Table 1. Clinical impact of resistance... | American Society of Hematology

Table 1.

Clinical impact of resistance mechanisms

Alteration	Disease stage	Frequency	Detection technique∗	Clinical impact	Reference(s)
16p loss (TNFRSF17)	Pretreatment screening	3%-4% of TCE-naive MM	WGS	May facilitate biallelic target inactivation by second hit	¹²,¹³
TNFRSF17 mutation	Pretreatment screening	1.1% (somatic) and 0.7% (germ line) of TCE-naive MM	WGS	May facilitate biallelic target inactivation by second hit	¹³
12p loss (GPRC5D)	Pretreatment screening	13%-15% of TCE-naive MM	WGS	May facilitate biallelic target inactivation by second hit	^12-14
GPRC5D mutation	Pretreatment screening	4% TCE-naive MM	WGS	May facilitate biallelic target inactivation by second hit	¹²
Low GPRC5D expression	Pretreatment screening	TBD	RNA-seq	Associated with reduced talquetamab efficacy in vitro. May facilitate epigenetic inactivation of the target	¹⁴,²⁰
Abundance of exhausted T-cell clones	Pretreatment screening	TBD	scRNA/VDJ-seq	Predicts response failure to BCMA-targeting TCE	¹⁹
TNFRSF17 homozygous deletion	At relapse	1/14 relapses after BCMA-targeting TCE	WGS	Precludes response to other BCMA-targeting therapy	¹²,¹³
TNFRSF17 p.Arg27Pro	At relapse	1/14 relapses after BCMA-targeting TCE	WGS	Confers resistance to teclistamab and elranatanab	¹³
TNFRSF17 p.Pro34del	At relapse	3/14 relapses after BCMA-targeting TCE	WGS	Confers resistance to teclistamab and elranatanab	¹³
TNFRSF17 p.Ser30del	At relapse	2/14 relapses after BCMA-targeting TCE	WGS	Confers resistance to teclistamab	¹³
Bi-allelic genetic GPRC5D inactivation	At relapse	5/7 post-talquetamab relapses	WGS	Likely precludes response to other GPRC5D-targeting therapy	¹³,¹⁴
Epigenetic GPRC5D inactivation	At relapse	2/3 post-talquetamab relapses	scMultiome (RNA-seq + ATAC-seq)	Likely precludes response to other GPRC5D-targeting therapy	¹⁴

Alteration	Disease stage	Frequency	Detection technique∗	Clinical impact	Reference(s)
16p loss (TNFRSF17)	Pretreatment screening	3%-4% of TCE-naive MM	WGS	May facilitate biallelic target inactivation by second hit	¹²,¹³
TNFRSF17 mutation	Pretreatment screening	1.1% (somatic) and 0.7% (germ line) of TCE-naive MM	WGS	May facilitate biallelic target inactivation by second hit	¹³
12p loss (GPRC5D)	Pretreatment screening	13%-15% of TCE-naive MM	WGS	May facilitate biallelic target inactivation by second hit	^12-14
GPRC5D mutation	Pretreatment screening	4% TCE-naive MM	WGS	May facilitate biallelic target inactivation by second hit	¹²
Low GPRC5D expression	Pretreatment screening	TBD	RNA-seq	Associated with reduced talquetamab efficacy in vitro. May facilitate epigenetic inactivation of the target	¹⁴,²⁰
Abundance of exhausted T-cell clones	Pretreatment screening	TBD	scRNA/VDJ-seq	Predicts response failure to BCMA-targeting TCE	¹⁹
TNFRSF17 homozygous deletion	At relapse	1/14 relapses after BCMA-targeting TCE	WGS	Precludes response to other BCMA-targeting therapy	¹²,¹³
TNFRSF17 p.Arg27Pro	At relapse	1/14 relapses after BCMA-targeting TCE	WGS	Confers resistance to teclistamab and elranatanab	¹³
TNFRSF17 p.Pro34del	At relapse	3/14 relapses after BCMA-targeting TCE	WGS	Confers resistance to teclistamab and elranatanab	¹³
TNFRSF17 p.Ser30del	At relapse	2/14 relapses after BCMA-targeting TCE	WGS	Confers resistance to teclistamab	¹³
Bi-allelic genetic GPRC5D inactivation	At relapse	5/7 post-talquetamab relapses	WGS	Likely precludes response to other GPRC5D-targeting therapy	¹³,¹⁴
Epigenetic GPRC5D inactivation	At relapse	2/3 post-talquetamab relapses	scMultiome (RNA-seq + ATAC-seq)	Likely precludes response to other GPRC5D-targeting therapy	¹⁴

The molecular alterations associated with TCE resistance and their clinical implications are summarized.

RNA-seq, RNA sequencing; TBD, to be determined; WGS, whole-genome sequencing.

∗

Indicated techniques are those used in the original references.

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