Approval of Teclistamab Opens Early Relapsed Myeloma to Bispecifics

The recent FDA approval of teclistamab (Tecvayli) and daratumumab and hyaluronidase-fihj (Darzelex Faspro) marks a major shift in the treatment paradigm, moving powerful bispecific antibodies from late-stage options into the early relapse setting for patients who have received at least 1 prior line of therapy.

The decision was driven by the results of the MajesTEC-3 trial (NCT05083169), a global study of 600 patients that demonstrated what experts describe as “unprecedented” efficacy. Data presented at the 2025 American Society of Hematology (ASH) Annual Meeting revealed a dramatic improvement in progression-free survival (PFS), with a hazard ratio of 0.17 (95% CI, 0.12-0.23; P <.0001), and a significant boost in overall survival (OS).¹ The regimen showed consistent benefits across all patient subgroups, including those with high-risk or extramedullary disease.

“This is a relatively simple regimen that brings unprecedented efficacy to a patient population that is much bigger and broader than where we previously used bispecific antibodies,” said Luciano Costa, MD. “This is also a validation of the putative synergistic mechanism between teclistamab and daratumumab, and again, a validation of the principle that the best therapies are better used early, where the impact  can be felt by more patients, and is even greater than in later lines of therapy.”

In this interview, Costa, who is Mary and Bill Battle Professor of Multiple Myeloma and director of the Multiple Myeloma Research and Treatment Program at the University of Alabama at Birmingham and primary investigator of MajesTEC-3, discusses the clinical impact of this approval. He addressed how bispecific antibodies provide a more accessible, scalable alternative to cellular therapies that are often restricted to specialized academic centers and stressed that strides have been made to optimize the safe administration of teclistamab.

As Costa notes, the approval establishes that teclistamab is no longer meant for exceptional cases but is now a mainstream second-line therapy that necessitates a new level of comfort and expertise among community oncologists nationwide.

Targeted Oncology: Could you summarize the key findings that led to the FDA approval of teclistamab and daratumumab?

Luciano Costa, MD: The FDA approval of teclistamab and daratumumab for patients with at least 1 prior line of therapy is based on the MajesTEC-3 trial. This was a large global trial of nearly 600 patients. They were patients with lenalidomide [Revlimid] and [proteosome inhibitor (PI)]-exposed multiple myeloma whose disease was not refractory to anti-CD38 monoclonal antibodies and not exposed to a BCMA [B-cell maturation antigen]-directed therapy. Patients were randomized between the experimental arm, which is teclistamab and daratumumab or a daratumumab-based triplets that could be Dara-Pd [daratumumab, pomalidomide (Pomalyst), and dexamethasone] or Dara-Vd [daratumumab, bortezomib (Velcade), and dexamethasone].

The study’s first interim analysis was recently presented at [the 2025 ASH Annual Meeting] and subsequently published in The New England Journal of Medicine, which showed that at a little over 34 months median [follow-up], there was a tremendous improvement in PFS on the experimental arm, with a hazard ratio of 0.17.1 That was also translated into an improvement in OS with a hazard ratio of 0.46. This supported regular approval of this combination but also led the FDA to issue a national priority voucher that accelerated the appraisal of the data so we could have a first data disclosure to treatment approval of 3 months.²

Where do you see the role of this combination being used following its approval?

Given the magnitude of the improvement that we see [vs] triplets, I think this is becoming an option, and I would even say a preferred option in patients with this treatment profile, because it’s hard to find any other therapy that is approved in the same setting that has similar efficacy—perhaps the only exception being CAR [chimeric antigen receptor] T cells, although trial populations are often different, and availability of that treatment is somewhat different, since it has to be administered in a cellular therapy center, and not every single patient has a cellular therapy center that is convenient. I think this is a scalable therapy that should be available to any oncology practice in the country that can deliver this unprecedented depth and duration of disease control to essentially just about any patient with relapsed/refractory disease.

Do any types of patients stand to benefit the most from this approval?

I like to say…that prognostication is predicated on the heterogeneity of outcomes. When you have a situation where you have a 3-year PFS [rate] of more than 83% and a PFS curve that looks more like a flat line, it’s hard to tell who does the best or who does the worst, because…the majority do very well.¹ There are very few episodes of disease progression in the whole study. At this point, we cannot really ascertain who benefits the least. The benefit in comparison to the triplets was seen across all patient subsets that were examined, including patients who are previously daratumumab-exposed, patients who never received a monoclonal antibody, patients with high-risk disease, patients even with extramedullary disease, [and] older patients. I think at this point it’s hard to pick out  data who would benefit the most [and] who would benefit the least. The benefit seems quite homogenous and covers essentially the entire spectrum of the patient population we see in this line of therapy.

Do you anticipate any challenges in translating this regimen from the clinical trial population into clinical practice?

I think that is really the biggest battle. The data are great; I think there’s a lot of resistance about embracing bispecific antibodies in just about any setting by primary oncologists. I think a lot of that is based on the perception of short-term toxicity with the cytokine release syndrome [CRS] and the fact that the patients require REMS [risk evaluation and mitigation strategy]…. On this trial, patients were admitted to the hospital during the step-up phase. I think for some centers, that becomes logistical, and for some even a financial barrier.

Perhaps the most important safety piece of this trial is that nobody died from CRS. Nobody had grade 3 or higher CRS.¹ So what we’re dealing with is a syndrome that for the majority of patients is nothing, or just a fever, and about 1 in 6 patients need a little bit more, which is short-term oxygen or fluids. So, this does not amount to the type of toxicity that would require, necessarily, a hospital setting. Many practices throughout the country are becoming familiar with administering this type of therapy entirely outpatient with some measures like tocilizumab [Actemra] given prophylactic or very proactively, or more liberal use of corticosteroids.

I think it’s going to take a little bit of time for the community to gain familiarity, which makes even more important the initiatives that we all have to educate and facilitate our peers to build comfort with this therapy, because it’s here to stay. It is no longer an exception, a treatment to be used at academic settings later in the disease. It’s a treatment that everybody who is treating myeloma needs to be comfortable with because it’s mainstream now, second line therapy.

Have you seen success in promoting the greater adoption of bispecifics among oncologists?

Absolutely. I think [we need] educational opportunities [and] building channels of communication between general oncologists and myeloma programs in academic centers, not with the message [to] send us your patients, because we’re special by doing this, but the message is, this is now mainstream treatment; we can share with you the mitigation strategies that we have. Learn, so you can use that in your practices. For the last couple of years we have seen, even in our area, several regional practices gain comfort and start adopting bispecific [antibodies] in the outpatient setting.

What else do you think clinicians should know about employing this regimen?

I think the take-home message is, it’s highly active therapy. There [are] some nuances about implementing that are worth going through because of what it delivers for patients long-term. What people need to know is CRS is a transient...inconvenience of the first week. When you treat 300 patients, [and] nobody dies, nobody gets sick, I don’t think we [should] call it a big problem....

What is really the biggest safety challenge is the increased risk of infection. There are now well developed, published, validated guidelines that greatly reduce the risk of infection in patients getting bispecific antibodies. The International Myeloma Working Group has one; there are several others.³ Anybody willing to use those therapies need to open those guidelines and implement fully at a minimum that includes IVIG [intravenous immunoglobulin] replacement, [Pneumocystisjirovecii pneumonia] prophylaxis, [Varicella-zoster virus] prophylaxis and aggressive workup and management of the patient every time they present with signs or symptoms that could indicate infection. I think so long you do that, you’re delivering great value to your patient.

REFERENCES

1. Costa LJ, Bahlis NJ, Perrot A, et al. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N EnglJ Med . 2026;394(8):739-752. doi:10.1056/NEJMoa2514663

2. FDA approves teclistamab in combination with daratumumab hyaluronidase-fihj for relapsed or refractory multiple myeloma. News release. US FDA. March 5, 2026. Accessed March 12, 2026. https://tinyurl.com/mry968za

3. Rodriguez-Otero P, Usmani S, Cohen AD, et al. International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma. Lancet Oncol. 2024;25(5):e205-e216. doi:10.1016/S1470-2045(24)00043-3