Expert Covers Burgeoning Role of CAR T-Cell Therapy in Myeloma

Maung Myo Htut, MD

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated potential for patients with relapsed/refractory multiple myeloma, and improvements in efficacy and safety may facilitate its transition into earlier-stage settings, says Maung Myo Htut, MD.

“At some point, it might replace the more targeted current standard of care, which is autologous stem cell transplant,” Htut explained.

Data from the phase I CRB-401 dose-escalation study presented at the 2017 ASH Annual Meeting showed that treatment with the BCMA-directed CAR T-cell therapy bb2121 induced complete remissions for 56% of patients with relapsed/refractory multiple myeloma.

The objective response rate for bb2121 was 94%, which consisted of a very good partial response or better for 89% of patients. After 40 weeks of follow-up, the median progression-free survival (PFS) had not yet been reached. The 9-month PFS rate was 71%.

Ongoing clinical trials are investigating other potential targets, such as CD44v6, CD8, and CD138. Htut suggests that in the future, researchers may even be able to combine these targets into 1 T-cell product.

OncLive: Please provide an overview of your presentation.

What is the protocol at City of Hope?

Were the response rates from the 2017 ASH Annual Meeting impressive?

How does the evolution of CAR T-cell therapy in multiple myeloma compare with other hematologic malignancies?

If CAR T-cell therapy is moved upfront, what are the sequencing challenges physicians would face with other agents?

Are there any other clinical trials that compare with the CRB-401 study of bb2121?

Are there any other clinical trials that you are excited about?

What about combination immunotherapies?

What area of research would you like to see move forward in the field?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Multiple Myeloma and Myeloproliferative Neoplasms, Htut, assistant clinical professor of hematology and hematopoietic cell transplantation, City of Hope, discussed the use of CAR T-cell therapy in multiple myeloma and the potential infusion of immunotherapy into treatment.Htut: [We went over] the basic structure of CAR T-cell therapy, how they are produced, and how CAR T-cell infusion works [in the] scheme of things. I also [provided] a general review of previous trials that have been published and presented at the 2017 ASH Annual Meeting in terms of potential toxicities, response rates, cell doses, and lymphodepletion regimens. Then, I went over the active protocol at City of Hope.City of Hope now has 2 different protocols for the use of CAR T-cell therapy in patients with multiple myeloma. First is the BCMA-targeted therapy protocol from Juno Therapeutics. The second protocol is high-affinity T-cell receptor—targeting NY-ESO-1/HLA-A. Both are active and currently enrolling patients. Physicians at City of Hope also plan to have a homegrown CAR T-cell therapy targeting CS1. Our research scientists produce them, and I will be their principal investigator.Yes. I went over 4 different presentations from that meeting. Response rates ranged from about 43% to 100%. That is really impressive, especially in heavily pretreated patients who have progressed on a median of 4 to 7, sometimes even 13, lines of treatment. It [provides] a new chapter [for patients] and opens a window for all kinds of cancer. The FDA just approved CAR T-cell therapy for acute lymphocytic leukemia, as well as lymphoma. [CAR T cells can] essentially target any kind of cancer. There is a potential for CAR T-cell therapy to be used not only in hematologic malignancies, but also in solid tumors, such as breast cancer, pancreatic cancer, prostate cancer, liver cancer, and so forth. I am not sure. For multiple myeloma, [CAR T cells] are still in the early stages. They will predominantly be limited to patients with relapsed/refractory myeloma. Depending on the efficacy and safety profile, it might be moved earlier like chemotherapy.Yes. There are similar trials with essentially the same target, but a different kind of structure and cell dose.Right now, my other interest is immunotherapy—using PD-1/PD-L1 inhibitors to modify a patient's immune system. Thus far, we have had a trial using the PD-1 inhibitor pembrolizumab (Keytruda). Unfortunately, there were some issues with safety, so the FDA stopped the trial. However, I know that there is an active pathway in myeloma. If in some way we can modify [the inhibitor] or use a different PD-1 inhibitor, we can revisit the issue. It may be too early to say, “this is it,” in terms of using PD-1/PD-L1 inhibitors. We usually combine agents in multiple myeloma, but at the very beginning we have to start out with a single agent to establish the safety profile. Like any other myeloma agent, we will end up combining it with more established drugs. Of course, [I would like to see more research with] CAR T cells; BCMA is only one of the targets. There are other potential targets like CD44v6, CD8, CD138. [We might be able to] build a T cell that can target CS1 molecules as well as BCMA; it would be like dual targeting. I don't know how it's going to pan out, but it's an interesting idea [that can kill] 2 birds with 1 stone.

Berdeja JG, Lin Y, Raje N, et al. Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 740.