Data from the phase 1b/2 RedirecTT-1 study (NCT04586426) revealed a progression-free survival (PFS) benefit with the combination of talquetamab (Talvey) and teclistamab (Tecvayli) in patients with relapsed/refractory multiple myeloma with extramedullary disease (EMD), marking a substantial improvement compared to historical outcomes in this challenging-to-treat group, according to Shahzad Raza, MD.
Findings presented during the 2025 EHA Congress revealed that, at a median follow-up of 12.6 months, the median PFS was 15.4 months (95% CI, 10.8-not evaluable) among patients who received the combination (n = 90). The 12-month PFS rate was 61.0% (95% CI, 49.6%-70.6%).1,2 Additionally, at a median follow-up of 12.6 months (range, 0.5-19.5), patients treated with talquetamab plus teclistamab achieved an overall response rate (ORR) of 78.9% (95% CI, 69.0%-86.8%). The complete response or better rate was 54.4%, and the very good partial response (VGPR) rate was 70.0%.
The FDA previously granted accelerated approval to teclistamab in October 2022 for adult patients with relapsed/refractory multiple myeloma who have received at least 4 previous lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.2 The regulatory agency granted accelerated approval to talquetamab for the same indication in August 2023.3
“I am optimistic about what we are seeing here, and I hope that we continue to explore these novel therapy options for many of our patients, because there is clear unmet need,” Raza, a hematologist/oncologist at the Cleveland Clinic in Ohio, shared with OncLive®.
In the interview, Raza discussed treatment challenges posed by the high-risk nature of patients with relapsed/refractory multiple myeloma complicated by EMD; the rationale for combining teclistamab and talquetamab in this study; key efficacy and safety outcomes; and the need for further exploration in a phase 3 population.
OncLive: Why are patients with multiple myeloma and EMD considered a challenging-to-treat population?
Raza: [RedirecTT-1] is a unique study. In multiple myeloma, we define studies based on [patients’] refractory status, how many lines of therapy [they have received], and the disease’s standard status, and we look for measurable disease. However, studies have never focused on EMD, where myeloma is present outside the bone marrow niche in places like the liver, kidney, or other areas. We have never had quality studies specifically answering this question; this is one unmet need we have.
This study [also] had unique criteria for how we define EMD, such as how it differentiates from paraskeletal diseases. These are different. We have figured that out, and this study uniquely defined these categories.
There are 2 different categories in myeloma: measurable—[or secretory]—disease and unmeasurable—or oligosecretory/nonsecretory—disease. This study allowed patients who were nonsecretory [to enroll] because these patients have unfortunately been excluded from many studies before.
Then the question always comes up: How do patients fare on these therapies? Generally, they do badly. This highlights one of the unmet needs: to explore therapeutic options and determine what type of therapies would be ideal. This study is trying to answer the question of whether we can improve survival for these patients.
How might the combination of teclistamab and talquetamab improve upon the efficacy of currently available treatments for this patient population?
To understand the efficacy, we first have to understand what options are available and how patients fare. [Patients with] EMD typically have poor outcomes, poor prognosis, and poor response rates. Historically, their ORRs are only [approximately] 24%, their median PFS is [approximately] 2.7 months, and their overall survival [OS] is also poor at [approximately] 7.2 months.
We know that bispecific antibodies are emerging, having shown promise in the management of relapsed/refractory multiple myeloma for patients in the United States who have received 4 or more lines of therapy. We have published on this, and other groups have also published studies on extramedullary and extra-osseous plasmacytomas, specifically on how [patients with these diseases] fare with CAR T-cell therapy.
In data with single-agent teclistamab, the ORR was approximately 43.4% in patients with EMD. This is compared with an ORR of approximately 78.9% seen in that broader study population. We can see that patients with EMD do poorly. [Research with single-agent] talquetamab has shown [an ORR of approximately] 43.5% [in patients with EMD].
These therapies by themselves have done a better job compared with historical drugs available for myeloma. However, as individual agents [in patients with EMD], they are not matching [the efficacy seen in] other patients. Therefore, this represents an unmet need to combine the 2 agents together to see how the patients do [with the combination] from an efficacy standpoint.
What should be known about the trial design, objectives, and patient population?
EMD was defined in this study as 1 or more nonradiated lesions independent of a bone lesion, such as a soft tissue lesion 2 cm in its greatest dimension. A PET scan indicated whether EMD was outside the bone marrow niche. These patients [also had] triple-class exposed, relapsed/refractory multiple myeloma. The study was unique because it allowed patients who had received prior CAR T-cell therapy [to enroll, which represented] 20.0% of the patients in this study. Additionally, patients who were nonsecretory and oligosecretory were included.
This study combining talquetamab and teclistamab [aimed to] first answer whether the approach was feasible. We already know from the earlier phase 1 [portion of] RedirecTT-1 that it is feasible. This was an extension arm to understand EMD. We administered talquetamab and teclistamab with the same step-up dosing, and after that, treatment was given every 2 weeks until disease progression.
However, the study allowed for treatment de-escalation: if patients achieved a VGPR after at least 4 to 6 cycles, they were permitted to transition to once-a-month treatment. Moving from every-other-week to once-a-month treatment [likely] allowed many patients in this study to follow this format.
We monitored patients by looking at PET scans, disease markers, and periodical evaluation to assess their outcomes. We also measured OS, PFS, the durability of the response rate, and, importantly, toxicity.
What efficacy results were reported from this study?
The median PFS reached 15.4 months, which is amazing, because standard therapy yields a median PFS of less than 3 months, and even the approved bispecific antibodies [only] provide a median PFS up to 4 months. It is astonishing that these patients have been doing so well.
The durability of the response was approximately 13.8 months. In total, 74.5% of the patients were alive at 1 year, and [approximately] two-thirds of the patients still had durable responses at 1 year. This is interesting because these are the kinds of data we have not seen before.
These patients had better PFS and OS than what we have heard about before; even their ORRs were better. This [patient population is] difficult to treat; they relapse quickly without many good treatment options available. From an efficacy point of view, [therefore, these data] are amazing and exciting.
What did this study show about the combination’s safety profile?
We have not noticed anything unusual beyond what we already know about bispecific antibodies. People are worried about cytokine release syndrome [CRS], but approximately 97% of CRS events and approximately 93% of immune effector cell–associated neurotoxicity syndrome [ICANS] events were resolved. They were mainly self-limiting and grade 1/2. One patient each experienced grades 3 and 4 ICANS. Otherwise, looking at the big picture, these were well managed and expected adverse effects [AEs]. They were managed with steroids.
Regarding hematological toxicities, the discontinuation rate due to these AEs was low. When combining the 2 agents, we noticed grade 3/4 neutropenia, anemia, and thrombocytopenia, but these are expected and well manageable.
Many colleagues ask us questions about [infections] with combining therapies. In this study, we noticed pneumonia and sepsis, but [the incidence of these was low, at] only 1 case, and this was nonfebrile. We noticed that some of these patients had aspiration and some respiratory pneumonias, but intravenous immunoglobulin [IVIG] in these patients would help many of them improve their infection risk. We noticed that IVIG helped mitigate those infections, but overall, we mostly observed grade 1/2 toxicities.
What next steps may further investigate teclistamab plus talquetamab in this patient population?
This [type of] study is difficult to do. This is not the type of study we are used to conducting in myeloma, because [it includes typically] excluded patients who [have poor prognoses]. They are symptomatic. [All treatments] need to be done quickly because they have poor survival. You have to act quickly. This is an area where there is an unmet need. We should continue to explore this [combination] in a broader population.
We already know from the phase 2 portion of the study, which involved 90 patients, that many of these patients are still doing well. The next phase would be to see if we can get this type of study into a phase 3 population, which will be challenging only because of the type of patients that are enrolling to receive this kind of therapy. However, these are compelling data, even in the phase 2 portion, and especially for patients who have EMD. I hope this combination will fill the gap of an unmet need, because many of these patients need [treatment] sooner rather than later. Combining [these 2] agents in patients who have high-risk disease, EMD, and early relapses can be a reasonable option because of the high response rates and manageable toxicity profile.
What future role might teclistamab plus talquetamab have in the overall myeloma treatment paradigm?
There are many studies ongoing with teclistamab and talquetamab either as single agents or combined with different agents. They are all ongoing studies. I encourage enrollment in clinical trials, because [RedirecTT-1] is a landmark study, and studies like that are trying to answer the question of whether we should use these agents in patients who are at high risk of dying early. For example, there are studies ongoing with bispecific antibodies in earlier lines of treatment.
The second [aspect of treatment with these agents that should be considered going forward] is the management of toxicity. We are learning and are encouraged by the results that the toxicities are manageable. As can be seen in the data from the RedirecTT-1 study, these toxicities can be managed. If patients are high risk, they can benefit from [this combination], and we should explore this option. These are strong data, and I expect they will be convincing for many providers and colleagues to use these agents together in patients who are high risk with poor survival [prognoses].
References
- Kumar S, Mateos MV, Ye JC, et al. Phase 2 study of talquetamab + teclistamab in patients with relapsed/refractory multiple myeloma and extramedullary disease: RedirecTT-1. Presented at: 2025 EHA Congress. June 12-15, 2025; Milan, Italy. Abstract LB4001.
- FDA approves teclistimab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed May 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma
- U.S. FDA approves Talvey (talquetamab-tgvs), a first-in-class bispecific therapy for the treatment of patients with heavily pretreated multiple myeloma. News release. Janssen. August 10, 2023. Accessed May 22, 2025. https://www.jnj.com/media-center/press-releases/u-s-fda-approves-talvey-talquetamab-tgvs-a-first-in-class-bispecific-therapy-for-the-treatment-of-patients-with-heavily-pretreated-multiple-myeloma