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bb2121: Is CAR T-Cell Therapy Moving to Myeloma?

December 30, 2021

Chimeric antigen receptor (CAR) T-cell therapies have revolutionized the treatment of acute lymphocytic leukemia and non-Hodgkin lymphoma, and might now be poised to shake up the myeloma treatment landscape, according to results from the CRB-401 trial presented at the 2018 ASCO Annual Meeting.

Nearly all of the participants with relapsed or refractory multiple myeloma (MM) who received bb2121, a second-generation CAR T-cell therapy targeting B-cell maturation antigen (BCMA) responded to treatment (overall response rate [ORR] = 95.5%), with responding patients also achieving minimal residual disease (MRD)–negativity.

Preliminary findings from this ongoing CRB-401 trial supported the U.S. Food and Drug Administration's decision to grant bb2121 breakthrough-therapy designation for patients with relapsed or refractory MM in November 2017. Based on these updated results, investigators have opened the global pivotal KarMMa trial for enrollment in North America and Europe, lead author Noopur S. Raje, MD, from Massachusetts General Hospital, noted during her presentation.

As of March 29, 2018 (data cutoff), 43 patients in the CRB-401 trial received bb2121: 21 in the four dose-escalation cohorts (median age = 58 years; range = 37-74 years) and 22 in the dose-expansion cohorts (median age = 65 years; range = 44-75 years).

All patients had relapsed or refractory MM and had received at least three prior lines of therapy (including a proteasome inhibitor and an immunomodulatory agent) or had disease that was refractory to bortezomib and thalidomide and/or lenalidomide (i.e., "double-refractory" disease). Participants also were required to have greater than 50 percent BCMA expression on malignant cells.

Patients were treated following a standard 3+3 design, with planned dose levels ranging from 50×106 to 800×106 CAR T cells/kg. Before CAR T-cell infusion, participants underwent leukapheresis and a lymphodepletion conditioning chemotherapy regimen consisting of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 for three days, followed by two days of rest.

After a median follow-up of 35 weeks (range = 6.6-69.0 weeks) post–bb2121 infusion, 27 of the 43 patients (63%) experienced cytokine release syndrome (CRS), a common and potentially fatal adverse event associated with CAR T-cell therapies. Fourteen patients (33%) experienced neurotoxicity. While there were two cases of grade ≥3 CRS (5%) and neurotoxicity (2%), the authors noted that there were no fatal CRS or neurotoxicity events. CRS was "mostly low-grade and manageable," Dr. Raje added.

Among 39 patients evaluable for efficacy (including those with at least two months of response data), the highest rates of overall response were seen in the >150×106 CAR T cells/kg dose group (see TABLE).

Patients responses appeared to be independent of BCMA expression level, the investigators observed. In the 450×106 CAR T cells/kg dosing group, which included eight patients with high BCMA expression and 11 with low, ORRs were 100 percent and 91 percent, respectively.

In addition, all 16 of the responders who were evaluable for MRD (treated with "active" doses of bb2121 ≥150×106 CAR T cells/kg) achieved MRD-negativity at one or more time points.

Dr. Raje also reported that the 18 evaluable patients in the active dosing groups experienced a modified progression-free survival (PFS) of 11.8 months (range = 8.8 months to not evaluable).

During her presentations, Dr. Raje said that "bb2121 shows promising efficacy at dose levels ≥150×106 CAR T cells with deep and durable ongoing responses and manageable cytokine release syndrome and neurotoxicity. These data support the potential of bb2121 anti-BCMA CAR T-cell therapy as a new treatment paradigm for relapsed or refractory MM."

This early-phase study is limited by its small patient population and the lack of a comparator arm. Several trials of bb2121 are ongoing, Dr. Raje noted, including as an earlier line of treatment and to determine predictors of response.

The authors report financial relationships with Bluebird Bio and Celgene, the manufacturers of bb2121.

Reference

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. Abstract #8007. Presented at the 2018 ASCO Annual Meeting, June 1, 2018; Chicago, IL.

TABLE. Response Outcomes in Efficacy-Evaluable Patients
50×106

(n=3)

150×106

(n=14)

>150×106

(n=22)

Median follow-up (range) 84 days (59-94) 87 days (36-638) 194 days (46-556)
Overall response 33.3% 57.1% 95.5%
Complete response 0% 42.9% 50%
Very good partial response 0% 7.1% 36.4%
Median duration of response 1.9 months Not estimable 10.8 months

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