Etentamig Shows Success With Focus on Tolerability, Administration in Relapsed Myeloma

B-cell maturation antigen (BCMA) has been established as the most successful target for relapsed/refractory multiple myeloma in recent years, with antibody-drug conjugates, chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies being used to bind to and destroy myeloma cells expressing this protein. Bispecific antibodies have been held back by administration and tolerability barriers, leading to prioritizing approaches that reduce the complexity and risks involved in their use.

The phase 3 CERVINO trial (NCT06158841) is investigating etentamig, a BCMA-targeting bispecific agent structured to mitigate class toxicities and require less step-up dosing, making treatment in the outpatient and community settings more practical. The significant efficacy benefit seen vs standard therapies in the first interim analysis led to a recommendation for unblinding of the study.

In an interview with Targeted Oncology, Peter Voorhees, MD, professor of cancer medicine at Atrium Health Levine Cancer Institute and associate director of Clinical Research at the Atrium Health Wake Forest Baptist Comprehensive Cancer Center, who presented the findings from CERVINO at the International Myeloma Society Annual Meeting, discussed the significance of these promising results and the role this novel agent could play in the relapsed setting and beyond.

Targeted Oncology: Can you discuss the mechanism of action and the background for using etentamig for multiple myeloma?

Peter Voorhees, MD: As many people increasingly recognize, BCMA is an excellent target in multiple myeloma, and we already have 2 CAR T-cell therapies and 3 bispecific antibody therapies that are directed against this particular target in the T-cell redirecting space.

What sets etentamig apart is that it is is a bispecific antibody as well, but it has a low-affinity CD3 binding domain, and it was designed that way intentionally to mitigate the risk of cytokine release syndrome [CRS], and in particular, more severe cases of CRS. There was also the potential to lower the risk of T-cell exhaustion and immunosuppression with the use of a bispecific antibody with a lower affinity CD3 binding domain.

The other thing that sets this particular bispecific antibody apart from the others is that it has a high avidity bivalent BCMA binding domain. There are 2 BCMA binding sites on this particular bispecific antibody, which allows it to engage its target more avidly, and it also has [a] retained FcRn binding, which extends its half-life. As a result of that, after a single step-up dose, you're able to dose this once every 4 weeks, right from the beginning of therapy. The other bispecific antibodies, after multiple step-up doses, will typically start at weekly dosing, and then it will become less frequent down the line. But this is a unique circumstance where we're able to do this every 4 weeks, right from day 1.

What was the study design and patient population that were enrolled in this trial?

This was a randomized phase 3 study that looked at patients with relapsed and refractory multiple myeloma who were triple class exposed—they've been exposed to the 3 core pillars of myeloma therapeutics: the proteasome inhibitor class, the immunomodulatory drug class, and the anti CD38 antibodies. They had to have had at least 2 prior lines of therapy in order to be eligible, and they had to be anti-BCMA treatment naive. In many ways, this patient population is very similar to the KarMMa-3 [NCT03651128] study, which led to earlier line approval of the CAR T-cell product [idecabtagene vicleucel; Abecma] for patients with relapsed/refractory multiple myeloma, so this is a somewhat more heavily pretreated patient population. Patients were assigned 1:1 to either etentamig or to standard available therapy, and those standard available therapies could include the combination of carfilzomib [Kyprolis] and dexamethasone, elotuzumab [Empliciti] with pomalidomide [Pomalyst] and dexamethasone, or selinexor [Xpovio] with bortezomib [Velcade] and dexamethasone.

There were 2 primary end points for the study, the first being overall response rate, and the second one being progression-free survival with key secondary end points including overall survival, depth of response, and safety considerations.

What findings have been reported from the CERVINO trial and what is their significance?

The median age of patients that participated in the study was 70, and a little over two-thirds of the patients were 65 years of age and older. We had respectable representation from the US at 14.5% of the patients enrolled. There were patients that were treated in community settings, and there were also patients in the US in particular that were treated exclusively in the outpatient setting. The median time from myeloma diagnosis was 5.2 years, and patients had received a median of 3 prior lines of therapy, 52% of the patients had…triple class refractory disease… [and] 90% of the patients had disease that was refractory to their last prior line of therapy. [Also], 86% of the patients had disease that was refractory to CD38 antibody therapy, so this was a more difficult patient population to treat.

Despite that, both of the primary end points were met for this particular trial. In the etentaming arm, the overall response rate was 74%, [whereas] it was 45.7% for those receiving a standard of care. The progression-free survival [PFS] was also superior, and this was statistically significant relative to standard of care, with a hazard ratio of 0.4, with a median follow-up of approximately 11 and a half months. Median [PFS] had not yet been reached for the etentamig, and it was just 6.2 months for standard of care. When you look at overall survival [OS], there have not been enough events yet to declare statistical significance, but the trends for [OS] highly favor etentamig over standard available therapy; 12-month [OS rate] is 88% for those receiving etentamig, in contrast to 72% for those in the control arm, and the P-value for this difference is .0012. It’s looking awfully good in early days.

What's exciting about the study just as much as the efficacy, is the safety profile. The initial group of patients received full-dose etentamig every 4 weeks right from the get-go. There was an amendment that was issued later in the study based on some phase 1 dose optimization results that became available that showed that the CRS signal, which was already good, could be mitigated even further with a single step-up dose, so we had patients who got a single step-up dose [and] those [who] did not.

But when you look at CRS in totality, it was 39.5%. When you look at those patients who got the single step-up dose, the CRS rate was 28.3% There were no grade 3 or higher CRS events in either dosing strategy, and the vast majority of the CRS that was seen in the study was grade 1 in severity. The total number of patients who experienced ICANS [immune effector cell–associated neurotoxicity syndrome] was 3.6%, and that drops to 0.9% for those [who] received the single step-up dose.

The other thing to mention is the infection signal. When you look at grade 3 and 4 infections for those receiving etentamig, that came in at 27.7% [vs 19.2% with standard of care] which compares highly favorably to other BCMA-targeted bispecific antibodies that are currently available for clinical use. It gets to this idea that this low-affinity CD3 binding domain may mitigate some of the toxicities that we expect to see with these agents like CRS and the infection signal. The important thing also to realize is the rates of fatal infections was higher in the control arm at 3.1% vs just 1.5% for those receiving etentamig, and that also compares favorably with other BCMA-targeted therapies that are currently available for use for patients. That is certainly a very attractive element of this particular antibody.

When you look at all fatal treatment-emergent adverse events, it was lower in the etentamig arm than it was in the standard of care arm. It was just 2.6% with etentamig in contrast to 5.7% for those receiving standard available therapy. This speaks to the favorable safety profile of this particular agent and will allow treating providers to feel more comfortable using this in a community setting right from the beginning.

Where do you see this agent potentially fitting into the relapsed myeloma landscape?

These data obviously look good, and hopefully the results from the study will translate into eventual regulatory approvals across multiple jurisdictions around the globe. The nice thing about this particular bispecific antibody is that the way that it is designed lends itself for utilization in a variety of different clinical scenarios. Based on the favorable CRS and ICANS signal with the single step-up dose, and the fact that you're able to dose this every 4 weeks right from the beginning, this lends itself well to use in community practices, and it lends itself very nicely to strictly outpatient administration. We know that adoption of bispecific antibody therapies in the US—and I'm sure this is the case in other jurisdictions of the world as well—but adoption of these incredibly effective therapeutics has been suboptimal, and that's not good for patients. We're hopeful that this will be a game changer and increase the comfort level of using these things in the community setting.

What are your next steps with this trial, and where could this research lead?

As with anything, when you see a favorable signal for your therapeutic, there's always a strong rationale to move it into earlier lines of therapy. There are plans underway to develop this bispecific antibody further in earlier relapse as well as newly diagnosed patients, and [there are] ongoing studies. There's a platform study [NCT06892522], for example, that's ongoing with etentamig that is evaluating it in a variety of different clinical scenarios, including patients with newly diagnosed disease. There are a couple of cohorts using it as maintenance therapy after autologous stem cell transplant, and there are also a cohort in the early relapse space as well.

REFERENCE

AbbVie announces positive topline results from the phase 3 CERVINO trial showing etentamig significantly improved response rate and progression-free survival in patients with relapsed/refractory multiple myeloma. News release. AbbVie. September 3, 2026. Accessed September 3, 2026. https://tinyurl.com/4nefthxt