Case 4: CAR T-Cell Therapy in Myeloma

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDC. Ola Landgren, MD, PhD:For a patient who has relapsed after 3 prior lines of therapy and comes back with aggressive presentation, like this patient, what are the projected outcomes with the established therapies that we have in our clinic, Ajai?

Ajai Chari, MD:I think this is a great example of how FISH [fluorescence in situ hybridization] may not encapsulate everything about a patient. This patient, when he was initially diagnosed, was categorized as intermediate risk. Within 1.5 years, this patient has gone through 3 lines of therapy. Sometimes, as clinicians, we have to recognize what’s happening in front of us, at the bedside. Going through so many regimens in a short time is telling you that they’re high risk. It doesn’t matter what the pathologist is telling you. You know this patient is high risk, and I think that’s an important consideration. With respect to the CAR T-cell study, the other feature that integrates this is it’s really an unprecedented number of lines of therapy for this population—a median of 7 lines of therapy. On the one hand, they weren’t high enough risk that they couldn’t get 7 lines. On the other hand, it’s a heavily treated population with an unmet medical need.

Data published inLeukemiain 2009 showed that double-refractory patients had an expected overall survival of only 9 months. At that time, this was based on treatment with an IMiD [immunomodulatory imide drug] or a PI [proteasome inhibitor]. Now, of course, we also have CD38 antibodies approved. Historically, somebody who has had such a short remission is an unmet medical need. There is no FDA-approved regimen for this patient that we are guaranteed to get benefit from.

The other point that I’d like to make, as we’ve said all along, and I think all of us agree, is that clinical trials are really always appropriate. But this patient’s presentation brings up another issue. We all know that there’s a tremendous selection bias in CAR T-cell therapy. From the day that you sign consent to the day that cells are collected to the day of the preparation and infusion of the CAR T-cell therapy, we’re talking 4 to 6 weeks. When you have explosive disease, those patients aren’t even getting signed…

I think there’s a real cherry-picking of patients who can wait through this period to get to the CAR T-cell infusion. That’s also important when we’re picking clinical trials. For this patient who has disease progression with bone disease, if you don’t pick an active therapy, by the time you finish screening, start a phase I agent, possibly at a homeopathic dose level, he is just going to progress and progress and have debilitating pain.

If a study was not appropriate, we may rapidly debulk with one of the 96-hour regimens, like DCEP [dexamethasone/cyclophosphamide/etoposide/cisplatin] or VD-PACE [bortezomib/ dexamethasone/cisplatin/adriamycin/cyclophosphamide/etoposide], so that you have a little bit of breathing room. You get them down. These regimens are not going to work forever, but if you debulk the disease and now have a biochemical progression that allows you to enter the study, that’s much better for this patient than getting in with such a high level of disease.

C. Ola Landgren, MD, PhD:I would agree with that. Nina, what’s your take on this patient?

Nina Shah, MD:I agree with a lot of what Ajai said. Right now, as this patient stands, I don’t think he would qualify for CAR T-cell therapy because he has an ECOG score of 2. I think it’s for EGOG 0-to-1 patients, and that’s something else we have to consider. I completely agree with you. It’s difficult putting people on this particular type of trial. You really have to thread the needle. You have to be good but not too good. You have to be bad but not too bad. It’s hard to know what would happen to this patient if they got CAR T-cell therapy. Hopefully, if there’s FDA approval at some point, we will know that better. In the absence of that, I think another important finding would be noting whether or not they had a t(11;14) translocation. We could consider something like venetoclax, although that’s off-label, as a potential salvage regimen. With these types of patients, you’re really grasping for whatever you can.

I like your idea about cytoreduction. Then, while that’s happening, you can potentially try to find some other drug, or venetoclax, or something like that. At this point, you really want to try to see whether you can improve the patient’s quality of life and get symptom reduction and disease reduction. They may or may not make it to a clinical trial, but you want to do the best that you possibly can.

Transcript edited for clarity.