Bispecific and Trispecific Antibodies Advance Earlier Treatment of Relapsed or Refractory Multiple Myeloma

Clinical Summary:

• Ajai Chari, MD, examines the evolving role of bispecific and trispecific antibodies in multiple myeloma, including earlier treatment integration, novel antibody constructs, combination regimens, and strategies to improve safety and treatment duration. 
• Recent phase 3 trials have demonstrated substantial progression-free and overall survival benefits with bispecific antibody-based regimens, while emerging trispecific antibodies and novel combinations offer opportunities to deepen responses and improve outcomes in earlier treatment settings.
• These findings support expanding access to the off-the-shelf immunotherapies while emphasizing the importance of infection prevention, cytokine release syndrome management, and individualized treatment duration to optimize long-term efficacy and tolerability outcomes.

Ajai Chari, MD, University of California, San Francisco, California, discusses advances in bispecific and trispecific antibody therapies for multiple myeloma, including emerging combination regimens, novel antibody constructs, and earlier treatment integration. 

Dr Chari reviews findings from recent phase 3 trials demonstrating substantial progression-free survival benefits with bispecific antibody-based regimens, supporting their use earlier in the treatment course. He also discusses strategies to improve safety and treatment convenience, including infection prevention, prophylactic tocilizumab, and fixed-duration therapy, while highlighting challenges surrounding treatment discontinuation and retreatment. 

Transcript:

Hi, my name is Ajai Chari, I'm a professor of clinical medicine and the director of the myeloma program at University of California, San Francisco (UCSF). It's my pleasure today to be attending the LL&M conference 2026 in New York. 

Today I presented an update on bispecific and trispecifics in myeloma. I think the reason these products are so important is because they're universally available. They're an off-the-shelf product, unlike CAR-Ts and transplants which are restricted in access and eligibility, no absolute contraindication to getting a bispecific, so that's important. 

As a single agent in heavily treated patients, we saw a response rate of around 70% and a remission duration, or PFS, of around 1 to 1.5 years. So, what are the ways we can improve on those? 

I went through several strategies. One, for example, perhaps bridging chemotherapy. In one study from Canada, we can see that when you give bridging therapy for aggressive patients, the response rate can be as high as 100%, if they are adequately debulked. 

Next, you can move it in earlier lines of therapy. Instead of getting 60% responses to 70% in smoldering myeloma, we're getting 100% MRD-negative. Same product but less beaten-up patients with better T-cells. 

We're also trying to do new constructs, lower affinity molecules, new targets like cevostamab, FCRH5, trispecifics combining to more than 1 antigen– those are other strategies we can do. Lastly, combinations, right? We don't have to use these as monotherapy. 

That's a good segue to the next part of my talk, which was taking these combination strategies, which have shown in single-arm studies to be approaching 100% response rate in newly diagnosed patients. For example, Tec-Dera, and MRD-negative 100%. 

We have four pivotal phase 3 studies that have now been resulted. We have MajesTEC-3, which is Tec-Dara versus standard of care. Then we heard about MajesTEC-9, which is teclistamab monotherapy, in more heavily treated patients compared to standard of care. Then we have MounumenTAL-3, which is Tal-Dara plus or minus pomalidomide versus standard of care, and most recently CERVINO, which is etentamig versus standard of care.

What I think the message is from all these phase 3 studies, is that they're giving unprecedented efficacy. We're seeing hazard ratios of 0.1 to 0.3. While that may be impressive, when you compound it with the fact that these are compared against aggressive triplet comparators, for example, in MajesTEC-3, the control arm had PFS of 18 months, in MonumenTAL-3 24 months. Despite that, you're getting hazard ratios of 0.17 to 0.3, which means this is like David's not beating up against a tiny little creature– it's David and Goliath head-to-head, and we're still winning. 

These PFS benefits also translate into overall survival (OS) benefits, which is why I think we should be using these products as early as first relapse, particularly if you're CD38 and lenalidomide double refractory.

Then the last part of my talk was how do we make these products safer, more convenient? 

One thing that we saw, for example, with MajesTEC-3, which was the earliest study, we did see a crossover in overall survival because we did see more infectious deaths early on, in part because it overlapped with COVID, and in part because we weren't good with IVIG. 

Subsequently, MajesTEC-9 and other studies like MonumenTAL-3, we don't see that OS crossover. IVIG use, prophylactic tocilizumab to reduce the rate of CRS. For talquetamab, paying attention to skin, nails, oral tox, educating the patient, encouraging oral supplements, reducing the dose when the patient's responding, all important.

Lastly, how do we make these products safer? 

We talked about prophylactic tocilizumab, which can reduce the rates of CRS from 60% to 70% to 20% to 30%. With the low T-cell affinity engagers in studies like ramantamig, and recently etentamig, the CRS rates can be below 10%, perhaps suggesting we may be able to not have a REMS for myeloma anymore, but to be determined.

Also, last question relating to safety and efficacy is, can we stop therapy sooner? Do we need to treat everybody to progression? 

Several data sets, we had a UCSF data set presented at ASH showing maybe 9 months of therapy does just as well. The LimiTEC study showed also that fixed duration teclistamab, giving a PFS of 19 to 20 months, comparable to the original study, which is encouraging. I think the only downside of the fixed duration we need to study is if you do fixed duration, can you then re-treat with the same antigen down the road? 

So far, the data for that does not look as good. Only 1 out of 15 patients who relapsed on LimiTEC responded, and cevostamab, which was fixed duration, only 1 out of 6 patients. Despite stopping for non-progression, we're not necessarily able to recapture the disease.

Bispecifics are the new monoclonal antibody. They are widely available and patients are eligible for these, no major comorbidities or contraindications for this. Safe, efficacious monotherapy combinations, and exciting option for our patients.