Dual antigen targeting immunotherapies in MM

Immune-based therapies in multiple myeloma (MM) include agents such as chimeric antigen receptor (CAR) T cells, as well as bispecific antibody therapies. These novel agents are often associated with high initial response rates compared with standard therapies, yet most patients go on to experience a relapse. In an effort to improve duration of response, dual antigen targeting and trispecific antibodies are currently being investigated in MM.¹

Here we summarize a presentation by Sham Mailankody¹ from the International Myeloma Society’s 5th Immune Effector Cell Therapies in Multiple Myeloma Workshop, 2024, on antigen-targeting CAR T cells and antibody therapies in MM.

Dual antigen-targeting¹

• The high incidence of relapse after immune therapies can be attributed to a multitude of resistance mechanisms; most commonly reduction or loss of the target antigen.
• Immune therapies such as CAR T cells and bispecific antibodies are often administered sequentially after relapse. However, use of these therapies in combination to target more than one antigen simultaneously could be applied to further reduce malignant cells and extend duration of response.
• In a mouse model, dual targeting of B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) resulted in a more durable response than either monotherapy in isolation.
• Dual antigen targeting can be achieved using combinations of CAR T-cell and bispecific antibody therapies (Figure 1).

CAR, chimeric antigen receptor; TCE, T-cell engager.
Created with BioRender.com.
*Adapted from Mailankody.¹

RedirecTT-1¹

• RedirecTT-1 (NCT04586426) is a phase I/II clinical trial investigating the combination of teclistamab and talquetamab to simultaneously target BCMA and GPRC5D for the treatment of relapsed/refractory MM.
  • The trial design and latest data from RedirecTT-1 have been reported by the Multiple Myeloma Hub here.
• Data collected from this trial provide evidence to support dual antigen targeting as a strategy to aid improve response rates, particularly in difficult-to-treat presentations such as extramedullary disease (EMD) (Figure 2).

CR, complete response; PR, partial response; Q2W, once every 2 weeks; sCR, stringent complete response; tal, talquetamab; tec, teclistamab; VGPR, very good partial response.
*Adapted from Mailankody.¹

Key learnings1
Preclinical data and early clinical trials suggest that dual antigen targeting could help to overcome resistance mechanisms to immune therapies. More research is required in the clinical setting to establish whether dual antigen targeting results in increased response rates and, most importantly, increased response duration.