Cellular Therapies Provide Hopeful Outcomes as Treatment of Patients With Myeloma

C. Ola Landgren, MD, PhD

The use of chimeric antigen receptor (CAR) T-cell therapies have excited the treatment landscape for a number of hematologic malignancies, and research is now demonstrating this cellular therapy may play an important role in the treatment of patients with multiple myeloma.

Most recently, the CAR T-cell therapy idecabtagene vicleucel (ide-cel; BB2121) had demonstrated promising responses in the pivotal phase 2 KarMMa study presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting. The data from this trial also served as the basis of a Biologics License Application that was submitted to the FDA in July 2020 for the use as treatment of adult patients with relapsed/refractory multiple myeloma.

The objective response rate with ide-cel was 73% in this study (95% CI, 65.8%-81.1%; P <.0001). Complete responses were observed in 33% of patients (95% CI, 24.7%-40.9%), and the median time to a complete response was 2.8 months (range, 1-11.8). The median duration of response was 10.7 months, and the median progression-free survival was 8.8 months with ide-cel (95% CI, 18.2-not evaluable).

The median OS was 19.4 months, but the OS were not yet mature at the time of the ASCO analysis. The 12-month OS rate was 78%.

In an interview with Targeted Oncology, C. Ola Landgren, MD, PhD, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, New York, discussed the development of CAR T-cell therapy in the treatment landscape of multiple myeloma. He also highlighted the importance of these data for ide-cel that were present at the ASCO meeting and other highlights from the American Society of Hematology (ASH) annual meeting.

TARGETED ONCOLOGY: Can you provide a brief overview of the role of CAR T-cell therapy in the multiple myeloma space?

Landgren: CAR T-cell therapy has been in development in the myeloma field for several years now, which started off with mouse work at the National Cancer Institute. At this current time, there are several autologous CAR T cells about to read out with strong results, and 1 of them is anticipated to reflect into hopefully an FDA approval later this year. There is also new data that will be presented soon hopefully for the allogeneic CAR T cells. There's a lot of excitement in the field.

TARGETED ONCOLOGY: What are some of the leading CAR T-cell therapies in this space?

Landgren: There are 3 leading CAR T cells in development for multiple myeloma that include the BB2121, which is part of the KarMMa study. There is also JCAR017 (lisocabtagene maraleucel; liso-cel), and the third CAR T cell is JNJ-68284528 (JNJ-4528). All these 3 CAR T cells are targeting BCMA, and they are all for relapsed and refractory patients with myeloma. They are all autologous CAR T cells.

TARGETED ONCOLOGY: What recent data have we seen regarding CAR T-cell therapy?

Landgren: Ide-cel, or BB2121, has been presented most recently at the ASCO virtual meeting in 2020. It has been reported at several meetings and also published in the New England Journal not very long ago. The data suggest that overall patients could benefit from this therapy for probably close to 7 or 8 months. Patients who have a deep response with minimal residual disease (MRD)-negativity could have more than a year of clinical benefit, and this is from a single infusion release CAR T cell.

TARGETED ONCOLOGY: How are the CAR natural killer (NK) cells different from the other CAR T cell products in the myeloma space?

Landgren: There are several new cell therapies in development. There are both multi-targeted CAR T cells, and they're also CAR NK cells in development. There are not yet any CAR NK cells presented for multiple myeloma. There was recent publication by the MD Anderson group using CAR NKs in lymphoma with fantastic results, and 1 of the benefits to the CAR NKs is that NK cells can be given across the board, so it could be an on the shelf product while the CAR T cells have to be, if they are autologous, from the individual patients and the multi-targeted CAR T cells, as indicated by the name, go after multiple targets. If the cancer cells in myeloma cells are trying to avoid therapy by down-regulating their antigens, obviously having more than 1 target would be a way to avoid these types of behaviors.

TARGETED ONCOLOGY: What are the challenges with using this modality in patients with multiple myeloma?

Landgren: As with every therapy, there are pluses and minuses, and 1 of the challenges when it comes to CAR T cells probably refers to the practical delivery of the CAR T cells. That's probably true across the board. Patients typically have to be hospitalized. They also have to undergo procedures, at least if it's autologous. Autologous CAR T cells imply patients have to come in, they have to go through T-cell harvesting, and then they typically come back about a month later when they can receive these CAR T cells in the hospital. With allogeneic CAR T cells, there is no need to harvest the cells because they come from donors, and that's also true for the NK cells.

There has also been work looking into possibilities to make this a therapy that potentially could be done as outpatient, but it all, of course, relates to management and side effects. Some of the CAR T cells have a delayed onset of cytokine release syndrome, so maybe that will be CAR T cells for myeloma that can be done in more of an outpatient setting, but this is to be proven going forward.

TARGETED ONCOLOGY: How do you see this CAR T-cell therapy research evolving in the multiple myeloma setting?

Landgren: I think the field is just about to reach its first step of maturation, and what I mean by that is there are several CAR T cells that are autologous. They're all going after the same target, so which will really be the winner or will there be room for multiple of these? I don't know the answer, but the data will tell us. I think it will all translate into which potentially is easier to give and if it could be done in the outpatient [setting]? Is it safer? Does it have better safety profile? If there is a difference in efficacy, that would also lead us to which is the winner, so right now, we don't know that.

In parallel with all these new developments, we also have the specific antibodies in development. For myeloma, there are many bi-specific antibodies in development. I think there are 5 to 10 of them right now that go after BCMA and CD3, and there are also tri-specific antibodies in development that have co-stimulatory domains, so the CAR T cells are moving very fast forward and shortly behind them, we also have the bi-specific and possible tri-specifics. The winner will be a combination, so the future will tell.

TARGETED ONCOLOGY: Was there any data at this year’s ASCO that stood out to you in the multiple myeloma space?

Landgren: I think the ASCO 2020 meeting had several updates. ASCO is not a big myeloma meeting. Typically, ASH is the big myeloma meeting, but this year, ASCO had couple of new pieces. I think the updates for all the CAR T cells were a good overview. They are not all at the same level, but the BB2121 is the furthest along. It hopefully will be approved later in 2020, while the others are a little bit behind.

TARGETED ONCOLOGY: What challenges remain in developing CAR T-cell therapies in multiple myeloma?

Landgren: Like any drug in development, there certainly are challenges and when it comes to CAR T cells, I think there will be many challenges. Thinking about the very first study that was presented at ASH about 5 years ago, there were 3 traditional patient groups in different dose cohorts stepping up in a phase 1 trial. It was not until the last cohort that there was 1 patient that responded, and that led him to the submission of an abstract that became a late-breaking abstract at ASH. I think finding the right dose is always very important and looking at all the different CAR T cells, I think they have all gone through the same kind of challenges, finding the right dose, optimizing how to do it, and trying to find no next step. Why patients relapse is also a big challenge, so there is a lot of work ahead of us.