Talquetamab 3mg/1.5ml solution for injection vials

Relapsed and refractory multiple myeloma (RRMM) remains a challenging condition despite advances in immunotherapies. Novel bispecific antibodies (BsAbs), including talquetamab, have shown promising efficacy in heavily pretreated patients, even those with triple- and penta-refractory disease. Talquetamab, recently approved by the FDA and EMA, is indicated for patients who have progressed after at least three or four prior lines of therapy (LOTs). Administered following a step-up dosing phase to manage cytokine release syndrome (CRS), talquetamab demonstrated a high overall response rate (ORR) of approximately 70%, including in patients previously treated with T-cell redirecting therapies. Its safety profile is consistent with other BsAbs, with hematologic adverse events such as anemia and neutropenia commonly reported, alongside unique on-target off-tumor toxicities like dysgeusia and skin-related events. Infections were less frequent compared to other BsAbs. The optimal sequencing of talquetamab and other therapies, including CAR-T cell treatments, remains an area of active research, as resistance to anti-BCMA therapies presents ongoing clinical challenges. Current trials are exploring the use of talquetamab in combination therapies, as well as therapeutic strategies post-treating progression. The real-world data further support talquetamab's efficacy, making it a valuable addition to the RRMM treatment landscape.

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BACKGROUND: Talquetamab is the first GPRC5D × CD3 bispecific antibody approved for relapsed or refractory multiple myeloma. In phase 1 of the MonumenTAL-1 study, initial results of subcutaneous talquetamab 0·4 mg/kg once a week and 0·8 mg/kg every 2 weeks showed preliminary clinical activity. We describe safety and activity results in patients treated with talquetamab, including patients who had received previous T-cell redirection therapy (TCR). This post-hoc analysis was done with more mature median follow-up to evaluate duration of response in patients treated with talquetamab 0·8 mg/kg every 2 weeks. METHODS: MonumenTAL-1 is a multicentre, open-label, phase 1-2 study of talquetamab, phase 1 of which has previously been published. The 0·4 mg/kg once a week and 0·8 mg/kg every 2 weeks recommended subcutaneous doses identified in phase 1 were evaluated in phase 2 in patients who were 18 years of age or older, had at least three previous lines of therapy, had an Eastern Cooperative Oncology Group performance status of 0 to 2, and were naive or exposed to previous TCR. The primary endpoint was overall response rate assessed by independent review committee in all patients who received at least one dose of talquetamab. Safety was assessed in all patients who received at least one dose of talquetamab. This study was registered with ClinicalTrials.gov, NCT03399799 (phase 1) and NCT04634552 (phase 2). FINDINGS: Between Jan 3, 2018, and Feb 20, 2023, 735 patients were screened across all phase 1-2 cohorts. Of these, 537 patients screened for inclusion were treated across phase 1 and 2 cohorts, of whom 198 (27%) patients were excluded from the study, most commonly due to not meeting eligibility criteria or not having measurable disease. As of Oct 11, 2023, 375 patients had received recommended talquetamab doses across three groups: 143 (0·4 mg/kg once a week group) and 154 (0·8 mg/kg every 2 weeks group) TCR-naive patients and 78 with previous TCR who received either recommended dose (previous TCR group). 217 (58%) of 375 patients were male and 158 (42%) were female. 325 (87%) of 375 patients were White and 32 (9%) patients were Black. Median follow-up was 25·6 months (IQR 8·5-25·9) in the 0·4 mg/kg once a week group, 19·4 months (9·2-20·7) in the 0·8 mg/kg every 2 weeks group, and 16·8 months (7·6-18·7) in the previous TCR group. Overall response rate was 74% (106 of 143 patients, 95% CI 66-81) in the 0·4 mg/kg once a week group, 69% (107 of 154 patients, 62-77) in the 0·8 mg/kg every 2 weeks group, and 67% (52 of 78 patients, 55-77) in the previous TCR group. Most common adverse events in the 0·4 mg/kg once a week, 0·8 mg/kg every 2 weeks, and previous TCR groups were cytokine release syndrome (113 [79%] of 143 patients, 115 [75%] of 154 patients, and 57 [73%] of 78 patients), taste changes (103 [72%], 110 [71%], and 59 [76%]), and infections (85 [59%], 105 [68%], and 59 [76%]). Most common grade 3-4 adverse events were neutropenia (44 [31%], 33 [21%], and 37 [47%]), anaemia (45 [31%], 40 [26%], and 21 [27%]), and lymphopenia (37 [26%], 40 [26%], and 13 [17%]). Fatal adverse events occurred in five patients in the 0·4 mg/kg once a week group, seven patients in the 0·8 mg/kg every 2 weeks group, and no patients in the previous TCR group; none were related to treatment. INTERPRETATION: Talquetamab continued to demonstrate high overall response rates in heavily pretreated patients with relapsed or refractory multiple myeloma with longer follow-up in this post-hoc analysis. Overall response rate was promising in patients with previous TCR, including therapies targeting BCMA. On-target, off-tumour adverse events were common but led to few treatment discontinuations. FUNDING: Janssen.

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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, non-rash, 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. Microabstract Talquetamab had a unique pattern of T-cell– and GPRC5D–associated AEs in MonumenTAL-1. Dermatologic toxicities were managed with corticosteroids and emollients, oral AEs with dose modification, and infections per standard of care. Cytokine release syndrome/immune effector cell-associated neurotoxicity syndrome were managed consistent with other T-cell redirection therapies. GPRC5D-associated adverse events may improve or resolve over time. Overall, the safety profile was manageable with minimal discontinuations due to AEs.

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Initial results of the phase I trial of talquetamab, a bispecific antibody targeting GPRC5D and CD3, were reported in December of 2022 for the treatment of relapsed or refractory multiple myeloma in the fourth line or later setting. It demonstrated a similar efficacy profile and durability of response to teclistamab, the first bispecific antibody therapy to be approved in multiple myeloma. Additionally, it has less infections than teclistamab but demonstrates unique class-specific side effects including skin, oral, and nail-related adverse events. Despite this, it is still a highly efficacious and well-tolerated therapy that will add to the armamentarium of therapeutics against heavily pretreated multiple myeloma.

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