CRB-401

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Raje N, et al. "Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma". The New England Journal of Medicine. 2019. 380(18):1726-1737.
PubMedFull textPDFClinicalTrials.gov

Clinical Question

In patients with relapsed or refractory multiple myeloma, is the anti-BCMA chimeric antigen receptor T-cell (CART) therapy bb2121 (idecabtagene vicleucel) a safe and effective treatment option?

Bottom Line

In this phase 1 study enrolling patients with relapsed/refractory multiple myeloma, the anti-BCMA CART therapy bb2121 (idecabtagene vicleucel) was associated with high rates of cytokine release syndrome (CRS) and neurotoxicity. In an as-treated analysis, overall response rate was 85% and median duration of response was about 11 months.

Major Points

CART therapy, in which T-cells are engineered to express a chimeric antigen receptor (CAR) that targets a specific antigen, has shown promise in a variety of hematologic cancers. Several CART products are in development, and they differ in many ways, most importantly in their target antigen, costimulatory domain, and signaling domains. The CRB-401 study was among the first to study CART therapy in patients with relapsed/refractory multiple myeloma. It specifically studied idecabtegene vicleucel (also called bb2121, ide-cel, and marketed by Celgene as Abecma), which targets B-cell maturation antigen (BCMA) and contains a 4-1BB costimulatory domain and CD3-zeta signaling domain.

This industry-sponsored phase 1 study was conducted in the US and consisted of dose-escalation and dose-expansion phases. Fit patients with measurable disease who had received 3 or more lines of prior therapy were eligible; during the expansion phase, additional eligibility criteria included prior daratumumab exposure and refractoriness to the most recent line of therapy. The median time since diagnosis of myeloma was 5 years, and median prior lines of therapy was 7. Patients underwent apheresis with goal collection of 2.5×109 mononuclear cells. About 40% of patients received bridging therapy (generally consisting of steroids, alkylators, immunomodulators, and proteasome inhibitors). Bridging therapy was discontinued ≥14 days before lymphodepletion with fludarabine and cyclophosphamide. CART dose ranged from 50-800×106 and 150-450×106 (±20%) during the dose-escalation and dose-expansion phases, respectively. The primary endpoint was safety; secondary endpoints included IMWG response rate and duration of response.

A total of 36 patients were enrolled and underwent leukapheresis; manufacturing yield was 100%. The analysis presented is for the 33 patients who received CART infusion; the 3 patients who progressed prior to infusion were excluded from the analysis. A relatively large proportion of patients had high-risk features including extramedullary disease (27%), high-risk FISH abnormalities (45%), and penta-refractoriness (18%). CRS occurred in three-quarters of patients, and was more frequent in patients receiving higher CART doses. CRS was grade 1/2 (70%) or grade 3 (6%), with median time to onset of 2 days and median duration of 5 days. Neurotoxicity occurred in 42% of patients. Responses were observed in 85% of patients (45% CR) and response depth appeared to be dose-dependent, with ≥VGPR observed only in patients receiving ≥150×106 cells. Among patients who achieved ≥PR, all achieved MRD negativity by NGS at 10-4 sensitivity. During a median follow-up of 11.3 months, 52% of patients experienced disease progression including 6 who had achieved an MRD-negative response. Median PFS was 11.8 months and median duration of response was 10.9 months. Response was independent of tumor-cell BCMA expression (≥50% and <50%).

The paper, which was supported by an industry-funded medical writer, concludes that bb2121 is an effective therapy in relapsed/refractory myeloma and that nonhematologic toxicities were generally mild. The main criticisms include the use of an as-treated analysis rather than a standard intention-to-treat analysis; the former selects for patients with more indolent disease biology and yields results which appear more favorable for the therapeutic intervention. The presented analysis also emphasizes rates of MRD negativity with bb2121, but absence of measurable disease does not necessarily translate into long-term survival as evidenced by the relatively high proportion of patients who achieved MRD negativity and subsequently progressed within 6-12 months. It's also important to consider the high cost of CART therapy: cost in excess of USD $400K may be justifiable in conditions like ALL and DLBCL where CART therapy can be curative, but such costs are difficult to rationalize in myeloma where cure remains elusive. Despite these caveats, ide-cel is clearly active, and strategies to mitigate CRS and neurotoxicity have improved. In March 2021, the FDA approved ide-cel for patients with relapsed/refractory myeloma who had received at least 4 prior lines of therapy.

Guidelines

NCCN Myeloma Guidelines (Version 5.2022, adapted)[1]

  • Therapies for patients with late relapse (4 or more prior therapies) including PI, immunomodulator, and anti-CD38 antibody:
    • Idecabtagene vicleucel
    • Ciltacabtagene autoleucel
    • Balantamab mafodotin

Design

  • Multicenter, open-label, phase 1 study
  • N=36 patients with relapsed/refractory myeloma, at least 3 prior lines of therapy
  • Setting: Multiple US centers
  • Enrollment: 2016-2018
  • Mean follow-up: 11.3 months (range, 6.2 to 22.8)
  • Analysis: As-treated
  • Primary outcome: Safety

Population

Inclusion Criteria

  • Age ≥18 years
  • ECOG 0-1
  • Measurable disease
  • 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or disease refractory to both drug classes
  • Adequate organ function
  • BCMA expression on ≥50% marrow plasma cells on immunohistochemical assay (for the dose-escalation phase)
  • Previous exposure to daratumumab and refractoriness to the most recent line of therapy per International Myeloma Working Group (IMWG) criteria (for the dose-expansion phase)

Exclusion Criteria

  • Known CNS disease
  • AST and/or ALT >2.5X ULN or Bili >1.5X ULN
  • Cr >1.6 mg/dL
  • INR >1.5 unless on stable anticoagulation
  • ANC <1.0, PLT <50K, HGB <9
  • EF <50%
  • Chronic immunosuppressant use (eg, cyclosporine or systemic steroids)
  • Active infection within 72 hours prior to lymphodepletion
  • Prior allogeneic transplantation or treatment with any gene therapy-based therapeutic for cancer
  • Significant comorbid condition which (per investigator) may interfere with study
  • Known HIV positivity
  • History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control
  • Other malignancy requiring therapy in the last 3 years or is not in complete remission
  • Pregnant or lactating women
  • Recent or complicated VTE or bleeding related to anticoagulation

Baseline Characteristics

  • Median age: 60 (37-75) years
  • Female 36%
  • ECOG: 0-30%, 1-64%, 2-6%
  • High-risk cytogenetics: 45%
  • Median prior lines of therapy: 7 (range 3-23)

Interventions

  • Non-randomized study
  • Leukapheresis targeted a collection of ≥2.5×109 mononuclear cells
  • Bridging therapy was allowed following leukapheresis, and was stopped ≥14 days prior to lymphodepletion (LD)
  • LD consisted of fludarabine (30 mg/m2/d) and cyclophosphamide (300 mg/m2/d) on days -5, -4, -3, followed by CART infusion on day 0
  • CART dose levels (×106) were 50, 150, 450, and 800 CAR+ T-cells in the dose-escalation phase and 150-450 CAR+ T-cells in the expansion phase

Outcomes

Primary Outcomes

Grade ≥3 adverse event (AE)
97%
Grade ≥3 hematologic AE
Neutropenia 85%
Anemia 45%
Thrombocytopenia 45%
Thrombocytopenia lasting >1 month 35%
Cytokine release syndrome (CRS)
76% (70% grade 1-2, 6% grade 3)
Median time to onset 2 days
Median duration 5 days
Neurologic toxicity
Grade 1-2: 39%
Grade 3: 0
Grade 4: 3%

Secondary Outcomes

Response rates
Objective response rate: 85%
Complete response: 45%
Duration of response
10.9 months

Subgroup Analysis

Subgroup analysis limited by small sample size, but showed no clear difference in safety or efficacy based on subgroups.

Adverse Events

See Primary Outcomes.

Criticisms

  • Medical writing was provided by a writer paid for by the pharmaceutical company.
  • Analysis was an as-treated analysis rather than intent-to-treat.

Funding

  • Blueberd Bio and Celgene

Further Reading