Creating Lasting Benefit With CAR T-Cell Therapy in Myeloma

Noopur Raje, MD

Triplet and quadruplet regimens comprised of immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies are increasing the odds of transforming multiple myeloma into what has traditionally been thought of as a chronic disease to a curative disease, explained Noopur Raje, MD, adding that cellular therapy is bound to increase these chances.

“We've been using CAR T-cell therapy for the last couple of years, and we've learned a lot from what we've done so far,” said Raje. “At the 2018 ASH Annual Meeting, there were lots of different products in multiple myeloma. We've seen early data that look very promising, but we're just at the beginning of learning how these therapies are going to fit into our treatment paradigm.”

The first CAR-T product to demonstrate encouraging efficacy was bb2121 in the phase I CRB-401 trial, updated results from which were presented at the 2018 ASCO Annual Meeting. At 194 days of follow-up, the rate of complete response (CR) or stringent CR (sCR) was 50% among patients with ≥3 prior lines of therapy, with 36.4% of patients in a very good partial response.¹ Furthermore, the median progression-free survival was 11.8 months with a median duration of response of 10.8 months.

At the 2018 ASH Annual Meeting, preliminary results with bb21217, an enhanced bb2121 construct, were presented. The product exposes bb2121 to the PI3K inhibitor bb007, therein enriching for T cells with a memory-like phenotype, explained Raje. The theory behind the construct is that it will extend T-cell persistence, thereby increasing response rates and remission durations. According to preliminary results from the phase I CRB-402 study, the CR/sCR rate was 25% among patients with ≥3 prior lines of therapy, with 50% of patients in a very good partial response.²

Based on these data, it has been posited that CAR T-cell therapy has the potential to be moved into earlier lines of therapy or replace stem cell transplant altogether. As this research is early, Raje emphasized that continuing clinical trials and cultivating more data on these constructs will be key in answering these questions.

OncLive: What does the current treatment landscape for multiple myeloma look like?

In an interview with OncLive, Raje, professor of medicine at Harvard Medical School and director of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center, discussed the current treatment landscape of multiple myeloma, with a specific focus on available triplet regimens and the recent data with CAR T-cell therapy.Raje: We have lots of FDA-approved drugs and different combinations. In the upfront setting, the majority of us will use a triplet regimen followed by transplant in the transplant-eligible population as well as maintenance. There is a move towards giving 4-drug regimens upfront, with the goal of getting to and maintaining a minimal residual disease (MRD)-negative state. By doing that, we hope to transform what we're seeing as a chronic disease in some patients into a fraction of cured patients.

At the time of relapse, the curves have shifted somewhat so that the first relapse happens approximately 3.5 to 4 years after diagnosis. There are more data now looking at triplet regimens. A lot of what we do at the time of relapse is dictated by what the patient has already received, the nature of relapse, and the risk associated with the relapse. Typically, we tend to use a triplet regimen.

Could you discuss the data with these triplet regimens?

How do these responses differ from those achieved with CAR T-cell therapy?

In the United States, the majority of our patients are progressing after having been on a lenalidomide (Revlimid) maintenance approach. We are mostly picking a pomalidomide (Pomalyst)-based approach, whether it's with daratumumab (Darzalex), carfilzomib (Kyprolis), or some other agent.We have good data with carfilzomib, pomalidomide, and dexamethasone (KPd). This regimen has been used in the relapsed/refractory setting with about a 60% to 70% response rate. Additionally, the duration of response can be close to 8 or 9 months. The regimens with daratumumab have been very impressive. We see response rates of 60% with daratumumab, pomalidomide, and dexamethasone and a duration of response close to 8 to 10 months. That’s pretty remarkable in the relapsed/refractory setting.With CAR T-cell therapy, we've seen response rates greater than 90%. However, this is a very different patient population. We're not talking about first relapse. On average, these patients have had 7 prior lines of therapy. Besides CAR T-cell therapy, these patients would not have anything else. These hospice-like patients who are quad- and penta-refractory have seen both immunomodulatory agents [lenalidomide and pomalidomide], both proteasome inhibitors [carfilzomib and bortezomib (Velcade)], and have also seen the monoclonal antibody daratumumab.

What were the main points you emphasized in your presentation on CAR T-cell therapy in myeloma?

CAR T-cell therapy has shown us that in even this heavily pretreated patient population, over 90% of patients will respond and have a remission duration of close to 1 year. We’re also seeing MRD-negative disease. If you look at the patients who are MRD negative, their remission duration has gone out close to 18 months. These are remarkable results for an otherwise extremely heavily pretreated patient population who would not have had a lot of available options. To see this kind of remission duration is heartening. It's a good step forward, but we still have a lot to learn.The big thing we've learned over the last couple years is that we've identified a good target. BCMA appears to be a universally acceptable target for CAR T-cell therapy. There are a lot of different CAR T-cell products. The good news is that the majority of these CAR T-cell agents have pretty high response rates. Thus far, we have used 4-1BB as a second costimulatory domain. We haven't done a lot with CD28. In fact, a CD28 CAR T-cell therapy did not show any responses. As such, that [product] is not going forward in clinical development.

We're always looking to improve upon what we have accomplished with CAR T-cell therapy. The T-cell persistence lasts for at least 6 to 9 months. To keep the disease in remission for a long time you want to see T-cell persistence. There were early data presented at the 2018 ASH Annual Meeting on bb21217; this product exposes CAR T cells ex vivo/in vitro to the PI3K AKT blocker, bb007.

The idea is that this product will improve the persistence of the CAR T cells and is going to invoke more of a memory T-cell response. The hope is that if you have T-cell persistence and more of a memory T-cell phenotype, you're going to have even more durable responses and remissions. The data presented at the 2018 ASH Annual Meeting were very preliminary. The trial comprised of only about 13 patients, and the data looked very similar to what was seen with bb2121. We'll have to wait and see whether or not these remission durations are more durable [than those observed with bb2121].

What do community oncologists need to know about CAR T-cell therapy in myeloma?

Lastly, we want to think about what we do from here. This is just the beginning of our understanding of cellular therapy in the world of multiple myeloma. We have a lot more to learn in terms of whether or not we can make a better product or whether we could be using it differently. All of these questions are being investigated in clinical trials.It's an exciting time for myeloma. We have many good treatment options. The one thing community oncologists need to understand is that CAR T-cell therapy is different from transplant. The toxicities are extremely different. That's something that oncologists in general don't understand. The age cutoffs that are being relaxed for transplant should not necessarily apply to CAR T-cell therapy.

Where do you see CAR T cell-therapy evolving?

The other important piece to recognize and appreciate is that CAR T-cell therapy is fairly well tolerated by patients. The toxicities are manageable. Physicians need to think about cellular therapy and start referring patients. However, we still haven't gotten to the point where we can produce CAR T cells and have enough slots for every patient with myeloma. We are doing more studies. As of right now, it's still in the context of clinical trials until a product gets approved [by the FDA] for the treatment of [patients with] myeloma.CAR T-cell therapy is going to be used in earlier lines [of therapy]. The big question is whether we can use CAR T-cell therapy instead of an autologous stem cell transplant. Ongoing clinical trials are investigating what [the optimal time to administer] CAR T-cell therapy is. Pending the data, we may be able to use CAR T-cell therapy upfront.

References

1. 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 15; abstr 8007). doi: 10.1200/JCO.2018.36.15_suppl.8007.
2. Shah N, Alsina M, Siegel DS, et al. Initial results from a phase 1 clinical study of bb21217, a next-generation anti bcma CAR T therapy. Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 488. ash.confex.com/ash/2018/webprogram/Paper116953.html.