Ankit Kansagra, MD, an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center and assistant director of the Outpatient Stem Cell Transplant Program, talks about the potential for changes to combination therapy for multiple myeloma (MM) with the approval of chimeric antigen receptor T-cell agents and the introduction of quadruplet therapy.

In part three of this interview with Dr. Kansagra, available December 15, he discusses newly approved therapies for MM and highlights drugs in the pipeline.

DocWire News: Do you foresee combination therapy for multiple myeloma changing in the next few years, and how would this impact the treatment paradigm and potentially guideline-directed care?

Dr. Kansagra: Let’s talk about patients with newly diagnosed multiple myeloma. Right now, we know that for the majority of the country, the standard of care is a combination of three different medication—may it be bortezomib or [carfilzomib], those are the proteasome inhibitors, lenalidomide, and dexamethasone.

There is a huge debate nationally, or internationally, about adding a fourth agent improves things. There are questions about improving response and the durability of response. Can you get the response, first? And can you sustain that response? Those are two different questions. We know most of the therapies, as of today, including the triplet therapies, are able to get a response; it’s the durability that is an issue, and can they persist for a longer time or getting the patients into minimal residual disease (MRD), or the lowest disease possible.

Some call it measurable residual disease, some call it minimal residual disease. The point that comes up too is, “Are we going to a quadruplet therapy?” And the answer to that is yes. I think we are going to a quadruplet therapy, but “For who?” is going to be a point and “For how long?” When do you increase the intensity of therapy? When you decrease the intensity of therapy? Would MRD be a guide to deciding how those therapies are done? Those are going to be some of the crucial factors in deciding. So I don’t think quadruplet is needed for every single individual with newly diagnosed myeloma. There are subsets who will benefit from it, and there are subsets who probably do not need that aggressive treatment.

For combination with CAR-T cells, I think that’s probably a more challenging question. The first question is, scientifically, should we combine something to CAR T-cell therapy to improve its response? As I mentioned earlier, CAR T-cell therapies in lymphoma have shown certainly more impressive responses than what we might have expected in myeloma. Having said that, the diseases are completely different; the biology is completely different. We certainly don’t want to compare apples and oranges here. But obviously, there is a challenge in front of us: How are we going to have these CAR T-cells persist to be effective for a longer period of time? Obviously, there has been an ongoing debate and also a lot of clinical trials ongoing, which are thinking of adding medications to the CAR T-cell therapy treatment.

And that may be medications like immunomodulatory drugs or proteasome inhibitors. IMiDs or [lenalidomide] or [pomalidomide], those are certainly key targets here to think of. Even checkpoint inhibitors have been used in some clinical trials, like PD-1 or PD-L1 inhibitors in some clinical trials. I think those are another avenue of interest.

The more important question, to me, is what combination to use rather than what are the potential mechanisms of relapse? Why is CAR-T not working for individual A compared to B compared to C? Is it because the cells are not persisting? Is it because they are losing the BCMA expression? Is it because the CAR-Ts are not expanding at all? And the intervention for each bucket is potentially going to be a different intervention. Some might need a BCMA-targeted ongoing therapy after a CAR T-cell therapy. That might be a strategy in one population, whereas other might need just augmentation with an IMiD. Maybe there is a third, who does not need any intervention at all.

Scientifically speaking, as a physician-scientist, I would think an important thing for us to understand is what are these different categories of patients where we would intervene differently and appropriately. If I’m talking to my patient as a physician, as a clinician, sitting in the patient’s room and thinking of the challenges in the healthcare system, we loved CAR T-cell therapy that we don’t have to combine with anything. The initial two years, we loved it, that you get CAR T-cell therapy. My patients tell me, “Hey doc, I feel like I don’t have myeloma at all.”

That’s the comment I get very often from my patients who have received CAR T-cell therapy. The majority of these guys have got stem cell transplant before and have been on maintenance therapies and some ongoing treatment. When it comes to us doing some combination along with CAR T-cell therapy, that is certainly a bummer from them saying, “Hey, this was kind of one of those hopes, where we would have done a one-time thing and it would work forever.”

From the patient’s perspective, from a healthcare cost perspective, from a physician sitting in front of them and trying to think what is the easiest in their patient-reported outcome standpoint, I’m not too excited about combining things, but I suppose that it is going toward that way to get the best efficacy. So I think rather than saying, “Everybody should get a maintenance therapy,” like we do for transplant for a big chunk of our patients or pretty much everybody in the United States, I think we will have to think of a much more scientifically-driven answer about who benefits from it.

Watch part 1 of the interview with Dr. Kansagra where he discusses CAR T-cells in development for MM.