Expert Discusses Ongoing CAR T-Cell Research in Myeloma

Nina Shah, MD

Chimeric antigen receptor (CAR) T-cell therapy could bring hematologists closer to a curative strategy in multiple myeloma; however, there are still areas of refinement that need to be addressed, said Nina Shah, MD.

Mainly, researchers now know that CAR T cells are tolerable, but Shah explained there are patient concerns with the therapy’s benefit before they face financial toxicity. Efficacy data are still in preliminary stages, and numerous clinical trials are ongoing.

Updated data presented at the 2018 ASCO Annual Meeting showed that the BCMA-directed therapy bb2121 induced a complete response rate of 50% in a heavily pretreated patient population. The median progression-free survival (PFS) was 11.8 months with a duration of response of 10.7 months. The phase II portion of the CRB-401 trial is ongoing.

Moreover, Shah, an associate professor of medicine at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, discussed the potential impact of moving CAR T-cell therapy into an earlier setting, and how combining it with an immunomodulatory (IMiD) agent could enhance the activity.

OncLive: Please provide an overview of your presentation.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Shah discussed the present and future of CAR T-cell therapy in myeloma.Shah: I spoke about where we are with CAR T-cell therapy in myeloma. We have had some great data in this area, but it was very interesting to hear the new ideas that were shared at the meeting. Right now, we know the body of literature for CAR T cells is very preliminary. It's only been presented at the 2018 ASCO Annual Meeting and 2017 ASH Annual Meeting. We know what the median PFS is for these patients. We know the median PFS is a little bit higher when patients have minimal residual disease (MRD) negativity. It's exciting when you consider how heavily pretreated these patients are, but there are areas we can do better.

What are some challenges with CAR T cells in myeloma?

IMiD agents with CAR T-cell therapy could make the response last longer because we think persistence is important. There could maybe be some novel ways to engineer or culture CAR T cells so that they could eventually last longer in therapy.If you would have asked me this 1 year ago, I would have said cytokine release syndrome. While this is common—probably around 63% of patients get this—it's relatively well-controlled. We have more experience with it, too. For example, we know when to give dexamethasone and other agents to make patients more comfortable. Safety has been replaced by efficacy as our biggest concern. Putting this patient through something that is a couple of months long, you want it to be worthwhile.

How important has depth of response been in multiple myeloma?

How does CAR T-cell therapy impact the role of transplant?

Another big concern is financial. We're not sure how much each product is going to cost, who will reimburse it, and who will be eligible to be reimbursed. Those things are going to have to be clearly written out before we move further. This all ties in with accessibility.It's becoming increasingly important. It could potentially be an endpoint in clinical trials if we could get the FDA on board with this. We know from many analyses that deeper response is better. We know that MRD negativity is also important, as we've seen in lymphoma. It's not to say that being MRD negative will prevent you from ever relapsing, but we know these patients have a much better prognosis. Using clinical trials to answer these questions will be very important. I'm looking forward to it.A lot of people have been wondering this with all the therapies we now have at our disposal. Transplant is still very effective and important. I offer it to nearly all of my patients. We now know that just because a patient is elderly doesn't mean they are transplant ineligible. There are ways to modify the transplant based on the patient. As far as what the transplant adds, in just about every clinical trial it's been looked at, we see it adds something. It affects PFS.

Are there studies looking at infusion of 2 different types of CAR T cells?

What has the evolution in treatment been like in recent years?

Could CAR T-cell therapy cure patients with myeloma?

Myeloma is a marathon of a disease, and we want to keep people in remission as long as possible. It's important for patients to live a normal life, and if we can keep them on maintenance therapy for as long as possible, we're happy. Transplant still has a role. These new therapies will soon be moved into earlier settings, at least that's what we hope. In that case, maybe it would affect the way we look at transplant.There are a number of studies doing this. They look at getting to the potential pre-plasma cell or myeloma stem cell aspect of the tumor. For example, they're looking at BCMA-directed and CD19 co-infusion of CAR T cells. Some of these preliminary data were presented. These combinations look safe, we just don't know about the efficacy.We are in the first parts of CAR T-cell therapy in myeloma. We have a lot of people working on the same target, and now that we're getting data we see that there is room for improvement. I hope that we don't abandon further innovation just because we have something that has been widely accepted.My prediction for this is that it will be effective for some, but not all, patients with myeloma. The reason I say this is because myeloma is still one of those diseases that is extremely difficult to get rid of. Perhaps you will get rid of the cells that are causing the problem, but you're not getting rid of the cells initiating the myeloma. People will have long-term good outcomes, but we have to make sure it's worth putting patients through [the treatment.]

Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007).