Talquetamab in multiple myeloma.

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Haematologica | 109 Marzo 2024
718
SPOTLIGHT REVIEW ARTICLE
Talquetamab in multiple myeloma
Correspondence: L. Liu
laliu@coh.org
Received: August 9, 2023.
Accepted: October 10, 2023.
Early view: October 19, 2023.
https:/ /doi.org/10.3324/haematol.2023.283931
©2024 Ferrata Storti Foundation
Published under a CC BY-NC license
Lawrence Liu and Amrita Krishnan
Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology
and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte,
CA, USA
Introduction
Historically, relapsed or refractory multiple myeloma (RRMM)
has been associated with a median overall survival of 6.6-8
months in penta-refractory or penta-exposed patients.1 The
arsenal of T-cell redirecting therapies like chimeric anti-
gen receptor (CAR) T cells and bispecific antibody (BsAb)
represent a step forward in improving outcomes. B-cell
maturation antigen (BCMA)-targeting agents were the first
approved including idecabtagene vicleucel demonstrating a
73% overall response rate (ORR) and complete response (CR)
or better rate of 33% and median progression-free survival
(mPFS) of 8.8 months in a heavily pretreated population in
the original report.2 This was followed by ciltacabtagene
autoleucel which demonstrated an impressive ORR of 97%,
CR/stringent CR (sCR) rate of 67%, and mPFS that was not
reached (12-month PFS was 77%) in a very similar patient
population.3 In August of 2022, the results of teclistamab
trial came out demonstrating an ORR of 63% with CR/
sCR of 39.4% and mPFS of 11.3 months4 transforming the
landscape of relapsed and refractory disease. However,
as we recognize that patients relapse post CAR T and te-
clistamab with different mechanisms including mutations
and deletions in the BCMA target there remains a need for
new targets and new drugs.
Talquetamab is an immunoglobulin (Ig)G4 BsAb binding to
G-protein-coupled receptor class 5 member D (GPRC5D)
and CD3 to recruit and activate T cells to target myeloma
cells.5 GPRC5D is cell surface receptor that was initially
discovered in highly keratinized tissue like nails and hair.6
Gene expression studies of MM bone marrow samples have
demonstrated high levels of GPRC5D in plasma cells and
the levels correspond to MM disease burden.7,8 It has been
demonstrated to have low RNA expression in other tissue,
like lung and inferior olivary nucleus neurons. However, ac-
tual GPRC5D protein expression in lung and inferior olivary
nucleus neurons was not identified.9,10 Although a preclinical
study noted low level GPRC5D RNA expression in the cere-
bellum,11 neither RNA transcript or protein expression was
noted in the translational studies of the trial. 5 Following
these findings, GPRC5D has become a therapeutic target
for MM via CAR T-cell and BsAb therapy.11 An initial CAR T
targeting GPRC5D demonstrated activity in MM resistant to
BCMA CAR T in studies of xenografts in mice.9 In preclinical
studies, talquetamab demonstrated high cytotoxicity in
bone marrow samples with MM.12,13 As such, this therapy
was an ideal candidate to move forward to clinical studies.
Efficacy
Talquetamab was initially studied in the phase I open-label
MonumenTAL-1 trial demonstrating high efficacy in a heavily
pretreated population with a median of six previous lines
of therapy. Especially notable was that 79% of the patients
were triple-class refractory and 30% were penta-refracto-
Abstract
Initial results of the phase I trial of talquetamab, a bispecific antibody targeting GPRC5D and CD3, were reported in Decem-
ber of 2022 for the treatment of relapsed or refractory multiple myeloma in the fourth line or later setting. It demonstrated
a similar efficacy profile and durability of response to teclistamab, the first bispecific antibody therapy to be approved in
multiple myeloma. Additionally, it has less infections than teclistamab but demonstrates unique class-specific side effects
including skin, oral, and nail-related adverse events. Despite this, it is still a highly efficacious and well-tolerated therapy
that will add to the armamentarium of therapeutics against heavily pretreated multiple myeloma.
Talquetamab in multiple myeloma
L. Liu and A. Krishnan et al.
https:/ /doi.org/10.3324/haematol.2023.283931

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L. Liu and A. Krishnan
ry. In the group treated with subcutaneous talquetamab,
almost a third had extramedullary disease, 17% had high
disease burden (60% or more bone marrow plasma cells),
and 16% had high-risk cytogenetic abnormalities.5 This is
similar to the study population for teclistamab, the first
approved BsAb in RRMM targeting BCMA,14 with the excep-
tion of talquetamab having had MM with extramedullary
disease (32% vs. 17%) and teclistamab with slightly more
high-risk cytogenetics (25.7% vs. 16%).4 Additionally, the
talquetamab trial had higher percentage of International
Staging System (ISS) class 2 (45% vs. 35.2%) and 3 (19%
vs. 12.3%).4,5
Talquetamab administered subcutaneously at 800 mcg/
kg every 2 weeks (Q2W) or 405 mcg/kg weekly (QW) with
step-up doses demonstrated similar efficacy across both
levels. At a median follow-up of 12.7 months, the 0.8 mg/
kg dose level had an ORR of 71.7% and very good partial
response (VGPR) or better rate of 60.7%: 9% with CR and
29.7% with sCR with a median duration of response of 7.8
months. At a median follow-up of 18.8 months, the 0.4 mg/
kg dose level achieved an ORR of 74.1% and 59.4% VGPR or
better: 9.8% CR and 23.8% sCR with a median duration of
response of 10.2 months.5 These results in patients with
heavily pretreated and very refractory disease led to the
US Food and Drug Administration granting Breakthrough
Therapy Designation for talquetamab on June 29, 2022.15
The updated phase II results reported at ASCO 2023 are
very similar.16 Additional benefits of talquetamab were high
efficacy in high-risk MM and extramedullary disease which
had ORR/CR/sCR of 55.6/33.3/11.1 and 40/6.7/6.7 for the 800
mcg/kg Q2W dosing respectively.5 These results are simi-
lar to those of teclistamab and offers another therapeutic
targeting option for patients.
Of special interest is the efficacy in patients who have had
prior T-cell redirection therapy such as CAR T-cell therapy
or other BsAb therapy due to concern for T-cell fatigue or
exhaustion.17-19 The MonumenTAL-1 phase II results were
recently presented at ASCO 2023 demonstrating an ORR
63%, 53% with VGPR or better at median follow-up of 11.8
months in patients with prior BsAb or CAR T. In this cohort,
71% had prior CAR T, 35% had prior BsAb, and 6% had both.
The mPFS was 5.1 months.16 The results demonstrate that
talquetamab retains efficacy even in a population with prior
T-cell redirection therapies. Combination therapies with
talquetamab could address this area of T-cell exhaustion/
fatigue. Of particular interest is whether daratumumab
can help overcome T-cell fatigue/exhaustion since it has
demonstrated the ability to alter T-cell subsets to promote
expansion of effector T cells and deplete regulatory T cells.
Initial results of the TRIMM-2 phase Ib study with correla-
tives showing that the combination increased proinflamma-
tory cytokines and levels of effector T cells supporting the
ability of a daratumumab to overcome T-cell exhaustion/
fatigue when administered with a BsAb.20
Talquetamab is also being studied in combination with da-
ratumumab in the TRIMM-2 trial in patients with three or
more prior lines of therapy, including a proteasome inhibitor
(PI) and immunomodulatory drug (IMiD). The phase II trial
recently reported results at ASCO 2023 in a population that
had a median five prior lines of therapy, 18% with high-risk
cytogenetics, 25% with extramedullary disease, and 58%
triple-class refractory (77% were refractory to anti-CD38
therapy). With a median follow-up of 11.5 months, the ORR
was 78% in the whole cohort (100% in patients without
prior anti-CD38 therapy) with 45% CR/sCR and 66% VG -
PR or greater. The mPFS was 19.4 months and 12-month
overall survival (OS) was 93%. Even in patients refractory
to anti-CD38, anti-BCMA, and BsAb therapy, the ORR was
76%, 64%, and 75% respectively.21
Beyond talquetamab, the GPRC5D target has been stud -
ied as a CAR T construct. Based on preclinical data from
Smith et al. of a GPRC5D CAR T with high efficacy in BCMA
CAR T resistant MM,9 Mailankody et al. studied this CAR T
in a phase I trial and found that in patients receiving the
MTD of 150x106 cells or lower, the response rate was 58%
with a median duration of response of 7.8 months. 22 Of
note, this trial had a broader inclusion criteria recruiting
patients suffering from MM with: history of allogeneic
stem cell transplantation (18%), extramedullary disease
(47%), prior BCMA-directed therapy (59%), triple-class
refractory status (94%), high-risk cytogenetic abnormal -
ities (76%). Other GPRC5D CAR T constructs have been
studied with ORR ranging from 86-100% and 60-64% CR/
sCR rates.23-25 Another BsAb with a two GPRC5D binding
sites, RG6234, is undergoing investigation and reported
ORR of 71.4% and 60.4% with CR/sCR rates of 28.5% and
18.8% for intravenous and subcutaneous administration
respectively.26 (Table 1)
Safety and tolerability
All patients had adverse events (AE) and grade 3 or 4
AE were 78%. However, there were no deaths related to
talquetamab use as compared to teclistamab with 5 deaths
(3%).4,16 CRS was experienced in 78% with a median duration
of 2 days. None of the CRS events were grade 3 or great-
er. Other common AE were hypogammaglobulinemia, oral
AE, infections, anemia, asthenia, and skin exfoliation (all
greater than 40%). Of the 63% with infections, 22% were
grade 3 or 4; however, there were two patients (3%) with
grade 5 (pneumonia) possibly related to the therapy. Neu-
tropenia was noted in 38% with 26% reaching grade 3 or
4. Hypogammaglobulinemia was noted in 85% of patients;
however, intravenous immunoglobulin supplementation
was only utilized in 32% of patients.
The initial MonumenTAL-1 phase I study reported four
dose-limiting toxicities: one was pancreatitis related to
extramedullary disease in the pancreas and the other three
were grade 3 rashes that resolved on stopping therapy with

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SPOTLIGHT REVIEW ARTICLE - Biology and targeted therapy for CNS lymphoma
L. Liu and A. Krishnan
two of those patients able to resume therapy without re-
currence of the rash. Skin AE (largely xeroderma, pruritis,
and peeling), taste issues, cytopenias, fatigue, rashes, nail
issues, dry mouth, dysphagia, weight loss, fevers, diarrhea,
and decreased appetite were the most common AE across
all dose levels.
Cytokine-release syndrome (CRS) was noted in around 80%
of the patients receiving subcutaneous talquetamab with
a median duration of 2 days. However, grade 3 or greater
CRS was rare (3% in the 405 mcg dose level and none in
the 800 mcg dose level). Most of the CRS events (81.7%)
occurred during the step-up doses. Recurrent CRS episodes
with the step-up and target doses occurred in around 30%
of patients for both subcutaneous dose levels; 63% of pa-
tients in 405 mcg dose level and 54% in the 800 mcg dose
level received tocilizumab. Corticosteroid administration
for CRS was relatively minimal (3% at the 405 mcg dose
and 7% at the 800 mcg dose). Vasopressor use occurred in
one patient at the 405 mcg dose level (3.3%). One patient
(3.3%) in the 405 mcg dose level and two patients (4.5%)
in the 800 mcg dose level required supplemental oxygen.
Overall, around half of patients in both subcutaneous dose
levels required other supportive care measures for CRS
including intravenous fluids and anti-pyretics.
Neurotoxicity was noted in 10% of patients receiving the
405 mcg dose and 5% of patients receiving the 800 mcg
dose and were grade 1 or two and resolved. In each subcu-
taneous dose level, there was one event of encephalopathy
occurring during the step-up doses and target dose. In the
group receiving intravenous talquetamab, 3% experienced
grade 3 ICANS. As such, the intravenous dose level was not
pursued for the phase II trial. In the phase II trial results,
ICANS was reported at a rate of 10.7% and 11% for the 0.4
mg/kg and 0.8 mg/kg groups respectively.
Nail issues and taste changes were frequent and likely re-
lated to the expression of GPRC5D in these tissue.5,10 Nail
AE tended to occur at a median of 50.5 days with a wide
range. These AE can range from nail thinning to complete
separation of the nail plate from the matrix due to disrup-
tion of growth, onychomadesis, as noted in an early case
report.27 In this report, topical corticosteroids were heavily
applied to the hands, feet, and skin in general due to the
patient’s diffuse xerosis and pruritis but only the pruritis and
xerosis resolved with the topical corticosteroids. Despite
the potential for severe nail-related AE, no discontinuations
resulted from them.16 In another study, nail and skin AE
were managed with ammonium lactate cream, triamcin-
olone cream, and Vaseline applied twice a day.28 Grade 3
rashes resolved with oral and topical corticosteroids and
treatment resumption was possible afterwards in most
patients.28 Oral antihistamines can also be employed to
reduce associated pruritis.29 The median time to skin tox-
BsAb Phase Acronym
(NCT number) Target
Minimum
prior
lines of
therapy
(median)
Median
follow-up
time in
months
Administration ORR
%
CR/
sCR
rate %
mDOR
in
months
mPFS
in
months
mOS
in
months
Talquetama b
(SC: 405 mcg
QW)16
2
Monumen
TAL-1
(NCT03399799)
GPRC5D
2 (6) 18.8 SC 74 33.6 9.5 7.5
76.4%
12-months
OS
Talquetamab
(SC: 800 mcg
Q2W)16
2 (5) 12.7 SC 73 38.7 NR 11.9
77.4%
12-months
OS
Talquetamab
(IV)5 2 (6) 10.2 IV 72 72.2 27.8 - -
Teclistamab4 1-2
MajesTEC-1
(NCT03145181/
NCT04557098)
BCMA 4 (5) 14.1 SC 63 65 18.4 11.3 18.3
Elranatamab36* 2
MagnetisMM
(NCT03269136
/NCT04649359
/NCT05014412)
BCMA 2 (7) 10.3 SC 45.3 17.4
NR (9
months
DOR was
72.4%)
4.8
NR (9-
months
OS was
60.1%)
Cevostamab37 1 NCT03275103 FcRH5 2 (6) 6.1 SC 100 62.5
50% had
DOR ≥ 6
months
NA NA
*These results were from the pooled results of MM-1, MM-3, and MM-9 which included patients in the initial dose finding and safety study
and later patients who received the subcutaneous 76 mg weekly dose. Additionally, all patients had prior B-cell maturation antigen (BCMA)-tar-
geting therapy.36 BsAb: bispecific antibody; NCT: national clinical trial; ORR: overall response rate; CR: complete response; sCR: stringent
complete response; mDOR: median duration of response; mPFS: median progression-free survival; mOS: median overall survival; SC: subcu-
taneous; IV: intravenous; GPRC5D: G-protein coupled receptor, class C, group 5 member D; FcRH5: Fc receptor-homolog-5; QW: weekly; Q2W:
every 2 weeks; NR: not reached; NA: not available.
Table 1. Bispecific antibody monotherapy trials.

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L. Liu and A. Krishnan
BsAb
Grade 3
or 4 AE
%
Anemia
grade
≥3, %
Neutr
grade
≥3, %
Lymph
grade
≥3, %
Thromb
grade
≥3, %
CRS any
grade
%
CRS
grade
≥3, %
ICANS
any
grade
%
ICANS
grade
≥3, %
Grade
5 AE
%
Dysg
%
SRE
%
NRE
%
Talquetamab 405 µg 87 30 60 40 23 77 3 10* 0 0 63 67 57
Talquetamab 800 µg 86 23 32 39 11 80 0 5* 0 0 57 70 27
IV Talquetamab 92 33 26 47 13 49 5 - 3 0 37 24 20
Teclistamab 94.5 37 64.2 32.7 21.2 72.1 0.6 14.5 0.6 3 NA NA NA
Elranatamab - 46.5 40.7 30.2 29.1 65.1 1.2 5.8 2.3 NA NA NA NA
Cevostamab 58.8 21.9 16.3 NA NA 80 1.3 13.1 NA 15
(0.6) NA NA NA
*In the phase II trial update at ASCO, these were reported at 10.7% and 11% for the 0.4 mg/kg subcutaneous weekly and 0.8 mg/kg subcuta-
neous every 2 weeks dosing respectively.16 AE: adverse events; BsAb: bispecific antibody; Neutr: neutropenia; Lymph: lymphopenia; Thromb:
thrombocytopenia; CRS: cytokine release syndrome; ICANS: immune effector cell associated neurotoxicity syndrome; IV: intravenous; Dysg:
dysgeusia; SRE: skin-related events; NRE: nail-related events: NA: not available.
Table 2. Bispecific antibody adverse events.
icities was 24 days in the subcutaneous dosing group with
close to half resolving at a median duration was 39 days.
Taste AE tended to occur at a median of 13.5 days. This
and other oral AE including dysphagia, appetite loss, dry
mouth can lead to significant malnutrition and weight loss.
Many clinicians recommend extra vigilance for oral and
esophageal candidiasis and early treatment if suspected.
Other management strategies include biotin sprays and
mouthwashes geared towards managing mucositis and the
incorporation of thin liquids and nutritional supplement
shakes to improve nutrition and caloric intake.29 Artificial
saliva has been tried with limited success. Early dose and
schedule adjustments seem the optimal management
strategy28 (Table 2).
Infections occurred in 58.7% at the 0.4 mg/kg dose (grade 3
or 4 in 19.6%) and 66.2% at the 0.8 mg/kg dose (grade 3 or
greater in 14.5%).16 Opportunistic infections were noted at
3.5% and 5.5% in the 0.4 mg/kg and 0.8 mg/kg dose groups
respectively. Overall, the most common infections noted
in real world studies were viral and bacterial.30,31 COVID-19
infection occurred in 13% at the 405 mcg dose and 2% at
the 800 mcg dose. However, there were no fatalities relat-
ed to COVID-19 infection with talquetamab use as com -
pared to teclistamab use (7.3%). A recent pooled analysis
demonstrated that in patients treated with BsAb, around
half developed an infection and BCMA-targeting BsAb had
almost three times more grade 3 or 4 infections compared
to non-BCMA targeting BsAb. Additionally, neutropenia was
lower in non-BCMA BsAb. COVID-19 infections were com-
mon although more frequent and more likely to be fatal in
the BCMA-targeting BsAb.32 Furthermore, a quarter of the
deaths were attributed to infections, including COVID-19,
Streptococcus pneumoniae, and influenza which further
supports the need for vaccination counseling.32 Opportu-
nistic infections like cytomegalovirus (CMV), Pneumocystis
jirovecii, herpes simplex virus (HSV), varicella-zoster virus
(VZV) were also reported. As such, prophylaxis with acy-
clovir or valacyclovir, shingles vaccination, and Bactrim is
routinely employed at our institution for patients receiving
BsAb therapy. Hypogammaglobulinemia was reported in 87%
at the 405 mcg dose and 71% at the 800 mcg dose. 5 Our
institution employed the practice of aggressive repletion
with intravenous immunoglobulins if patients have recur-
rent infections or immunoglobulin levels under 400 mg/dL
(Table 3).
Serious AE (SAE) occurred in 43% of patients receiving
the 405 mcg dose and 34% of patients receiving the 800
mcg dose per the original report by Chari et al.5 In the
phase II update, 14.7% and 8.3% of patients had dose
reductions and 4.9% and 8.3% of patients had dose dis -
continuations in the 0.4 mg/kg QW and 0.8 mg/kg Q2W
groups respectively.16 Despite the potential for extensive
skin AE and oral AE, there were only five discontinuations
for these events across the combined cohort including
288 patients.
Initiation of therapy
Talquetamab offers the advantage of subcutaneous admin-
istration with a QW and Q2W dosing schedule depending on
patient preference. At our institution, patients are admitted
for the step up dosing to monitor for CRS or other complica-
tions. The 405 mcg QW dosing strategy offers the advantage
of quicker arrival at target dose since it only requires two
step-up doses (10 and 60 mcg per kg). The 800 mcg Q2W
dose requires three step-up doses (10, 60, and 300 mcg)
which means a longer admission to reach the target dose
but with the benefit of less frequent administration and
visits for the patient. Side effects, as mentioned above, are
similar between both dosing strategies with the 805 mcg
Q2W dosing strategy having less infections, hypogamma-
globulinemia, and neurotoxicity but with slightly increased
incidence of grade 3 or greater rashes.

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L. Liu and A. Krishnan
BsAb Infections
%
Infections
grade ≥3, %
Hypogammaglobulinemia
%
COVID-19
%
CMV
%
PJP
%
PML
%
Talquetamab 405 µg 47 7 87 13 0 NA NA
Talquetamab 800 µg 34 7 71 2 0 NA NA
IV talquetamab NA NA NA NA NA NA NA
Teclistamab 76.4 44.8 74.5 17.6 (12.1 grade
≥3; 11 deaths) NA NA 0.01
Elranatamab38,39 73.6 26.4 NA 25.3 NA NA NA
Cevostamab 42.5 18.8 NA NA NA NA NA
CMV: cytomegalovirus; PJP: Pneumocystis jirovecii; PML: progressive multifocal leukoencephalopathy; IV: intravenous; NA: not available.
Table 3. Infectious complications of bispecific antibodies
Managing toxicities
First, and foremost, talquetamab should be initiated with
close monitoring in a setting with direct access to tocili-
zumab, critical care facilities, and capacity of neurologic
evaluation and treatment.
Adverse events related to the nails can be managed with
ammonium lactate cream, Vaseline, and various topical
steroid ointments. Skin changes like xerosis and pruritis
can be managed similarly with topical steroids and oral
antihistamines for itchiness. Grade 3 rashes in the original
study resolved after oral or topical corticosteroid use and
talquetamab was able to be restarted in most patients with
this issue.
Taste and other oral adverse events can lead to significant
malnourishment and weight loss and need extra vigilance.
Artificial saliva, biotin sprays and anesthetic mouthwashes
can improve dry mouth, mucositis, oral cavity pain. Close
monitoring for candidiasis and early treatment is necessary.
It can be helpful to encourage softer diets and nutritional
supplements in the form of shakes.
Infections remain a significant challenge in the field of MM
immunotherapies. At our institution, acyclovir/valacyclovir
and Bactrim for prophylaxis is regularly employed. Patients
are encouraged to get shingles, COVID, and influenza vac-
cination and any other vaccines that are indicated. We
regularly check immunoglobulin levels and our institution
recommends intravenous immunoglobulin repletion for
recurrent infections or levels below 400 mg/dL.
Sequencing of therapy
The ideal time to use talquetamab in MM is a challenging
NCT number Acronym Combination Minimum prior
lines of therapy Primary outcome Start date Primary
completion ate
NCT05455320 MonumenTAL-3 Talq/Dara vs. Talq/
Dara/Pom vs. DPd 1 PFS 10/13/2022 2/6/2026
NCT04586426 RedirecTT-1 Talq/Tec with or
without Dara
Triple class
exposed Toxicity 12/15/2020 6/27/2025
NCT05050097 MonumenTAL-2
Combination with
Talq, CFZ, Dara,
Len, Pom
NS Toxicity 9/22/2021 9/30/2024
NCT05552222 MajesTEC-7
Tec/Dara/Len vs.
Talq/Dara/Len vs.
DRd
NDMM PFS and sustained
MRD-negative CR 10/25/2022 5/25/2029
NCT05338775 TRIMM-3 Talq or Tec with
PD-1 inhibitor RRMM* Toxicity 5/25/2022 9/21/2024
NCT05849610 GEM-TECTAL
DaraVRd followed
by Tec/Dara or
Talq/Dara***
NDMM** MRD negative CR
rate 5/2023 1/2025
NCT04108195 NA Dara/Talq/Tec/Pom 3 Toxicity 2/21/2020 9/9/2024
*Cannot be a candidate for an available therapy. **High risk MM only. ***After DaraVRd, patients will receive intensification with Tec/Dara. If
MRD-negative after, patients will receive Tec/Dara for 2 years. MRD-positive patients or those who become MRD positive or relapse in the
Tec/Dara arm will receive Talq/Dara for 6 cycles. If MRD-negative after, patients will receive Talq/Dara for 2 years as maintenance and if
MRD-positive, they will receive salvage therapy per investigator choice. NCT: national clinical trial; Talq: talquetamab; Dara: daratumumab;
Pom: pomalidomide; Dpd: daratumumab/pomalidomide/dexamethasone; PFS: progression-free survival; CFZ: carfilzomib; Len: lenalidomide;
DRds: daratumumab/lenalidomide/dexamethasone; NDMM: newly diagnosed multiple myeloma; RRMM: relapsed/refractory multiple myeloma;
DaraVRd: daratumumab/bortezomib/lenalidomide/dexamethasone; MRD: measurable residual disease; CR: complete response; Tec: teclis -
tamab; NA: not available; NS: not specified.
Table 4. Bispecific antibody combination therapy trials.

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L. Liu and A. Krishnan
question to answer. It can depend on many factors in -
cluding, but not limited to, prior therapies (especially BC-
MA-directed ones), speed of progression, and institutional
time from leukapheresis to CAR T administration. It has
utility in post-BCMA CAR T relapse as a quick off-the-shelf
option to get disease control while using a different tar-
get. Additionally, it could be utilized as a bridge to BCMA
CAR T in rapid progressors or MM with high disease bur-
den. In patients with frequent or chronic infections, this
may present a therapeutic option with less suppression
of humoral immunity compared to the BCMA-directed
therapies. A major consideration is the potential for T-cell
fatigue related to chronic antigenic stimulation from BsAb
therapies which can provide a rationale not to use it before
CAR T-cell therapy leukapheresis.
Combination therapies with
talquetamab
Furthermore, preclinical studies have demonstrated mech-
anisms of antigen escape from BCMA and GPRC5D directed
immunotherapy involving mutational changes in the proteins
leading to disruption of BsAb or CAR T binding to the epi-
tope.33 Preclinical studies of BsAb CAR T constructs target-
ing BCMA and GPRC5D demonstrated higher survival than
CAR T directed to either target alone.34,35 This suggests that
the simultaneous targeting of BCMA and GPRC5D or other
targets may lead to improved efficacy whether it be via im-
munotherapies with two targets or combination therapies.
In addition to the previously mentioned TRIMM-2 study
evaluating the daratumumab/teclistamab and daratumum-
ab/talquetamab combinations in RRMM, there are many
other studies evaluating combination therapies to improve
on the efficacy of talquetamab. These combinations span
the range of different lines of therapy to elucidate the best
combination with talquetamab and inform the sequencing
of therapy (Table 4).
Conclusion
Talquetamab represents yet another T-cell redirection op-
tion for patients with RRMM. Future trials are ongoing to
answer the question of optimal sequencing of these T-cell
redirecting therapies as well as optimal combinations.
Disclosures
LL has received honoraria from CancerNetwork; AK acts as
a consultant/speaker for AbbVie (relationship has ended),
Adaptive Biotechnologies, Bristol Myers Squibb, GlaxoSmith-
Kline, Regeneron Pharmaceuticals (relationship has ended),
Sanofi, Sutro Biopharma, and Takeda Pharmaceuticals USA.
Contributions
LL performed data search, literature review, and manuscript
writing. AK provided supervision, performed manuscript
writing and editing.
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SPOTLIGHT REVIEW ARTICLE - Biology and targeted therapy for CNS lymphoma
L. Liu and A. Krishnan
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