Teclistamab Combo Approval is ‘Excellent’ for R/R Multiple Myeloma

In March, the FDA approved teclistamab-cqyv (Tecvayli) plus daratumumab and hyaluronidase-fihj (Darzalex Faspro), introducing a new therapeutic option for patients with at least 1 prior line of treatment for relapsed/refractory multiple myeloma.¹ Furthermore, the results achieved with this combination in the phase 3 MajesTEC-3 trial (NCT05083169) represent some of the “best efficacy data” reported in the relapsed/refractory treatment setting, according to María-Victoria Mateos, MD, PhD.²

Following the approval, Mateos, investigator of the MajesTEC-3 trial, spoke with CancerNetwork® about how this regulatory decision will impact the multiple myeloma paradigm. She also detailed prophylactic strategies for mitigating the most common toxicities observed with teclistamab/daratumumab and how emerging treatment classes like CELMoDs may continue to expand the treatment armamentarium.

“This is one of the most exciting combinations we’ve seen for relapsed/refractory [multiple] myeloma,” Mateos stated. “This combination is going to be available in many centers, indicating that many patients can benefit from this combination. This is going to be excellent, especially for the patients with multiple myeloma.”

Mateos is the director of the Myeloma Program, a consultant physician in the Haematology Department, and associate professor of medicine at the University of Salamanca in Spain. She also serves as the treasurer of the International Myeloma Society.

CancerNetwork: What does the approval of teclistamab/daratumumab mean for patients with relapsed/refractory multiple myeloma? What might this regimen offer compared with other therapeutic options?

Mateos: The approval of teclistamab plus daratumumab in [patients with] relapsed/refractory multiple myeloma after at least 1 prior line of therapy represents the first BCMA bispecific monoclonal antibody–based combination for patients with [multiple] myeloma after at least 1 prior line of therapy.

The first important take-home message, based on all efficacy data we’ve seen with the BCMA-targeted therapies, is that after at least 1 prior line of therapy, when we have a patient [with myeloma] relapse, it is a good option to move immediately to BCMA-targeted therapies because all these combinations demonstrated, in phase 3 clinical studies, benefits in progression-free survival [PFS] and [OS]. If we focus specifically on teclistamab and daratumumab, this combination resulted in a synergistic combination, and the efficacy data were maybe the most exciting data and the best efficacy data we’ve seen in [patients with] relapsed/refractory myeloma with this combination. In addition, this combination is based on anti-CD38 BCMA bispecific monoclonal antibodies, and it is an off-the-shelf combination that does not require any manufacturing process. This combination is going to be available in every center, not only academic but also community-based centers.

How do findings from the phase 3 MajesTEC-3 trial support the efficacy and clinical utility of teclistamab/daratumumab in this patient population?

This is a phase 3 clinical trial, and teclistamab/daratumumab was compared with daratumumab plus pomalidomide [Pomalyst] and dexamethasone [DPd] or daratumumab plus bortezomib and dexamethasone [DVd]. The most important part is the primary end point. It was PFS, and after a medium follow-up of approximately 3 years, we’ve seen the lowest hazard ratio in a phase 3 clinical trial conducted in this population, with a hazard ratio of 0.17. The median PFS in the control arm was 18 months, so even longer than expected, according to the phase 3 clinical study that resulted in the approval of DPd.³ But in the teclistamab/daratumumab arm, at 3 years, 83% of the patient remained alive and progression free. In the PFS cure, there was a plateau phase from month 6, indicating that some patients could be potentially or functionally cured with this combination.Of course, this significant benefit in PFS translated into a benefit of OS, with 83% of the patients alive at 3 years.

What did MajesTEC-3 show regarding the safety profile of this regimen?

In MajesTEC-3, teclistamab/daratumumab was compared with 2 standards of care: DPd and DVd. These 2 standards of care are well known for [patients with] relapsed/refractory [multiple] myeloma. When we combine teclistamab with daratumumab, we have to consider that teclistamab is a BCMA bispecific monoclonal antibody. This means that cytokine release syndrome [CRS] is specific for the combination, and it presented in approximately 60% of the patients. But in a majority of the patients, 44% of the CRS was grade 1, and only 16% of the patients experienced grade 2 CRS. In terms of immune effector cell-associated neurotoxicity syndrome [ICANS], it was reported only in 1.1% of the patients.

Hematological toxicity is specific not only to teclistamab/daratumumab but also to the control arm, and neutropenia is the most frequent one. Teclistamab/daratumumab resulted in 75.6% of [patients having] grade 3/4 neutropenia. But in [the control arm], the incidence of grade 3/4 neutropenia was slightly higher: 78.6%. We must, however, focus on another specific type of adverse event that may be the most relevant one: infections. Infections were quite frequent in both arms. With teclistamab/daratumumab, 96.5% of the patients presented any-grade infections, and 54.1% had grade 3/4 [infections]. In the control arm, the rate of any infection was 84.1%, and the grade 3/4 [rate was] 43.4%. This means that infections are frequent in both arms.

How can clinicians best mitigate toxicities and protect quality of life among patients who receive this combination?

We need to educate the physicians on how to use this in clinical practice, especially in terms of infection management and strategies to mitigate and prevent these infections. The most frequent ones were COVID-19, upper respiratory tract infections, and COVID-19 pneumonia. The majority of these patients developed hypogammaglobulinemia; approximately 85% of the patients. Indeed, it’s important to recognize that 13 patients died in the teclistamab/daratumumab arm because of severe infections. However, we learned a lot about this process because 12 of these 13 patients died during the first 6 months of treatment; 3 of them because of COVID-19, and 9 had not received any dose of intravenous immunoglobulin. There is an explanation for this observation because MajesTEC-3 recruited patients between 2021 and 2023. At the beginning, when the study started to recruit patients, teclistamab monotherapy had not been approved yet, and there were no specific guidelines for the management of infections once this was observed. At the same time teclistamab approved, the protocol was amended, and this amendment included the strong recommendation for the use of support with immunoglobulins as well as adequate antiviral prophylaxis and anti-PJP prophylaxis.

What has been the result of these recommendations? As I previously said, 13 patients died during the during the first period of [the study]. Twelve of these 13 patients died during the first 6 months, but after this amendment, there has been only 1 patient who died beyond these first 6 months, indicating that this approach is, or has been, quite effective. Indeed, when we evaluate the grade 3/4 infections over time, these grade 3/4 infections are more frequent during the first 6 months. Beyond month 6, the incidence clearly decreased. In addition, [the rate was] quite comparable to the control arm.

There are 2 reasons for explaining this fact. The first one was prophylaxis. Also, teclistamab/daratumumab is given weekly during cycles 1 and 2, every other week for cycles 3 to 6, and monthly from cycle 6. When we moved to less frequent doses for teclistamab/daratumumab, the incidence of infections also reduced. From the practical point of view, my recommendation is to be alerted to the development of infections, especially upper respiratory tract infections, because COVID-19 is not a major issue right now. This is the reason why we have to implement adequate prophylaxis and support immunoglobulins from the beginning.

Opportunistic infections can also occur. We hope the incidence of infections, especially at the beginning, will decrease in comparison with the infection rate [along with] the number of patients who die because of infections in other trials that are coming. When we compare efficacy and safety, there is a good benefit/risk balance. Indeed, the efficacy we’ve seen with teclistamab/daratumumab is so impressive that it works to utilize this combination for [patients with] relapsed/refractory myeloma while trying to protect them from severe infections.

What are the next steps for researching daratumumab plus teclistamab in multiple myeloma?

The next step is to have much more data about the bispecific monoclonal antibodies in general. One of the limitations, or potential limitations, for this combination is all patients included in this study were sensitive to daratumumab, and there were 5% of the patients previously exposed to daratumumab or isatuximab. Patients [who were] refractory to daratumumab were not included in this study, and based on the treatment landscape for multiple myeloma in 2026 and beyond, a majority of our newly diagnosed [patients with] [multiple] myeloma are going to be treated with proteasome inhibitors, immunomodulatory drugs [IMIDs], and anti-CD38 monoclonal antibodies. Although not all patients are going to be refractory to daratumumab, a significant fraction of patients will be, and this combination may not be the ideal one [for them].

This is the reason why, in terms of next steps, we are going to have data from MajesTEC-9 [NCT05572515] very soon, in which teclistamab monotherapy is going to be compared with PVd or Kd. But the most important fact is the majority of the population is going to be refractory to both lenalidomide and daratumumab. Teclistamab monotherapy is the next step for this population. BCMA bispecific monoclonal antibodies are [not the only] future in early relapses. We will also soon have also data from the MonumenTAL-3 study [NCT05455320]. In this study, talquetamab is going to be combined with daratumumab or with daratumumab and pomalidomide. This combination represents another opportunity; talquetamab targets GPRC5D, and this is going to be extremely useful in order to sequence this T-cell–redirecting therapy, including BCMA CAR T bispecific monoclonal antibodies.

Looking ahead, what other potential developments in the multiple myeloma field have the potential to impact the treatment paradigm?

Other CAR T-cell therapies are moving to earlier lines of therapy, and this is the case for anitocabtagene autoleucel [anito-cel]. That it is being investigated in the phase 3 iMMagine-3 clinical trial [NCT06413498]…. I would like to complement this with combinations based on CELMoDs: iberdomide and mezigdomide. We recently had press releases about 2 new combinations: iberdomide [plus] daratumumab and [dexamethasone], and mezigdomide in combination with carfilzomib and dexamethasone.^4,5 What it is going to be the utility of theses combinations? They are going to be 2 additional standards of care, but from my point of view, they are extremely useful to sequence these T-cell–redirecting therapies because we have plenty of possibilities.

But the sequencing is not easy because we have to consider the target as well as the T cell fitness. Sometimes, to sequence these T-cell–redirecting therapies, we need a break to enhance the immune system. Why not utilize these new combinations based on CELMoDs because of their ability to enhance the immune system? Their future is exciting for [patients with] relapsed/refractory myeloma. All these new options are moving to earlier lines of therapy, and the next step will be to go to the first line of therapy.

References

1. FDA grants third approval under the National Priority Voucher Program. News release. FDA. March 5, 2026. Accessed April 3, 2026. https://tinyurl.com/45hhbpau
2. Mateos MV, Bahlis N, Perrot A, et al. Phase 3 randomized study of teclistamab plus daratumumab versus investigator’s choice of daratumumab and dexamethasone with either pomalidomide or bortezomib (DPd/DVd) in patients (pts) with relapsed refractory multiple myeloma (RRMM): results of MajesTEC-3. Blood. 2025;146(suppl 2):LBA-6. doi:10.1182/blood-2025-LBA-6
3. FDA approves daratumumab and hyaluronidase-fihj with pomalidomide and dexamethasone for multiple myeloma. News release. FDA. July 9, 2021. Accessed April 3, 2026. https://tinyurl.com/3bp4w53u
4. US Food and Drug Administration accepts Bristol Myers Squibb’s new drug application for iberdomide in patients with relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. February 17, 2026. Accessed April 3, 2026. https://tinyurl.com/4c8mb6ex
5. Bristol Myers Squibb announces positive phase 3 results from the SUCCESSOR-2 study of oral mezigdomide in relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. March 9, 2026. Accessed April 3, 2026. https://tinyurl.com/nc2m7cj4