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IMW 2021 | The future myeloma treatment landscape

Jesús San Miguel, MD, PhD, University of Navarra Clinic, Pamplona, Spain, talks on the future of myeloma treatment, highlighting research into precursor B-cells, the impact of the microenvironment on outcomes, circulating plasma cells, and resistance. Prof. San Miguel discusses the importance of tools for the identification of measurable residual disease (MRD) and early detection, and how these can be used to direct myeloma treatment. In addition, Prof. San Miguel gives an overview of the benefits of immunotherapies including antibodies and chimeric antigen receptor T-cell (CAR-T) therapies, and their potential use in earlier lines of treatment. This interview took place during the 18th International Myeloma Workshop (IMW 2021) congress.

Transcript (edited for clarity)

It’s really a pleasure just to be back again and to meet all the colleagues. And you asked me about the future of myeloma. And I like to think similarly to a football match. First of all, if you don’t know the Achilles’ heel of the enemy, you will not win the football match. And for the reason, our group in our lab, leaded by Bruno Paiva, we have decided to concentrate in four cell compartments that I think they may responsible for disease dissemination and resistance...

It’s really a pleasure just to be back again and to meet all the colleagues. And you asked me about the future of myeloma. And I like to think similarly to a football match. First of all, if you don’t know the Achilles’ heel of the enemy, you will not win the football match. And for the reason, our group in our lab, leaded by Bruno Paiva, we have decided to concentrate in four cell compartments that I think they may responsible for disease dissemination and resistance.

First, the clonal compartment. And we have identified that precursor B-cells are already mutated and have gene rearrangement, in other words, our message is that probably this pre-malignant situation that predispose to multiple myeloma early on.

Second, we have also concentrate in the microenvironment. Not only on the T-cells, also in the myeloid compartment because they influence the outcome of the patients clearly.

The third player that we are trying to control is the circulating plasma cell. It’s like Messi, the football player, very difficult to control, and they are responsible for disease dissemination. And now we know, we have data that this circulating plasma cell influence in the speed of progression in a smoldering multiple myeloma, and also has a clear, clear impact at diagnosis in active multiple myeloma. Probably is one of the most relevant diagnostic factors for prognostication.

Last but not least the resistant cells. Because I mean, this is the reservoir for potential relapses and we are investigating what are the genetic difference between the presenting and the resistant cells. With this in mind, the next step for me, for the future is to have the best tools to identify the efficacy of the treatment. And these are the tools for the identification of residual disease, minimal residual disease, inside and outside the bone marrow. If you don’t know the efficacy of the treatment, you are blinded.

So, early detection and early intervention, this is a paradigm in all the diseases. Obviously, it’s also, or should be also, in multiple myeloma. And now there is data that in high-risk smoldering myeloma, we can either delay the time to progression or probably trying to have a curative strategy at this time in point. And the other area is the active myeloma, everybody is expecting, okay. Most of the patient present with active myeloma. Standard and high-risk, in both situation, again, minimal residual disease is critical, and this should be the goal of the treatment, to try to eradicate the residual cells, this is obvious. And for this, I think will be a wrong philosophical approach, not to use the best treatment in a standard-risk and to reserve this for the high-risk.

For the high-risk, you need a different approach, more experimental approaches. And here brings the immunotherapy and this will be a major change and we are facing this change. Now we have data in later lines of therapy with bispecific antibodies, with CAR-Ts that demonstrate high efficacy. Particularly, if you think in complete responders that may have already a plateau in fifth line of therapy. Why not move this early on, particularly starting with the high-risk patients, then probably we’ll use in the standard-risk. Also, you can think not only in the immunotherapy, but we have also other new targets. We have selinexor, we have melflufen. We have the new generation of IMiDs that could be also better relevant. And also target therapies. Target therapy based on the genetic lesions. Therefore, I think the paradigm has clearly changed, and this is the future.

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