Exploring MRD Testing and Data in Myeloma to Guide Treatment Decisions

Bispecific antibodies represent a promising advancement in the treatment of relapsed/refractory multiple myeloma, offering targeted immune activation against cancer cells. An in-person Case-Based Roundtable meeting in Dallas, Texas, on bispecific treatment was moderated by Jeffrey V. Matous, MD, clinical professor of medicine at the University of Colorado Health Sciences Center and acting chair of the Myeloma Committee at Sarah Cannon Research Institute at HealthONE in Denver, Colorado. He highlighted the unprecedented response rate and durable remissions seen with teclistamab [Tecvayli] in heavily pretreated patients, as demonstrated in the MajesTEC-1 trial (NCT03145181, NCT04557098). However, challenges remain in managing the adverse events seen with this type of therapy.

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: What were the baseline characteristics from the MajesTEC-1 trial of teclistamab in relapsed/refractory multiple myeloma?

Jeffrey V. Matous, MD: There was a median of 5 prior lines of therapy, all patients were triple-class exposed, many penta-class exposed, and most had prior transplants. These were the kind of patient, where doctors were seeing these patients and thinking they do not know what to do next. Those are the patients who went on these bispecific studies.

What were the response rates and duration of responses in these patients?

When pomalidomide [Pomalyst] came out, the response rate was 30% for pomalidomide/dexamethasone.¹ There were very few complete responses [CRs], mostly partial responses [PRs]. It got FDA approved. Carfilzomib [Kyprolis] had the same thing. Daratumumab [Darzalex] monotherapy had the same thing. The bar was at 30% response rate. That's where the bar was for the patients who were relapsed and refractory. The response rates here with teclistamab were an overall response rate of 63%;² not just responses, but we're seeing very deep responses, stringent CRs, CRs, and very good PR. There were high quality responses. This was unprecedented, and this is what resulted in FDA approval for teclistamab.

The duration of response is impressive in these patients. If you look at data before in these patients, their median survival was less than a year prior to the bispecifics. If they had CR, the median duration of response was not reached. Otherwise, other patients were getting very durable responses. We still have patients experiencing progression early here, but we're getting a lot of very durable responses.²

Do you stop therapy at some point for patients with multiple myeloma who receive teclistimab?

The [efficacy] is unprecedented. I have patients on these trials who are still in ongoing remission, sometimes off of therapy. These are amazing treatments. The label says [to treat] until progression or adverse events. That's normally what I do. When I'm using this off trial, I'll give it until adverse events or progression, but I'm lengthening out the treatment intervals. I have stopped for a few patients for various reasons—for toxicity, especially when we're giving it weekly, I've stopped.

I have some patients who ask after a while if they can stop. The answer is we don't know that. We're trying to learn if we can stop and retreat a progression. But one thing I've done in my practice is I'll check minimal residual disease [MRD], and I'll do a bone marrow test by clonoSEQ for MRD. If they're negative by MRD, I'll say it's reasonable for you to think about stopping and [telling them] “We can retreat you if you'd like to do that.” Now, if I have a patient who's in their sixth, seventh, or eighth line, and they had horrible disease that we reined in, I'm going to be less enthusiastic about stopping therapy in that patient. But if I'm using it in earlier relapse, and it's behaving, and it wasn't a horribly aggressive relapse, then it can be considered.

What were the characteristics of patients who didn’t respond to teclistimab in MajesTEC-1?

Part of that is there are certain patients who don't have much BCMA [B-cell maturation antigen], for example, on their cell surface. And there are patients who rapidly lost BCMA on therapy. Their disease mutated and lost the target. That's been seen a lot as well. Those are 2 of the major mechanisms for resistance to the bispecifics. [If] you give teclistimab and then didn't get a response, they must not have much BCMA. In the future, when it's easier to look for BCMA, I think we will.

What was the safety summary for these patients?

For safety, one thing to point out is that all these studies with the bispecifics were done during the height of the [COVID-19] pandemic. The COVID infections included grade 3 and 4 infections. Infections are the Achilles heel of the BCMA bispecific therapies…. Over half the patients had grade 3 or 4 infections. Part of this is that BCMA therapies, both chimeric antigen receptor T cells and bispecifics cause significant hypogammaglobulinemia. So when you're starting with BCMA bispecifics, you count on getting hypogammaglobulinemia. During the conduct of these studies, after a while they asked if we should be giving these patients intravenous immunoglobulin [IVIG]. The answer was an overwhelming yes, that we should be doing that. So the standard of care if you're giving a BCMA bispecific is, if you have an immunoglobulin G [IgG] level below 400 mg/dL, you should be giving prophylactic IVIG.

A common question I get from physicians is, what if my patient has IgG myeloma, and their M-protein spike is 0.6, and their IgG level is 1000 mg/dL. I go, that's 1000 minus 600 ballpark, give them the IVIG. If you put somebody on a BCMA bispecific, count on giving them IVIG. One thing we've seen is when we decrease the interval between the doses, we've seen IVIG requirements decrease. Especially when you go to monthly or every other month dosing, we've seen that that happen.

The cytokine release syndrome [CRS], I have found, is the biggest worry to physicians giving the bispecifics…. That seems to be the biggest hurdle in my experience with adoption of the T-cell redirecting therapies. Three quarters of patients get CRS with teclistamab. Almost all of that is grade 1 or grade 2. Rarely is it more severe than that.

DISCLOSURES: Matous previously reported serving on advisory committees for BeiGene and Janssen, and serving on a data monitoring board for BeiGene.

REFERENCES:

1. Fotiou D, Gavriatopoulou M, Terpos E, Dimopoulos MA. Pomalidomide- and dexamethasone-based regimens in the treatment of refractory/relapsed multiple myeloma. Ther Adv Hematol. 2022;13:20406207221090089. doi:10.1177/20406207221090089

2. Garfall AL, Nooka AK, van de Donk NWCJ, et al. Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(suppl 16):7540. doi:10.1200/JCO.2024.42.16_suppl.7540