloma with different BCMA-targeted therapies
.
Blood Adv
.
In press
.
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