Bispecific T-Cell Engagers and Novel Approaches for the Treatment of Multiple Myeloma

Teclistamab, Talquetamab, Cevostamab, and IFNα2b-Targeting Agent Modakafusp Alfa

At the 2022 Lymphoma, Leukemia & Myeloma Congress in New York, Dan Vogl, MD, University of Pennsylvania, Philadelphia, PA, provides insights into different options for bispecific T-Cell engagers, such as teclistamab, talquetamab, cevostamab, in the treatment of multiple myeloma. Dr Vogl also touched on the novel molecule modakafusp alfa. 

Transcript:

Hi, I'm Dan Vogl, associate professor of medicine at the Abramson Cancer Center at the University of Pennsylvania. I'm here at the Lymphoma, Leukemia & Myeloma Congress 2022. I was invited to present an overview of bispecific T-Cell engaging antibodies for multiple myeloma—which ones to use and when. 

In my talk, I covered both an overview of bispecific T-Cell engagers and an introduction to a new molecule that I'm very excited about called modakafusp alfa. For bispecific T-Cell engagers, we're all really excited because these molecules are moving into the clinic hopefully in the coming days with the introduction of teclistamab, which is a bispecific T-Cell engager aimed at B-cell maturation antigen (BCMA), an exciting new target in multiple myeloma. Teclistamab will soon be followed by several other molecules that are making their way through clinical trials, all aimed at BCMA, which share high response rates, a manageable toxicity profile and will be exciting options for our patients.

We do think that we're going to be administering these agents initially in the hospital for the first few doses, because of the risk of cytokine release syndrome, which although usually not severe, can still cause fevers and fatigue for patients, and may require management with tocilizumab. But over time, we're hoping that we'll be able to move these agents completely into outpatient administration and will have a choice of several different agents with different modes of administration, frequency of dosing, and perhaps different efficacy and side effect profiles.

We're also excited that 2 additional agents aimed at different targets—FcRH5 for cevostamab, or GPRC5D for talquetamab, are also in clinical trials. Because these agents are aimed at different targets, the mechanisms of resistance to bispecific T-Cell engagers are likely going to be different. We're already starting to see in our trials that patients who have a good response to a bispecific T-Cell engager aimed at 1 target and then have progression while receiving therapy can be switched to another T-Cell engager aimed at a different target, and still get a good response. And so, in the future, we'll probably be using these agents in sequence and also in combination.

We're starting to see combination trials come out, especially of teclistamab and talquetamab in combination with daratumumab, showing both high response rates and overall good tolerability with no clear increase in side effects. In the future these agents will probably also move earlier in lines of therapy, although for the near future, we'll probably be using them in patients with at least 3 prior lines of therapy who are refractory to all 3 classes of currently highly effective agents.

I also reviewed an exciting new molecule that really doesn't fit into other categories: modakafusp alfa, which is an antibody-interferon-fusion protein that directs interferon alpha (IFNα2b) signaling to CD38-positive cells. The results of early trials of modakafusp have recently been presented showing response rates of 43% in a highly refractory patient population, including a response rate of 39% in patients who were previously refractory to an anti-CD38 monoclonal antibody, and responses in patients who were previously refractory to anti-BCMA therapy.

So, ongoing trials with modakafusp are defining the response rate in a larger patient population and looking at 2 fixed doses.

Source: 

Vogl D. T Cell Engagers (Bispecifics) Which and When. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-22, 2022. New York, NY.