The evolution of bispecific antibodies in multiple myeloma

Introduction

The treatment landscape of multiple myeloma (MM) has significantly shifted in recent decades with the emergence of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), as well as the incorporation of autologous stem cell transplant in eligible patients (1-4). By the same token, in the last ten years, daratumumab, a monoclonal antibody directed against CD38, has emerged as a game changer in the treatment of MM, both for transplant eligible and non-eligible patients. The integration of daratumumab has truly reshaped the standard of care in MM with the first-line treatment in transplant-eligible patients being the combination of daratumumab, bortezomib lenalidomide, and dexamethasone (D-VRD), based on the GRIFFIN phase II trial and the PERSEUS phase III trial (5,6). Daratumumab was also approved as first-line treatment in transplant-ineligible patients in combination with, lenalidomide, and dexamethasone (DRD), bortezomib, melphalan and prednisone (VMP), or VRD (7-9). Isatuximab is another monoclonal antibody anti-CD38 that also shown activity in patients with newly diagnosed MM eligible to transplantation or transplant-ineligible patients (10,11).

Nonetheless, despite the considerable advances in the treatment of MM, there still exists an unmet need for patients with relapsed and/or refractory (R/R) disease. With successive lines of therapy, this patient population suffers from dismal clinical outcomes due to their poor performance status and decreased durability of response (12,13). More specifically, patients who are penta-refractory (meaning that they have already received two IMiDs, two PIs, and an anti-CD38 monoclonal antibody) have been shown to have very poor outcomes with a median overall survival (OS) of less than 6 months (14). Given that MM is currently an incurable disease, resistance mechanisms to treatment eventually emerge, causing a 5-year OS of only 50%. Recent advances in the last decade have been developed to overcome this obstacle; this includes the development of chimeric antigen receptor (CAR)-T cell therapy, antibody drug conjugates (ADCs), and aftermost, bispecific antibodies (BiAbs).

Belantamab mafodotin, a B-cell maturation antigen (BCMA)—directed ADC, was considered as a breakthrough therapy for patients with R/R MM. Its efficacy and safety were investigated in the pivotal DREAMM-2 trial which was a phase II trial evaluating patients with R/R MM with disease progression after three or more lines of treatment. Belantamab mafodotin was approved by the U.S. Food and Drug Administration (FDA) in August 2020 based on this trial, which confirmed the anti-tumor activity of this drug, showing an overall response rate (ORR) of approximately 31%, a median duration of response (DOR) of 11.0 months, and a median progression-free survival (PFS) of 13.7 months (15,16). Belantamab mafodotin was also evaluated in combination with pomalidomide plus dexamethasone compared to bortezomib and pomalidomide plus dexamethasone in the DREAMM-8 phase III trial. The study met its primary endpoint of PFS with a hazard ratio (HR) for disease progression or death of 0.52 (P<0.001) (17). Belantamab mafodotin in combination with bortezomib and dexamethasone was compared in a head-to-head phase III trial with daratumumab with bortezomib and dexamethasone in the DREAMM-7 trial. The trial also met its primary endpoint of PFS with a median PFS of 36.6 months in the belantamab mafodotin arm versus 13.4 months in the daratumumab arm (HR, 0.41; P<0.001) (18).

Moreover, two BCMA-directed CAR-T cell treatments got approved, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), in March 2021 and February 2022, respectively. Ide-cel has shown clinical activity with an ORR of more than 50% and a median DOR of 10.7 months in the KarMMa trial (19). As for cilta-cel, the CARTITUDE-1 trial proved its efficacy showing an impressive ORR of approximately 97% (20).

The enthusiasm caused by the clinical success of anti-BCMA targeted therapy prompted further clinical development of novel BCMA-directed agents at a fast-moving pace, some of which are BiAbs. We review in this paper the most studied BiAbs, their mechanism of action, clinical activity and discuss their place in the therapeutic arsenal of MM.

Structure and mechanism of action of BiAbs

BiAbs are a promising class of therapeutics with the ability to simultaneously bind two different antigens. There has been a fast-growing tremendous structural diversity in the development of these agents, with more than 100 formats developed, but there have been challenges facing the making of these antibodies, including quality, stability, solubility, and affinity to antigens. Unlike the naturally occurring conventional monoclonal antibodies, BiAbs are artificial antibodies constructed by fusing two antibody-producing cells resulting in not only the desired bispecific IgG molecule, but also other non-functional or monospecific molecules (21,22). This promiscuous mispairing of heavy and light chain has been one of the main challenges of engineering BiAbs and various strategies have been established to overcome this hurdle. Classically, BiAbs are classified into two groups based on the presence or absence of an Fc region. Those that include an Fc region, also called IgG-like BiAbs, retain Fc-mediated effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular phagocytosis (ADCP). They usually have a prolonged half-life and enhanced stability due to their Fc region. This format includes “knob-into-hole” IgG, crossMab, ortho-Fab IgG, DVD-Ig, two in one IgG, IgG-scFv, and scFv2-Fc. BiAbs that lack an Fc region or are non-IgG-like BiAbs usually have a smaller size, allowing better penetration into tumor tissue. This format includes tandem scFvs, diabody format, single-chain diabodies, tandem diabodies, dual-affinity retargeting molecules (DARTs), and “dock-and-lock” (22-24).

As the name indicates, BiAbs target simultaneously both tumor-associated antigens on malignant plasma cells, as well as CD3 on cytotoxic immune effector T and natural killer (NK) cells, thereby bringing them into close proximity, leading to T/NK-cell proliferation and activation, resulting in tumor cell lysis and the elimination of plasma cells (25). Figure 1 schematizes different available BiAbs used for the management of MM. This occurs mainly via the release of inflammatory cytokines as well as cytolytic mediators such as granzyme B by T-cells (26). Importantly, these agents bypass the T cell receptors by activating T-cells regardless of the antigen presentation on major histocompatibility complex class I. Moreover, they also activate T-cells in the absence of co-stimulation, further bypassing the need for antigen presenting cells or cytokines (27). They also maintain sustained T-cell activation by inducing T-cell proliferation and cytolytic activity as well as promoting the differentiation of T-cells into memory T-cells (central memory, effector memory, and stem cell-like memory T-cells) (28). This is of particular importance in the management of MM due to a phenomenon known as the tumor permissive microenvironment, a hallmark of MM where complex interactions between MM cells, T-cells, and bone marrow stromal cells cause dysfunction in the immunity, thereby permitting MM cell survival (29). This dysfunction is multifactorial. T-cell dysfunction is partly caused by the upregulation and expression of programmed death-ligand-1, leading to reduced cytokine production and impaired cell lysis. It has been shown that T cells retrieved from patients with monoclonal gammopathy of uncertain significance produce cytokine, while that is not the case with T cells from patients with MM (30,31). T-cell anergy is further worsened with multiple anti-MM treatments as well autologous stem cell transplantation (ASCT), whereby patients with R/R MM have a decrease in the CD4/8 ratio and naive CD4⁺ T-cells, as well as an increase in effector memory T-cells and PD-1-expressng CD4⁺ T-cells (32). Moreover, given the median age at diagnosis of MM is approximately 70 years, age-associated immune dysfunction may also contribute to impaired T-cell fitness that may influence response to BiAbs.

Figure 1 Different bispecific antibodies used for the management of multiple myeloma. BCMA, B-cell maturation antigen; GPRC5D, G protein-coupled receptor family C group 5 member D.

BiAbs and MM cell targets

Blinatumumab, an anti-CD-19/CD3 BiAb, was the first approved BiAb, back in 2014, for the use in acute lymphoblastic leukemia (33). Since then, efforts have been made to implement the use of various BiAbs in different conditions, including MM. Various MM antigens are currently being investigated including CD38, CS1/SLAMF7, GPRC5D, FcRH5, and more importantly, BCMA.

BCMA

BCMA is a member of the tumor necrosis family (TNF) receptor superfamily that is widely and preferentially expressed in mature B cells, plasma cells, and MM cells, making it the perfect target in MM (34,35). Patients with MM have been shown to have higher levels of serum BCMA than healthy individuals; this correlates with higher disease burden and poorer outcomes, suggesting that BCMA could be a useful biomarker in MM patients (36). Activation of BCMA occurs through a proliferation-inducing ligand (APRIL) which is secreted by macrophages and monocytes. Their engagement was shown to induce MM cell growth and survival via the protein kinase B (AKT), MAPK, and NF-κB signaling pathways. More importantly, activated BCMA promotes MM progression in vivo (37). As discussed above, anti-BCMA therapy has been the focus of many researchers, especially after the approval of several anti-BCMA agents in the setting of relapsed or refractory MM. Here we will be discussing some of the BCMA-directed BiAbs showing promising results.

Teclistamab (JNJ-64007957)

Teclistamab, a humanized anti-BCMA/CD-3 bispecific IgG4 antibody, is the first of its kind to be approved and readily available in the setting of R/R MM. It works by redirecting CD3⁺ T cells to BCMA on the surface of MM cells, thereby inducing subsequent lysis and death of these MM cells.

It initially proved to be potent and cytotoxic against BCMA-positive MM cells in vitro in preclinical studies. It also led to the depletion of these cells in the bone marrow. This activity was further potentiated in the presence of γ-secretase inhibitor (LY-411575) (38). In the phase 1-2 MajesTEC-1 trial, 165 patients with triple-class-exposed R/R MM received once-weekly subcutaneous injections of teclistamab at a dose of 1.5 mg/kg, preceded by step-up doses of 0.06 and 0.3 mg/kg. Of the 148 patients with available cytogenetics, 38 patients had high-risk cytogenetic profiles including del(17p), and t(4,14). Median follow-up was 14.1 months. Responses were seen in 63% of patients with complete response (CR) occurring in 39.4% and very good partial response (VGPR) or better in 58.8% of patients. Of the patients with CR, minimal residual disease (MRD) negativity was seen in 46% of patients. Responses were higher in patients who had received less than or equal to three previous lines of treatment and lower in those who had extramedullary disease (EMD), were stage III, and had more than 60% plasma cells in the bone marrow. The latter three were not represented well due to the small population size. Low response in patients with EMD is expected due to the poor prognosis in this patient population. The median DOR was 18.4 months with a median PFS of 11.3 months, and a median OS of 18.3 months. Moreover, serum levels of soluble BCMA were monitored; decreasing levels of BCMA was seen in 88% of patients with a partial response (PR) or better during the first four cycles. As for the treatment-related adverse events (TRAEs), hematological toxicities, most notable neutropenia occurred in 70.9% of patients. Infections occurred in 76.4% of patients with 44.8% having grade 3–4 infections. Cytokine release syndrome (CRS) occurred in 72.1%, but it was mostly grade 1–2 and neurotoxic events happened in 8.5% of patients (39). Based on the promising results of this trial, teclistamab was the first BCMA-directed antibody to receive FDA approval in patients with R/R MM. Moreover, the efficacy of the combination of teclistamab and daratumumab is now being evaluated after the promising results of the phase 1b TRIMM-2 trial (40). This trial included 65 patients with R/R MM that were given daratumumab at a dose of 1800 mg subcutaneously with three different teclistamab dosing cohorts. ORR were impressive (76.5%), suggesting synergy between these two agents (41). These results were confirmed in the MajesTEC-3 phase III trial that compared the combination of teclistamab plus daratumumab versus daratumumab combined with dexamethasone plus the investigator’s choice of pomalidomide (DPD) or bortezomib (DVD) in patients who received one to three previous lines of therapy. The study met its primary endpoint of PFS. At a median follow-up of 34.5 months, median PFS was not reached in the teclistamab-daratumumab group versus 18.1 months in the DPD or DVD group. The estimated 36-month PFS was 83.4% in the teclistamab-daratumumab group versus 29.7% in the DPD or DVD group [HR, 0.17; 95% confidence interval (CI): 0.12–0.23; P<0.001]. The teclistamab-daratumumab group was associated with higher CR or better (81.8% vs. 32.1%, P<0.001), ORR (89.0% vs. 75.3%, P<0.001) and MRD negativity at 10⁻⁵ sensitivity (58.4% vs. 17.1%, P<0.001). Serious adverse events (AEs) occurred in 70.7% of patients in the teclistamab-daratumumab group versus 62.4% in the DPD or DVD group (42). The combination of teclistamab and daratumumab was also evaluated in elderly patients with newly diagnosed MM and ineligible for ASCT in the IFM2021-01 phase II trial. The primary results were presented at the 2025 American Society of Hematology annual meeting. Thirty seven patients were enrolled in the cohort A with a median age of 73 years. The VGPR rate or better after 4 cycles was 78%. The ORR was 100%with 97% of patients achieving VGPR or better. The MRD negativity rate at 6 months by next-generation sequencing (NGS) at 10⁻⁶ was 51% in the intention-to-treat population and 100% in the 21 evaluable patients. The safety profile was comparable with previously reported (43). In a retrospective cohort of patients with R/R MM previously treated with BCMA and GPRC5D-targeting therapies, teclistamab was associated with an ORR of 60% (9/15 patients), including 50% in the subgroup of patients previously treated with anti-BCMA therapy (5/10 patients). To be noted that CRS and neurotoxicity were reported in 41% and 13% of patients. The MajesTEC-9 is a phase III trial comparing teclistamab as monotherapy versus bortezomib + pomalidomide + dexamethasone, or carfilzomib + dexamethasone in patients with R/R MM (NCT05572515). Moreover, two real-world experiences had been presented at the 2023 American Society of Hematology annual meeting. In the first report of the US myeloma innovations Research Collaborative (USMIRC), the ORR were 64% in the whole cohort (65/102 patients), and 57% in patients who previously received an anti-BCMA targeted therapy such as CAR T-cell or BiAb (32/56 patients). CRS was reported in 65% of patients and immune-effector cell associated neurotoxicity syndrome (ICANS) occurred in 15% of patients (44). Similarly in the second report, the ORR among evaluable patients (42/76 patients). In this report, 37% of patients had already received anti-BCMA targeted therapy. Multivariate analysis showed a trend toward worse ORR in patients previously exposed to anti-BCMA targeting drugs that was not significant (HR, 0.38; 95% CI: 0.07–1.04; P=0.065) (45). Recently, Razzo and colleagues reported a real-world experience with teclistamab in patients with R/R MM in the US MM Immunotherapy Consortium. Five hundred nine patients were included, among them 89% would have been ineligible for the MajesTEC-1 trial. PR or better was reported in 53%, and 45% of them had at least VGPR. The median PFS was 5.8 months, while 12-month OS rate was 61%. CRS occurred in 54% of patients (including 1.4% of grade 3 and higher), and ICANS was observed in 11% of patients (2.2% of grade 3 and higher). Interestingly, 42% of patients had infections that contributed to death in 5% of patients. The authors found that BCMA-directed CAR T-cell therapy in the previous 9 months, high burden of disease, lymphopenia and elevated ferritin were independent predictors of lower VGPR rate and shorter PFS (46). Table 1 resumes the major ongoing trials evaluating teclistamab in patients with MM.

Elranatamab (PF-06863135)

Elranatamab is another humanized anti-BCMA/CD3 BiAb. In preclinical trials, it was shown to be effective in in vitro assays against MM cells; moreover, this effect was potentiated in the presence of IMiD agents (such as lenalidomide). Also, pretreatment with inhibitors of γ-secretase hindered the formation of soluble BCMA, therefore causing MM cell lysis (47). It was then evaluated in the phase 1 MagnetisMM-1 trial, which included 55 patients with R/R MM that received subcutaneous injections of elranatamab. 27% of these patients had a high-risk cytogenetic profile and 22% of patients have already received prior BCMA-directed treatment. Approximately 31% of patients achieved CR with an ORR of 64%. The median time to response was approximately 36 days. As seen with teclistamab, the level of soluble BCMA also went down with disease response. As for TRAEs, patients most commonly experienced CRS (67%), neutropenia, and anemia (48). Then came the phase 2 MagnetisMM-3 study that evaluated 123 patients with R/R MM. These patients received a weekly 76 mg subcutaneous injection of elranatamab with a step-up dosing regimen. 25.2 % of these patients had high risk cytogenetics, 15.4% had stage III disease, and 31.7% had EMD. The ORR were 61%, which was seen across all subgroups including 32% of CR at a median follow-up of 12.8 months. The 12-month DOR, PFS and OS rates were 74%, 57%, and 62% respectively. Treatment-emergent adverse events (TEAEs) occurred in approximately all patients, most commonly CRS (57.7%), anemia (45.5%), and neutropenia (43.1%) (49,50). This trial has led to an accelerated approval of elranatamab by the FDA in August 2023 for patients with R/R MM who failed at least four prior lines of therapy. More recently, Bahlis et al. reported the safety of the MagnetisMM-17, an ongoing, open-label, single-arm trial for patients with triple-class refractory R/R MM and who had not previously received anti-BCMA therapy. Grade 3 or 4 AEs occurred in 65% of patients (13/20). CRS was reported in 65% of patients (13/20), all were Grade 1 or 2, and ICANS occurred in 10% of patients (2/20) and were grade 1 (51). At the last 2025 American Society of Clinical Oncology annual meeting, Quach and colleagues reported the initial results of the part 1 of the MagnetisMM-6 phase III trial that randomized patients to receive elranatamab in combination with lenalidomide +/− daratumumab versus DRD in patients with newly diagnosed transplant-ineligible MM. The part 1 of the study evaluates the optimal dose of elranatamab plus lenalidomide +/− daratumumab in patients with R/R MM or newly diagnosed disease in order to determine the recommended phase 3 dose. A total of 37 patients were enrolled among them 34 received the combination of elranatamab plus lenalidomide and daatumumab. The confirmed ORR was 91.9%, including 81% of VGPR or better. The combination was associated with 97% of TEAEs (grade 3 to 4 TEAEs were 94.6%), hematological TEAEs occurred in 78.4% of patients including 70.3% of grade 3 or higher, while infections were reported in 64.9% of patients including 18.9% of grade 3 or higher. CRS occurred in 62% of patients, all cases were grade 2 or lower, while grade 2 ICANS was reported in one patient. There was one grade 5 candida pneumonia (52). Table 2 summarizes the major ongoing trials evaluating elranatamab in patients with MM.

Pacanalotamab (AMG 420)

Pacanalotamab is an anti-BCMA-anti-CD3 BiAb as well. In preclinical trials, it was shown that pacanalotamab effectively results in the lysis and apoptosis of BCMA-expressing myeloma cells in vitro and in vivo; that is by inducing the activation of T cells in part through the secretion of cytokines, upregulation of CD25 and CD69, and a Fas-mediated mechanism (25,53). A phase 1 inhuman dose escalation multicenter trial evaluated 42 patients with R/R MM with disease progression after 2 lines of treatment, where they received pacanalotamab at multiple doses for as much as 10 cycles. The median number of previous therapies was five, where 29% of patients had previously received daratumumab, 10% prior elotuzumab, and 86% prior autologous stem cell transplant. Of all patients, 3 received the 10 cycles of treatment, 2 were still receiving treatment, 25 discontinued treatments because of disease progression and 7 because of TRAEs. Regarding the efficacy of this drug, 70% of patients (n=7) receiving a dose of 400 µg/d (n=10) had a response, 5 of which had MRD-negative CR, 1 VGPR, and 1 PR. The depth of response was directly correlated to the serum concentration of free AMG 420. 16 patients developed CRS; however, they were mostly grade 1 with only 2 grade 2 and 1 grade 3. The most commonly occurring serious AEs were infections, occurring in 14 patients and polyneuropathy, in only 2 patients (54).

Linvoseltamab (REGN5458)

Linvoseltamab, a fully humanized BCMA-CD3 BiAb, is also currently under investigation. In a phase 1/2 trial first in-human trial (LINKER-MM1), patients with heavily pretreated MM, 252 patients received linvoseltamab. Most patients had received a median of five prior lines of treatments, of which 81% were triple-class refractory. 13.6% of patients had a high-risk cytogenetic profile and 18.6% had a stage III disease. Treatment with linvoseltamab was shown to induce rapid, deep, and durable responses in this patient population, with an ORR of 64% (n=58) in patients receiving dose of 200 mg and 50% in those receiving dose of 50 mg (n=104). This was also true in patients with unfavorable profiles including high-risk cytogenetic, stage III disease, and high bone marrow plasmacytosis. TEAEs occurred in 95% of patients in the 200 mg cohort (grade ≥3 in 66%), and 100% of patients in the 50 mg cohort (grade ≥3 in 80%). The most commonly occurring were CRS, fatigue and anemia. Overall, the dosage of 200 mg showed higher efficacy than the dosage of 50 mg with a comparable safety, and 200 mg was the recommended dose of linvoseltamab for further development (55). In the phase II updated results, the ORR was 71% in the cohort of patients treated with 200 mg (83/117 patients) including 50% achieving CR and a medina DOR of 29.4 months, while the ORR was 48% in the cohort of patients treated with 50 mg (56). Based on the results of the LINKER-MM1 study, the FDA granted accelerated approval to linvoseltamab for R/RMM in July 2025. The LINKER-MM2 trial is a phase Ib trial evaluating the combination of linvoseltamab in combination with other cancer agents in patients with R/R MM. The first results of the cohort of linvoseltamab in combination with bortezomib were presented at 2025 American Society of Medical Oncology annual meeting. A total of 22 patients received the treatment. The combination was associated with high response rates with an ORR of 79% among evaluable patients (11/14 patients), and the 6-month DOR and PFS rates were 90% and 79%. The most common TEAEs were neutropenia of any grade in 59% and thrombocytopenia 50%. CRS occurred in 55% of patients while ICANS was reported in 4 patients of grade 1 to 2. Moreover, infections occurred in 82% including 36% of grade 3 or higher (57). Furthermore, the initial results of the combination of linvoseltamab and carfilzomib were also presented. A total of 18 patients were treated to date [12 patients received dose level 1 (DL1) of 100 mg, and 6 patients DL1b of 150 mg]. Among evaluable patients, the ORR was 91% in the DL1 group (10/11 patients) and 100% in the DL1b group (6/6 patients). The 6- and 12-month PFS rates were 91% and 73% respectively for DL1 group. No PFS events had occurred at DL1b. Once again, the most common TEAEs were neutropenia occurring in 78% of patients and thrombocytopenia occurring in 61% of patients. CRS was reported in 61% of patients of grade ≤2, no grade 3 or higher were reported. Only one patient experienced grade 1 ICANS. Moreover, infections occurred in 89% including 44% of grade 3 or higher (58). Jagannath and colleagues reported the results of an unanchored matching-adjusted indirect comparison to compare the efficacy of linvoseltamab and elranatamab. Linvoseltamab was associated with statistically significantly higher ORR and CR rate, and numerically higher VGPR, and longer DOR, PFS, and OS versus elranatamab (59). Linvoseltamab is currently under investigation in patients with high-risk smoldering MM in the LINKER-SMM1 phase II trial (60).

TNB-383B (ABBV-383)

ABBV-383, formerly known as TNB-383B is a fully humanized IGg4 BCMA-CD3 BiAb, comprised of two BCMA-binding domains and one low-affinity CD3-binding domain. It was developed in a way that the low affinity to CD3 preferentially activates effector T cells rather than regulatory T cells, thereby increasing efficacy and decreasing toxicity, mainly CRS. In a preclinical study, ABBV-383 was shown to induce T-cell activation and myeloma cell cytotoxicity both in vitro and ex vivo, while maintaining reduced cytokine production. It also reduced tumor load and increased survival in ex vivo models (61). This substantially lead to further efforts to investigate the efficacy and safety of this BiAb, that allegedly, based on preclinical data, had a more desirable safety profile and is more efficacious. This was put to test in the first in-human phase I trial where 124 heavily pretreated patients with R/R MM received ABBV-383. Of these 124 patients, 73 were in the dose escalation cohort (0.025–120 mg) and 51 in the dose expansion cohort (60 mg). For all efficacy-evaluable patients, the ORR was 57% with a VGPR or better (≥ VGPR) occurring in 43% of patients. Recently, the efficacy and safety of ABBV-383 at the dosage of 20, 40, and 60 mg were reported. The ORR was 44% in the 20 mg cohort, 64% in the 40 mg cohort, and 60% in the 60 mg cohort. The median PFS was 3.8 months at 20 mg, 13.7 months at 40 mg, and 11.2 months at 60 mg. Approximately all patients experienced TEAEs (97%, 100%, and 100% in the 20, 40, and 60 mg cohorts respectively), of which CRS occurred in 57% of patients. Most patients had grade 1 or 2 CRS (35% and 19%, respectively), with only 2% of patients (n=3) experiencing grade ≥3 CRS. The median time to onset of CRS was one day, typically occurring in the first cycle (62,63). Rodriguez and colleagues reported the results of a phase Ib dose-escalation and safety expansion study of the combination of ABBV-383 plus daratumumab and dexamethasone in patients with R/R MM. A total of 74 patients were enrolled. The aggregate ORR for the total evaluable population was 70%, ORR was 50% in the 20-mg cohort, 74% in the 40-mg cohort, and 82% in the 60-mg cohort at a median follow-up of 5.6 months. The median PFS was not reached at time of analysis. CRS occurred in 20 patients (27%) (64).

Alnuctamab (CC-93269, EM 801)

Alnuctamab is an asymmetric two-arm IgG1 BiAb. It binds bivalently, with high affinity, to BCMA, and monovalently, with low affinity, to CD3, in a 2+1 format, thereby decreasing unspecific T cell activation. In preclinical studies, alnuctamab resulted in the coupling of BCMA-expressing myeloma cells with T cells, leading to upregulation of CD69 and CD 25 expression as well as the release of granzyme B and proinflammatory cytokine, eventually activating CD3 downstream signaling pathways. This results in MM cell lysis and apoptosis at nanomolar concentrations of alnuctamab (65). In the first clinical phase 1 study of alnuctamab, 19 patients with R/R MM received therapy intravenously in a dose escalation strategy. Alnuctamab was shown to be efficacious in this patient population with 58.3% of patients achieving a ≥ VGPR and 33.3% achieving a stringent CR. However, the high occurrence of CRS was a major concern with approximately 89.5% of patients experiencing it. The majority of patients had grade 1 CRS (57.9%) or grade 2 (26.3%); however, 5% of patients experienced ≥ grade 3 CRS and one patient died in the setting of CRS despite treatment (66). In efforts of improving the toxicity profile, the safety and efficacy of subcutaneous injections (as opposed to the intravenous formulation) of alnuctamab was evaluated. Seventy-three patients with R/R MM received alnuctamab in the dose escalation and dose expansion cohorts. The ORR was 54% (39/72 efficacy-evaluable patients) across all dose regimens, 63% at target doses ≥30 mg and 69% at the 30-mg target dose. Subcutaneous alnuctamab had an obviously improved toxicity profile with essentially no patients experiencing grade 3 CRS, and 56% of grade 1–2. TEAEs of all grade occurred in 99% of patients while grade ≥3 TEAEs were reported in 81% of patients (67). This is largely due to the fact that subcutaneous formulation of alnuctamab reduces and delays the secretion of cytokine factors thereby widening its therapeutic index and improving its tolerability (68).

G protein-coupled receptor family C group 5 member D (GPRC5D)

GPRC5D is an orphan receptor that has been recently identified as a novel MM antigen given its high expression on malignant plasma cells. Only low expression of this antigen is detected in normal tissue, notably in hard keratinized tissue, making it a suitable and promising target (69). Its expression on myeloma cells has been associated with plasma-cell burden, genetic aberrations, poor prognosis, and inferior outcomes (70). More importantly, it was proved that pretreatment with agents such as IMiDs, PIs, and anti-CD38 do not affect the expression of GPRC5D on MM cells (71).

Talquetamab (JNJ-64407564)

Talquetamab is a novel humanized GPRC5D-CD3 IgG4 BiAb, targeting GPRC5D on myeloma cells and CD3 on T cells. Its activity was evaluated in a preclinical study where talquetamab effectively induced CD4⁺ and CD8⁺ T-cell activation, pro-inflammatory cytokine secretion, and T-cell degranulation, thereby leading to MM cell lysis. It was also shown that co-treatment with talquetamab and daratumumab or pomalidomide enhanced MM cell lysis. Interestingly, it was also shown talquetamab-induced MM cell lysis was significantly lower in samples with high Treg counts, partly due to the impaired ability of effector T cells to kill MM cells (71). Moreover, the safety and efficacy of intravenous or subcutaneous talquetamab were reported in the phase I/II MonumenTAL-1 study, evaluating 375 patients with R/R MM. At the two recommended subcutaneous doses of talquetamab (0.4 mg/kg weekly, n=143 and 0.8 mg/kg every other week, n=154) for a phase 2 study in TCR-naïve patients, ORR was 74%, and 69%, with a median DOR of 9.5 and 16.9 months, respectively. The median time to response was 1.2 and 1.3 months, respectively, and the median PFS was 7.5, 11.9 months, respectively. Among the 78 patients with prior T-cell redirection therapy and who received either recommended dose, 57 patients (73%) received BCMA-directed CAR T-cell, 26 patients (33%) a BiAb, and 5 patients (6%) received both of them both. The ORR in this cohort was 67%, and the median PFS was 7.7 months. The median time to first response was 1.2 months. As for the safety data, the most common AE was CRS with 79% of patients developing CRS in the 0.4 mg/kg cohort and 75% in the 0.8 mg/kg cohort. Other TRAEs included cytopenias (67% vs. 36%) and skin or nail-related disorders (83% vs. 75%) (72,73). Based on this study, talquetamab received accelerated approval from the FDA in August 2023 for the treatment of patients in this setting. Interestingly, in the MonumenTAL-1 trial, most patients who switched to reduced intensity dosing deepened or maintained response to talquetamab. TEAEs improved over time (74). The RedirecTT-1 is a phase Ib/II trial evaluating the combination of talquetamab and teclistamab in patients with R/R MM. In the first results reported, the ORR across all dose levels was 84% (52/62 patients). Interestingly, the ORR in patients with EMD was 73% (19/26 patients). Moreover, the ORR at the recommended phase 2 regimen was 92% (12/13). The most frequent TEAEs were CRS occurring in 81%, neutropenia in 76% and anemia occurring in 60% (75). The updated results were recently published with a total of 94 patients among them 44 patients treated with the recommended phase 2 regimen. The ORR in the whole population was 78%, and was 80% among patients treated with recommended phase 2 regimen including in 61% of patients with EMD. The most common AEs were CRS and neutropenia, grade 3 or 4 AEs occurred in 96% of patients while grade 3 or 4 infections occurred in 64% of patients (76). The association of talquetamab and teclistamab was also evaluated in a phase II trial in patients with drug-resistant EMD. The study enrolled 90 patients and received treatment. The combination was associated with ORR of 79%. The 12-month PFS and OS rates were 61% and 74% respectively. The safety profile was comparable to that observed in the RedirecTT-1 trial (77). Furthermore, talquetamab in combination with pomalidomide is evaluated in patients with R/R MM in the MonumenTAL-2 phase Ib trial. To date, 35 patients were enrolled divided into two cohorts: 0.4 mg/kg QW (n=16) and 0.8 mg/kg Q2W (n=19). The ORR was 87% and 83% respectively. Median DOR and median PFS were not reached. All patients presented at least one AE, the most frequent was dysgeusia, CRS and neutropenia. In addition, grade 3 or higher AEs occurred in 89% of patients (78).

Fc receptor-homolog 5 (FcRH5)

FcRH5 is a type I membrane protein that is broadly and exclusively expressed on B-cell lineage, including plasma cells with higher level on MM cells than on normal B cells. Cevostamab is the first available FcRH5-CD3 BiAb investigated in patients with R/R MM. It showed encouraging activity in patients with heavily pretreated MM in the GO039775 phase I trial. The confirmed ORR was 54.5% with durable responses as 78% of patients remained in remission after 17 cycles of treatment (79). An updated analysis was reported at the 2024 American Society of Hematology annual meeting. The ORR in all patients treated with cevostamab at the dosage of 160 mg was 43.1% (72/167 patients) with a VGPR or better rate of 25.7%. The median DOR was 10.4 months. Interestingly, the ORR was 30.2% (29/96 patients) in patients who was previously treated with BCMA-targeted therapy and 60.6% (43/71 patients) in those who did not receive BCMA-targeted treatment (80). Cevostamab was evaluated in patients with prior exposure to anti-BCMA targeted therapy in the subsequent CAMMA-2 phase I-II trial. Interestingly, cevostamab was associated with an ORR of 67% and VGPR or higher rate of 38% in patients with triple-class refractory disease with prior BCMA-targeted therapy exposure. In this trial response was higher among patients previously treated with BCMA-targeting CAR T-cells (73% of ORR) in comparison with patients who previously received prior antibody-drug conjugate (60% of ORR) (81).

Decoding resistance mechanisms

BiAb, as previously mentioned, have resulted in promising outcomes in patients with heavily pretreated R/R MM but these responses were not universal. In fact, approximately one third of patients are primary refractory to BiAbs. Moreover, disease relapse occurs among responders to these agents. The mechanisms of resistance are complex and could be divided into tumor intrinsic related to tumor biology, loss of target antigen, and major histocompatibility complex dysfunction or immune dependent related to T-cell dysfunction or tumor microenvironment (TME).

Tumor intrinsic factors

As previously mentioned, patients with advanced disease defined as R-ISS stage III, EMD, and more than 50% to 60% of baseline bone marrow plasma cells as well as high-risk cytogenetics are associated with lower response to anti-BCMA BiAbs (39,82,83). Interestingly, these factors were also associated with high levels of serum soluble BCMA (sBCMA). Available data demonstrated that sBCMA is an independent predictor of poor response to BCMA-targeting BiAbs (84-88). Moreover, in vitro studies demonstrated that high concentrations of sBCMA contributed to lower binding and catalytic function of BCMA-targeting antibodies. Consequently, higher concentrations of these antibodies can partially overcome the reduced BiAbs cytotoxicity (89,90). Moreover, the addition of a gamma secretase, inhibitor improves the availability of BCMA on cell surfaces and depletes shedding of BCMA, thereby enhancing and augmenting BiAb cytotoxicity. To be noted that gamma secretase is responsible of the cleavage of BCMA transmembrane domain (91). The MajesTEC-2 is a phase Ib multi-cohort trial evaluating the combination of teclistamab with other drugs. One of these cohort explore the addition of nirogacestat, a gamma secretase inhibitor, to teclistamab in patients with double refractory to a PI and IMiD and triple exposed to a PI, IMiD and anti-CD38 antibody presenting progression of their disease within 12 months of their last therapy. The ORR was 74%, including 52% of patients with CR. The median DOR was not reached. The major problem with the combination was the occurrence of five grade TEAEs including sepsis, septic shock, coronavirus disease 2019 (COVID-19), cardiac arrest, and Pneumocystis jirovecii pneumonia raising the question of the future of gamma secretase inhibitor in the management (92). Nirogacestat is also under investigation in combination with elranatamab in the MagnetisMM-4 umbrella study. Linvoseltamab and ABBV-383 are also under evaluation in patients with R/R MM (NCT05137054 and NCT05259839 respectively). Furthermore, it seems that high burden of disease might decrease the efficacy of BiAbs independently of sBCMA as supported by talquetamab trials (72,93). These data suggest that combination strategies of BiAbs with MM backbone agents such as IMiDs, PIs, and anti-CD38 monoclonal antibodies could increase the efficacy of BiAbs.

Antigen escape is the most common mechanism of acquired resistance to BCMA and GPRC5D-targeting BiAbs. TNFRSF17 (TNF receptor superfamily member 17) is the gene encoding for BCMA antigen and is located on the chromosome 16. Monoallelic deletions in TNFRSF17 were reported in 4% to 6% of patients with MM and naïve of T-cell immunotherapy (94). However, biallelic deletions or monoallelic deletions associated with mutations of BCMA extracellular domain resulted in loss of BCMA expression and are found in nearly 40% of patients relapsing following BCMA-targeting BiAbs (95). Concerning GPRC5D, monoallelic deletion is found in approximately 15% of patients naïve to BiAbs. Lee and colleagues reported that nearly all patients who progressed on talquetamab presented biallelic deletion of GPRC5D (95). Consequently, the appearance of this antigen escape should shed the light on the importance of dynamic follow-up of antigen escape. As previously mentioned, the RedirecTT-1 trial showed that the combination teclistamab and talquetamab was associated with an impressive ORR of 80% among patients treated with the recommended phase 2 dose. These results spur the opportunity for dual targeting with trispecific antibodies. The JNJ-79635322 is a next-generation trispecific antibody and dually targeting BCMA and GPRC5D via T-cell redirection. It has been evaluated in a first-in-human phase I trial presented at 2025 American Society of Clinical Oncology annual meeting. As a data cutoff on January 2025, 126 patients with a median age of 64 years received at least of dose of JNJ-79635322, among them 36 patients received the recommended phase 2 dose (RP2D). JNJ-5322 was associated with impressive efficacy. The ORR was 86% among patients treated with RP2D and 73% in the overall population. Interestingly, the ORR was 100% among BCMA/GPRC5D-naïve patients and who were given the RP2D with a CR rate of 70.4%. The median time to first response was 1.2 months. The most common AEs was CRS observed in 59% all grade 1 or 2, followed by taste AEs (56%), nail AEs (56%), and neutropenia (48% mostly grade 3 to 4 in 42%). Only 2% of patients presented grade 1 ICANS (96). The TRILOGY-4 is an ongoing phase III trial comparing JNJ-79635322 with teclistamab in patients with R/R MM (NCT07258511).

Modulation of the TME

T-cell exhaustion is a major mechanism of resistance to BCMA-targeted therapy. Responses to CAR T-cells and BiAbs have been linked to a high CD4/CD8 ratio, as well as increased frequency of CD45RO-CD27⁺CD8⁺ T-cells whereas features of treatment resistance included low CD4/CD8 ratio and an enrichment of terminally exhausted T cells (97). This indicates that T-cell directed treatments may be more efficacious if used in earlier stages of the disease, when patients have less exhausted T-cells. Moreover, we have little to no knowledge on the changes that occur in the TME in response to T-cell directed therapies and its role in drug resistance. Therefore, further studies are needed to help explore the possible role of the TME in the failure and resistance of BCMA-targeted therapy.

Optimizing treatment strategies and sequencing

Knowledge of the mechanisms of resistance to anti-BCMA therapies is vital and will provide better understanding on how to use them sequentially. One important unanswered question that has been raised is the sequencing of all available therapies, given the current state of various T-cell redirection therapies. This is particularly interesting in the setting of recent approvals of several BCMA-targeting agents, including the BCMA-directed ADC belantamab mafodotin and the BCMA-directed CAR-T-cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel. Data on optimal sequencing of these agents is scarce; however, retrospective data are available to help clinicians navigate and weigh their options. One multicenter retrospective study included a total of 50 patients who had received previous BCMA-targeted therapies to receive idecabtagene vicleucel. This study suggested that this patient population had worse outcomes with lower ORR (74% vs. 88%), lower best response of ≥ CR (29% vs. 48%), and inferior median PFS (3.2 vs. 9.0 months). Moreover, compared to patients who had BCMA-targeted therapy >6 months prior to receiving idecabtagene vicleucel, those with a less than 6 months interval had inferior outcomes including ORR (60% vs. 83%), CR (20% vs. 34.5%), and median PFS (3.0 vs. 5.3 months) (98). These results were similar to the most recent update of these data, where patients who have been treated with prior BCMA-targeted therapy (n=33) had dismal outcomes, including PFS (9.0 vs. 3.2 months) and OS (12.5 vs. 7.4 months), compared to patients who had not received BCMA-targeted treatment (99). Based on the mentioned data, one might lean towards not using prior BCMA-targeting agents if the patient is planned to receive CAR T-cell, to optimize response and improve survival outcomes. However, these findings are now challenged by the data published in Blood by Cohen et al., where 20 patients with prior exposure to anti-BCMA therapy and heavily pretreated MM received cilta-cel. At a median follow-up of 11.3 months, 35% of patients were MRD negative. Cilta-cel was shown to be efficacious in this setting with an ORR of 60%, median DOR of 11.5 month and a PFS of 9.1 months. It is also worth mentioning that patients who responded to cilta-cel had a shorted median duration of exposure to prior anti-BCMA treatments and had a longer median time between their last anti-BCMA treatment and the cilta-cel infusion (100).

Unfortunately, the number of patients included in these studies is small and the type of prior anti-BCMA therapies that patients received was heterogeneous. In this setting, it is difficult to draw conclusions on whether CAR-T cell is effective after BCMA-targeting biAbs or ADCs. Another thing to consider is the difficult access to CAR-T cell treatment; some physicians may prefer using other readily available anti-BCMA therapies including BiAbs.

Moreover, there are some data on the use of BiAbs after prior BCMA-targeting agents including CAR-T cells. One study evaluated the efficacy teclistamab in patients who were previously exposed to other BCMA-targeted therapy. It included 38 patients, 25 of which were efficacy-evaluable patients. 16 patients received prior ADC, 11 prior CAR-T cells, and 2 received both. The ORR was 40% and the CR or better was seen in 5 patients. Among patients who were previously exposed to CAR-T cell, ORR was 45% (101). Moreover, in the Magnetismm-3 trial of elranatanab, cohort B specifically included patients who were previously exposed to anti-BCMA therapies. However, results are not yet available.

Another thing to consider would be the potential use of sBCMA as a marker of treatment response. This has been seen in studies of BCMA-targeted CAR-T cells where reduced levels of sBCMA were seen with treatment response (19,102,103). Moreover, in the analysis of patients from the MajesTEC-1 and MonumenTAL-1 trials, patients responding to teclistamab or talquetamab had a declining level of sBCMA with the degree of reduction corresponding to the depth of response. All patients that achieved ≥ CR had almost 100% reductions in sBCMA levels (87).

Conclusions

The advent of BiAbs has revolutionized the treatment landscape of MM and provided a glimmer of hope to patients in the relapsed or refractory setting. Despite the promising clinical outcomes, challenges remain in understanding the resistance mechanisms to treatment and sequencing of all BCMA-targeting innovative agents. Efforts are underway to optimize and incorporate these immunotherapeutic agents in the treatment of MM. Overcoming resistance to BiAbs and deciding of correct sequence of myeloma therapy will require tightly integrated clinical and translational research. Clinical trials are now evaluating the role of BiAbs in earlier stages of the disease as well as their efficacy in combination with other immunomodulatory agents. This could ultimately pave the way for improved patient outcomes, transforming the way clinicians treat patients with MM.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-110/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-110/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016;374:1621-34. [Crossref] [PubMed]
2. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372:142-52. [Crossref] [PubMed]
3. Richardson PG, Oriol A, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol 2019;20:781-94. [Crossref] [PubMed]
4. Al Hamed R, Bazarbachi AH, Malard F, et al. Current status of autologous stem cell transplantation for multiple myeloma. Blood Cancer J 2019;9:44. [Crossref] [PubMed]
5. Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol 2023;10:e825-37. [Crossref] [PubMed]
6. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2024;390:301-13. [Crossref] [PubMed]
7. Facon T, Kumar S, Plesner T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med 2019;380:2104-15. [Crossref] [PubMed]
8. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med 2018;378:518-28. [Crossref] [PubMed]
9. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med 2025;31:1195-202. [Crossref] [PubMed]
10. Mai EK, Bertsch U, Pozek E, et al. Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma: Final Part 1 Analysis of the GMMG-HD7 Trial. J Clin Oncol 2025;43:1279-88. [Crossref] [PubMed]
11. Facon T, Dimopoulos MA, Leleu XP, et al. Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2024;391:1597-609. [Crossref] [PubMed]
12. Kumar SK, Dimopoulos MA, Kastritis E, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia 2017;31:2443-8. [Crossref] [PubMed]
13. Yong K, Delforge M, Driessen C, et al. Multiple myeloma: patient outcomes in real-world practice. Br J Haematol 2016;175:252-64. [Crossref] [PubMed]
14. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia 2019;33:2266-75. [Crossref] [PubMed]
15. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol 2020;21:207-21. [Crossref] [PubMed]
16. Lonial S, Lee HC, Badros A, et al. Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study. Cancer 2021;127:4198-212. [Crossref] [PubMed]
17. Dimopoulos MA, Beksac M, Pour L, et al. Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma. N Engl J Med 2024;391:408-21. [Crossref] [PubMed]
18. Hungria V, Robak P, Hus M, et al. Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med 2024;391:393-407. [Crossref] [PubMed]
19. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med 2021;384:705-16. [Crossref] [PubMed]
20. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 2021;398:314-24. [Crossref] [PubMed]
21. Cao Y, Suresh MR. Bispecific antibodies as novel bioconjugates. Bioconjug Chem 1998;9:635-44. [Crossref] [PubMed]
22. Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs 2017;9:182-212. [Crossref] [PubMed]
23. Wang Q, Chen Y, Park J, et al. Design and Production of Bispecific Antibodies. Antibodies (Basel) 2019;8:43. [Crossref] [PubMed]
24. Ma J, Mo Y, Tang M, et al. Bispecific Antibodies: From Research to Clinical Application. Front Immunol 2021;12:626616. [Crossref] [PubMed]
25. Hipp S, Tai YT, Blanset D, et al. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia 2017;31:1743-51. [Crossref] [PubMed]
26. Frerichs KA, Broekmans MEC, Marin Soto JA, et al. Preclinical Activity of JNJ-7957, a Novel BCMA×CD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab. Clin Cancer Res 2020;26:2203-15. [Crossref] [PubMed]
27. Caraccio C, Krishna S, Phillips DJ, et al. Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions. Front Immunol 2020;11:501. [Crossref] [PubMed]
28. Cho SF, Lin L, Xing L, et al. The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models. Blood Adv 2020;4:4195-207. [Crossref] [PubMed]
29. Swan D, Routledge D, Harrison S. The evolving status of immunotherapies in multiple myeloma: the future role of bispecific antibodies. Br J Haematol 2022;196:488-506. [Crossref] [PubMed]
30. Dhodapkar MV, Krasovsky J, Osman K, et al. Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy. J Exp Med 2003;198:1753-7. [Crossref] [PubMed]
31. Park JJ, Omiya R, Matsumura Y, et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 2010;116:1291-8. [Crossref] [PubMed]
32. Cooke RE, Quinn KM, Quach H, et al. Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells. Front Immunol 2020;11:2153. [Crossref] [PubMed]
33. Przepiorka D, Ko CW, Deisseroth A, et al. FDA Approval: Blinatumomab. Clin Cancer Res 2015;21:4035-9. [Crossref] [PubMed]
34. Laabi Y, Gras MP, Brouet JC, et al. The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed. Nucleic Acids Res 1994;22:1147-54. [Crossref] [PubMed]
35. Rennert P, Schneider P, Cachero TG, et al. A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth. J Exp Med 2000;192:1677-84. [Crossref] [PubMed]
36. Ghermezi M, Li M, Vardanyan S, et al. Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients. Haematologica 2017;102:785-95. [Crossref] [PubMed]
37. Tai YT, Acharya C, An G, et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood 2016;127:3225-36. [Crossref] [PubMed]
38. Pillarisetti K, Powers G, Luistro L, et al. Teclistamab is an active T cell-redirecting bispecific antibody against B-cell maturation antigen for multiple myeloma. Blood Adv 2020;4:4538-49. [Crossref] [PubMed]
39. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med 2022;387:495-505. [Crossref] [PubMed]
40. Mateos MV, Bahlis NJ, Costa LJ, et al. MajesTEC-3: Randomized, phase 3 study of teclistamab plus daratumumab versus investigator’s choice of daratumumab, pomalidomide, and dexamethasone or daratumumab, bortezomib, and dexamethasone in patients with relapsed/refractory multiple myeloma. J Clin Oncol 2022;40:TPS8072.
41. Rodríguez-Otero P, D’Souza A, Reece DE, et al. A novel, immunotherapy-based approach for the treatment of relapsed/refractory multiple myeloma (RRMM): Updated phase 1b results for daratumumab in combination with teclistamab (a BCMA x CD3 bispecific antibody). J Clin Oncol 2022;40:8032.
42. Costa LJ, Bahlis NJ, Perrot A, et al. Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma. N Engl J Med 2025; Epub ahead of print. [Crossref]
43. Manier S, Lambert J, Macro M, et al. A phase 2 Study of teclistamab in combination with daratumumab in elderly patients with newly diagnosed multiple myeloma: The IFM2021-01 teclille trial, cohort a. Blood 2025;146:367.
44. Dima D, Davis JA, Ahmed N, et al. Real-World Safety and Efficacy of Teclistamab for Patients with Heavily Pretreated Relapsed-Refractory Multiple Myeloma. Blood 2023;142:91.
45. Mohan M, Monge J, Shah N, et al. Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study. Blood Cancer J 2024;14:35. [Crossref] [PubMed]
46. Razzo BM, Midha S, Portuguese AJReal-World Experience with Teclistamab for Relapsed/Refractory Multiple Myeloma from the US Myeloma Immunotherapy Consortium, et al. Blood Cancer Discov 2025;6:561-71. [Crossref] [PubMed]
47. Karwacz K, Hooper AT, Chang CPB, et al. Abstract 4557: BCMA-CD3 bispecific antibody PF-06863135: Preclinical rationale for therapeutic combinations. Cancer Res 2020;80:4557.
48. Jakubowiak AJ, Bahlis NJ, Raje NS, et al. Elranatamab, a BCMA-targeted T-cell redirecting immunotherapy, for patients with relapsed or refractory multiple myeloma: Updated results from MagnetisMM-1. J Clin Oncol 2022;40:8014.
49. Bahlis NJ, Tomasson MH, Mohty M, et al. Efficacy and Safety of Elranatamab in Patients with Relapsed/Refractory Multiple Myeloma Naïve to B-Cell Maturation Antigen (BCMA)-Directed Therapies: Results from Cohort a of the Magnetismm-3 Study. Blood 2022;140:391 3.
50. Tomasson M, Iida S, Niesvizky R, et al. Long-Term Efficacy and Safety of Elranatamab Monotherapy in the Phase 2 Magnetismm-3 Trial in Relapsed or Refractory Multiple Myeloma (RRMM). Blood 2023;142:3385.
51. Bahlis NJ, Trudel S, Maisel C, et al. Safety of Elranatamab in Patients with Triple-Class Refractory Relapsed/Refractory Multiple Myeloma (RRMM) in Magnetismm-17, a North American Expanded Access Protocol. Blood 2023;142:6737.
52. Quach H, Pour L, Grosicki S, et al. Elranatamab in combination with daratumumab and lenalidomide (EDR) in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant: Initial results from MagnetisMM-6 part 1. J Clin Oncol 2025;43:7504.
53. Ross SL, Sherman M, McElroy PL, et al. Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing. PLoS One 2017;12:e0183390. [Crossref] [PubMed]
54. Topp MS, Duell J, Zugmaier G, et al. Anti-B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma. J Clin Oncol 2020;38:775-83. [Crossref] [PubMed]
55. Bumma N, Richter J, Brayer J, et al. Updated Safety and Efficacy of REGN5458, a BCMAxCD3 Bispecific Antibody, Treatment for Relapsed/Refractory Multiple Myeloma: A Phase 1/2 First-in-Human Study. Blood 2022;140:10140 1.
56. Bumma N, Richter J, Jagannath S, et al. Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma. J Clin Oncol 2024;42:2702-12. [Crossref] [PubMed]
57. Rodríguez-Otero P, Delimpasi S, Oriol A, et al. Linvoseltamab (LINVO) + bortezomib (BTZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): First results from the LINKER-MM2 trial. J Clin Oncol 2025;43:7510.
58. Manier S, Ocio EM, Martinez-Chamorro C, et al. Linvoseltamab (LINVO) + carfilzomib (CFZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Initial results from the LINKER-MM2 trial. J Clin Oncol 2025;43:7513.
59. Jagannath S, Lee HC, Richter JR, et al. Indirect comparison of linvoseltamab versus elranatamab for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 2025;43:7531. [Crossref] [PubMed]
60. Rodriguez Otero P, Mateos MV, Aina O, et al. Trial in Progress: A Phase 2 Study of Linvoseltamab for the Treatment of High-Risk Smoldering Multiple Myeloma (LINKER-SMM1). Blood 2023;142:3393.
61. Buelow B, Choudry P, Clarke S, et al. Pre-clinical development of TNB-383B, a fully human T-cell engaging bispecific antibody targeting BCMA for the treatment of multiple myeloma. J Clin Oncol 2018;36:8034.
62. D'Souza A, Shah N, Rodriguez C, et al. A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma. J Clin Oncol 2022;40:3576-86. [Crossref] [PubMed]
63. Vij R, Kumar SK, D’Souza A, et al. Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma. Blood 2023;142:3378.
64. Rodriguez C, Mielnik M, Kazandjian D, et al. ABBV-383 Plus Daratumumab-Dexamethasone in Relapsed or Refractory Multiple Myeloma: A Phase 1b Dose-Escalation and Safety Expansion Study. Blood 2024;144:496.
65. Seckinger A, Delgado JA, Moser S, et al. Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment. Cancer Cell 2017;31:396-410. [Crossref] [PubMed]
66. Costa LJ, Wong SW, Bermúdez A, et al. First Clinical Study of the B-Cell Maturation Antigen (BCMA) 2+1 T Cell Engager (TCE) CC-93269 in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Interim Results of a Phase 1 Multicenter Trial. Blood 2019;134:143.
67. Bar N, Mateos MV, Ribas P, et al. Alnuctamab (ALNUC; BMS-986349; CC-93269), a 2+1 B-Cell Maturation Antigen (BCMA) × CD3 T-Cell Engager (TCE), Administered Subcutaneously (SC) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from a Phase 1 First-in-Human Clinical Study. Blood 2023;142:2011.
68. Boss IW, Thompson E, Gaudy AM, et al. Soluble Factors Correlated with High-Grade Cytokine Release Syndrome (CRS): A Comparison of Subcutaneous (SC) Versus Intravenous (IV) Delivery of Alnuctamab (ALNUC; BMS-986349; CC-93269) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM). Blood 2022;140:7116 7.
69. Inoue S, Nambu T, Shimomura T. The RAIG family member, GPRC5D, is associated with hard-keratinized structures. J Invest Dermatol 2004;122:565-73. [Crossref] [PubMed]
70. Atamaniuk J, Gleiss A, Porpaczy E, et al. Overexpression of G protein-coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma. Eur J Clin Invest 2012;42:953-60. [Crossref] [PubMed]
71. Verkleij CPM, Broekmans MEC, van Duin M, et al. Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma. Blood Adv 2021;5:2196-215. [Crossref] [PubMed]
72. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. N Engl J Med 2022;387:2232-44. [Crossref] [PubMed]
73. Chari A, Touzeau C, Schinke C, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1-2 study. Lancet Haematol 2025;12:e269-81. [Crossref] [PubMed]
74. Chari A, Oriol A, Krishnan A, et al. Efficacy and Safety of Less Frequent/Lower Intensity Dosing of Talquetamab in Patients with Relapsed/Refractory Multiple Myeloma: Results from the Phase 1/2 MonumenTAL-1 Study. Blood 2023;142:1010.
75. Inc MG. FIRST RESULTS FROM THE REDIRECTT-1 STUDY WITH TECLISTAMAB (TEC) +... by Dr. María-Victoria Mateos [Internet]. [cité 3 août 2025]. Available online: https://library.ehaweb.org/eha/2023/eha2023-congress/387890/mara-victoria.mateos.first.results.from.the.redirectt-1.study.with.teclistamab.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D41
76. Cohen YC, Magen H, Gatt M, et al. Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med 2025;392:138-49. [Crossref] [PubMed]
77. Kumar S, Mateos MV, Ye JC, et al. Dual Targeting of Extramedullary Myeloma with Talquetamab and Teclistamab. N Engl J Med 2026;394:51-61. [Crossref] [PubMed]
78. Matous J, Biran N, Perrot A, et al. Talquetamab + Pomalidomide in Patients with Relapsed/Refractory Multiple Myeloma: Safety and Preliminary Efficacy Results from the Phase 1b MonumenTAL-2 Study. Blood 2023;142:1014.
79. Trudel S, Cohen AD, Krishnan AY, et al. Cevostamab Monotherapy Continues to Show Clinically Meaningful Activity and Manageable Safety in Patients with Heavily Pre-Treated Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from an Ongoing Phase I Study. Blood 2021;138:157.
80. Richter J, Thomas SK, Krishnan AY, et al. Cevostamab in Patients with Heavily Pretreated Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from an Ongoing Phase I Study Demonstrate Clinically Meaningful Activity and Manageable Safety and Inform the Doses and Regimen for Combination Studies. Blood 2024;144:1021.
81. Kumar S, Bachier CR, Cavo M, et al. CAMMA 2: A phase I/II trial evaluating the efficacy and safety of cevostamab in patients with relapsed/refractory multiple myeloma (RRMM) who have triple-class refractory disease and have received a prior anti-B-cell maturation antigen (BCMA) agent. J Clin Oncol 2023;41:TPS8064.
82. Bahlis NJ, Costello CL, Raje NS, et al. Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial. Nat Med 2023;29:2570-6. [Crossref] [PubMed]
83. Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med 2023;29:2259-67. [Crossref] [PubMed]
84. Lee HC, Bumma N, Richter JR, et al. LINKER-MM1 study: Linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma. J Clin Oncol 2023;41:8006.
85. Cortes-Selva D, Perova T, Skerget S, et al. Correlation of immune fitness with response to teclistamab in relapsed/refractory multiple myeloma in the MajesTEC-1 study. Blood 2024;144:615-28. [Crossref] [PubMed]
86. Miao X, Wu LS, Lin SXW, et al. Population Pharmacokinetics and Exposure-Response with Teclistamab in Patients With Relapsed/Refractory Multiple Myeloma: Results From MajesTEC-1. Target Oncol 2023;18:667-84. [Crossref] [PubMed]
87. Girgis S, Wang Lin SX, Pillarisetti K, et al. Effects of teclistamab and talquetamab on soluble BCMA levels in patients with relapsed/refractory multiple myeloma. Blood Adv 2023;7:644-8. [Crossref] [PubMed]
88. Elmeliegy M, Kei Lon H, Wang D, et al. Soluble B-Cell Maturation Antigen As a Disease Biomarker in Relapsed or Refractory Multiple Myeloma (RRMM): Evaluation from Elranatamab (ELRA) Magnetismm Studies. Blood 2023;142:3345.
89. Lee H, Durante M, Ahn S, et al. The Impact of Soluble BCMA and BCMA Gain on Anti-BCMA Immunotherapies in Multiple Myeloma. Blood 2023;142:4688.
90. Chen H, Li M, Xu N, et al. Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells. Leuk Res 2019;81:62-6. [Crossref] [PubMed]
91. Chen H, Yu T, Lin L, et al. γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation. Blood Cancer J 2022;12:118. [Crossref] [PubMed]
92. Inc MG. EFFICACY AND SAFETY OF TECLISTAMAB IN PATIENTS WITH... by Luciano J. Costa [Internet]. [cité 3 août 2025]. Available online: https://library.ehaweb.org/eha/2024/eha2024-congress/420987/luciano.j.costa.efficacy.and.safety.of.teclistamab.in.patients.with.relapsed.html
93. Schinke CD, Touzeau C, Minnema MC, et al. Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 2023;41:8036.
94. Truger MS, Duell J, Zhou X, et al. Single- and double-hit events in genes encoding immune targets before and after T cell-engaging antibody therapy in MM. Blood Adv 2021;5:3794-8. [Crossref] [PubMed]
95. Lee H, Ahn S, Maity R, et al. Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma. Nat Med 2023;29:2295-306. [Crossref] [PubMed]
96. van de Donk NWCJ, Vega G, Perrot A, et al. First-in-human study of JNJ-79635322 (JNJ-5322), a novel, next-generation trispecific antibody (TsAb), in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Initial phase 1 results. J Clin Oncol 2025;43:7505.
97. Leblay N, Maity R, Barakat E, et al. Cite-Seq Profiling of T Cells in Multiple Myeloma Patients Undergoing BCMA Targeting CAR-T or Bites Immunotherapy. Blood 2020;136:11-2.
98. Ferreri CJ, Hildebrandt MAT, Hashmi H, et al. Idecabtagene Vicleucel (Ide-cel) Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Who Have Received a Prior BCMA-Targeted Therapy: Real World, Multi-Institutional Experience. Blood 2022;140:1856-8.
99. Hansen DK, Sidana S, Peres LC, et al. Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium. J Clin Oncol 2023;41:2087-97. [Crossref] [PubMed]
100. Cohen AD, Mateos MV, Cohen YC, et al. Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents. Blood 2023;141:219-30. [Crossref] [PubMed]
101. Touzeau C, Krishnan A, Moreau P, et al. S184: Evaluating teclistamab in patients with relapsed/ refractory multiple myeloma following exposure to other b-cell maturation antigen (BCMA)-targeted agents. HemaSphere 2022;6:85-6.
102. Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016;128:1688-700. [Crossref] [PubMed]
103. Brudno JN, Maric I, Hartman SD, et al. T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. J Clin Oncol 2018;36:2267-80. [Crossref] [PubMed]