Abstract

Bispecific antibodies that engage T cells to target B-cell maturation antigen or G-protein–coupled receptor class C group 5 member D have demonstrated remarkable efficacy in heavily pretreated relapsed or refractory multiple myeloma (MM), leading to the recent accelerated approval of teclistamab, elranatamab, and talquetamab by health agencies. Future challenges, however, remain to define their optimal dosing schedule and duration, sequencing, and integration with established anti-MM therapeutics as well as delineating the biological and clinical mediators of immune escape.

1.
Mateos
MV
,
Weisel
K
,
De Stefano
V
, et al
.
LocoMMotion: a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma
.
Leukemia
.
2022
;
36
(
5
):
1371
-
1376
.
2.
Gandhi
UH
,
Cornell
RF
,
Lakshman
A
, et al
.
Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy
.
Leukemia
.
2019
;
33
(
9
):
2266
-
2275
.
3.
Karwacz
K
,
Hooper
AT
,
Chang
C-PB
, et al
.
Abstract 4557: BCMA-CD3 bispecific antibody PF-06863135: preclinical rationale for therapeutic combinations
.
Cancer Res
.
2020
;
80
(
suppl 16
). 4557-4557.
4.
Pillarisetti
K
,
Powers
G
,
Luistro
L
, et al
.
Teclistamab is an active T cell-redirecting bispecific antibody against B-cell maturation antigen for multiple myeloma
.
Blood Adv
.
2020
;
4
(
18
):
4538
-
4549
.
5.
Moreau
P
,
Garfall
AL
,
van de Donk
N
, et al
.
Teclistamab in relapsed or refractory multiple myeloma
.
N Engl J Med
.
2022
;
387
(
6
):
495
-
505
.
6.
van de Donk
NW
,
Moreau
P
,
Garfall
AL
, et al
.
Long-term follow-up from MajesTEC-1 of teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM)
.
J Clin Oncol
.
2023
;
41
(
suppl 16
). 8011-8011.
7.
Bahlis
NJ
,
Costello
CL
,
Raje
NS
, et al
.
Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial
.
Nat Med
.
2023
;
29
(
10
):
2570
-
2576
.
8.
Lesokhin
AM
,
Tomasson
MH
,
Arnulf
B
, et al
.
Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results
.
Nat Med
.
2023
;
29
(
9
):
2259
-
2267
.
9.
Usmani
SZ
,
Karlin
L
,
Benboubker
L
, et al
.
Durability of responses with biweekly dosing of teclistamab in patients with relapsed/refractory multiple myeloma achieving a clinical response in the majesTEC-1 study
.
J Clin Oncol
.
2023
;
41
(
suppl 16
):
8034
.
10.
Lee
HC
,
Bumma
N
,
Richter
JR
, et al
.
LINKER-MM1 study: linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma
.
J Clin Oncol
.
2023
;
41
(
suppl 16
). 8006-8006.
11.
Wong
SW
,
Bar
N
,
Paris
L
, et al
.
Alnuctamab (ALNUC; BMS-986349; CC-93269), a B-cell maturation antigen (BCMA) x CD3 T-cell engager (TCE), in patients (pts) with relapsed/refractory multiple myeloma (RRMM): results from a phase 1 first-in-human clinical study [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
400
-
402
.
12.
Bar
N
,
Mateos
MV
,
Ribas
P
, et al
.
Alnuctamab (ALNUC; BMS-986349; CC-93269), a 2+1 B-cell maturation antigen (BCMA) × CD3 T-cell engager (TCE), administered subcutaneously (SC) in patients (Pts) with relapsed/refractory multiple myeloma (RRMM): updated results from a phase 1 first-in-human clinical study [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
2011
.
13.
D'Souza
A
,
Shah
N
,
Rodriguez
C
, et al
.
A phase I first-in-human study of ABBV-383, a B-cell maturation antigen × CD3 bispecific T-cell redirecting antibody, in patients with relapsed/refractory multiple myeloma
.
J Clin Oncol
.
2022
;
40
(
31
):
3576
-
3586
.
14.
Madan
S
,
Costello
CL
,
Lipe
B
, et al
.
Results from the completed dose escalation portion of the phase 1 study of HPN217, a half-life extended tri-specific T cell activating construct (TriTAC®) targeting B cell maturation antigen (BCMA) for relapsed/refractory multiple myeloma (MM) [abstract]
.
Blood
.
2023
;
142
(
suppl 1
). 1012-1012.
15.
Vij
R
,
Kumar
SK
,
D’Souza
A
, et al
.
Updated safety and efficacy results of Abbv-383, a BCMA x CD3 bispecific T-cell redirecting antibody, in a first-in-human phase 1 study in patients with relapsed/refractory multiple myeloma [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
3378
.
16.
Chari
A
,
Minnema
MC
,
Berdeja
JG
, et al
.
Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma
.
N Engl J Med
.
2022
;
387
(
24
):
2232
-
2244
.
17.
Schinke
CD
,
Touzeau
C
,
Minnema
MC
, et al
.
Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM)
.
J Clin Oncol
.
2023
;
41
(
suppl 16
):
8036
.
18.
Carlo-Stella
C
,
Mazza
R
,
Manier
S
, et al
.
RG6234, a GPRC5DxCD3 T-cell engaging bispecific antibody, is highly active in patients (pts) with relapsed/refractory multiple myeloma (RRMM): updated intravenous (IV) and first subcutaneous (SC) results from a phase I dose-escalation study [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
397
-
399
.
19.
Harrison
JS
,
Riley
CH
,
Manier
S
, et al
.
Efficacy of forimtamig, a GPRC5DxCD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: analysis of patient- and disease-related factors associated with responses
.
Clin Lymphoma Myeloma Leuk
.
2023
;
23
:
S3
-
S4
.
20.
Mailankody
S
,
Devlin
SM
,
Landa
J
, et al
.
GPRC5D-targeted CAR T cells for myeloma
.
N Engl J Med
.
2022
;
387
(
13
):
1196
-
1206
.
21.
Jakubowiak
AJ
,
Anguille
S
,
Karlin
L
, et al
.
Updated results of talquetamab, a GPRC5D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma with prior exposure to t-cell redirecting therapies: results of the phase 1/2 MonumenTAL-1 study [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
3377
.
22.
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
.
23.
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
.
24.
Cortes-Selva
D
,
Casneuf
T
,
Vishwamitra
D
, et al
.
Teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): correlative analyses from MajesTEC-1 [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
241
-
243
.
25.
Miao
X
,
Wu
LS
,
Lin
SXW
, et al
.
Population pharmacokinetics and exposure-response with teclistamab in patients with relapsed/refractory multiple myeloma: results from MajesTEC-1
.
Target Oncol
.
2023
;
18
(
5
):
667
-
684
.
26.
Girgis
S
,
Wang Lin
SX
,
Pillarisetti
K
, et al
.
Effects of teclistamab and talquetamab on soluble BCMA levels in patients with relapsed/refractory multiple myeloma
.
Blood Adv
.
2023
;
7
(
4
):
644
-
648
.
27.
Elmeliegy
M
,
Kei
Lon H
,
Wang
D
, et al
.
Soluble B-cell maturation antigen as a disease biomarker in relapsed or refractory multiple myeloma (RRMM): evaluation from elranatamab (ELRA) magnetismm studies [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
3345
.
28.
Lee
H
,
Durante
M
,
Ahn
S
, et al
.
The impact of soluble BCMA and BCMA gain on anti-BCMA immunotherapies in multiple myeloma [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
4688
.
29.
Chen
H
,
Li
M
,
Xu
N
, et al
.
Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells
.
Leuk Res
.
2019
;
81
:
62
-
66
.
30.
Kei
Lon H
,
Hibma
J
,
Williams
J
, et al
.
Elranatamab exposure-efficacy analysis in patients with relapsed or refractory multiple myeloma: insights from pooled magnetismm studies [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
1995
.
31.
Chen
H
,
Yu
T
,
Lin
L
, et al
.
γ-Secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation
.
Blood Cancer J
.
2022
;
12
(
8
):
118
.
32.
Offner
F
,
Decaux
O
,
Hulin
C
, et al
.
S194: TECLISTAMAB (TEC) + NIROGACESTAT (NIRO) IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): THE PHASE 1B MAJESTEC-2 STUDY
.
Hemasphere
.
2023
;
7
(
suppl
):
e1257964
.
33.
Landgren
O
,
Kazandjian
D
,
O’Connell
A
,
Finn
G
,
Raje
N
.
Magnetismm-4: an open label, phase 1b/2 umbrella study of elranatamab in combination with other anti-cancer treatments for patients with multiple myeloma [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
10172
-
10173
.
34.
Meermeier
EW
,
Welsh
SJ
,
Sharik
ME
, et al
.
Tumor burden limits bispecific antibody efficacy through T-cell exhaustion averted by concurrent cytotoxic therapy
.
Blood Cancer Discov
.
2021
;
2
(
4
):
354
-
369
.
35.
Hansen
JD
,
Correa
M
,
Nagy
MA
, et al
.
Discovery of CRBN E3 ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma
.
J Med Chem
.
2020
;
63
(
13
):
6648
-
6676
.
36.
Cho
SF
,
Lin
L
,
Xing
L
, et al
.
The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models
.
Blood Adv
.
2020
;
4
(
17
):
4195
-
4207
.
37.
Frerichs
KA
,
Broekmans
MEC
,
Marin Soto
JA
, et al
.
Preclinical activity of JNJ-7957, a novel BCMA×CD3 bispecific antibody for the treatment of multiple myeloma, is potentiated by daratumumab
.
Clin Cancer Res
.
2020
;
26
(
9
):
2203
-
2215
.
38.
Matous
J
,
Biran
N
,
Perrot
A
, et al
.
Talquetamab + pomalidomide in patients with relapsed/refractory multiple myeloma: safety and preliminary efficacy results from the phase 1b MonumenTAL-2 study [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
1014
.
39.
Friedrich
MJ
,
Neri
P
,
Kehl
N
, et al
.
The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients
.
Cancer Cell
.
2023
;
41
(
4
):
711
-
725.e6
.
40.
Lee
H
,
Ahn
S
,
Maity
R
, et al
.
Immune and genome profiling of myeloma patients treated with sequential immunotherapies reveal differential non-overlapping mechanisms of resistance [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
1945
.
41.
Rasche
L
,
Truger
M
,
Munawar
U
, et al
.
OA-24 sequential and persistent loss of BCMA and GPRC5D after bispecific antibodies in multiple myeloma revealed by whole genome sequencing
.
Clin Lymphoma Myeloma Leukemia
.
2023
;
23
:
S15
.
42.
Duell
J
,
Dittrich
M
,
Bedke
T
, et al
.
Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL
.
Leukemia
.
2017
;
31
(
10
):
2181
-
2190
.
43.
Vafa
O
,
Trinklein
ND
.
Perspective: designing T-cell engagers with better therapeutic windows
.
Front Oncol
.
2020
;
10
:
446
.
44.
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
.
45.
Firestone
RS
,
McAvoy
D
,
Shekarkhand
T
, et al
.
CD8 effector T cells enhance response in BCMA-exposed and -naïve multiple myeloma
.
Blood Adv
.
Published online 25 October 2023
.
46.
van de Donk
NW
,
Bahlis
N
,
Mateos
M-V
, et al
.
S183: novel combination immunotherapy for the treatment of relapsed/refractory multiple myeloma: updated phase 1B results for talquetamab (a GPRC5D X CD3 bispecific antibody) in combination with daratumumab
.
HemaSphere
.
2022
;
6
:
84
-
85
.
47.
Lee
H
,
Neri
P
,
Bahlis
NJ
.
Current use of bispecific antibodies to treat multiple myeloma
.
Hematology
.
2023
;
2023
(
1
):
332
-
339
.
48.
Lee
H
,
Ahn
S
,
Maity
R
, et al
.
Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma
.
Nat Med
.
2023
;
29
(
9
):
2295
-
2306
.
49.
Truger
MS
,
Duell
J
,
Zhou
X
, et al
.
Single- and double-hit events in genes encoding immune targets before and after T cell-engaging antibody therapy in MM
.
Blood Adv
.
2021
;
5
(
19
):
3794
-
3798
.
50.
Da Vià
MC
,
Dietrich
O
,
Truger
M
, et al
.
Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma
.
Nat Med
.
2021
;
27
(
4
):
616
-
619
.
51.
Samur
MK
,
Fulciniti
M
,
Aktas Samur
A
, et al
.
Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma
.
Nat Commun
.
2021
;
12
(
1
):
868
.
52.
Mi
X
,
Penson
A
,
Abdel-Wahab
O
,
Mailankody
S
.
Genetic basis of relapse after GPRC5D-targeted CAR T cells
.
N Engl J Med
.
2023
;
389
(
15
):
1435
-
1437
.
53.
Derrien
J
,
Gastineau
S
,
Frigout
A
, et al
.
Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation
.
Nat Cancer
.
2023
;
4
(
11
):
1536
-
1543
.
54.
Samur
MK
,
Aktas Samur
A
,
Corre
J
, et al
.
Monoallelic deletion of BCMA is a frequent feature in multiple myeloma
.
Blood Adv
.
2023
;
7
(
21
):
6599
-
6603
.
55.
Santich
BH
,
Park
JA
,
Tran
H
,
Guo
HF
,
Huse
M
,
Cheung
NKV
.
Interdomain spacing and spatial configuration drive the potency of IgG-[L]-scFv T cell bispecific antibodies
.
Sci Transl Med
.
2020
;
12
(
534
):
eaax1315
.
56.
Bacac
M
,
Colombetti
S
,
Herter
S
, et al
.
CD20-TCB with obinutuzumab pretreatment as next-generation treatment of hematologic malignancies
.
Clin Cancer Res
.
2018
;
24
(
19
):
4785
-
4797
.
57.
Cohen
YC
,
Morillo
D
,
Gatt
ME
, et al
.
First results from the RedirecTT-1 study with teclistamab (tec) + talquetamab (tal) simultaneously targeting BCMA and GPRC5D in patients (pts) with relapsed/refractory multiple myeloma (RRMM)
.
J Clin Oncol
.
2023
;
41
(
suppl 16
):
8002
.
58.
Trudel
S
,
Cohen
AD
,
Krishnan
AY
, et al
.
Cevostamab monotherapy continues to show clinically meaningful activity and manageable safety in patients with heavily pre-treated relapsed/refractory multiple myeloma (RRMM): updated results from an ongoing phase I study [abstract]
.
Blood
.
2021
;
138
(
suppl 1
):
157
.
59.
Hansen
DK
,
Sidana
S
,
Peres
LC
, et al
.
Idecabtagene vicleucel for relapsed/refractory multiple myeloma: real-world experience from the Myeloma CAR T Consortium
.
J Clin Oncol
.
2023
;
41
(
11
):
2087
-
2097
.
60.
Cohen
AD
,
Mateos
M-V
,
Cohen
YC
, et al
.
Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents
.
Blood
.
2023
;
141
(
3
):
219
-
230
.
61.
Van Oekelen
O
,
Nath
K
,
Mouhieddine
TH
, et al
.
Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy
.
Blood
.
2023
;
141
(
7
):
756
-
765
.
62.
Touzeau
C
,
Krishnan
AY
,
Moreau
P
, et al
.
Efficacy and safety of teclistamab (tec), a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients (pts) with relapsed/refractory multiple myeloma (RRMM) after exposure to other BCMA-targeted agents
.
J Clin Oncol
.
2022
;
40
(
suppl 16
):
8013
.
63.
Dholaria
BR
,
Weisel
K
,
Mateos
M-V
, et al
.
Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): updated TRIMM-2 results
.
J Clin Oncol
.
2023
;
41
(
suppl 16
):
8003
.
64.
Kumar
S
,
Bachier
CR
,
Cavo
M
, et al
.
CAMMA 2: a phase I/II trial evaluating the efficacy and safety of cevostamab in patients with relapsed/refractory multiple myeloma (RRMM) who have triple-class refractory disease and have received a prior anti-B-cell maturation antigen (BCMA) agent
.
J Clin Oncol
.
2023
;
41
(
suppl 16
):
TPS8064
.
65.
Philipp
N
,
Kazerani
M
,
Nicholls
A
, et al
.
T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals
.
Blood
.
2022
;
140
(
10
):
1104
-
1118
.
66.
Lesokhin
AM
,
Richter
J
,
Trudel
S
, et al
.
Enduring responses after 1-year, fixed-duration cevostamab therapy in patients with relapsed/refractory multiple myeloma: early experience from a phase I study [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
4415
-
4417
.
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