Treating Relapsed/Refractory Multiple Myeloma With CAR T-Cell Therapy

Nikhil C. Munshi, MD:Now, you had mentioned that this drug [JNJ-4528] came out of the original LEGEND study. There’s a downstream LEGEND-2 study being presented. Any thoughts on that?

Parameswaran Hari, MD, MRCP:That, again, is cause for hope. We know that the responses are tracking the LEGEND study from China, so Dr [Bai-Yan] Wang from China presented data on the long-term follow-up of these patients. I think he reported a median duration of response of 22 months, which means half of the people at 2 years or close to 2 years are still relapse-free. And I think that bodes well for our future. But again with the caveat that those patients were less heavily pretreated than our other patients.

Nikhil C. Munshi, MD:Do you think these results are practice changing? And I’m trying to be provocative because we sometimes use the wordspractice changingloosely. But in this case, is it going to change what we do?

Parameswaran Hari, MD, MRCP:I’m absolutely certain [that it is]. I think we have to say that these are definitely practice changing. The relapsed/refractory myeloma population, triple-class refractory, penta-exposed in the majority, have a median overall survival rate of 6 months. For those patients to get into complete responses and MRD [minimal residual disease] negativity, which, even if they are not sustained for as long as we want, is changing the natural history of patients with relapsed/refractory, triple-class refractory myeloma.

Nikhil C. Munshi, MD:Let’s say this drug is approved. What patient population will we consider it for? I would keep in mind that it’s going to be approved in the situation where we are using it right now.

Parameswaran Hari, MD, MRCP:Right now, in trials.

Nikhil C. Munshi, MD:We all know that we already, in earlier stages of disease, utilizing this drug in the second line and third line; and we even have studies in the first line with high-risk patients, etcetera. And we can talk a little bit about it later. But if it is approved based on what we are doing right now, which patients would you think should get it? How would you sequence it?

Parameswaran Hari, MD, MRCP:Myeloma doctors are the most eternal optimists. We want to get the drug approved, and then we want to move it earlier and earlier. And I’m in the same boat as you. To be provocative, I would say we might even see better results and much longer progression-free survivals when we move it in the earlier space. So I think I’m itching just like you are, to get this drug into earlier relapse and even into the never-relapsed setting for a patient as a consolidation, perhaps.

Nikhil C. Munshi, MD:I’m totally with you. Do you think we will be using it in the heavily pretreated patient population? What do you think about the age, the patient’s performance status? The question ends up being, is it something that will require similar eligibility criteria as you do for allotransplant or autotransplant?

Parameswaran Hari, MD, MRCP:That is a very provocative question. If you look at the transplant uptake in this country, it’s about 30% to 35% of patients who get myeloma, even below the age of 70 who actually get an autotransplant. That is still a low number, and maybe more patients should be getting it.

But CAR T cells, at least in the LEGEND study, are actually less toxic even than a transplant. I think even older patients can handle this. There was no age limit on this study. Patients could be enrolled even in advanced stage. Most of our transplant studies in the past have kept the age at about 70. We have now clearly broken through that ceiling. Our population is aging. Our patients are older. We really need to do this for them. I would certainly be happy doing it in a patient who is not a traditional transplant-eligible patient, where myeloma is affecting their performance status. Allotransplant, I think, is probably going to go away because allotransplant is a crude form of doing T-cell therapy. Now we have a sophisticated, much more refined form of doing T-cell therapy, and I don’t think we will be using that technology.

Nikhil C. Munshi, MD:I share the same thought. I think we do not have to have the same level of stringency as we need for allotransplants, but even for autologous transplants, I think age limit is not as critical. We all have patients with CAR T-cell therapy who are about age 75 or in that range.

Parameswaran Hari, MD, MRCP:Absolutely, yeah.

Nikhil C. Munshi, MD:So I think that’s going to be quite clear. But do you think we would need to have patients use a certain treatment before we start giving a commercially available product? I would presume they should have it based on current eligibility criteria. They should have had prior exposure to a proteasome inhibitor, an immunomodulator, and an antibody, and those would be required. But that’s a 3-line treatment, and we now use 4-drug regimens, for which all those things are included. So do you think we would need to have, in younger patients, a transplant before we do it? Also, if they are given all 3 drugs in the first line, what can be given in the second line? Again, there’s no clear answer.

Parameswaran Hari, MD, MRCP:It’s a very provocative thought—that you have exposed a patient to something that incorporates all 3 lines, all 3 drugs. And then when they relapse, or when they have a really good induction and then relapse, why not go to the next class—the BCMA [B-cell maturation antigen] class? And the most powerful BCMA class, perhaps, in terms of response, is CAR T-cell therapy. I think that’s a thought that I espouse, and I think all physicians treating patients with aggressive myeloma will be thinking in that line. Again, it’s a 1-and-done treatment. Essentially, we can probably provide, for a longer time, a better quality of life for a patient instead of something that keeps happening every week or every 2 weeks.

Nikhil C. Munshi, MD:To that point, what do we do with the high-risk patient population? Use of CAR T-cell therapy, which gets us such a deep response and a good response and MRD-negative response. In high-risk patients, that might be a little bit different with this kind of treatment.

Parameswaran Hari, MD, MRCP:I agree that MRD negativity is even more important for the high-risk patient than the standard-risk patient. We all have standard-risk patients who respond for a really long time. But high-risk patients need to get to a CR [complete response] and MRD negativity. And clearly, from the data that we have so far, this seems to be the best method of getting somebody to be MRD negative in a very short time. And I think that, again, is where people like us would want to use this technology earlier than what’s being done now.

Nikhil C. Munshi, MD:So I think we have consensus. We actually are like-minded people who are discussing these very exciting developments.

Transcript edited for clarity.