IMiDs in Relapsed/Refractory Multiple Myeloma - Episode 7

How Do IMiDs Fare In Comparison With Emerging RRMM Treatment Options?

Drs Joshua Richter and Jonathan L. Kaufman consider where IMiDs fall in the RRMM treatment landscape in comparison with emerging treatment options, such as bispecific antibodies and CAR T-cell therapy.

Joshua Richter, MD: There’s an exciting world in front of us with immune therapies, specifically the bispecific antibodies and CAR T-cell therapies. One of the biggest questions is where do IMiDS [immunomodulatory drugs] fit in that paradigm, and there is going to be a very key role for them. CAR T therapy still represents the promise land of “one and done” where patients receive the CAR T therapy, and there is no need for further treatment after that. However, this is not proven to be a curative modality, so my prediction is that CAR T-cell therapy will evolve much like transplants have where, over time, we found that transplant is one and done, but we can improve progression-free and overall survival by adding drugs like lenalidomide. There are ongoing studies looking at plant maintenance after CAR T, and my feeling is that there is likely benefit for an oral maintenance therapy after CAR T. Again, this is an inability for patients to potentially improve their survival outcomes without having to get continued parenteral therapy. The same is true with bispecific antibodies, although those are not one and done. We know that every drug that comes along in myeloma tends to be approved in later-line therapy as a single agent, and over time, we move it further up and combine it, whereas the bispecific antibodies are not yet approved. Teclistamab is slated to be the first FDA-approved bispecific in August 2022. The likelihood is long-term based on some data from therapy, such as the TRIM trial. We are going to see combinations of drugs like teclistamab, talquetamab, Regeneron 5458, cevostamab, and all other bispecifics to be given in combination with IMiDs to help boost T cell responses and improve outcomes. IMiDS represent an optimal oral companion to some of our evolving immunotherapies.

Jonathan L. Kaufman, MD: We have a lot of new agents coming out: the antibody-drug conjugates, bispecific antibodies, CELMoDs, and CAR T cells, amongst others. CELMoDs are the next generation of IMiDs. We named IMiDs before we really understood what their mechanism of action was. Now that we understand IMiDs are really cereblon binding and modulating medications, we classify that the next generation of similar type drugs as CELMoDs. The first one that is being investigated is a drug called iberdomide, and then there are subsequent ones that are currently in clinical trials. Iberdomide has shown activity in the relapse setting, and it’s very likely that iberdomide is going to compete or relapse lenalidomide in the upfront setting or in the setting of smoldering myeloma. These are the types of clinical trials that we are currently doing and thinking about. When we think about the antibody-drug conjugate belantamab mafodotin, which is currently our first and only antibody-drug conjugate, when it works, the median duration of response is somewhere around 11 months. The downside is in the clinical trials, it works in about 1 in 3 patients and has significant toxicity like keratopathy. There are a fair number of combination studies asking the question: can we combine IMiDS like lenalidomide or pomalidomide with belantamab mafodotin to increase that response rate and lengthen that duration of benefit? With bispecific antibodies, these are very potent therapies being studied in the third-line and beyond settings, and there are combination studies being looked at, but the combination studies are with monoclonal antibodies. There will likely be a future state—this is not clinical practice yet but investigational—where somebody might have the bispecific antibody therapy, get a remission, and then use some sort of IMiDs as a maintenance therapy. Those questions are currently being asked in clinical trials with CAR T cells. Typically, when we first studied CAR T-cell late-line therapy, patients would get CAR T-cell therapy and solely go on observation. Despite the fact that they are very effective, it does not appear to be curative in myeloma, so there is a lot of investigation and asking if we can use IMiDS or CELMoDs as maintenance therapy after CAR T-cell therapy. The benefit could potentially be 2-fold; first, it could lengthen the progression-free survival, but can IMiDs or CELMoDs actually help with persistence of CAR T cells? [The second would be] allowing the CAR T cells to work better over time.

This transcript has been edited for clarity.