Bispecific antibodies (BsAbs) like teclistamab (tec) and talquetamab (tal) have been a breakthrough for triple-class refractory multiple myeloma (MM), achieving overall response rates (ORRs) of 60% to 70% — a stark contrast to the 20% to 30% seen prior to T-cell redirection.1,2 Moreover, because tec and tal target distinct MM antigens (B-cell maturation antigen [BCMA] and G protein-coupled receptor, class C, group 5, member D [GPRC5D], respectively), they can still elicit a response even when the other has failed. Unfortunately, recent studies have highlighted a marked decrease in durability of those responses in patients previously exposed to another BsAb, even when the target antigen is changed. Possibly due to T-cell exhaustion, the diminishing returns with each successive BsAb have tempered enthusiasm for administering a BsAb as a monotherapy after failure of another BsAb. There is now interest in combination strategies for maximizing progression-free survival (PFS) with BsAbs, with the phase Ib/II RedirecTT-1 study posing an obvious question: Are tec and tal better together?
Although the question was an obvious one, the answer was not. Tec and tal each come with significant overlapping toxicities. Hypogammaglobulinemia, neutropenia, and infections are most pronounced with tec but can occur with both. There are also concerns about exhausting two key treatment options simultaneously and the negative impact on future chimeric antigen receptor (CAR) T-cell therapy targeting the same antigens. For example, ciltacabtagene autoleucel’s 35-month PFS drops to nine months in BCMA-exposed patients.3 Conversely, targeting BCMA and GPRC5D simultaneously could better address the intratumoral heterogeneity at play in relapsed/refractory MM (RRMM) while hindering the outgrowth of subclones resistant to either BCMA- or GPRC5D-targeted therapies, as reported with BsAb monotherapy.
In the phase I dose escalation portion of RedirecTT-1, 116 patients were screened between December 9, 2020, and April 26, 2023, overlapping with the COVID-19 pandemic.4 A total of 94 patients were treated with tec and tal, with 44 receiving the recommended phase II dose (RP2D) of tal 0.8 mg/kg every two weeks (an approved monotherapy dose schedule) plus tec 3.0 mg/kg every two weeks (as compared to the monotherapy dose of 1.5 mg/kg weekly). For all doses, both agents were administered on the same day, approximately 30 minutes apart. Median follow-up was 20.3 months (range, 0.5 to 37.1 months). Patients had a median age of 64.5 years, with a median of four prior lines of therapy, and 86% of patients were triple-class refractory, 36% had extramedullary disease (EMD), 41% had high-risk cytogenetics, 7% had prior BsAb, and 4% had prior CAR T cells.
Three patients experienced dose-limiting toxicities: grade 3 oral herpes (at the tal 0.2 mg/kg plus tec 0.75 mg/kg weekly dose level); grade 3 transaminitis (at the tal 0.4 mg/kg plus tec 1.5 mg/kg weekly dose level); and grade 4 thrombocytopenia at the RP2D. Grade 3 or 4 adverse events (AEs) occurred in 90 patients (96%), with frequent grade 3 or greater AEs including neutropenia (68%), anemia (38%), thrombocytopenia (30%), pneumonia (20%), and COVID-19 (18%). Cytokine release syndrome occurred in 79% of patients (grade 3, 2%), while immune effector cell-associated neurotoxicity syndrome occurred in three patients (3%), with just one grade 3 event reported. Frequently observed low-grade toxicities included taste changes (65%), rash (39%), and nail-related AEs (52%).
Of greatest note, infections occurred in 89% of patients, with 64% experiencing grade 3 or 4 infections. The most common infections were COVID-19 (40.4%; grade ≥3, 18.1%); pneumonia (36.2%; grade ≥3, 20.2%); and upper respiratory tract infections (24.5%; grade ≥3, 3.2%). As a result, the regimen proved difficult to tolerate, with 93% of patients experiencing cycle delays or dose modifications due to AEs (most commonly due to infections [68%]), and one or both agents discontinued due to AEs in 16% of patients. Additionally, 15% of patients died due to AEs (12% from infections). Supportive care practices evolved during the study, with 49% of patients receiving Pneumocystis jiroveci pneumonia prophylaxis and 57% of patients with non-immunoglobulin G myeloma receiving intravenous immunoglobulin replacement therapy.
The combination did, however, generate high response rates, with an overall response rate (ORR) of 80% (77% ≥ very good partial response, ≥52% complete response) at the RP2D (n=44), with a median time to response of 1.4 months. Response rates remained high among high-risk subgroups, including International Staging System stage 3 (7 of 8 patients [88%]); high-risk cytogenetics (6 of 8 patients [75%]); and bone-independent EMD (11 of 18 patients [61%]).
Crucially, the responses were durable. At the RP2D, the likelihood of ongoing response at 12 and 18 months was 91% and 86%, respectively, while among patients with EMD (n=18), the likelihood was 82% at both 12 and 18 months. Estimated PFS at the RP2D at 12 and 18 months was 74% and 70% overall, while among patients with EMD, PFS was 53% at both time points.
In Brief
A number of important lessons can be gleaned from the results of RedirecTT-1. First of all, the responses with the combination of tec plus tal were highly durable, and from an efficacy perspective the combination could certainly surpass tec monotherapy followed by tal monotherapy. Acknowledging the limitations of cross-trial comparisons, the 86% 18-month PFS of tec plus tal compares favorably to a sequential tec followed by tal approach; tec monotherapy generated an 11.3-month median PFS in BsAb-naive RRMM, while tal monotherapy in BsAb-exposed patients resulted in only a 58% ORR and 4.1-month PFS.1,5 Finally, although only 18 EMD patients were treated, the 53% estimated 18-month PFS among this high-risk subgroup is encouraging.
Unfortunately, the concerning number of AE-related deaths, as well as the cost of co-administering two BsAbs, makes this combination unlikely to be widely employed among RRMM patients, reminding us once more that a PFS must come secondary to overall survival (OS). Tec plus tal may still find use among high-risk subgroups such as patients with EMD, particularly given the challenge of attrition (patients may not live to receive multiple salvage regimens). Currently, no phase III RCT with tec and tal is planned. Instead, focus is shifting to BCMAxGPRC5DxCD3 trispecific antibodies, designed for greater affinity towards BCMA and GPRC5D co-expressing myeloma cells than normal cells, potentially providing a wider therapeutic window. Where the tec and tal combination fell short, trispecific antibodies may succeed in delivering durable responses with fewer off-tumor toxicities.
However, concurrent dual-antigen targeting must also be compared head to head with a sequential approach (from a PFS, PFS2, and OS perspective) with novel combinations (e.g., tal with concurrent CD38 monoclonal antibodies has shown durable responses, even in patients with prior BCMA BsAb therapy).6 Finally, addressing relapse after BCMA- and GPRC5D-directed BsAbs is becoming a pressing clinical challenge, given the emergence of both tumor-intrinsic (reduced target expression) and tumor-extrinsic (T-cell exhaustion) resistance mechanisms.
Disclosure Statement
Dr. Pan has received honoraria from Sanofi. Dr. Kumar indicated no relevant conflicts of interest. Dr. Lipof has received honoraria from Sanofi and has served on the advisory board of AstraZeneca. Dr. Chung has received research funding from AbbVie, Bristol Myers Squibb, Caelum Biosciences, CARsgen Therapeutics, Cellectis, Johnson & Johnson, K36 Therapeutics, and Merck and has served on the advisory boards of Bristol Myers Squibb and Johnson & Johnson. Dr. Chari has received grant/research support from Janssen and has served as a consultant and/or advisor for Abbvie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genetech/Roche, GlaxoSmithKline, Janssen, Karyopharm, Millenium/Takeda, and Sanofi/Genzyme.
