The Lowest-Ever Hazard Ratio in Multiple Myeloma Bispecific Trials?

CancerNetwork^® spoke with Ajay K. Nooka, MD, MPH, FACP, professor and director of the Myeloma Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and associate director for clinical research at Winship Cancer Institute of Emory University, about topline results from the phase 3 MonumenTAL-6 trial (NCT06208150). The trial showed that teclistamab-cqyv (Tecvayli) plus talquetamab-tgvs (Talvey), a dual BCMA- and GPRC5D-targeting regimen, reduced the risk of disease progression or death by 89% (HR, 0.11; 95% CI, 0.08-0.16; P <.0001) and the risk of death by 62% (HR, 0.38) compared with investigator’s choice of elotuzumab (Empliciti) plus pomalidomide (Pomalyst) and dexamethasone (EPd) or pomalidomide plus bortezomib (Velcade) and dexamethasone (PVd) in patients with relapsed/refractory multiple myeloma who received 1 to 4 prior lines of therapy, including an anti-CD38 antibody and lenalidomide.¹ Talquetamab plus pomalidomide reduced the risk of progression by 73% (HR, 0.27; 95% CI, 0.2-0.35).

Nooka discussed what these results mean for how he counsels patients, the barriers to community deployment, and where the multiple myeloma therapy field is headed next. He framed the results from MonumenTAL-6 as an early signal of a broader shift, with several more phase 3 readouts of bispecific and CAR T-cell combinations expected in earlier lines of multiple myeloma therapy over the next several years. Altogether, the current data represent the beginning of the “immunotherapy deluge” in multiple myeloma practice, according to Nooka.

CancerNetwork: This is the first phase 3 study of a dual-antigen BCMA/GPRC5D regimen in relapsed/refractory multiple myeloma, and the teclistamab/talquetamab combination posted an HR of 0.11, reportedly the lowest for any phase 3 bispecific study in this setting. What does a risk reduction of that magnitude mean for how you would counsel a patient with relapsed disease today, even ahead of the full data?

Nooka: If you start to think about the evolution of multiple myeloma therapies, bispecific antibodies have changed the entire landscape of multiple myeloma and how we treat it in the relapsed/refractory setting. The BCMA-targeting bispecific antibodies and the GPRC5D-specific antibodies set new benchmarks.

The first study presented for a BCMA bispecific antibody, teclistamab, is the MajesTEC-3 trial [NCT05083169], presented at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.² There, teclistamab plus daratumumab and hyaluronidase-fihj [Darzalex Faspro] were compared against standard-of-care therapies, daratumumab plus pomalidomide/dexamethasone [DPd] and daratumumab plus bortezomib/dexamethasone [DVd], for an HR of 0.17 in patients who were daratumumab naive. That was the best HR reported at the time, about 6 to 7 months ago.

Now, the GPRC5D bispecific, talquetamab, is approved in the late-relapse setting; in that setting, response rates were 70% to 75% against an expected response rate of less than 30% in that population. We know it is a very good agent. In one of the earlier trials exploring talquetamab combinations, talquetamab plus pomalidomide showed a lot of correlative data on how the immunomodulatory agents help with immune activation, which is why that became the second arm of MonumenTAL-6. The primary arm uses talquetamab and teclistamab together. The [phase 1/2 RedirecTT-1 trial (NCT04586426)] had shown that this combination, even in heavily refractory patients, including those with extramedullary disease, achieved a response in close to 80% of patients.³

That is how the 3 arms of MonumenTAL-6 were designed, compared against a control arm of [investigator’s choice of EPd or PVd]. For the experimental arm of teclistamab plus talquetamab, the PFS HR is 0.11, the best HR we have ever seen in the history of multiple myeloma. This has also been shown in the secondary end point of overall survival, where the HR was 0.38, a 62% reduction in the risk of death in early-relapse myeloma. These are all favoring the use of talquetamab and teclistamab as a combination.

This is how I counsel my patients: the traditional therapies we use—[daratumumab plus pomalidomide and dexamethasone or daratumumab plus bortezomib and dexamethasone]—should now be considered second-line therapies. The primary focus should be on engaging the new targets, BCMA and GPRC5D.

How does MonumenTAL-6 fit into this broader shift toward moving bispecifics earlier in the treatment journey alongside trials like MajesTEC-3?

We struggle with exactly where the space is for all of these, but I will try to give my best explanation. If you think back 5 years, we were using traditional therapies in the early-relapse setting. The current standard of care is a 4-drug therapy as induction, whether patients are transplant eligible or ineligible. Then, patients either get a transplant or no transplant, and go on to maintenance. When the patient progresses for the first time, that becomes the most crowded area.

Before the advent of these immunotherapy combinations, we had traditional therapies using combinations of carfilzomib [Kyprolis], a proteasome inhibitor, or the other proteasome inhibitor, bortezomib, in combination with daratumumab and others. All these combinations achieved category 1 recommendations in the NCCN guidelines based on the superiority of 1 regimen over another in randomized phase 3 trials, and that accounted for 100% of patients receiving those regimens.

Now, when we look at the [phase 3 MajesTEC-3 trial (NCT05083169)], you can see these standard regimens are inferior to the combinations of BCMA bispecific therapies or GPRC5D bispecific therapies, and they should be supplanted with the new therapies. Do I expect the change to happen right away? It takes time, but eventually, these bispecifics should take over completely for patients in that first or second relapse. We also have BCMA CAR T-cell therapies in this space approved based on the KarMMa-3 trial [NCT03651128] and the CARTITUDE-4 trial [NCT04181827].^4,5 All of these should ultimately be offered to the patient first, and it needs community engagement, where the community is ready to accept these treatments and offer them, so there can be wider acceptability of these combinations in the early-relapse setting.

From your perspective of running a high-volume academic myeloma program, how realistic is broad community deployment of a 2-drug bispecific regimen such as teclistamab and talquetamab given their toxicity profiles?

If you think about the uptake of bispecific antibodies in the community, there have been several barriers. Barrier number 1 is the step-up dosing: how should it be given? We have a Risk Evaluation and Mitigation Strategy (REMS) program for these. [When] patients should be hospitalized, there are charge models where hospitals do not get reimbursed. Hospitals have not had as much buy-in for engaging community physicians to do this safely. That has been one logistical barrier.

The second [barrier] is that these are new treatments, and the barrier comes from community physicians: if there is cytokine release syndrome or neurotoxicity, even though the higher grades happen very rarely, can they take care of these patients when they are dealing with 30 other patients in clinic that day? The third [barrier] is understanding these new drugs’ unique adverse effect [AE] profiles. GPRC5D has a lot of gastrointestinal toxicity, weight loss, skin rash, and nail toxicities. How do we come up with the right education for community physicians? At the same time, the third stakeholder is the patient: how much are they willing to accept these AEs?

Unless there is a comprehensive understanding of all of this, the education gap between the community physician and the patient will remain a barrier. These are complex barriers that could mainly be addressed through education and access. When that can happen, there will be a free flow of use of bispecific antibodies in the community, and that is what we want, so patients can get these drugs and have access to them close to home.

Beyond the MonumenTAL-6 trial, what other potential developments or ongoing studies in multiple myeloma may further impact the paradigm?

What we are seeing, currently, is just the beginning of this immunotherapy deluge. We talked about the bispecific antibodies currently approved: teclistamab, linvoseltamab-gcpt [Lynozyfic], and elranatamab-bcmm [Elrexfio] are the 3 BCMA bispecific antibodies, and talquetamab is the GPRC5D bispecific antibody. What we expect is similar phase 3 results in earlier phases, in maintenance, and in the frontline setting in the future with combinations of all these treatments. These are all randomized phase 3 studies that are ongoing and have completed enrollment.

MajesTEC-3 and MonumenTAL-6 showed HRs of 0.17 and 0.11, the best ever reported. In the future, do we expect these numbers to be beaten? I do not know, but I am optimistic about the good new treatments that will be available for our patients, without access issues.

What do you hope others take away from these topline results?

Our treatment landscape has changed drastically over the last 20 years, more prominently in the last 5, with immunotherapy. With all the advances, we have BCMA CAR T-cell therapies, a GPRC5D CAR T-cell therapy in development, antibody-drug conjugates targeting BCMA that are approved, and GPRC5D antibody-drug conjugates in clinical trials. We have moved away from those older targeted therapies; we are in the immunotherapy era, and we are expecting improved versions of CAR T-cell products with more persistence, more durable responses, and lower AE profiles. There are several of these in the pipeline as well. More is good in this space. We want the approvals so we can choose the right treatment for the patient, and this is all in service of having a myeloma-free outcome for our patients.

References

1. Tecvayli + Talvey reduced the risk of disease progression or death by 89% and the risk of death by 62% in earlier-line relapsed/refractory multiple myeloma. News release. Johnson & Johnson. July 23, 2026. Accessed August 4, 2026. https://tinyurl.com/3ee86wxk
2. Mateos M-V, 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. Kumar S, Mateos MV, Ye JC, et al. Dual targeting of extramedullary myeloma with talquetamab and teclistamab. N Engl J Med. 2026;394(1):51-61. doi:10.1056/NEJMoa2514752
4. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614
5. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379