Bispecific-Based Approaches Highlight Key Multiple Myeloma Data Set to Emerge at EHA 2026

As the 2026 EHA Congress draws closer, multiple myeloma experts have their eyes set on several key presentations poised to address sequencing questions and the use of the bispecific antibody–based regimens earlier in the disease course.

To prepare for the meeting, OncLive^® gathered insights from key experts in the multiple myeloma field, including:

• Rahul Banerjee, MD, FACP, an assistant professor in the Division of Hematology and Oncology at the University of Washington and an assistant professor in the Clinical Research Division at Fred Hutchinson Cancer Center in Seattle, as well as a member, of the Content Committee for the American Society for Transplantation and Cellular Therapy, a member of the Plasma Cell Disorders Working Committee at the Center for International Blood & Marrow Transplant Research, and a member of the International Myeloma Working Group (IMWG)
• Joshua Richter, MD, an associate professor of medicine in the Division of Hematology and Medical Oncology at the Tisch Cancer Institute and director of Multiple Myeloma at the Blavatnik Family- Chelsea Medical Center at Mount Sinai in New York, New York
• Diana Cirstea, MD, an attending physician in the Center for Multiple Myeloma at Massachusetts General Hospital, as well as an assistant professor of medicine at Harvard Medical School, in Boston, Massachusetts
• Lore Gruenbaum, PhD, chief scientific officer and senior vice president of Research at Blood Cancer United

“Some of the biggest themes [in multiple myeloma at EHA 2026] are immunotherapy and how can we optimize that for patients, both in terms of, at one point in time, giving a bispecific plus additional drugs, and how we want to position CAR T-cell therapy and any maintenance therapy after that,” Richter said. “How are we best suited to mix and match some of these targets that we know work amazing as monotherapies? Can we use them all together?”

Phase 3, randomized study of talquetamab (tal) plus daratumumab (dara) ± pomalidomide (pom) vs dara plus pom and dexamethasone (DPd) in relapsed/refractory multiple myeloma (RRMM): MonumenTAL-3

Presentation time: Saturday, June 13, 2026, 12:00-12:15pm CEST

Richter: We've become enamored with BCMA and very familiar with it. At the current time, we have two FDA-approved BCMA CAR T-cell therapies and we have three FDA-approved BCMA-based bispecific antibodies, but we recognize that BCMA is not the answer for everyone, because BCMA is expressed on other cells besides malignant plasma cells. The immune suppression and infection rate are real. We also recognize that patients may not optimally respond to BCMA[-directed therapy]. Approximately 3% to 4% of [patients with] myeloma will have a biallelic 16p deletion and [do] not express BCMA; therefore, [targeting] it doesn't work. What talquetamab-tgvs [Talvey] allows us to do is harness the amazing power of T-cell redirection but use a different target [with GPRC5D].

One of the great things about [the phase 3] MonumenTAL-3 trial [NCT05455320] is that it allows us to follow the adage [that treatment] is not one-size-fits-all. Right now, a lot of talquetamab is used as bridging therapy to control disease before we get to CAR T. Well, what if talquetamab is not going to be enough? Now we can use this data to say, let's up the ante, add daratumumab [Darzalex], and [maybe] add pomalidomide [Pomalyst]. [We can also see] what happens when [patients] progress rapidly after a BCMA-directed therapy with bulky disease. We [may] now have a multifaceted combination with talquetamab at its core to deal with some of the more difficult-to-treat myelomas.

Banerjee: This is going to be the year of bispecifics. MonumenTAL-3 will be a plenary session at EHA presented by Peter Voorhees, MD, [of Atrium Health], and colleagues, and that will be of talquetamab, a GPRC5D-directed bispecific antibody in earlier lines [of therapy]. Interestingly, there was of a three-part randomization: talquetamab plus daratumumab, talquetamab plus daratumumab and pomalidomide , or daratumumab plus pomalidomide and dexamethasone [DPd]. Talquetamab is a great drug, but it can be a tricky drug in terms of [adverse] effects [AEs], [specifically] in terms of skin, nail, and tongue AEs. Some parts of talquetamab are spectacular. BCMA, for example, is found on basically every activated lymphocyte, so if you give someone a BCMA[-directed] bispecific, you are obliterating their immune system, and they absolutely need intravenous immunoglobulin [due to the] high risk of infections. Talquetamab only targets the malignant plasma cells—not the normal ones, not the B-cells. That sounds wonderful, but the protein is also found in skin, nail, and tongue cells, [leading to] these other AEs.

[Therefore, we have] a couple things [to note] here: one is with talquetamab plus other drugs—talquetamab plus daratumumab, for example—we know that teclistamab-cqyv [Tecvayli] plus daratumumab in [the phase 3] majesTEC-3 trial [NCT05083169] did phenomenally. How will talquetamab plus daratumumab do? We'll be really interested in finding out. Number 2, in this particular trial, the talquetamab is de-escalated aggressively, similar to how teclistamab can be de-escalated to every-4-week dosing, but even earlier. In MonumenTAL-3, if a patient achieved a very good partial response [or better], which, if you're responding, you do within a couple of months, you could move to monthly dosing as early as cycle 5, day 1. I'll be very curious to see how that does in terms of efficacy and holding the line against the myeloma, but also safety. Do you actually see that the dysgeusia, skin, and nail changes are improved when you rapidly go to monthly dosing, as opposed to [the phase 2] MonumenTAL-1 trial [NCT04634552], where it was 1-to-2-week dosing [with talquetamab] until the very end, so that's really exciting.

Talquetamab plus daratumumab with or without pomalidomide is also BCMA-sparing. I love BCMA targeting with an antibody-drug conjugate, CAR T-cell therapy, or bispecific, but not everybody wants that. Not everybody qualifies for [these therapies], and some people have gotten BCMA-targeting therapy and had a relapse. I have patients on MonumenTAL-3 right now, and many of them chose this trial because they were apprehensive about BCMA-directed CAR T-cell therapy so early [in the treatment course]. They wanted to wait a little bit until BCMA CAR T gets better, which indeed it is getting better year by year. Therefore, they picked a BCMA-sparing regimen like MonumenTAL-3, and I think that was an excellent choice. We'll see what the data show.

Gruenbaum: [It] is going to be really interesting to see whether talquetamab can actually be moved from the highly pretreated patient population to earlier lines of therapy. There are always concerns around infections and around immune toxicity, and then there are some target-specific toxicities that have been observed with talquetamab that are related to that. [GPRC5D] is expressed in keratinized tissue, so there's some oral toxicity, some dysgeusia/ taste alteration, severe dry mouth, dysphagia, etc, [along with] some skin/nail toxicities. Those have been observed, and so there's a question: Have we learned enough about how we use this agent and combination earlier that these toxicities don't become really limiting in terms of its use.

Teclistamab plus daratumumab (tec-dara) in patients (pts) with relapsed refractory multiple myeloma (RRMM): analysis of MajesTEC-3 based on cytogenetic and functional risk

Presentation time: Saturday, June 13, 2026, 6:00-6:15pm CEST

Banerjee: The subgroup analysis of MajesTEC-3 based on cytogenetic risk and functional high risk—full disclosure, I am presenting this at EHA, so I'm excited about it—but I am actually very excited about it because high-risk [disease] has been one of the most challenging things for us as a field, on 2 levels. One, high-risk, meaning early relapse, is devastating when it happens, because everything kind of falls apart. We have multiple studies showing that for patients who have early relapse, their subsequent survival is worse, regardless of when they had the relapse.

Two, our prognostication is not perfect for [defining high-risk]. The fact that we have a word called functional high-risk, when someone has an early relapse without you expecting it, shows us that our IMWG high-risk criteria are great, but they're not perfect. I still have patients where, unpredictably, the myeloma relapses earlier than expected, and it's tricky.

The question is whether the era of bispecifics can change this dismal paradigm for those patients. The short answer is, basically, yes. I encourage you all to look for the presentation; the abstract that's available online right now, including the Kaplan-Meier curves, and you can see that, for example, functional high-risk patients, as expected, do much worse with DPd [compared with] patients who don't have functional high-risk, meaning that patients who had relapse within 18 months of frontline therapy, and then go on to DPd, do way worse than patients who had a longer duration of response or had subsequent therapies thereafter. For teclistamab plus daratumumab, the difference [in outcomes] between [the functional high-risk subgroup and non–functional high-risk subgroup] is minimal at best. Stay tuned for more information here, but I'm hopeful for a world where functional high-risk no longer carries that fear factor the way that it does in all of our hearts, and I think that era is coming.

Richter: We're really trying to find out, are there subsets [of patients who] do better or worse with the individual therapy? Remember, a lot of our approvals and data are coming through with shorter readouts like minimal residual disease [MRD]–negativity rates, so we're looking at what happens with safety and efficacy in the long-term picture. Additionally, MajesTEC-3 brings us the question: what is the role of daratumumab [with teclistamab]? We think about daratumumab as an anti–plasma cell therapy and anti-myeloma therapy, but in the context of giving it with a bispecific, it also functions as an immune modulator to reduce regulatory T- and B-cells. Daratumumab is doing double duty in a regimen like this, fighting the myeloma and making the teclistamab work better to treat the myeloma.

MajesTEC-9: A phase 3 randomized study of teclistamab monotherapy vs investigator’s choice of pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone (PVd/Kd) in patients (pts) with relapsed refractory multiple myeloma (RRMM)

Presentation time: Saturday, June 13, 17:15-17:30 pm CEST

Cirstea: [The phase 3] MajesTEC-9 trial [NCT05572515] is arguably one of the most practice-relevant studies because it basically shifts [a bispecific antibody] up from a salvage therapy to an early-relapse immune therapy option as monotherapy, not as a daratumumab/teclistamab combination. In MajesTEC-9, teclistamab monotherapy was compared with pomalidomide, bortezomib [Velcade], and dexamethasone, or carfilzomib [Kyprolis] plus dexamethasone, after 1 to 3 previous lines of therapy in a population that was previously exposed to an anti-CD38 antibody and lenalidomide [Revlimid]. The important aspect here is that these are patients who have seen anti-CD38 monoclonal antibody therapy, as opposed to the MajesTEC-3 trial, where only approximately 5% of patients in those cohorts were [previously] exposed to daratumumab.

Richter: MajesTEC-3 was conducted in a population [that was not entirely refractory to daratumumab]. The MajesTEC-9 [population] more accurately represents what we might want to do in a patient who is daratumumab refractory; however, because daratumumab does have some immune modulation components, there may still be a role for this combination in patients [who are] refractory to daratumumab. What it comes down to is risk and benefit, recognizing that it probably works better giving these 2 drugs in combination, but when you block CD38 and BCMA, your infection risk really rises. If you have a patient that needs the benefit of a bispecific, but you worry about the infections, monotherapy may be your answer. Approximately 75% of patients in the United States are not CD38-refractory going into early relapse, and especially with bulky disease and that flat PFS curve we saw in MajesTEC-3, the combination of teclistamab and daratumumab may be more optimal for that patient.

See the MajesTEC-9 data initially shared at the 2026 ASCO Annual Meeting.¹

Daratumumab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: final analysis of transplant-ineligible patients in the phase 3 CEPHEUS study

Presentation time: Saturday, June 13, 2026, 17:30-17:45pm CEST

Richter: For many, many decades now, we have been thinking in the myeloma world that we should give high-dose therapy and autologous transplant to those who are eligible for it, and what CEPHUES is telling us is that some of our older, frailer patients who may not be eligible for transplant can still get these unbelievable outcomes. What we're starting to understand is that this is a well-tolerated, long-term regimen with a medium progression-free survival of approximately 100 months. You can take a patient in their 80s, start them on a regimen like CEPHEUS that, in the long term, has them coming in once a month for a subcutaneous shot with some pills at home, and your expected survival will exceed their [expected natural] survival, meaning they won't die of myeloma. For me, when I look at the long-term data from CEPHEUS, I want to know that when I start a patient on this journey, how can I negotiate the rest of their outcome to optimize both safety and efficacy?

See the final CEPHEUS data initially shared at the 2026 ASCO Annual Meeting.²

References

1. Mina R, Touzeau C, Hungria V, et al. MajesTEC-9: a phase 3 randomized study of teclistamab monotherapy vs investigator’s choice of pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone (PVd/Kd) in patients (pts) with relapsed refractory multiple myeloma (RRMM). J Clin Oncol. 2026;44(suppl 16):7507. doi:10.1200/JCO.2026.44.16_suppl.7507
2. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) in patients with newly diagnosed multiple myeloma: final analysis of transplant-ineligible (TIE) patients in the phase 3 CEPHEUS study. J Clin Oncol. 2026;44(suppl 16):7513. doi:10.1200/JCO.2026.44.16_suppl.7513