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Emerging Bispecific T-Cell Engagers in Myeloma: Promises and Hurdles
Key Takeaways
- TCEs, targeting BCMA and GPRC5D, have shown efficacy in heavily pretreated RRMM patients, with response rates between 60% and 70%.
- Ongoing trials are exploring TCE combinations and novel agents to enhance efficacy and overcome resistance in MM treatment.
The multiple myeloma landscape is evolving, with bispecific T-cell engagers offering hope.
The treatment landscape for multiple myeloma (MM) has rapidly evolved. Early use of monoclonal antibodies such as daratumumab (Darzalex; Janssen Biotech, Inc) combined with proteasome inhibitors (PIs) and immunomodulators (IMiDS) has led to significant improvements in survival and patient outcomes; however, these advancements present a new dilemma when the disease inevitably relapses. To address this, therapies that harness the power of immune T-cells, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers (TCEs), are emerging as game-changers for relapsed/refractory (RRMM) patients and potentially in earlier stages of MM with their ability to deliver deep and durable responses with a predictable safety profile.1 This article explores the current use and challenges of these agents while also delving into upcoming developments as they transform the MM treatment paradigm.
Visualization of bispecific antibodies | Image Credit: © huenstructurebio.com - stock.adobe.com
Approved Bispecific T-cell Engagers
TCEs in MM involve the binding of 2 specific targets: B-cell maturation antigen (BCMA) or G protein-coupled receptor family C group 5 member D (GPRC5D) on MM cells; and CD3 receptors on T-cells facilitating the recruitment and activation of these cells that lead to targeted tumor cell elimination. Since 2022, the FDA has approved 3 bispecific TCEs—teclistamab (Tecvayli; Janssen Biotech, Inc), elranatamab-bcmm (Elrexfio; Pfizer Medical Information), and talquetamab (Talvey; Janssen Biotech, Inc)—for the treatment of heavily pretreated RRMM.2-4 Teclistamab, elranatamab, and talquetamab were approved based on respective findings in MajesTEC-1 (NCT04557098), MagnestisMM-3 (NCT04649359), and MonumenTAL-1 (NCT03399799). 5-7 Each study evaluated patients who had received greater than or equal to 3 prior lines of therapy (including a PI, an IMiD, and an anti-CD38 antibody) and demonstrated comparable efficacy with response rates between 60% and 70% and a median progression free survival (PFS) of approximately 1 year.8-10
Common class-wide adverse events (AEs) associated with TCEs included cytokine release syndrome (CRS), cytopenia, and infections. Specific toxicities such as nail disorders, dysgeusia, weight loss, and rash were noted with talquetamab due to its GPRC5D-targeting mechanism. TCEs are also easily accessible as off-the-shelf treatments for patients whose disease progresses too rapidly for CAR-T-cell manufacturing. Nevertheless, while these therapies have substantially improved patient outcomes, MM remains an incurable disease with a 5-year survival rate of 61%; this highlights an ongoing need for innovation in therapeutic strategies to further improve MM patient outcomes and quality of life.8-11
New Horizons: Ongoing trials
The future of TCEs in MM holds great promise as these therapies continue to evolve. Moving forward, research is focused on optimizing the use of these regimens by integrating them earlier in patient’s disease course, including in newly diagnosed patients, or by combining them with other agents to enhance their efficacy. Findings from the MajesTEC-1 study showed that patients who responded clinically to teclistamab had higher baseline T-cell counts, a greater proportion of naïve CD8+ T-cells, and a lower proportion of regulatory T-cells compared to non-responders. These results suggest that administering TCEs at earlier stages of the disease—when treatment-induced T-cell exhaustion and immune suppression are likely to be less severe—may lead to better outcomes.12 Furthermore, ongoing development of other TCEs such as those targeting fragment crystallizable receptor-like 5 (FcRH5), is expanding the potential for more targeted treatments.12
The RedirecTT-1 trial (NCT04586426) explored combining talquetamab and teclistamab in triple refractory patients to enhance efficacy and to overcome resistant mechanisms that may limit their use as monotherapies. While teclistamab targets BCMA and talquetamab targets GPRC5D, both TCEs engage CD3 on T-cells to redirect them to kill MM cells.2-3 The rationale for combining these agents is based on their complementary mechanisms of action and the potential to address common resistant mechanisms to TCEs such as tumor heterogeneity or antigen escape.13 The RedirecTT-1 trial (n = 165) reported an overall response rate (ORR) of 80%, very good partial response (VGPR) of 77%, and 52% complete response (CR) or better (greater than or CR) at the recommended phase 2 doses with a median follow-up of 20.3 months. The study also revealed a manageable safety profile consistent with known AEs (i.e. CRS, infection, etc.), albeit at a higher rate compared to monotherapies. The high response rates suggest that incorporating both agents can lead to deeper and more durable responses compared to monotherapies. Additionally, the synergistic effects of dual-antigen targeting not only improved response but may have helped mitigate the risk of T-cell exhaustion and thereby prolong T-cell activation. This was demonstrated by the high response rates seen in patients with high-risk features (76%) and extramedullary disease (61%), both of which traditionally confer poor prognosis.13
As previously mentioned, one of the proposed mechanisms of resistance to TCEs is suboptimal T-cell fitness, as several studies have observed more exhausted T-cells, more regulatory T-cells, greater expression of inhibitive checkpoint molecules, fewer effector T-cells, and weaker clonal expansion in non-responders.12,14 Since IMiDs have shown to enhance T-cell cytotoxicity by impeding with regulatory T-cell proliferation and inducing cytokine production that is necessary for clonal expansion, a few current clinical trials are underway to see if there are synergistic effects when combining a TCE with pomalidomide.
In MonumenTAL-2 (NCT05050097), RRMM patients with greater than or equal to 2 prior lines of therapy (n = 35) received talquetamab and pomalidomide (Pomalyst;Bristol Myers Squibb; Tal-P).15 Response rates in both cohorts exceeded that of TCE monotherapies with ORR, VGPR, and greater than or equal to CR of 86.7%, 86.7%, and 60% in the weekly subgroup and 83.3%, 77.8%, and 44.4% in the biweekly subgroup, all respectively. Importantly, ORR remained above 80% in patients with prior IMiD or CAR-T exposure. Six-month PFS were 93.3% and 88.9%, respectively, in the weekly and biweekly cohorts, and median DOR and PFS were not reached in either group. Most common AEs were dysgeusia (77.1%), CRS (74.3%), infections (71.4%; grade 3/4, 22.9%), nail toxicities (65.7%), neutropenia (60%), and skin toxicities (40%).
Additionally, 2 studies evaluating the combination of teclistamab, daratumumab, and pomalidomide (tec-DP) reported initial aggregate results at the 2024 ASH Annual Meeting.16 Patients (n = 27) with RRMM who had 1 to 3 prior lines (MajesTEC-2 cohort A) or greater than or equal to 3 prior lines of therapy (TRIMM-2) received tec-DP. At a median follow up of 25.8 months, most patients responded to treatment with an ORR of 88.5%, VGPR of 84.6%, and greater than or equal to CR of 61.5%. The median time to first response was 0.95 months, median PFS was 26.5 months, and median duration of response (DOR) was not reached. Most common AEs were infections (92.6%; grade 3/4, 63%), neutropenia (77.8%), cough (59.3%), and CRS (55.6%). Fatal infections occurred in 6 patients, all of which occurred prior to the implementation of intravenous immunoglobulin (IVIG) supplementation and an intensified antimicrobial prophylaxis regimen. Results from Tal-P and Tec-DP studies demonstrated that TCE/IMiD regimens—such as the combination of teclistamab and talquetamab—yielded better efficacy outcomes at the cost of higher incidence of adverse effects.
Pipeline Regimens
Linvoseltamab (Regeneron Pharmaceuticals), a BCMA-CD3 TCE, has demonstrated promising efficacy in the LINKER-MM1 trial with an ORR of 71%, greater than or equal to CR of 50%, and median DOR at 29.4 months, indicating deep and durable responses.17 Based on favorable data, linvoseltamab is currently under priority review by the FDA for use in patients who have failed greater than or equal to 3 prior lines of therapy. A decision is expected by early July 2025.
ABBV-383 (TNB-383B; AbbVie and TeneoOne) is another BCMA-CD3 TCE with a lower binding affinity to CD3, which reduces the risk of T-cell exhaustion and need for step-up dosing. Findings showed an ORR of 65% and greater than or equal to VGPR of 50%, alongside a lower incidence of CRS that allowed for a tapered premedication schedule and shortened CRS monitoring period.18-20
Other pipeline agents include cevostamab (Genentech), an IgG1-based TCE designed to target FcRH5 on MM cells and CD3 on T-cells. Given the promising initial results shown in the CAMMA-1 trial (NCT04910568) with an ORR of 56.7% in RRMM patients, cevostamab is currently being explored in combination with other MM agents such as pomalidomide and daratumumab.21 In additiona, cevostamab is also being evaluated in patients who had prior anti-BCMA exposure as optimal sequencing continues to be elusive in the RRMM setting.22 Finally, CAMMA-3 trial is investigating a subcutaneous formulation of cevostamab, which may offer advantages such as ease of administration, reduced chair time, and potentially improve CRS rates due to slower absorption.23
Forimtamig (RG6234; F. Hoffmann-La Roche) is a novel TCE with 2 GPRC5D-binding domains, which enable a stronger binding affinity for MM cells. Monotherapies and combinations involving forimtamig with standard of care agents such as anti-CD38 antibodies, IMiDs, and PIs have shown improved depth and DOR.24-25 These investigational agents represent significant advancements in the treatment of RRMM, offering new therapeutic options for heavily pretreated patients. These ongoing trials will further elucidate their efficacy and safety profiles.
Challenges and Supportive Care Strategies
Despite their clinical benefits, TCEs are expensive with many insurance providers imposing strict reimbursement criteria, requiring prior authorization and evidence of clinical necessity before approving coverage. Insurance policies vary widely, with some payers categorizing TCEs as investigational or non-essential while others restrict where TCEs can be administered, favoring outpatient or community infusion centers over specialized hospital settings. This can be problematic as TCEs require close monitoring of toxicities such as CRS, especially during the step-up phase, where inpatient monitoring is often recommended. Additionally, the management of TCE-related toxicities often involves the use of expensive supportive care medications, which can further add to the financial and logistical barriers that patients and the care team may face.
Hypogammaglobulinemia, an expected AE with TCEs in MM due to the abundant expression of BCMA and GPRC5D epitopes in plasma cells, was reported in over 70% of patients in each of the landmark TCE trials.11-13 Although immunoglobulin replenishment with IVIG is now standard of care and usually covered by insurance, we are observing more scenarios where payers would only pay for IVIG as specialty dispenses (“white bagging”) and/or at non-hospital-or-clinic associated infusion centers. This practice requires the product to be dispensed by a third-party specialty pharmacy rather than a hospital or outpatient clinic, even if the same drug is readily available. It differs from the usual buy-and-bill model where providers purchase and store medications and are reimbursed after administration.26 Although the “white bagging” policy is intended to control costs, this creates a lag time between when a patient’s IgG level falls below 400 mg per dL and when they can receive IVIG infusion, as well as diverting staff from clinical duties to help patients locate eligible centers.27-28 Furthermore, if a patient switches treatment or is hospitalized before receiving the shipped medication, the provider cannot reallocate either drug, leading to unnecessary waste.
As T-cell activation and subsequent clonal expansion are integral to TCE mechanism, CRS is another expected AE of bispecific therapy, occurring in 58% of patients who received elranatamab (Elrexfio; Pfizer Medical) and over 70% of those who received teclistamab or talquetamab.8-10 Tocilizumab (Actemra; Genentech), an IL-6 antibody often used in CRS management, is increasingly studied in the prophylactic setting. After tocilizumab 8 mg per kg was given 1 to 4 hours prior to the first or second teclistamab ramp-up dose, CRS rate significantly decreased to 10.3% to 26.3% across several retrospective, single-center experiences and a cohort of the prospective MajesTEC-1 trial while maintaining similar efficacy.29-34 More recently, the University of Miami group updated their results to include patients treated with talquetamab and elranatamab, which continued to show much lower CRS rate when given with tocilizumab.31 Based on these data, prophylactic tocilizumab before teclistamab recently received an NCCN category 2A recommendation, which allows for its use in Medicare patients, and we are starting to see approvals from commercial payers as well for use before any of the 3 FDA-approved MM TCEs.1
Conclusion
Since the approval of teclistamab less than 3 years ago, TCEs have become a mainstay in the RRMM treatment paradigm given their efficacy in heavily pretreated patients. As TCE combination regimens continue to demonstrate superior efficacy outcomes but more AEs, it is especially pertinent for oncology pharmacists to stay up to date not only on new drugs or combinations on the horizon but also new challenges to optimal care and innovative supportive care strategies to combat them.
