Nahas on Emerging Topics of Importance in Multiple Myeloma

George R. Nahas, DO

Trials have shown the continued and encouraging benefit of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies for the treatment of patients with multiple myeloma as a later line of therapy. However, ongoing research may show their potential in earlier lines of therapy.

At the 2023 ASCO Annual Meeting, a number of studies demonstrated promising data with these therapies, including the CARTITUDE-4 trial (NCT04181827) of ciltacabtagene autoleucel (cilta-cel) in lenalidomide (Lenvima)-refractory patients with multiple myeloma, and the MajesTEC-1 study (NCT04557098) of teclistamab (Tecvayli) in patients with relapsed/refractory multiple myeloma.

Another study, the phase 1 DREAMM 9 trial (NCT04091126) of belantamab mafodotin (Blenrep) which targets BCMA, showed early activity with a promising safety profile for patients with relapsed/refractory multiple myeloma.

“The idea that myeloma is not really treated with chemotherapy anymore is great. The field just keeps moving further. The thing that's going to be interesting to see is, as these trials and as more data mature, we will see CAR T-cell therapies and bispecifics moved up in the earlier lines of therapy, as early as second-line, so that's exciting,” said George Nahas, DO, in an interview with Targeted Oncology^TM.

In the interview, Nahas, attending physician, and hematology and oncology specialist at Miami Cancer Institute, discussed relevant research on chimeric antigen receptor therapy, bispecifics, and more that are moving the needle in multiple myeloma research.

Targeted Oncology: What is the most relevant topic in the multiple myeloma space today? What are your thoughts on this topic?

Nahas: The most relevant topic in the current landscape is probably the use of immunotherapy, specifically CAR T cells and bispecific T-cell engagers in later lines and even earlier lines of therapy, and when to use them. These are new therapies. They are available for later lines of therapy. For example, I mentioned CAR T cells first because they are the most talked about and have the greatest efficacy so far. We have the updates to the CARTITUDE-4 trialfor our patients with relapsed/refractory myeloma. This is a phase 1/2 trial. These are patients who are triple-class refractory with 4 lines or later treatment. Originally, results demonstrated 95% plus, 98% overall response rate with high complete response rates as well. This is a later line treatment for patients who are difficult to find good responses like this for.

With the 2023 ASCO updates, these are patients who again are fourth-line therapy and on, almost all of them are refractory to a prior line of therapy, with a median of 6 lines of therapy. This extended follow-up demonstrated that these patients still have a prolonged response rate. The other thing that's relevant is minimal residual disease, including minimal residual disease-positive vs -negative and how relevant 1 vs the other is. We strive to achieve minimal residual disease negativity in our patients with multiple myeloma, and quite frankly, 1 of the more relevant points with the CARTITUDE trial was demonstrating that those patients who did achieve MRD negativity remain negative. They achieved negativity, and many of them stayed with that MRD negativity for a longer period of time as well, which did translate into a longer progression-free survival [PFS].

What are the key highlights from the CARTITUDE-4 trial?

The biggest highlight was probably for patients who did achieve MRD negativity. For a lot of those patients, or at least half of those patients, they retained their MRD-negative status with this longer time point that was evaluated, and it did translate into a longer PFS.

What ongoing research do you think will be important for the future of the treatment landscape?

It's important to mention bispecific trials because not only do we have the MajesTEC trials demonstrating a similar patient population of patients who are relapsed/refractory with later lines of therapy, these are patients who are refractory to the most recent therapy as well, these patients also had a great overall response rate of 60 plus percent with CR rates as high as 40% or so percent. We have a BCMA bispecific, but are there other bispecifics that we can combine too. Recent data at ASCO also demonstrated that combining 2 biospecifics did have an overwhelmingly amazing overall response rate of up to 90 plus percent. That is going to be something moving forward. Can we combine bispecific T-cell engagers? The other question is, when we have to use bispecifics for CAR T, how early can we use them? These are important research points that are certainly being studied now and they'll give us a lot of information in the future on how to treat our patients.

We saw long-term results of the MajesTEC-1 trial at ASCO this year. What are the key findings you can discuss?

[The] overall response rate was 60 plus percent with a CR rate of 40% or so. The duration of response at 24 months is something else that we saw in the MajesTEC trial, and quite frankly, for those who achieved CR, the median duration of response was not reached. More importantly too is that safety signals weren't there or similar to what they were in the previous trials. There were no increased safety signals or worsening safety signals that we saw with these updated results.

We also saw results from the phase 1 DREAMM 9 study. Can you discuss belantamab mafodotin and its history in the relapsed/refractory space? Do you think this drug will have better success in the newly-diagnosed patient population?

This is the first drug that was available targeting BCMA. This is not bispecific, it's not a CAR T-cell, but it's an antibody drug conjugate. It's a little bit different and off-the-shelf, it can be used. By itself in an earlier DREAMM study, it demonstrated around a 31% overall response rate with around a CR rate of 1%. I just gave you these amazing CR rates, complete response rates, and overall response rates with these other 2 agents. Now, I'm talking about a drug that only has this pretty small efficacy rate here.

This is the updated trial. It is phase 1, and it [looks at,] can we add this BCMA agent, belantamab mafodotin to [bortezomib, lenalidomide, and dexamethasone] VRd for transplant in eligible frontline patients. They can use different dose levels. The highest dose level did demonstrate a whole 100% overall response rate, which is great, and deep responses with regard to MRD negativity, as high as about 80% or so. This is promising. This is a drug that's being added to a backbone of VRd. We've seen this before in patients, so it is kind of like adding another target in a quad-based regimen as opposed to our traditional triplet with VRd. I think there's something to be said here about its efficacy. There is still an adverse effect that's unique to belantamab, which is keratopathy. But just like a lot of our adverse effects, it's something that we hopefully will get better at, identifying and treating with those adjustments and delays as time goes on. This is certainly an interesting drug that as of right now, is not on the market or commercially available, but it probably still has a role at some point. I think we're slowly discovering how to use it in a better way.

Are there any other studies or topics in the multiple myeloma space that you're excited about?

The idea that myeloma is not really treated with chemotherapy anymore is great. The field just keeps moving further. The thing that's going to be interesting to see is, as these trials and as more data mature, we will see CAR T-cell therapies and bispecifics moved up in the earlier lines of therapy, as early as second-line, so that's exciting. As much as CAR T cells are amazing, there's a lack of access that we have. We need to expand the ability to not only produce it faster, but to make them more readily available. Technology always gets better, and I'm confident that those issues will be resolved as time goes on, and we'll be able to broadly use these agents in early lines of therapy.

Overall, clinical trials are key to moving the field forward. Otherwise, we wouldn't have these amazing, these amazing agents that are being studied and going to be available sooner rather than later.