Navigating the Later-Line Landscape: Insights from the MajesTEC-1 Trial

The treatment paradigm for relapsed/refractory multiple myeloma has undergone a seismic shift, yet the triple-class exposed patient population remains one of the most clinically demanding cohorts in oncology. For these patients—many of whom have exhausted proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies—the historical outlook was often measured in a few short months of progression-free survival. However, the emergence of B-cell maturation antigen (BCMA)–targeted therapies has redefined what advanced disease means for both clinicians and patients.

The MajesTEC-1 trial (NCT04557098)^1,2 focusing on the bispecific antibody teclistamab (Tecvayli), stands as a landmark study in this space. Conducted during the unique logistical and clinical pressures of the global pandemic, the trial accrued with remarkable speed. This rapid enrollment was driven by a critical unmet need: at the time, long waiting lists for chimeric antigen receptor (CAR) T-cell therapies left many high-risk patients without viable options. As noted by Amrita Krishnan, MD, FACP, City of Hope Medical Center, the trial population was exceptionally heavily pretreated, with a median of 5 prior lines of therapy—and some patients having navigated as many as 22 prior regimens.

A New Benchmark for Efficacy

The results of MajesTEC-1 provided a stark contrast to the historical performance of single-agent therapies in the later-line setting. Where clinicians were accustomed to modest response rates of 24% to 30%, teclistamab demonstrated an unprecedented overall response rate (ORR) of 63%. Perhaps most significant for clinical practice was the depth of these responses, which included stringent complete responses (sCRs).

The durability of these outcomes is equally compelling. For those achieving a very good partial response (VGPR), the median duration of response (DOR) reached approximately 25 months, while the median DOR for those in a complete response (CR) was not even reached at the time of analysis. With an overall median progression-free survival (PFS) of 11.4 months, these data suggest that bispecific antibodies offer a potent, “off-the-shelf" alternative to cellular therapies.

Lessons in Safety and Prophylaxis

Beyond efficacy, the trial offered a steep learning curve regarding the safety profile of bispecific antibodies. The intersection of the pandemic and the immunosuppressive nature of BCMA-targeted therapy highlighted the necessity of rigorous supportive care. Early data revealed that 18 out of 22 grade 5 infections were attributable to COVID-19, underscoring the vulnerability of this population. These findings have since solidified the role of intravenous immunoglobulin (IVIG) supplementation and prophylaxis against opportunistic pathogens like Pneumocystisjirovecii (PJP) as standard components of the treatment protocol.

The clinical focus is shifting toward precision selection. The current frontier of research aims to utilize immune profiling and disease characteristics to identify "super-responders" before therapy initiation. By understanding the biomarkers of response, clinicians can better navigate the complex choice between bispecifics and CAR T-cell therapies, ensuring the right treatment reaches the right patient at the optimal time.

During a live Community Case Forum event in Huntington Beach, California, Krishnan reviewed the results of the MajesTEC-1 trial and discussed the efficacy of teclistamab.

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Targeted Oncology: Which efficacy outcomes are most significant to you?

Amrita Krishnan, MD, FACP: This trial was done during the [COVID-19] pandemic, so it was pretty challenging times for us. The trial accrued extremely quickly, though, because first of all, at that point, there were very few spots for CAR T cells. Literally, our patients had 5 to 6 months waiting lists. So this wasn't the issue then of, how do you choose? There was no choice. So it was a good thing in terms of the trial. Realistically, it was a good thing for patients, because the drug worked quite well. The median age of [patients was] 64, [with] 5 median prior lines of therapy, [and] some up to 22 lines. One of my patients on this had 21 lines of prior therapy. So, [we] clearly had a very challenging group of patients.

How do the latest outcomes compare with other therapies used in the later relapsed/refractory setting?

When we started this trial, we all did this around the world. We were used to the drugs, I won't mention their names, [with] response rates [of] 24% to 30% as single agent. So, we were pretty shocked to see a response rate of 63% including CRs and [sCRs]. Our only comparator was CAR T in this advanced disease population. So, to be able to get CRs was pretty unprecedented for us, and a good [DOR] as well. The median [DOR] of patients in a CR wasn't reached; in patients [with] VGPR, it was about 25 months. Pretty decent for those responders. Just as an aside, I can tell you the biggest area of research now is trying to figure out who are these responders. Can you figure out before you start this, based on immune profiling, based on disease characteristics, who is going to respond to the drug, because clearly that's what you want to be able to do when you choose a therapy. This is just in terms of PFS data. Median PFS overall was about 11.4 months. But in patients in CR, the median PFS was not reached.

If you look at safety…this was during the pandemic…these were the days where we didn't really have any treatment for COVID-19. So not surprisingly, 18 of the 22 grade 5 infections were due to COVID-19. This was our first bispecific. We didn't know you had to give IVIG. We didn't know you had to prophylax against PJP. All these things were a big learning curve for us.

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REFERENCES:

1.A study of teclistamab in participants with relapsed or refractory multiple myeloma (MajecTEC-1). ClinicalTrials.gov. Updated February 13, 2026. Accessed February 23, 2026. https://clinicaltrials.gov/study/NCT04557098

2.Moreau P, Garfall A, van de Donk N, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med 2022;387:495-505. doi: 10.1056/NEJMoa2203478