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bb2121 Continues to Show Potential in Multiple Myeloma

Jason Harris
Published: Thursday, Aug 02, 2018

Noopur Raje, MD
Noopur Raje, MD
Results from the multicenter phase I CRB-401 study evaluating the anti-BCMA chimeric antigen receptor T-cell therapy bb2121 in patients with relapsed/refractory multiple myeloma are highly encouraging, according to Noopur Raje, MD.

“As a proof-of-principle, first-in-human study, we have an active target—an active cellular therapy—with very little toxicity and pretty durable responses, which has been great,” said Raje, who is the lead study author of CRB-401.

In the trial, which accrued heavily pretreated patients with relapsed/refractory disease, bb2121 induced a median progression-free survival (PFS) of 11.8 months with a median duration of response of 10.8 months, according to the updated findings that were presented at the 2018 ASCO Annual Meeting.

The median follow-up was 194 days for patients treated with a >150 x 106 dose at the March 29, 2018 data cutoff. Results showed that the objective response rate (ORR) was 95.5%. Additionally, the complete response (CR) or stringent CR rate was 50% and 36.4% had a very good partial response. In contrast, patients treated with an inactive dose (50 x 106) had an ORR of 33.3% and a 1.9-month median duration of response.

Raje, director of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center, also explained that bb2121 was found to be well tolerated. The rate of grade ≥3 cytokine release syndrome (CRS) was 5% and the rate of grade ≥3 neurotoxicity was 2%.

In November 2017, the FDA granted bb2121 a breakthrough therapy designation for previously treated patients with relapsed/refractory disease.

In an interview with OncLive, Raje discussed the updated results from the CRB-401 trial and next steps with bb2121 in multiple myeloma.

OncLive: What was the rationale for CRB-401?

Raje: CAR T-cell therapy is clearly an exciting strategy not just in hematologic cancers, but a lot of solid tumors, where it is also being investigated. What we've done with the bb2121 product is use a CAR using a lentivirus vector, which recognizes a humanized BCMA. Along with that, for the costimulatory domain, we used 4-1BB. What we think is happening here is that, with the 4-1BB, we get a slow and consistent expansion of those T cells. Part of the reason for seeing less toxicity, we believe, is because of the 4-1BB costimulatory molecule.

Preclinically, we have studied BCMA in myeloma for a long time now. Most of us agree that BCMA is a good target in the treatment of [patients with] myeloma, and for us to be able to create and generate this CAR has been an exciting development going to a very targeted approach.

There were a couple of concerns prior to going into this study. Patients with myeloma can have circulating levels of BCMA and high BCMA levels. The question was, “Is that going to impact a BCMA-targeted strategy?” Preclinical work, at least, did not suggest that.

We also wanted to figure out whether BCMA-receptor density impacted whether a targeted agent such as a CAR T-cell therapy would work or not. Again, our preclinical data did not suggest that patients had to have a certain level of BCMA expression.

Having done all of this preclinical work, we then went forward and studied this product in patients. We did a very classic dose-escalation study. We started with 50 million cells and went all the way to 800 million cells. It was generally required that we collect patients’ lymphocytes— that's the leukapheresis process. It takes a few weeks to generate the CARs.

In that time frame from us collecting, and us giving back the leukapheresis or CAR T-cell product, we actually were allowed to give our patients bridging therapy. These are sick patients who need active myeloma therapy. The majority our patients were on some form of bridging therapy.

They then come into the hospital to get lymphodepletion, which can be either in-hospital or as an outpatient. It's very simple chemotherapy. I'd like to highlight that because there is a lot of confusion between this kind of an approach and autologous [stem cell] transplant, and they are very different.

The lymphodepletion chemotherapy we use is cyclophosphamide and fludarabine. These are at low doses and the treatment can happen on an outpatient basis. It's done over 3 days; then patients have a 2-day rest period, and we give them back this CAR T-cell product.

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