Dual target combination therapy demonstrates promise in extramedullary myeloma

Extramedullary myeloma remains one of the most difficult forms of myeloma to manage due to limited effective therapies. True extramedullary disease (EMD) refers to plasmacytomas that are non-contiguous with bone and arise from hematologic spread. This is different from paramedullary disease that extends contiguously from bone following cortical erosion (1). EMD is associated with poorer outcomes and is associated with a higher risk of relapse (2,3).

Conventional medullary myeloma cells rely on the stromal signals within the bone marrow microenvironment to proliferate. In contrast, EMD can proliferate independently of these factors, allowing it to survive outside its usual environment (4). It is also associated with higher-risk genetic features, including increased rates of TP53 mutations, 1q21 amplification, and MYC dysregulation (5). EMD downregulates the expression of known therapeutic targets, such as G protein-coupled receptor family C member D (GPCR5D), CD38, and B-cell maturation antigen (BCMA), potentially limiting effective treatment targets (6).

Historically, due to the aggressiveness of the disease, patients with EMD have been underrepresented in clinical trials, limiting prospective data and forcing clinicians to rely on retrospective analyses. Currently, there is no clear standard treatment for relapsed/refractory EMD, and it remains an unmet need within myeloma care. Salvage combination chemotherapy regimens, including DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin), DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), and CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), have shown some responses; however, these are typically short-lived and function more as bridging therapies to transplant or chimeric antigen receptor T cell (CAR-T) therapy rather than definitive treatment (7-9).

The recently published phase 2 RedirecTT-1 trial (NCT04586426) aimed to address this care gap by evaluating dual-antigen targeting with the bispecific antibodies (BsAbs) talquetamab (GPRC5D/CD3) and teclistamab (BCMA/CD3) in patients with triple-class-exposed, relapsed/refractory myeloma and true EMD (10). The biological rationale for simultaneous dual-target therapy is straightforward. One of the major hurdles in treating EMD is antigen escape, where tumor cells reduce or eliminate the expression of specific antigens, allowing them to evade targeted therapies. Antigen escape has been particularly relevant in targeted immune treatments, including BsAbs and CAR-T, where it can limit future treatment options (11). Simultaneously targeting BCMA and GRPC5D theoretically mitigates clonal escape and, therefore, increases the potential for deep responses and longer survival.

RedirecTT-1 included 90 patients with true EMD who had failed previous lines of therapy (median =4). 58% of patients had 2 or more extramedullary plasmacytomas, with 45% being 25 cm or greater in size. In addition, 22% of patients had high-risk cytogenetic profiles [del(17p), t(4;14), or t(14;16)]. All patients completed 3 step-up doses 2–4 days apart before continuing with teclistamab and talquetamab simultaneously on a biweekly schedule. During step-up dosing, patients were premedicated with dexamethasone, diphenhydramine, and acetaminophen. Once patients achieved a good response to therapy, they were able to move to a monthly injection regimen. Intravenous immunoglobulin (IVIG) replacement was recommended per institutional guidelines. Using positron-emission tomography (PET) scans, the study demonstrated an impressive overall response rate (ORR) of 79% with a 12-month response durability of 64%. Overall survival (OS) and progression-free survival (PFS) at 12 months were 74% and 61%, respectively.

There is a lack of prospective outcome data for patients with both refractory and EMD against which to compare these results. The most reliable comparison of RedirecTT-1 is a recent meta-regression analysis using Bayesian multilevel, random-effects modeling of patients with and without EMD across nine historical clinical studies of standard treatment regimens (12). Patients with EMD had a pooled ORR of 20.7% [95% confidence interval (CI): 11.7–33.9%] and a pooled median PFS of 6.3 months (95% CI: 4.2–9.5). The depth and consistency of response in RedirecTT-1, therefore, suggest the dual BsAb approach is clinically meaningful in this high-risk population.

The authors suggest that combination BsAb therapy has a synergistic effect. This conclusion appears very reasonable, as reports from recent real-world experiences in patients with EMD treated with single-agent BCMA or GPRC5D BsAb demonstrated response rates of 38–71%, and PFS of 1.4–4.1 months (13-15). The RedirecTT-1 trial also cites an ORR of 44% with talquetamab and 43% with teclistamab monotherapies in patients with EMD from Johnson and Johnson’s unpublished data (10). The 12-month durability data from RedirecTT-1 are promising; however, the median follow-up is relatively short at 12.6 months, and data concerning longer-term outcomes are eagerly awaited.

This combination approach aligns with a broader paradigm shift in myeloma treatment following the introduction of immune therapies. The first class of myeloma immune therapy, anti-CD38 monoclonal antibodies, was combined with traditional therapies such as proteasome inhibitors and immunomodulatory agents. Combinations were used sequentially, moving from one class to another with disease progression. Following the demonstration of high response rates and long PFS in relapsed-refractory disease, these combinations were moved to earlier relapses and the newly diagnosed setting. Given the high response rates of 60–70% seen with BsAb targeting BCMA and GPRC5D, it was initially thought that single-agent BsAb therapy was adequate (16,17); however, another recent study has also shown that combinations of immune therapies are superior. In the MajesTEC-3 trial, the combination of teclistamab (BCMA/CD3) and daratumumab (anti-CD38) in relapsed myeloma patients (1–3 prior lines) was superior to standard relapsed chemotherapy with an estimated 36-month PFS of 83.4% in the teclistamab-daratumumab group and 29.7% in the DPd (daratumumab, pomalidomide, and dexamethasone) or DVd (daratumumab, bortezomib, and dexamethasone) group (hazard ratio, 0.17; P<0.001) (18).

As with all BsAb therapy, effective management of side effects is key to good outcomes. In this study of dual BsAb therapy in patients with EMD, all patients experienced an adverse event, with 76% experiencing grade 3 or 4 toxicities related predominantly to cytopenias. Oral adverse effects (e.g., dysgeusia), known to be related to talquetamab, were the most common complications (87%), with more than half remaining unresolved by the end of the study. Although grade 1 and grade 2 cytokine release syndrome (CRS) were observed in 78% of patients, there were no grade 3 CRS events. The CRS was readily manageable by treatment consisting of acetaminophen (57%), tocilizumab (57%), and corticosteroids (19%). Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 12% of patients, including one occurrence of grade 4 ICANS treated with anakinra and tocilizumab.

Infections were also common, occurring in 79% of patients, with 5.6% resulting in death. While the authors note similarities to the safety profiles seen in the single-agent studies, MonumenTAL-1 and MajesTEC-1 trials, direct comparisons are difficult given differences in supportive care measures (16,17). The International Myeloma Society recently provided guidance for the management of CRS and ICANS, as well as the use of prophylactic antibiotics and immunoglobulin supplementation (19). Clearly, one concern pre-study was that combining two BsAbs may amplify the immunosuppressive effects already associated with this therapy class; hence, strict infection management is important. So, while the response rate in RedirecTT-1 does show a promising signal in the right direction, it is important to be mindful of infection and treatment-related mortality from combination immunotherapy. Patients, caregivers, and clinical staff must be properly educated in implementing preventative strategies, recognizing early warning signs, and promptly managing CRS/ICANS and infections (20).

In conclusion, the RedirecTT-1 study represents meaningful clinical progress in high-risk patient populations where current treatment strategies are inadequate. It demonstrates that dual-targeting strategies can produce significant responses in EMD and provides a foundation for future trials. It is important to note that the study excluded patients with CNS involvement, where BsAbs have shown limited effectiveness, and where CAR-T therapy may be more appropriate (15).

Given the impressive response rates and the recent approval of teclistamab with daratumumab for patients who have failed 1–3 lines, it is interesting to postulate the effectiveness of other bispecific combinations, such as those used in RedirecTT-1, in other patient populations. The key to such an approach will be balancing efficacy with side effects and identifying when it is worth being more aggressive with treatment regimens.

Overall, this study represents a step forward in the treatment of extramedullary myeloma. It offers promising results in a difficult-to-treat population and sets the stage for future investigation on how to best utilize these therapies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0935/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0935/coif). F.E.D. reports participation on advisory board member for AstraZeneca, BMS, GSK, Johnson and Johnson, Kite, Regeneron, and Takeda. The other author has 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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