[Development and prospects of bispecific antibodies for multiple myeloma].

Patients with triple-class refractory multiple myeloma once had a poor prognosis, but recently developed bispecific antibodies (bsAbs) targeting B-cell maturation antigen (BCMA), G protein-coupled receptor 5D (GPRC5D), and Fc receptor-homolog 5 (FcRH5) have shown significant clinical activity in these patients. However, responses to bsAbs are not universal, and resistance often develops during therapy. Mechanisms that mediate resistance may be tumor-intrinsic or immune-dependent. Tumor-intrinsic factors include antigen loss (biallelic or functional) due to deletion or mutation of target genes, increased soluble BCMA (for BCMA targeting bsAbs), high tumor burden, and extramedullary disease. Immune-mediated resistance highly depends on T cell fitness and the resistant immune environment. This article describes bispecific antibodies against multiple myeloma that are currently being developed.

Matching-adjusted indirect comparison of talquetamab vs selinexor-dexamethasone and vs belantamab mafodotin in patients with relapsed/refractory multiple myeloma.

OBJECTIVE: Talquetamab is the first GPRC5D-targeting bispecific antibody approved for the treatment of triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). This matching-adjusted indirect comparison (MAIC) study was conducted to compare the effectiveness of talquetamab vs selinexor-dexamethasone (sel-dex) and vs belantamab mafodotin (belamaf) in patients with TCE RRMM. METHODS: An unanchored MAIC was performed using individual patient-level data from patients treated with subcutaneous talquetamab 0.4 mg/kg weekly (QW) and 0.8 mg/kg every other week (Q2W) from MonumenTAL-1 (NCT03399799/NCT04636552) and published summary data for sel-dex from STORM (NCT02336815) and belamaf from DREAMM-2 (NCT0325678). Patients from MonumenTAL-1 who met key eligibility criteria for STORM and DREAMM-2 were included. Outcomes of interest were overall response rate (ORR), complete response or better (≥CR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: After adjustment for cross-trial differences, patients treated with both dosing schedules of talquetamab showed significantly better ORR, ≥CR, and DOR vs sel-dex and significantly higher ORR and ≥ CR vs belamaf; DOR was relatively similar to belamaf. PFS was significantly improved with talquetamab Q2W and numerically in favor of talquetamab QW vs sel-dex and significantly improved with both dosing schedules of talquetamab vs belamaf. OS was significantly improved with both dosing schedules of talquetamab vs sel-dex and was numerically in favor of both dosing schedules of talquetamab vs belamaf. CONCLUSION: These analyses show superior effectiveness of both talquetamab dosing schedules vs sel-dex and vs belamaf for most outcomes and highlight talquetamab as an effective treatment option for patients with TCE RRMM.

Talquetamab Versus Real-World Physician's Choice Treatment: Comparative Effectiveness in Patients With Triple-Class Exposed Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Talquetamab is approved for treatment of triple-class exposed (TCE) patients with relapsed/refractory multiple myeloma (RRMM). We evaluated the comparative effectiveness of talquetamab in the MonumenTAL-1 study versus real-world physician's choice (RW) treatment. MATERIALS AND METHODS: An external control arm for MonumenTAL-1 was created from patients in the Flatiron Health database who satisfied MonumenTAL-1 eligibility criteria (n = 629 with 1169 eligible lines of therapy). Patient-level data from MonumenTAL-1 were included for patients who received subcutaneous talquetamab 0.4 mg/kg QW (n = 143) and 0.8 mg/kg Q2W (n = 145). After adjusting for baseline covariate imbalances, comparative effectiveness was assessed for progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). RESULTS: Baseline covariates were comparable across cohorts after adjustment. Talquetamab 0.4 mg/kg QW and 0.8 mg/kg Q2W cohorts, respectively, showed significant improvement in PFS (HR, 0.55 [95% CI, 0.44-0.69; P < .0001; median, 7.5 vs. 4.0 months] and 0.40 [95% CI, 0.31-0.53; P < .0001; median, 14.2 vs. 4.0 months]), TTNT (HR, 0.59 [95% CI, 0.47-0.74; P < .0001; median, 9.1 vs. 5.1 months] and 0.45 [95% CI, 0.35-0.59; P < .0001; median, 13.3 vs. 5.1 months]), and OS (HR, 0.56 [95% CI, 0.40-0.78; P = .0007; median, NR vs. 16.5 months] and 0.48 [95% CI, 0.33-0.70; P = 0.0002; median NR vs. 15.9 months]) versus RW treatment. CONCLUSION: Both talquetamab schedules demonstrated superior effectiveness over RW treatment for all outcomes assessed. These data suggest talquetamab as an effective immunotherapy option in patients with TCE RRMM.

T-cell redirecting bispecific antibody treatment in multiple myeloma: current knowledge and future strategies for sustained T-cell engagement.

INTRODUCTION: T-cell redirecting bispecific antibodies (BsAbs), targeting B-cell maturation antigen (BCMA) or G-protein - coupled receptor class C group 5 member D (GPRC5D), are efficacious new agents for the treatment of patients with relapsed or refractory MM. AREAS COVERED: This review discusses the pharmacokinetic properties, efficacy, and safety profile of T-cell redirecting BsAbs in MM, with a special focus on their optimal dosing schedule, resistance mechanisms and future strategies to enhance efficacy, reduce toxicity, and maximize duration of response. EXPERT OPINION: To further improve the efficacy of BsAbs, ongoing studies are investigating whether combination therapy can enhance depth and duration of response. An important open question is also to what extent response to BsAbs can be improved when these agents are used in earlier lines of therapy. In addition, more evidence is needed on rational de-intensification strategies of BsAb dosing upon achieving a sufficient response, and if (temporary) treatment cessation is possible in patients who have achieved a deep remission (e.g. complete response or minimal residual disease-negative status).

Structural Basis for the Recognition of GPRC5D by Talquetamab, a Bispecific Antibody for Multiple Myeloma.

Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal antibody production from plasma cells. Despite advances in the treatment, many patients experience disease relapse or become refractory to treatment. G-protein-coupled receptor class C group 5 member D (GPRC5D), an orphan GPCR predominantly expressed in MM cells, is emerging as a promising target for MM immunotherapy. Talquetamab, a Food and Drug Administration-approved T-cell-directing bispecific antibody developed for treatment of MM, targets GPRC5D. Here, we elucidate the structure of GPRC5D complexed with the Fab fragment of talquetamab, using cryo-electron microscopy, providing the basis for recognition of GPRC5D by the bispecific antibody. GPRC5D forms a symmetric homodimer with the interface between transmembrane helix (TM) 4 of one protomer and TM4/5 of the other protomer. A single talquetamab Fab interacts with the GPRC5D dimer with its orientation toward the dimer interface. All six complementarity-determining regions of talquetamab engage with extracellular loops and TM3/5/7. In particular, the side-chain of an arginine residue from the antibody penetrates into a shallow pocket on the extracellular surface of GPRC5D. The structure offers insights for optimizing antibody design against GPRC5D for relapsed or refractory MM therapy.

Fast and furious: Changing gears on the road to cure with chimeric antigen receptor T cells in multiple myeloma.

Based on the pivotal KarMMa-1 and CARTITUDE-1 studies, Idecabtagene vicleucel (Ide-cel) and Ciltacabtagene autoleucel (Cilta-cel) have been approved to treat multiple myeloma patients, who have been exposed to at least 1 proteasome inhibitor, immunomodulatory drug and anti-CD38 antibody after 4 or 3 lines of therapy, respectively. The unprecedented rates of deep and long-lasting remissions have been meanwhile confirmed in multiple real-world analyses and more recently, the KarMMa-3 and CARTITUDE-4 studies lead to the approval in earlier lines of therapy. It is currently believed that ultimately all patients with relapsed/refractory multiple myeloma experience relapse after anti-BCMA CAR T-cell therapies. There is a plethora of CAR T-cell therapies targeting novel antigens, with the aim to overcome current CAR T-cell resistance. In this review, we will summarize current evidence of novel antigens and their clinical potential. Together with current CAR T-cell therapy and T-cell engagers, these approaches might lead us to the next frontier in multiple myeloma: total immunotherapy and the road to chemotherapy-free cure.

Clinical Management of Patients With Relapsed/Refractory Multiple Myeloma Treated With Talquetamab.

BACKGROUND: Talquetamab is a bispecific antibody targeting the multiple myeloma-associated antigen G protein-coupled receptor family C group 5 member D (GPRC5D). In the phase 1/2 MonumenTAL-1 trial (NCT03399799/NCT04634552), overall responses rates were > 71% in patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM). Due to the distribution of the target antigen, a unique pattern of GPRC5D-associated adverse events (AEs) was observed, together with T-cell redirection-associated AEs. Management strategies for talquetamab-associated AEs are described. DISCUSSION: GPRC5D-associated AEs included dermatologic (rash, nonrash, and nail toxicities) and oral AEs (dysgeusia, dysphagia, and dry mouth). The incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were consistent with other T-cell redirection therapies. The incidence of high-grade infections was lower than observed with B-cell maturation antigen-targeting bispecific antibodies, with less frequent use of intravenous immunoglobulin required. GPRC5D-associated AEs were mostly low grade and led to few discontinuations. Skin toxicities were managed with emollients, topical corticosteroids, and oral corticosteroids (for high-grade, persistent, or AEs that progress). Nail toxicities were commonly managed with emollients. Based on investigator experience, dose modification may be effective for controlling oral events. Observation for potential weight changes is required. Infections were managed per standard of care. CRS and ICANS were effectively managed, consistent with other trials of T-cell redirection therapies. CONCLUSION: Although talquetamab had a distinct safety profile, AEs were considered clinically manageable and mostly low grade. With appropriate education and support, health care practitioners can ensure patients with RRMM maintain quality of life and treatment adherence. VIDEO ABSTRACT.

B-cell maturation antigen-based therapies post-talquetamab in relapsed or refractory multiple myeloma.

Talquetamab recently received approval for relapsed refractory multiple myeloma. However, there is currently no available data on how patients perform with BCMA based agents after progression on talquetamab. Herein, we present the outcome of 10 patients who received BCMA based therapies following talquetamab. The median follow-up was 9.5 months (range: 6-24 months). The median progression free survival was 5.5 months (range: 1-10 months). Patients had varying grades of cytokine release syndrome and Immune effector cell-associated neurotoxicity syndrome. Our results suggest that treatment with talquetamab followed by BCMA based therapies is feasible and can be considered as clinically indicated.

Timing antigenic escape in multiple myeloma treated with T-cell redirecting immunotherapies.

Recent data highlight genomic events driving antigen escape as a recurring cause of chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engager (TCE) resistance in multiple myeloma (MM). Yet, it remains unclear if these events, leading to clonal dominance at progression, result from acquisition under treatment selection or selection of pre-existing undetectable clones. This differentiation gains importance as these immunotherapies progress to earlier lines of treatment, prompting the need for innovative diagnostic testing to detect these events early on. By reconstructing phylogenetic trees and exploring chemotherapy mutational signatures as temporal barcodes in 11 relapsed refractory MM patients with available whole genome sequencing data before and after CART/TCE treatment, we demonstrated that somatic antigen escape mechanisms for BCMA- and GPRC5D-targeting therapies are acquired post-diagnosis, likely during CART/TCE treatment. Longitudinal tracking of these mutations using digital PCR in 4 patients consistently showed that genomic events promoting antigen escape were not detectable during the initial months of therapy but began to emerge nearly 1 year post therapy initiation. This finding reduces the necessity for a diagnostic panel to identify these events before CART/TCE. Instead, it underscores the importance of surveillance and identifying patients at higher risk of acquiring these events.

Targeting GPRC5D in multiple myeloma.

INTRODUCTION: The prognosis of multiple myeloma (MM) continues to improve. Recent progress in therapies, using immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies, has greatly improved patients' outcomes. Despite these advancements, relapses still happen often, and patients can become resistant to the usual treatments. Newer treatments, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA), have resulted in excellent outcomes in patients with limited treatment options. G protein - coupled receptor, class C group 5 member D (GPRC5D) is considered a very promising target with early results from clinical trials showing high response rates in patients with relapsed or refractory multiple myeloma. AREAS COVERED: This review covers the efficacy and safety of CAR-T and BsAbs targeting GPRC5D in MM, focusing on talquetamab - the inaugural FDA-approved BsAb targeting GPRC5D. Talquetamab has exhibited promising response rates alongside a distinctive side effect profile. Additionally, ongoing trials examining talquetamab in combination with agents like daratumumab and teclistamab are discussed. EXPERT OPINION: We offer insights into the potential utilization of various GPRC5D-based therapies in the treatment paradigm for MM, either independently or in combination with established therapies.

Long noncoding RNA GPRC5D-AS1 in renal cell carcinoma: a molecular mechanism study.

Background: Clear cell renal cell carcinoma (RCC) is the most common subtype of RCC. Although targeted therapy can provide superior treatment outcomes, it is prone to drug resistance, and individual responses to immunotherapy vary greatly. Therefore, finding new diagnostic and therapeutic targets for RCC is of considerable importance. Long noncoding RNA (lncRNA) GPRC5D-AS1 can serve as a biomarker in clinical applications and the prognosis of lung squamous cell carcinoma. However, the specific mechanism of action of lncRNA GPRC5D-AS1 in RCC has not yet been clarified. Therefore, this paper explores the expression of lncRNA GPRC5D-AS1 in the renal cancer cell line 786-0, and conducts a preliminary study of its molecular mechanism. Selecting nude mice for tumor experiments is because of the high genomic and physiological similarity between mice and humans. Conducting tumor research on mice allows for better control of experimental conditions, aiding researchers in more accurately observing and analysing tumor characteristics and responses. Methods: Small interfering RNA (siRNA) and plasmid cloning DNA (pcDNA) 3.1 were used to transfect renal cancer cell line 786-0 to silence and overexpress the lncRNA GPRC5D-AS1 gene. Quantitative real-time fluorescence polymerase chain reaction was used to detect the difference in lncRNA GPRC5D-AS1 expression in blank control group, negative control group, siGPRC5D-AS1 group and oeGPRC5D-AS1 group. The effects of silence and overexpression of lncRNA GPRC5D-AS11 on the proliferation of 786-0 cells were detected in cell colony formation experiments; the changes in the migration and invasion of 786-0 cells were detected via cell scratch assay and transwell assay, respectively; the differences in tumor growth between groups were determined via tumorigenesis experiments in nude mice; and the expression of proliferation-related protein [ß-catenin, Ki67 and proliferating cell nuclear antigen (PCNA)] and invasion-related protein (N-cadherin and E-cadherin) were detected via Western blotting. Results: Compared with blank control group and negative control group, the siGPRC5D-AS1 group showed a significant decrease in the relative expression of lncRNA GPRC5D-AS1 (P<0.05), a significant increase in the number of proliferating cells and migrating cells (P<0.05), a significant increase in the tumor volume of nude mice (P<0.05), a significant increase in ß-catenin, Ki67, PCNA and N-cadherin protein expression (P<0.05), and a significant decrease in E-cadherin protein expression (P<0.05); conversely, these results were opposite for the eGPRC5D-AS1 group. Conclusions: Silencing the expression of lncRNA GPRC5D-AS1 can enhance the proliferation, invasion, and migration ability of renal cancer cell line 786-0, which can be weakened by the overexpression of lncRNA GPRC5D-AS1.

Quad-class exposed/refractory myeloma is associated with short survival.

Very scarce data exist about outcomes of relapsed multiple myeloma patients who have failed proteasome inhibitor, immunomodulatory drug, anti-CD38 monoclonal antibody and therapies targeting B-cell maturation antigen (BCMA) (Quad-class exposed [QCE]). In this retrospective single-centre study, we determined progression-free survival (PFS) and overall survival (OS) from anti-BCMA failure in 45 QCE patients. Seven (16%) patients received antibody-drug conjugate, 20 (44%) bispecific antibodies and 18 (40%) CAR-T cell. Thirty patients (67%) received ≥1 subsequent line of treatment. PFS was 4.4 months (95% CI = 2.4-12.5) and OS 6.3 months (95% CI = 3.9-14.4). Having an adverse prognosis, QCE myeloma patients remain an unmet medical need.

lncRNA GPRC5D-AS1 as a ceRNA inhibits skeletal muscle aging by regulating miR-520d-5p.

Sarcopenia induced by muscle aging is associated with negative outcomes in a variety of diseases. Long non-coding RNAs are a class of RNAs longer than 200 nucleotides with lower protein coding potential. An increasing number of studies have shown that lncRNAs play a vital role in skeletal muscle development. According to our previous research, lncRNA GPRC5D-AS1 is selected in the present study as the target gene to further study its effect on skeletal muscle aging in a dexamethasone-induced human muscle atrophy cell model. As a result, GPRC5D-AS1 functions as a ceRNA of miR-520d-5p to repress cell apoptosis and regulate the expression of muscle regulatory factors, including MyoD, MyoG, Mef2c and Myf5, thus accelerating myoblast proliferation and differentiation, facilitating development of skeletal muscle. In conclusion, lncRNA GPRC5D-AS1 could be a novel therapeutic target for treating sarcopenia.

BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma.

At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to MM has become a priority. Independently of BCMA expression, G-protein-coupled receptor family C group 5 member D (GPRC5D) is mainly expressed in the plasma cells of MM patients, while it is expressed in a limited number of normal tissues. Combining MM-specific antigen GPRC5D and T-cell-mediated therapies would be a promising therapeutic strategy for MM. Recently, we constructed a new anti-GPRC5D × anti-CD3 T-cell-engaging bispecific antibody (TCB), BR109, which was capable of binding to human GPRC5D and human CD3ε. Moreover, BR109 was proven to have relatively good stability and antitumor activity. BR109 could specifically trigger T-cell-mediated cytotoxicity against many GPRC5D-positive MM cells in vitro. Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials.

Beyond BCMA, why GPRC5D could be the right way: treatment strategies with immunotherapy at relapse after anti-BCMA agents.

Multiple Myeloma remains incurable, and there is a need for therapies with novel mechanisms of action. Recently, B cell maturation antigen targeted therapy has demonstrated deep and durable responses in a largely treated population. However, the relapse rate of myeloma patients after anti-BCMA treatment strategies is increasing worldwide, and one of the most challenging issues for them is to choose the best therapy sequencing. After anti-BCMA treatment, retreatment with anti-BCMA drugs remains an option, but new targets are emerging strongly. One of them is G protein-coupled receptor, class C group 5 member D (GPRC5D), that due to the very promising data from the use of chimeric antigen receptor T-cells (CAR-T) and bispecific antibodies (BsAb) seems to be the ideal candidate in the relay of myeloma treatment at relapse. In this literature review, we discuss data from treatment with the new drugs at relapse after anti-BCMA therapies, observing an undeniable benefit from the use of drugs directed against GPRC5D.

Bispecific antibodies targeting BCMA, GPRC5D, and FcRH5 for multiple myeloma therapy: latest updates from ASCO 2023 Annual Meeting.

Several bispecific antibodies (bsAbs) targeting BCMA, GPRC5D, and FcRH5 are in clinical trials for heavily pretreated multiple myeloma (MM) patients. Teclistamab was approved for relapsed/refractory MM therapy in 2022, while elranatamab, linvoseltamab, F182112, talquetamab, and cevostamab are currently undergoing clinical trials. This study summarizes several latest reports on bsAbs for the treatment of MM from the ASCO 2023 Annual Meeting.

Chimeric Antigen Receptor T Cells in Multiple Myeloma.

Multiple myeloma is the second most common hematological malignancy with an approximate incidence of up to 8.5 cases per 100,000 persons per year. Over the last decade, therapy for multiple myeloma has undergone a revolutionary change. Chimeric antigen receptor (CAR) T-cell therapy has played a major role in this evolution. In this review, we discuss the existing state of CAR T-cell therapy in myeloma while evaluating several newer therapies and targets expected in the near future.