CAR T-Cell Therapy Shows Promise in Relapsed/Refractory Myeloma

Jesus Berdeja, MD

The second-generation BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy bb2121 induced complete remissions (CRs) in 56% of patients with relapsed or refractory multiple myeloma, providing a potentially promising option for a heavily pretreated population.

In a study of 21 patients, doses were administered in a range of 150 to 300 × 10⁶ CAR+ T cells. Prior to infusion of the CAR T-cell therapy, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²).

Treatment with bb2121 was generally well tolerated with an objective response rate of 94%, and a very good partial response rate or better of 89%, according to results presented at the 2017 ASH Annual Meeting. After 40-weeks of follow-up, the median progression-free survival (PFS) had not yet been reached, but the 9-month PFS rate was 71%.

In November 2017, the FDA granted bb2121 a breakthrough therapy designation, based on preliminary clinical data from the ongoing phase I CRB-401 study.

OncLive: Can you provide an overview of the study of bb2121 in myeloma presented at ASH?

In an interview with OncLive during the 2017 ASH Annual Meeting, lead investigator Jesus Berdeja, MD, director of Multiple Myeloma Research at Sarah Cannon Research Institute, discussed ongoing research with bb2121 in patients with relapsed/refractory myeloma.Berdeja: bb2121 is a CAR-T product directed at BCMA that uses a 4-1BB costimulatory domain and it is for patients with relapsed/refractory multiple myeloma. We presented the completed phase I dose-escalation portion of the trial. We have started the dose-expansion, but we are not presenting those data just yet. Twenty-four patients were accrued and 21 patients were infused with the CAR T cells, so only 3 patients actually deteriorated. This is a patient population that is very heavily pretreated, with 7 median prior lines of therapy; they had basically exhausted all other treatments. It is quite impressive that only 3 patients were not able to move through.

Of the 21 patients who did move through, they were enrolled on a subsequent escalation of doses starting at 50 mg CAR T-cell therapy, then 150 mg, 450 mg, and then 800 mg. We were planning to go up to 1200 mg but did not. The dose escalation completed and all patients were assessable for toxicity and response.

The cells were, to our surprise, quite well tolerated. The 2 toxicities that we worry about the most with CAR T cells are cytokine release syndrome (CRS) and neurotoxicity. As expected, 71% of our patients had CRS, but they were all grade 1 and 2. Very few patients had grade 3 CRS, and these were all reversible within 24 hours after 1 dose with tocilizumab (Actemra). A few patients did experience neurotoxicity, which was also grade 1/2. One patient required steroids as part of the grade 3 CRS that occurred and all of it was reversible. There were no on-study deaths.

In terms of the response, the first dose level was therapeutic, so those 3 patients had a transient response and progressed very quickly. After that, at the 150 mg dose, all patients but 1 had a response that was durable. Therefore, our overall response in patients treated at the therapeutic dose levels was 94% with a 56% CR rate. If you compare that with the data presented at the [2017 ASCO Annual Meeting], at that time we had 27% CR rates, and now we have a 56% CR rate. The responses continue to improve with time, and as far as 15 months out, we’ve see a patient revert to CR.

This therapy is working so quickly; it is inducing a little bit of a complex assessment in myeloma because we are seeing that the tumor cells are killed, but then the pair of proteins that are required to become negative are lagging behind. We are starting to see something that we have never seen before, which is minimal residual disease (MRD) negativity in patients who are even in partial remission. In the 10 patients who were assessed for MRD, 9 were MRD negative.

What is the take-home message from this study?

What are the next steps?

Thus far, we have not met our median PFS; it is a median follow-up of 4 weeks. At 6 months, 81% of patients remained progression free.This is unprecedented data in this population of relapsed or refractory patients. If you look at drugs that have been approved for this indication, we are talking response rates in the 20% range with very few CRs and a PFS of less than 4 months. These are the kind of data that we would be seeing in frontline patients, so we are all very gratified by how effective these cells appear to be. We have seen durability—several patients are out 1 year or further, so that is reassuring.We are already in the process of enrolling into the expansion phase, 12 patients have been enrolled in that. Celgene is going to be taking these cells from Bluebird, and they have actually already started the pivotal trial in a similar patient population. The next step would be a pivotal trial in the same relapsed/refractory population of close to 100 patients. Hopefully, this will take [the treatment] to market.

There are already plans to move the cells earlier, and there will be a randomized trial that is also being planned for a potential third-line indication. There is even a potential for frontline use in a subset of patients.

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. In: Proceedings from the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 740.