GPRC5D has emerged as a promising immunotherapeutic target in patients with R/R MM. Currently, safety and efficacy of two BsAb and seven CAR T-cell products have been reported, while numerous GPRC5D-targeting agents are under investigation in preclinical trials (Fig. 4).

Fig. 4

Structures of GPRC5D-targeted products. A The structure of bispecific antibodies encompasses the anti-CD3, anti-GPRC5D, and Fc regions; B The generalized structures of anti-GPRC5D CAR T cells are depicted; C-D Cartoon graphs illustrate the GPRC5D-targeting CAR-NK cells and anti-GPRC5D ADC

Efficacies of GPRC5D-targeted therapiesEfficacies of anti-GPRC5D BsAb

Talquetamab (JNJ-64407564) is an off-the-shelf, humanized immunoglobulin G4 BsAb with a proline, alanine, alanine (IgG4-PAA) scaffold that can bind to both GPRC5D on target cells and the epsilon chain of CD3 on T cells [27, 31, 45] (Fig. 4A). A first-in-human, multi-center, phase 1 MonumenTAL-1 trial of talquetamab (NCT03399799), was initiated in 232 patients with R/R MM (Table 2). All enrolled patients had received a median of 6 lines of previous therapies, of whom 79% had triple-refractory disease, 30% had penta-refractory disease. Of these patients, 102 (44%) received talquetamab intravenously (IV), and 130 (56%) received talquetamab subcutaneously (SC), including 30 (23%) patients with 405 μg SC weekly (QW), and 44 (34%) patients with 800 μg SC every 2 weeks (Q2W) [45]. The objective response rate (ORR) was 70% with 23% complete response (CR) or stringent CR (sCR) in the 405 μg SC cohort, and was 64% with 23% CR/sCR in the 800 μg SC cohort. Among patients who received the most active intravenous doses (20–180 μg/kg QW), the ORR was 72%, including 28 (39%) patients achieving CR/sCR. The median time to response were 0.9 months (rang 0.2–3.8) and 1.2 months (rang 0.3–6.8), to a CR or better were 9.3 months (rang 1.7–17.1) and 2.3 (rang 2.1–6.8) months, and the median duration of response were 10.2 months (95% confidence interval [CI], 3.0 to not reached) and 7.8 months (95% CI, 4.6 to not reached) in the 405 μg and 800 μg SC cohort, respectively. Eleven (69%) achieved minimal residual disease (MRD) negativity among 16 patients with samples available for analysis of MRD [45] (Table 3). Talquetamab demonstrated significant efficacy against myeloma cells in patients with R/R MM, regardless of administration via SC or IV routes. In comparison to other recommended treatment regimens, such as selinexor plus dexamethasone or belantamab mafodotin, talquetamab exhibited superior clinical responses among patients with triple-class-refractory diseases. Given the promising efficacy observed in the phase 1 trial, a pivotal phase 2 MonumenTAL-1 trial evaluating talquetamab has been initiated [52]. The trial enrolled 288 patients who received talquetamab 0.4 mg/kg QW (n = 143) or 0.8 mg/kg Q2W (n = 145). In the QW and Q2W cohorts, 74% and 69% of patients were triple-refractory; 29% and 23% were penta-refractory [52]; the ORR were 74% (with a median follow-up of 14.9 months) and 73% (with a median follow-up of 8.6 months); the CR or better rates were 34% and 32%; the median duration of response (DOR) were 9.3 (95% CI 6.6–12.7) and 13.0 months (95% CI, 10.6 to not reached). After an extended follow-up period, a larger cohort of patients (n = 297) was included in the safety analysis. In the QW and Q2W cohorts, the ORR were 74.1% (with a median follow-up of 29.8 months) and 69.5% (with a median follow-up of 23.4 months), respectively; the CR or better rates were 32.9% and 40.3%; the median DOR were 9.5 (95% CI 6.7–13.4) and 17.5 months (95% CI, 12.5 to not reached); median progression free survival (PFS) were 7.5 (95% CI, 5.7–9.4) and 11.2 months (95% CI, 8.4–14.6) [53](Table 3).

Table 2 Properties of GPRC5D-targeted agentsTable 3 Clinical data of GPRC5D-targeted BsAbs

RG6234 (also known as Forimtamig) is a novel T-cell BsAb targeting GPRC5D and CD3 with a unique 2:1 configuration [54,55,56] (Table 2, Fig. 4A). A phase 1 clinical trial of RG6234 (NCT04557150) enrolled 108 patients who received at least 2 prior lines of therapies, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Of these patients, 51 patients received RG6234 IV (dose range: 6–10,000 µg) and 57 received RG6234 SC (dose range: 30–7200 µg) in the dose-escalation phase. The ORR were 71.4% (with a median follow-up of 11.6 months) and 63.6% (with a median follow-up of 8.0 months), and CR or better rates were 34.7% and 25.5% in the IV and SC cohort, respectively. Median time to first response were 1.4 (95% CI, 1.2–1.8) and 1.6 months (95% CI, 1.2–2.1), and median duration of response were 10.8 (95% CI, 0.0–17.6) and 12.5 months (95% CI, 1.2–12.5) in the IV and SC cohorts [56] (Table 3). Similarly, RG6234 demonstrated comparable anti-tumor efficacy in both IV and SC cohorts, resembling the BsAb talquetamab. Notably, RG6234 can be conveniently accessed off the shelf and administered via SC route, thereby circumventing potential setbacks, attrition rates, and burdens associated with personalized CAR T-cell therapy generation.

Other GPRC5D-targeted BsAb BR109 exhibits binding affinity towards human GPRC5D and CD3ε. BR109 demonstrates favorable stability and antitumor activity, specifically inducing T-cell-mediated cytotoxicity against numerous GPRC5D-positive MM cell lines in vitro. Furthermore, the antitumor efficacy of BR109 is validated in xenograft mouse models with reconstituted human immune cells [42]. GPA0039 mediated target-dependent cell cytotoxicity via activation of human T cells by ligating human CD3+ T cells and GPRC5D-expressing cells. In vitro and in vivo xenograft models demonstrated that GPA0039 suppressed tumor growth of GPRC5D-positive myeloma cells via T cell activation [47]. Although BR109 and GPA0039 exhibited potent anti-tumor cytotoxicity in animal models, no clinical data regarding safety and efficacy have been reported thus far.

Efficacies of GPRC5D-targeted CAR T cells

Currently, all clinically utilized anti-GPRC5D CAR T cells are second-generation CAR T-cell therapies incorporating a single anti-GPRC5D scFv derived from human B-cells or a dual-specific scFv, a 4-1BB (or CD28) costimulatory domain, and a CD3ζ signaling domain (Fig. 4B).

MCARH109 For the manufacture of MCARH109, patients’ T cells were combined at a 1:1 ratio of CD4:CD8, activated, and transduced with the MCARH109 lentivirus and expanded [38]. A phase 1 trial (NCT04555551) of MCARH109 was initiated in a single center, enrolling 17 patients with R/R MM who had failed in at least 3 (median 6) previous lines of therapy, including a PI, an IMiD, a CD38 monoclonal antibody, and high-dose chemotherapy followed by autologous stem cell transplantation. Doses of 25 × 106, 50 × 106, 150 × 106, and 450 × 106 total CAR T cells were infused in the dose-escalation phase, of which a dose of 150 × 106 total CAR T cells was selected for the dose-expansion phase. The ORR was 71%, including 6 (35%) achieving CR or better, 4 (24%) very good partial response (VGPR), and 2 (12%) PR. The median duration of response was 7.8 months (95% CI, 5.7 to not reached). Eight (47%) patients with a response achieved MRD negativity [38] (Table 4). Even at a remarkably low dosage of 25 × 106, MCARH109 exhibited efficacy, underscoring the active targeting potential of GPRC5D in MM. Furthermore, it is noteworthy that diminished expression of the GPRC5D antigen, prior allogeneic hematopoietic stem cell transplantation, and extramedullary disease (EMD) do not impede the therapeutic activity of MCARH109.

Table 4 Clinical data of GPRC5D-targeted CAR T cells

OriCAR-017 A single-center, single-arm phase 1 trial (NCT05016778) of OriCAR-017 enrolled 10 patients with heavily pre-treated R/R MM who had a median of 5.5 previous lines of therapy. A single infusion dose ranging from 1 × 106 to 6 × 106/kg CAR T cells was administrated in the dose-escalation phase and the dose of 3 × 106/kg CAR T cells was selected in the dose-expansion phase [44]. By the cutoff date (January 16, 2024), an ORR of 100% was achieved, including 8 (80%) sCRs and 2 (20%) VGPRs. The median time to best response was 3.1 months (interquartile range [IQR], 2.0–5.1) and the median time to CR or better was 4.1 months (IQR, 2.0–5.9). All patients with a response achieved MRD negativity on day 28. The median DOR was 10.4 months (95% CI, 5.0–17.0) and median PFS was 11.4 months (95% CI, 5.9–18.0), while the median OS has not reached [57](Table 4). The positive responses observed in OriCAR-017 may be attributed to the utilization of nanobodies as targeting moieties for the development of functional CARs against two epitopes of GPRC5D. These nanobodies exhibit high humanization and low immunogenicity, potentially enhancing the persistence of CAR T cells in patients. Unlike scFv, nanobodies are more likely to adopt a double VHH structure, enabling recognition of two epitopes and potentially increasing the affinity of antigen binding by CAR T cells, thereby leading to enhanced antitumor capacity. Furthermore, nanobodies demonstrate greater stability as monomers compared to scFv, which have a tendency to aggregate and induce tonic signaling that contributes to CAR T-cell exhaustion.

BMS-986393 A first-in-human, multi-center, open-label, phase 1 trial (NCT04674813) of BMS-986393 enrolled 70 patients who received ≥ 3 prior treatment regimens, including a PI, an IMiD, an anti-CD38 therapy, and an autologous stem-cell transplantation (ASCT) (if eligible). Twenty-four (34%) patients had penta-refractory disease. Doses of 25 × 106, 75 × 106, 150 × 106, 300 × 106 and 450 × 106 total CAR T cells were tested in the dose-escalation phase, and doses of 75 × 106, 150 × 106, 300 × 106 and 450 × 106 total CAR T cells were selected for the dose-expansion phase (Table 3). ORR was 86% (55/64) in the entire cohort, including 24 (38%) CRs/sCRs and 11 (17%) PRs and 20 (31%) VGPRs [58] (Table 4). BMS-986393 showed durable responses and promising efficacy at all tested dose levels, including patients with high-risk cytogenetics, penta-refractory disease or extramedullary plasmacytomas.

GPRC5D CAR T (YK-CAR-042) A single-arm, phase 2 clinical trial of anti-GPRC5D CAR T (YK-CAR-042) in 33 patients with R/R MM has been completed. All enrolled patients had a median of 4 previous lines of therapy. The dose of 2.0 × 106/kg total CAR T cells was selected in the phase 2 trial based on the findings in the phase 1 dose-escalation trial. The ORR was 91%, including 21 (63%) sCRs/CRs, 4 (12%) VGPRs, and 5 (15%) PRs. The median time to first response was 0.5 month (range, 0.5–3.0), and the median time to best response was 1.8 months (range, 0.5–6.0). Twenty-six of 33 patients (79%) achieved bone marrow MRD negativity. Disease progression occurred in 3 (10%) of 30 patients who had clinical responses with a median follow-up of 5.2 months. Twenty-five of 26 (96%) patients with MRD negativity remained progression-free by the cutoff date [43] (Table 4). Compared to other second-generation CAR T-cell products with similar designs, such as MCARH109 and BMS-986393, YK-CAR-042 demonstrated higher rates of CR or superior responses. One possible explanation for this disparity could be due to the highly efficient transduction and suitable infusion dose of the CAR T cells. Additionally, it is noteworthy that the patients enrolled in Chinese clinical trials appeared to have undergone less intensive prior treatment compared to those participating in clinical trials conducted in Europe and the USA. More clinical studies and longer follow-up are needed to compare the early response and long-term efficacy between different GPRC5D-targeted CAR T-cell products in larger numbers of patients with similar disease characteristics and prior treatment.

GPRC5D CAR T(Li et al.) In a phase 1 trial (NCT05739188) of anti-GPRC5D CAR T cell conducted by Li et al., 10 R/R MM patients were enrolled. Doses of 3.0 × 106/kg, 6.0 × 106/kg, and 1.0 × 107/kg of CAR T cells were evaluated in the dose-escalation phase. The ORR was 90%, comprising 5 CRs/sCRs, 4 PRs, and 1 no response [59] (Table 4).

CT071 In a phase 1 trial (NCT05739188) of CT071, CT071 was administered as a single infusion at doses of 1.0 × 105/kg or 3.0 × 105/kg CAR T cells in 10 patients who had a median of 3 prior lines of therapies. The ORR was 90%, including 4 (40%) sCR, 1 (10%) CR, 1 (10%) VGPR, 3 (30%) PR a with a median follow-up of 2.76 months. All 9 patients with evaluable MRD assessment achieved MRD negativity [51] (Table 4).

BCMA/GPRC5D Bispecific CAR T (YK-CAR-069) A single-arm, phase 1 clinical trial of anti-BCMA/GPRC5D bispecific CAR-T (YK-CAR-069) enrolled 21 patients with R/R MM who had a median of 3 previous lines of therapy. A single infusion dose ranging from 0.5 × 106 to 4.0 × 106/kg CAR T cells was administrated in the dose-escalation phase and the dose of 2.0 × 106/kg CAR T cells was selected in the dose-expansion phase (Table 3). The ORR was 86%, including 13 (62%) sCRs/CRs, 5 (24%) VGPRs. In 12 patients who received dose of 2.0 × 106 CAR T cells/kg, the ORR was 92% (11/12), including 9 (75%) sCRs/CRs and 2 (17%) VGPRs. The median time to best response was 1 month (IQR, 0.75 to 2.5). Seventeen of 21 patients (81%) achieved bone marrow MRD negativity. Disease progression occurred in 2 (10%) of 21 patients who had clinical responses with a median follow-up of 5.8 months. During the follow-up, 16 (76%) patients remained in remission state including 15 (71%) patients with bone marrow minimal residual disease negativity by the cutoff date [60] (Table 4). The clinical responses of BCMA/GPRC5D bispecific CAR T cells were comparable to those of BCMA or GPRC5D single-targeted CAR T cells in the short term. However, the bispecific CAR T cells demonstrated enhanced efficacy in patients with negative expression of either BCMA or GPRC5D, which could potentially prevent relapse caused by antigen down-regulation or escape. Longer follow-up is necessary to assess the long-term outcomes.

In summary, CAR T-cell products targeting GPRC5D exhibited superior early response compared to BsAbs; however, no significant differences were observed in terms of median time to first or best response. Although GPRC5D CAR T-cell therapies have demonstrated better early clinical responses than GPRC5D × CD3 BsAbs, the preparation of CAR T-cell products requires a series of procedures including apheresis and manufacturing, which typically takes at least one month. On the other hand, BsAb products are readily available off-the-shelf, making them an ideal option for rapidly progressing patients who cannot afford to wait for the manufacture of CAR T cells. Additionally, compared with BCMA-targeted CAR T-cell, GPRC5D CAR T-cell showed similar efficacy (Table 5), which needs to be further confirmed in randomized controlled trials. Therefore, the choice between BsAb and CAR T-cell products targeting different myeloma antigens for R/R MM treatment should depend on patient prior therapies, disease conditions and clinical demands. Further investigations are warranted to elucidate the long-term outcomes of diverse GPRC5D-targeted immunotherapies.

Table 5 Comparison of efficacy in CAR T-cell therapies targeting different antigensEfficacies of GPRC5D-targeted CAR-NK cells

Recently, progress in CAR-NK cell therapy has been made in NK cell engineering, target design and combination with other agents to treat relapsed or refractory hematological malignancies, especially acute myeloid leukemia and MM [49]. Three CAR-NK agents targeting GPRC5D were undergoing preclinical trials (Fig. 4C).

Anti-GPRC5D CAR-iNK (Fu et al.) The induced pluripotent stem cells (iPSC)-derived CAR-NK cell was constructed by transducing anti-GPRC5D CAR into an iPSC line derived from a healthy donor [48] (Table 1). The anti-GPRC5D CAR-iNK expressed a high level of CD45 and CD56 (> 99.9%), CD16 (63.6%), the NK cell activating receptor NKG2D (96.3%), NKp30 (98.7%), the co-stimulatory receptors CD244 (99.6%) and CD226 (97.8%) (Fig. 4C). Cytotoxicity assay in vitro demonstrated that anti-GPRC5D CAR-iNK had similar cytotoxicity against K562 cells (No GPRC5D antigen) to cord blood-derived NK cells (CB-NK), wide type (WT) iNK and anti-BCMA CAR-iNK. However, anti-GPRC5D CAR-iNK showed stronger abilities (approximately 90% killing rate) against myeloma cells (with high level of BCMA and GPRC5D expression) than the CB-NK (no killing) and WT iNK (around 10% killing rate). Furthermore, the anti-GPRC5D CAR-iNK also showed superior abilities to kill MM cells to anti-BCMA CAR-iNK [48].

FT555 FT555 was another iPSC-derived anti-GRPC5D CAR-NK cell (Table 1), which showed persistent specific anti-tumor activity against GPRC5D-positive myeloma cells compared to isogenic GPRC5D knockout targets in the preclinical study. In the disseminated in vivo xenograft model of MM, FT555 exhibited robust killing kinetics and tumor clearance, which contributed to prolonging the duration of disease remission and improving survival. The study also demonstrated that a combination of daratumumab with FT555 was able to further enhance the durability of FT555 and deepen tumor growth inhibition in mouse models [61].

BCMA/GPRC5D dual-targeted CAR-NK cells To prevent BCMA-antigen escape and achieve a deeper and more persistent response in MM, Yang et al. developed a new dual-targeted CAR-NK cell product (Table 1) consisting of anti-BCMA VHH and anti-GPRC5D VHH antibodies, NKG2D and 2B4 co-stimulation signaling domains, and IL-15. BCMA/GPRC5D CAR-NK cell showed high activity to kill of both BCMA+ and GPRC5D+ myeloma cells with remarkable persistence and antigen-mediated amplification. Compared with single-targeted BCMA CAR-NK cell, BCMA/GPRC5D CAR-NK cell could also effectively lyse BCMA-negative MM cells. Additionally, it achieved more sustained tumor control than single-targeted BCMA CAR-NK cells in BCMA-antigenic escape model. They also demonstrated that combination of BCMA/GPRC5D CAR-NK with anti-PDL1-IL15 showed more durable tumor control [62].

Efficacy of anti-GPRC5D ADC drug

LM-305 was a novel anti-GPRC5D ADC drug (Fig. 4D). Anti-tumor evaluation in vitro revealed that LM-305 could bind to GPRC5D over-expressing cell lines and GPRC5D endogenously expressing MM cells with high affinity in a dose-dependent manner. LM-305 displayed potent cytotoxicity when co-cultured with MM tumor cells (NCI-H929 and MM.1R). In vivo xenograft models demonstrated that LM-305 resulted in dose-dependent inhibition of tumor growth. Additionally, LM-305 exhibited CR in the GPRC5D high-expressing MM cell line derived xenograft models at a dose of 3 mg/kg. Therefore, this study suggested that LM-305 could be a promising therapeutic candidate for the treatment of R/R MM patients expressing GPRC5D [63] (Table 1). A phase 1/2 trial (NCT05647512) of LM-305 has been initiated to enroll R/R MM patients, but the interim analysis of the trial has not been reported.

Response for patients with prior BCMA-targeted immunotherapies

The potential efficacy of immunotherapies targeting GPRC5D in patients with R/R MM following BCMA-targeted immunotherapies represents a significant clinical challenge.

GPRC5D × CD3 BsAb A total of 70 patients with prior T-cell redirection therapy were enrolled in the phase 2 trial for talquetamab. Of these patients, 58 (83%) and 29 (41%) were triple- and penta-refractory, respectively. Forty-three of 70 patients received prior BCMA CAR T cells, 18 received prior BCMA BsAb, and 5 received both. The ORR was 65.7%, while the ORR in patients receiving prior BCMA BsAb was lower than that in patients receiving prior BCMA CAR T (52.2% versus 72.9%). Median DOR in patients receiving prior BCMA CAR T was similar to that in the whole cohort (12.3 months versus 12.3 months), but longer than that in patients receiving prior BCMA BsAb (6.5 months) [64]. In patients who received RG6234 in the IV and SC cohorts, 5 (5/10) patients and 6 (6/11) patients who had received prior anti-BCMA therapies obtained responses in the IV and SC cohorts [56] (Table 3). It is intriguing that patients with prior BCMA CAR T-cell therapy exhibited enhanced clinical responses and prolonged DOR following anti-GPRC5D BsAb treatment, in comparison to those who received prior BCMA BsAb therapy. This disparity in outcomes may be attributed to distinct mechanisms of action employed by T cells against myeloma cells, which could potentially result from the exhaustion and resistance of anti-tumor effector T cells due to repeated activation strategies.

GPRC5D CAR T After the therapy of MCARH109, 47% of patients had received previous BCMA CAR T-cell therapies. A PR or better response was noted in 6 of 8 (75%) patients in this cohort [38]. All 5 (100%) patients with prior anti-BCMA CAR T-cell therapies achieved responses, including two (20%) patients with a sCR and 3 (30%) with a VGPR after infusion of OriCAR-017 [44]. In the phase 1 clinical trial of BMS-986393, 32 (46%) patients had received prior BCMA-targeted therapy, including BCMA-directed CAR T-cell therapy in 25 (36%) patients. In efficacy-evaluable patients, 21 of 28 (75%) patients who were treated with prior BCMA-directed therapies achieved a PR or better response, including 10 (63%) patients with CRs/sCRs. In refractory patients to prior BCMA-directed therapies, ORR was 85% (11/13), and CR rate was 46% (6/13) [58] (Table 3). After the treatment of YK-CAR-042, all 9 (100%) patients with prior anti-BCMA CAR T-cell therapy obtained a PR or better response, including 4 patients achieving a CR [43]. In the phase 1 clinical trial of GPRC5D CAR T by Li et al., 3 patients had prior BCMA CAR T-cell treatment. Of these patients, two patients achieved responses, including 1 CR and 1 PR, and 1 patient with no response [59]. Both of the 2 patients who received CT071 with prior BCMA/CD19 CAR T achieved responses (1 sCR and 1 PR) [51]. No patients with prior BCMA-directed therapies were enrolled in the phase 1 trial of YK-CAR-069 [60] (Table 4). Despite small sample sizes in various clinical trials, current studies have demonstrated the potential of GPRC5D-targeted immunotherapies as alternative options for MM patients who have progressed after or are refractory to BCMA-targeted therapy. However, there is a lack of data comparing the efficacy of GPRC5D-targeted CAR T-cell between patients with prior BCMA BsAb and those with prior BCMA CAR T-cell treatment, which requires further investigation.

Efficacy for EMD in patients with R/R MM

EMD represents an uncommon and aggressive manifestation of MM. Extramedullary progression, especially extra-osseous plasmacytomas, is inherently a high-risk stage of MM and the current literature has identified it as a poor prognostic feature. Despite several significant advances in MM treatment strategies, treatment outcomes remain less than satisfactory for EMD in MM patients [65]. The pivotal phase 2 trial for talquetamab enrolled 26 patients with EMD in the SC cohort. The ORR was 45.5% with 9.1% CR/sCR in the 405 μg SC cohort, and was 40% with 13.4% CR/sCR in the 800 μg SC cohort [52]. However, the efficacy significantly increased after the combination with teclistamab (a GPRC5D × CD3 BsAb) in the RedirecTT-1 study [66]. The ORR was 73% (19/26) among evaluable patients with EMD and the rate of CR/sCR was 31% (8/26). Four (40%) patients with EMD were enrolled in the phase 1 trial of OriCAR-017. All of the 4 patients (100%) achieved a response, including 3 patients with complete resolution of extramedullary lesion after CAR T-cell infusion [44]. In the phase 1 trial of YK-CAR-069, 4 (19%) patients had EMD at baseline. Three (75%) patients obtained PR or better response, including 1 (25%) patient with VGPR and 2 (50%) patients with sCR [60]. The RedirecTT-1 study showed superior clinical response in the treatment of EMD, which revealed that a combination of immunotherapies targeting different myeloma antigens might be a feasible strategy to improve the efficacy of EMD, and even to improve the long-term outcomes for patients with R/R MM. It would be valuable to also explore the safety and efficacy in the treatment of EMD with a combination of CAR T-cell therapies targeting different antigens, since there are no relevant clinical data presented up to now.

Toxicities of GPRC5D-targeted therapiesHematological toxicities

Therapy-related adverse events (AEs) is an important consideration for new CAR T-cell products, which might elicit exacerbation of conditions and treatment-related deaths. Hematological toxicities were the most common AEs in GPRC5D-targeted immunotherapy. Early hematological toxicity was regarded to be a result of lymphodepleting chemotherapy. Immunotherapy related hematological toxicity is causing more and more attention [67]. Baseline hematopoietic reserve and the systemic inflammation induced by the host might play essential role in the mechanisms of CAR T cells related hematological toxicity [68]. There are some unique features in CAR T cells related hematological toxicity. Cytopenias can persist long after the resolution of clinical CRS and has been reported as long as months to years following CAR T-cell infusion [69]. Additionally, patients can develop very severe bone marrow aplasia that is often refractory to therapeutic measures such as growth factor support [70, 71].

GPRC5D × CD3 BsAb In the MonumenTAL-1 trial for talquetamab, hematological toxicities were the most common grade 3 or 4 AEs, including neutropenia [405-μg SC cohort (60%), 800-μg SC cohort (32%), IV cohort (26%)], anemia (30%, 23%, 33%), and thrombocytopenia (23%, 11%, 13%) [45]. In the 0.4 mg/kg QW and 0.8 mg/kg Q2W cohort of the phase 2 trial for talquetamab, grade ≥ 3 hematologic toxicities were including anemia (31.5%, 25.3%) and neutropenia (30.8%, 21.4%) [53]. In the IV and SC cohort of the phase 1 trial for RG6234, grade ≥ 3 hematologic AEs included anemia (IV 15.7%, SC 38.6%), thrombocytopenia (IV 13.7%, SC 19.3%), and neutropenia (IV 11.8%, SC 15.8%) [56] (Table 3). The incidence of hematological toxicity was lower in patients treated with GPRC5D-targeted BsAb than those treated with CAR T cells. Hematological toxicities after GPRC5D-targeted BsAb recovered more quickly, and prolonged hematological toxicities were seldom reported. One of the important reason was that patients did not need to receive lymphodepleting chemotherapy before the BsAb treatment, while they must receive lymphodepletion before CAR T-cell treatment. Therefore, GPRC5D-targeted BsAb might be better choices for patients with serious hematological toxicities at baseline.

GPRC5D CAR T In the phase 1 trial for MCARH109, grade 3 or 4 hematologic toxicities included neutropenia (100%), thrombocytopenia (65%), and anemia (41%) [38]. After infusion with OriCAR-017, grade 3 or 4 hematologic toxicities were observed as neutropenia (100%), thrombocytopenia (90%), and anemia (70%) [44]. Grade 3 or 4 hematologic toxicities occurred in 64/70 (91%) patients who received BMS-986393 therapy, including neutropenia (69%), anemia (31%), and thrombocytopenia (30%) [58]. Grade 3 or 4 neutropenia(100%), anemia (52%), and thrombocytopenia (45%) occurred in patients with the treatment of YK-CAR-042 [43]. In the phase 1 trial for GPRC5D CAR T by Li et al., grade 3 or higher hematological toxicities were noted as neutropenia (85.7%), anemia (43%), and thrombocytopenia (43%) [59]. In the phase 1 trial for CT071, the grade 3 or higher hematological toxicities included lymphopenia (100%), leukopenia (80%), neutropenia (60%), anemia (50%) and thrombocytopenia (50%) [51]. In patients who received YK-CAR-069, the grade 3 or 4 hematological toxicities manifested as neutropenia (76%), anemia (48%), and thrombocytopenia (38%) [60] (Table