Promising Early Phase Results With bb2121 CAR T Treatment in Relapsed Refractory Multiple Myeloma

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At the 2018 American Society of Clinical Oncology Annual Meeting, June 1-5, Chicago, Illinois, Noopur S. Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, presented results from the phase 1 multicenter study with a second-generation chimeric antigen receptor (CAR) T-cell therapy called bb2121.

Innovation around developing safe and effective chimeric antigen receptor (CAR) T cells to treat cancer continues, and at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, June 1-5, Chicago, Illinois, Noopur S. Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, presented results from the phase 1 multicenter study with a second-generation CAR T-cell therapy called bb2121.

The therapy bb2121, which uses biomarker-directed targeting of T cells to recognize and kill malignant myeloma cells in patients diagnosed with multiple myeloma, was tested for safety and efficacy in a dose-escalation phase of the CRB-401 trial, and Raje reported updated safety and efficacy results on 43 patients enrolled in this ongoing study. The modified T cells were devised to target the B-cell maturation antigen (BCMA). Raje confirmed that based on preclinical results, bb2121 is not inhibited by high levels of soluble BCMA in serum by myeloma cells.

Patients with relapsed/refractory multiple myeloma (RRMM) who were selected for the dose-escalation treatment had received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were double refractory. BCMA expression on plasma cells was 50% or higher. Patients in the dose expansion phase had to have received daratumumab and been refractory to their last line of therapy; BCMA expression was not required. A single infusion of bb2121 was administered to the patients following a 3-day lymphodepletion procedure with fludarabine (30 mg/m2)/cytarabine (300 mg/m2) given daily for 3 days.

Safety concerns with CAR T-cell administration have lingered—cytokine release syndrome (CRS) and neurotoxicity CAR T cell—related encephalopathy syndrome are frequently documented in this patient population. One such treatment that was being developed for the treatment of acute lymphocytic leukemia registered 5 fatalities following cerebral edema and had to be terminated. The ROCKET was initially halted following an FDA directive, and the company made changes to its preconditioning regimen (leukapheresis), eliminating fludarabine from the preconditioning process. This, however, did not prove an effective solution and the trial was shelved.

When the abstract was submitted for presentation at the annual meeting in October 2017, 21 patients had received bb2121 in the 4 dose escalation cohorts, and the median follow-up was 35 weeks. Majority of the patients were male and the median age was 58 years. All 21 patients had received a prior autologous stem cell transplant (ASCT) and had received a median 7 prior lines of treatments (range, 3-14).


The authors observed no dose-limiting toxicities and no grade 3 or higher neurotoxicities. However, grade 1-2 CRS was reported in 15 patients (71%), 2 of whom had grade ≥ 3 CRS that resolved in 24 hours.

Surprisingly, 2 patients who had achieved a complete response (CR) and whose disease had not progressed, died. Of the remaining 19 evaluable patients, the overall response rate in the dose escalation cohorts, who received at least 150×106 CAR T cells, was 94%: 10 of 18 patients (56%) patients had CR or unconfirmed CR; 9 of 10 evaluable patients were minimal residual disease—negative.

At a median follow-up of 40 weeks in the 150×106 or greater dose escalation cohorts, median response duration and progression-free survival (PFS) had not been reached. PFS rates at 6 and 9 months were 81% and 71%, respectively. In the expansion phase, patients were administered 150 to 300×106 CAR T cells.

At ASCO, Raje also presented results of 22 patients who were in the dose expansion cohort—10 had less <50% BCMA expression and 12 had ≥50% BCMA expression. The majority of patients in this cohort were male, as well, and the median age of the patients in this cohort was 65 years. Nineteen of these patients had received prior ASCT and had received a median 8 lines of treatment (range, 3-23).

In the updated results presented Friday, Raje showed that 27 of the total 43 patients experienced CRS, of which 2 were grade 3 or higher. Only 9 patients needed treatment with tocilizumab for their CRS. Fourteen patients experienced neurotoxicity, 35 had neutropenia, 26 had thrombocytopenia, and 24 had anemia. There were no grade 4 CRS events.

The overall response rate (ORR) was 33.3% in the low dose patients (50x106), 57.1% in patients who received the 150x106 dose, and 95.5% in those who received an even higher dose. ORR was not much difference between low BCMA expressing patients (100%) versus high BCMA expressing patients (91%).

Finally, Raje showed a significant improvement in progression-free survival (PFS) in patients receiving a high dose of bb2121. mPFS in 18 patients in the dose escalation phase was 11.8 months, while it was 17.7 months in 16 subjects who were negative for minimal residual disease.

A lingering question with the approved CAR T-cell treatments, tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), is the cost. Tisagenlecleucel costs $475,000 for B-cell acute lymphoblastic leukemia, while axicabtagene ciloleucel costs $373,000. While these numbers may seem steep, the Institute for Clinical and Economic Review released a report earlier this year on their analysis that concluded that the prices align with the clinical value that both treatments present.

Novartis, meanwhile, has negotiated a value-based contract with CMS for tisagenlecleucel.


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; abstr 8007).