Where should CAR-T cell therapy be positioned in the RRMM setting?

Where should CAR-T be positioned in the relapsed refractory myeloma setting?

I think it's a question that comes up a lot in our conversations with our community partners. You know, when do I refer a patient? And for patients themselves who read an article and are like, is this the right time? And, you know, the answer is always it depends.

So I think to my earlier point where every patient is unique, I think one of the privileges we have with this growing number of tools in our toolkit is to pick the right one for the right patient at the right time and be able to put all of that together.

So originally we got two different Car-T products for myeloma. They're both autologous, meaning we need to use the patient's own cells. They both target BCMA, but they work slightly differently. And they were both originally approved in patients on their fourth line of therapy. And they've both now gotten a second approval in earlier lines, slightly different, just based on the clinical trial that led to the approval.

So IDE-Cel is for patients in their second relapse. And Cilta-Cel is for patients in their first relapse. So they have to be exposed to certain therapies, be refractory to certain therapies. So there's some fine print separating the two.

On April 5th, 2024, the FDA approved new indications for both CARVYKTI and ABECMA. The FDA approved CARVIKTY for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to lenalidomide. The FDA approved ABECMA for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, and an anti Cd38 monoclonal antibody.

But I think the idea being as soon as second therapy patients could now be candidates for Car-T cells and Car-T cells are not an easy therapy, right? It's a very complicated therapy to administer. It requires specialized centers. And so proximity and availability of Car-T centers. I think the first deciding point for a patient who lives down the street would be very different than the patients who come to see me from out of state and need to have both themselves and a caretaker come be out of town. And all of those barriers to be overcome.

But as far as the myeloma part of things, you know, I have patients who get into their first remission and stay in remission for ten years. You know, they do very well that myeloma is contained. And so that's very different than a patient who has 2 to 3 therapies in the first year just to try to contain that disease.

So patients who relapse quickly, regardless of whether or not they have known high-risk features like cytogenetics, are really recognized as functionally high risk. And I think that is my top population of patients that I would offer Car-T earlier in that line of therapy, because we know the standard options we have are not being able to contain so functionally high risk.

I would go earlier rather than later, maybe an older patient who could really benefit from disease control off therapy. I had a number of patients who are approaching 80 and really have a hard time coming in for multiple therapies, and if we can get the expected three-year average, that may be the only therapy they need. You know, when they will be in remission, sort of in permanence. So I think that's a really good place for that as well.

But in a patient who's responded very well, who has good disease control, who maybe is in a second remission that is very easily contained, maybe that patient doesn't need to come to Car-T quite so soon.

We were very happy last year when Car-T cells were moved from the FDA approval for four plus lines, meaning and through four different lines of therapy to earlier lines that IDE-Cel is now approved for first line. And those that are refractory to lenalidomide. IDE-Cel, ABECMA is approved for those that have gone through two lines of therapy. This is tricky because here, it's very personalized. Should we move forward with this early? Because we have the indication, or should we wait because it is still a fairly new medication, it's still a fairly new treatment.

And there are side effects with these medications. There is a thought that these would be one and done and no maintenance, which of course is appealing. I think these are excellent treatments, but it is still a tough treatment. And it is a process. There's a lot of logistics involved and there are some side effects long term with infections. Also, we're seeing some, like still low risk but second malignancies and parkinsonism as well. So it's not obvious that our patients should get this in second line.

I'm very excited that we have these approved for early and earlier lines, particularly for those that have high-risk disease or have gone through the standard therapies. It's very, very good that we can use these early. However, it's a very long and informed and weighing the risk and benefit with each and every patient.

Is there something that we should do, when should we do it and when is it appropriate and for which patient? And I have very long conversations with my patients to say, when is a good time? Is this something that we should move forward with? And there's a lot of information, both in terms of the logistics, the short-term effects, side effects, and the long-term side effects.

So I would say to summarize, for those that have functionally high risk or high-risk patients, this is an excellent option to do early. For those that have had very long remissions and maybe not have gone through all of the standard of care therapies, that's a discussion that you need to have with each and every patient. It depends on a lot of the patient also what the patient's wish is in terms of going through that process of—it's somewhat similar to a transplant. So it is a tough treatment.

However, for most patients, there is a long time interval afterwards where there is no maintenance. There's no right answer. There's no wrong answer. It's very good that we have these available early, but it might not be appropriate for everyone to have them early. I think everyone should have the opportunity to have them and to have that discussion. And then it's up to the patient and the doctor to decide when is a good time.