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. 2023 Nov 1;35(6):601-611.
doi: 10.1097/CCO.0000000000000983. Epub 2023 Jul 24.

T-cell redirecting bispecific and trispecific antibodies in multiple myeloma beyond BCMA

Niels W C J van de Donk  1   2 , Chloe O'Neill  1   2 , Maaike E M de Ruijter  1   2 , Christie P M Verkleij  1   2 , Sonja Zweegman  1   2
Affiliations

T-cell redirecting bispecific and trispecific antibodies in multiple myeloma beyond BCMA

Niels W C J van de Donk et al. Curr Opin Oncol. .

Abstract

Purpose of review: B-cell maturation antigen (BCMA)-directed T-cell immunotherapies, such as chimeric antigen receptor T-cells (CAR T-cells) and bispecific antibodies (BsAbs) have markedly improved the survival of triple-class refractory multiple myeloma (MM). However, the majority of patients still develops disease progression, underlining the need for new agents for these patients.

Recent findings: Novel T-cell redirecting BsAbs targeting alternative tumor-associated antigens have shown great promise in heavily pretreated MM, including patients previously exposed to BCMA-directed therapies. This includes the G-protein-coupled receptor class 5 member D (GPRC5D)-targeting BsAbs talquetamab and forimtamig, as well as the Fc receptor-homolog 5 (FcRH5)-targeting BsAb cevostamab. Toxicity associated with these BsAbs includes cytokine-release syndrome, cytopenias, and infections. In addition, GPRC5D-targeting BsAbs are associated with specific 'on target/off tumor' toxicities including rash, nail disorders, and dysgeusia. Trispecifc antibodies targeting two different MM-associated antigens to prevent antigen escape are in early clinical development, as well as trispecific antibodies (TsAbs) that provide an additional co-stimulatory signal to T-cells to prevent their exhaustion.

Summary: Various T-cell redirecting BsAbs are in advanced stages of clinical development with promising activity and a manageable toxicity profile. Ongoing studies are evaluating combination strategies, fixed-duration treatment, and use of BsAbs in earlier lines of therapy. TsAbs hold great promise for the future.

Keywords: Fc receptor-homolog 5; G-protein-coupled receptor class 5 member D; bispecific antibody; multiple myeloma; trispecific antibody.

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Conflict of interest statement

N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis and BMS, and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier, all paid to institution; S.Z. has received research funding from Celgene, Takeda, Janssen, and serves in advisory boards for Janssen, Takeda, BMS, Oncopeptides and Sanofi, all paid to institution; all other authors declared no conflicts of interest.

Figures

Box 1
Box 1
no caption available
FIGURE 1
FIGURE 1
Cell surface expression of GPRC5D, BCMA and CD38. Protein levels on the surface of plasma cells from healthy donors or MM patients were assessed by flow cytometry. Expression of GPRC5D is lower on normal plasma cells compared to malignant plasm cells, while there is no difference for BCMA and expression of CD38 is higher on normal plasma cells. The violin plots visualize the distribution of target expression levels with the black line representing the median and the colored lines represent the first and third quartiles. Adapted from Verkleij et al.[37] with permission. ∗P < .05; ∗∗∗P < .001; ∗∗∗∗P < .0001. DARA-R MM, daratumumab-refractory MM; HD, healthy donor plasma cells; NDMM, newly diagnosed MM; ns, not significant; RRMM, daratumumab naïve relapsed/refractory MM.
FIGURE 2
FIGURE 2
BsAbs targeting GPRC5D and FcRH5 in advanced stages of clinical development for the treatment of MM. (A) A T-cell redirecting bispecific antibody binds simultaneously to CD3 on the T-cell and a target antigen on the MM cell. This results in the formation of an immune synapse and then T-cell activation/degranulation with release of granzymes and perforins, and subsequent MM cell death. (B) Molecular configuration of talquetamab, forimtamig, and cevostamab. Picture is created with BioRender.com.
FIGURE 3
FIGURE 3
On target/off tumor toxicities associated with GPRC5D-targeting BsAbs. (A) Nail changes. (B) Palmar desquamation.
See this image and copyright information in PMC

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