T-cell redirecting therapies (TCRs) such as chimeric antigen receptor T cell (CAR T-cell) therapies and bispecific antibodies targeting BCMA have revolutionised the outcomes of historically difficult-to-treat relapsed multiple myeloma. However， clonal plasticity driven by selective therapeutic and microenvironmental pressure continues to drive relapses. Ongoing drug development of novel agents and deployment of innovative combinations remains paramount in chasing the elusive cure.
GPRC5D is an orphan transmembrane receptor located on plasma cells with little expression in normal cells (primarily on hard keratinised tissues).Talquetamab is a GPRC5D-directed bispecific antibody with evidence of safety and activity in patients with heavily pretreated multiple myeloma with an overall response rate of 64–70%.
In The Lancet Haematology， Ajai Chari and colleagues present the updated results of the phase 1–2 MonumenTAL-1 study. This report includes the safety and activity of the recommended phase 2 doses of talquetamab (0·4 mg/kg once a week and 0·8 mg/kg every 2 weeks) with longer follow-up in 375 participants， including 78 patients with previous TCR.
The overall depth of response of talquetamab was encouraging including in traditionally difficult-to-treat patient populations such as those with high-risk cytogenetic abnormalities and previous TCR. The progression-free survival in the TCR-naive cohort is similar to the now-ubiquitous BCMA bispecific antibodies. In the BCMA TCR-exposed cohort， the overall response rate following CAR T-cell therapy was 67% (52 of 78 patients， 95% CI 55–77)， similar to that of the TCR-naive cohort， 74% in the 0·4mg/kg once a week group (106 of 143 patients， 66–81) and 69% in the 0·8 mg/kg every 2 weeks group (107 of 154 patients， 62–77). The comparable response is probably due to an immunological reset following the so-called one-and-done approach of a CAR T-cell therapy allowing for reuse of TCR without compromising efficacy. Conversely， the overall response rate following immediate bispecific antibody remains dismal， highlighting the issue of T-cell dysfunction， even with use of an alternate target.
imilar outcomes of talquetamab in the real-world setting further validate its efficacy.
In terms of safety profile， on-target， off-tumour adverse events involving the hard-keratinised tissues were seen in most patients. For treating physicians， the learning curve of grading and managing the on-target， off-tumour adverse events has been quite steep. Due to their unique nature， the Common Terminology Criteria for Adverse Events falls short in adequately characterising and scoring these toxic effects. Despite meaningful improvements in overall health-related quality of life due to its robust efficacy， a small pilot study showed rapid development of objectively measured and patient-reported dysgeusia， resulting in a marked decrease in oral health-related quality of life.The ongoing TALISMAN study (NCT06500884) aims to evaluate prophylactic strategies to mitigate these toxic effects with talquetamab and will probably be applicable to other GPRC5D targeting strategies. The relative B-cell sparing effect has resulted in lower rates of high-grade infections (grade ≥3 18–26%) compared with BCMA targeting bispecific antibodies (grade ≥3 41–55%).
Early data from other GPRC5D targeting strategies such as CAR T-cell therapy， arlocabtagene autoleucel seem encouraging. When targeting GPRC5D with a CAR T-cell therapy approach， the on-target， off-tumour adverse events pertaining to hard keratinised tissues appear to be less frequent， lower grade， and transient， probably owing to the one-time nature of CAR T-cell therapy. However， a higher frequency of poorly understood non-immune effector cell-associated neurotoxicity syndrome effects (dizziness， ataxia， gait disturbances) is noted with the CAR T-cells and less frequently with talquetamab. The suspected mechanism is on-target， off-tumour adverse events due to GPRC5D expression in the inferior olivary nucleus and remains an important area of future investigation. However， contrary to the relative importance of BCMA to plasma cell survival， the yet unknown functional relevance of GPRC5D combined with frequent target modulation (such as antigen loss via biallelic gene loss or inactivating mutations) following therapy fuel the possibility that GPRC5D might only be stricken once (unlike BCMA)
Therefore， differentiating and choosing between available GPRC5D strategies will be key in the future based on safety and efficacy balance.
The rapid pace of drug development presents a clinical conundrum for treating physicians both in terms of how best to sequence targets and methods engaging those targets， particularly sequential bispecific antibody usage which might compromise T-cell fitness. GPRC5D is a promising therapeutic target for immunotherapy in multiple myeloma based on its selective expression， structural advantage facilitating tighter immunological synapse， and its mutually independent expression from BCMA， enabling simultaneous and sequential treatment.10The timeline of development of GPRC5D strategies have predominantly poised these agents in the post-BCMA setting. However， the ongoing development of GPRC5D directed therapies in earlier lines of disease and in combination with anti-BCMA immunotherapies and other novel agents particularly with immunomodulatory approaches will provide key insights to pertaining to sequencing of available immunotherapies.
Ultimately， the promising activity of talquetamab demonstrated in a larger cohort of patients with longer follow-up expands our therapeutic repertoire with greater confidence in marching one antigen closer towards curing myeloma.
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