Table 2.

Preclinical and early-phase TCRT targets for myeloma

Targeta	Reported on-tumor expression	Reported off-tumor expression	Advantages	Disadvantages	Additional notes
GPRC5D	MGUS, SMM, PCL, and MM59	healthy PCs.59 hair follicles, nail beds, filiform papillae of the tongue and inferior olivary nucleus62,63	highly expressed in myeloma with no B cell expression and minimal PC expression. This may reduce the severity and/or frequency of infections as seen with BCMA-TCRTs.58,322 Clinical trial results support this, with lower rates of severe infections54,55,56,57,62 GPRC5D TCRTs have shown efficacy in patients with prior BCMA-targeting therapies exposure55,56,62 as a GPCR, exposed epitopes are likely to be membrane-proximal, which may enable the formation of more efficient immune synapses to enhance anti-tumor efficacy59	high frequency of nail- and skin-related AEs and dysgeusia in clinical trials due to off-target expression.55,56 OTOT expression may also be the reason for the cerebellar toxicities reported for two GPRC5D-CAR-T cell products54,62 GPRC5Dlow/neg progressive disease has reported in patients receiving CAR T cells and TCEs52,62	clinical trial results have shown promising efficacy, with both TCEs and CAR T cells achieving >70% ORRs across multiple trials54,55,56,57,62,323 talquetamab (GPRC5DXCD3 bispecific TCE) recently received accelerated approval and conditional marketing authorization in Europe for triple-class exposed R/R MM60,61 although cerebellar toxicities have been reported for two CAR-T cell products, no neural toxicities have been reported for a third CAR-T cell product or any bispecific TCEs54,55,56,57,62
FCRL5/FCRH5	MGUS, MM (and HCL, CLL, and MCL)64,67	B lineage: pre-B cell to PC64,67	low risk for OTOT with no know expression outside the B cell compartment67 lower expression on B cells and healthy PCs may limit cytotoxicity toward these cells64,66,67 higher and more uniform expression than BCMA, and expression is retained in patients post BCMA TCRT.66,67 FCRL5XCD3 TCEs have shown efficacy in patients who have previously received BCMA-targeted immunotherapies69 expression is associated with 1q21 gain, a poor prognostic marker in MM65,66,67	cleavage of FCRL5 could provide a means for antigen escape and may impair CAR-T cell cytolytic activity67	phase I results for an FCRL5-ADC (DFRF4539A, NCT01432353) were disappointing with two (5%) PR, one (3%) MR, and 18 (46%) SD as best response.68 TCRTs may be a more effective means to target FCRH5 as suggested by early clinical results69,71 early results suggest lower response rates for FCRL5-TCEs than GPRC5D- and BCMA-TCEs (54.5% ORR at the 160-mg dose level, NCT03275103) but responses are durable69,71 may also be a target of interest for MCL, HCL, and CLL67
SLAMF7 (CS1)	MGUS, SMM, MM324	pro-B cells, plasma cells, NK cells, T cells, activated monocytes, dendritic cells324,325	SLAMF7 is expressed in all MM patients and is retained in relapsed disease, including post BCMA-CAR-T cell therapy51,324,325 pro-tumorigenic326	SLAMF7 is expressed on nearly all CD8+ T cells, resulting in fratricide325 SLAMF7 can be cleaved, providing a mechanism for antigen escape, and CAR-T cell binding of soluble protein may limit efficacy327 Off-tumor expression on other immune cell subsets poses a serious risk for lymphopenia325	the FDA-approved SLAMF7-targeting mAb (elotuzumab) has shown anti-MM activity when used in combination for R/R MM, but activity in newly-diagnosed MM is limited328 SLAMF7-CAR-T cell trials are currently ongoing with results pending. Results from a bispecific BCMA-SLAMF7 CAR-T cell trial suggest that SLAMF7-targeting does not increase the rate of infections compared to BCMA CAR T cells alone, but these bispecific CAR T cells do have reduced cytolytic activity329
Kappa-light chain	late-stage immature/mature B cell neoplasms (B-NHL, CLL/SLL) and kappa-restricted MM46,303	late-stage immature/mature B cells expressing the kappa-light chain (approximately half)303	CAR T cells selectively eliminate clonal malignant cells while sparing normal B cells with the reciprocal light chain (approximately half)45,303 although surface immunoglobulin is minimal on MM cells, surface immunoglobulin is expressed on myeloma-initiating cells330	kappa-light-chain immunoglobulins are secreted by myeloma cells, and so the low surface expression may limit efficacy. In addition, the high level of secreted immunoglobulins in MM might lead to excessive stimulation and exhaustion45	in a phase I trial for kappa-CAR T cells for NHL/CLL and MM, modest anti-myeloma effects were observed (four of seven achieving SD as best response)45 KMA is a membrane-bound form of kappa-light chain found in kappa-restricted MM. KappaMab (MDX-1097), a KMA-targeting mAb, demonstrated efficacy in a phase IIb trial, which may support the targeting of KMA instead of surface kappa Ig for MM331
CD229	B-NHL, MM, and PCL72,73,74,332	NK cells, mature B and T cells, and plasma cells72,74,332	expression is highly restricted to the hematopoietic compartment72 pro-survival role may reduce the risk for antigen escape72 expressed on the chemo-resistant myeloma-initiating/propagating cells73,74	OTOT expression on other immune cells will likely result in cytopenias. CD229 is downregulated following CD3/CD28 stimulation, which may limit CAR-T cell fratricide during manufacturing, but it is currently unknown if this downregulation will be sustained post infusion74 soluble CD229 (sCD229) is increased in advanced disease.332 It is currently unknown if CAR T cells recognize sCD229 but it may abrogate activity	affinity-tuned CD229 CAR T cells retain anti-myeloma activity but lack cytolytic activity toward healthy lymphocytes75
CD1d	MGUS and MM333	antigen-presenting cells, B cells, epithelial cells, thymocytes, activated T cells, and HSCs334,335,336,337	CD1dXVδ2 bispecific Vγ9Vδ2-TCE can recruit both NKT- and Vγ9Vδ2 T cells, which preferentially target malignant cells over healthy cells (reducing the risk for OTOT toxicities) and have a lower risk for CRS334	high risk for antigen escape as CD1d ligation induces B cell and PC death, and expression is lost with disease progression333,334 Expressed on in vitro activated T cells which may preclude CAR-T cell development335	low expression in advanced disease may limit efficacy in the R/R patient populations likely to constitute early-phase clinical trial cohorts334 CD1d is also a target of interest for (myelo)monocytic AML and CLL334 early clinical trial results for a CD1dXVδ2 TCE suggest limited efficacy in MM/CLL (disease stabilization in two of eight patients)338
SEMA4A	MGUS, SMM, and MM79,80	monocytes, granulocytes, healthy PCs, and a subset of T cells79	pro-survival role in MM may reduce the risk for antigen escape79 SEMA4A is expressed in the majority (>90% of patients) and is retained in advanced R/R disease. Expression is higher than BCMA, FCRL5, and GPRC5D79,339	OTOT expression may pose a risk for cytopenias. However, expression is much lower than malignant cells and no cytopenias were seen in a murine toxicity model using a cross-reactive SEMA4A-ADC79 increased expression in T cells post activation poses a risk for fratricide during manufacturing but does not appear to affect cytolytic capabilities in vitro339	–
CD46 (MCP)	MGUS, SMM, MM78	PC, monocytes, granulocytes, placenta, and prostate78	expressed in myeloma-initiating cells76 higher expression in MM than healthy PCs may reduce the risk for hypoglobulinaemia78 expression is associated with 1q21 gain, a poor prognostic marker in MM78	moderate monocyte and granulocyte expression may pose a risk for cytopenias78	phase I results of a CD46-ADC (FOR46) have shown modest efficacy (three PR in six patients) with severe cytopenia (3 Gr four neutropenia and one Gr 4 thrombocytopenia)77
ILT3 (LILRB4)	MM80,82	monocytes, macrophages, and dendritic cells80	an ILT3XCD3 bispecific TCE has shown activity against samples from relapsed patients post BCMA-CAR-T cell therapy80 ILT3 is a negative immune receptor and can suppress T cell proliferation in MM and AML, providing a strong rationale for therapeutic targeting121	OTOT expression on other immune cells may pose a risk for cytopenias80	also a target of interest for monocytic AML340
CCR10	MM82	healthy PCs, T cells82	low risk for OTOT toxicities as minimal expression on other hematopoietic cell subsets82 Expression is increased in R/R advanced disease82	CCR10 is upregulated on activated T cells, which resulted in fratricide and CAR-T cell manufacturing difficulties in a preclinical study of an anti-CCR10-CAR T cell82	–

^aAEs, adverse events; GPCR, G-protein-coupled receptor; HCL, hairy cell leukemia; KMA, kappa myeloma antigen; MGUS, monoclonal gammopathy of undetermined significance; MR, minimal response; PC, plasma cell; PCL, plasma cell leukemia; SMM, smoldering multiple myeloma. Other abbreviations as in Table 1.