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.
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Clinical Question

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

Bottom Line

In this phase 1 study, the anti-BCMA CART therapy bb2121 (idecabtagene vicleucel) showed promising efficacy and a favorable safety profile among patients with relapsed or refractory multiple myeloma.

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. CART products differ in several ways, most importantly by 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 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 lines of prior therapy were eligible; during the expansion phase, additional eligibility 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 30 mg/m2 and cyclophosphamide 300 mg/m2 on days -5, -4, and -3, and CART infusion was administered on day 0. 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, while secondary endpoints included IMWG response rate and duration of response.

A total of 36 patients were enrolled and underwent leukapheresis, with 100% manufacturing yield. 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%). Cytokine release syndrome (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 phase 2 KarMMa study (2021) evaluated ide-cel in a similar patient population, and confirmed the efficacy of this approach. In March 2021, the FDA approved ide-cel for patients with relasped/refractory myeloma who had received at least 4 prior lines of therapy.

Guidelines

Design

  • Multicenter, open-label, phase 1 study
  • N=33
  • 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, as defined by:
  • 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
  • Inadequate hepatic function: AST and/or ALT > 2.5 ULN and direct bilirubin > 1.5 xULN
  • Inadequate renal function defined by serum creatinine > 1.6 mg/dL
  • INR or PTT > 1.5 x ULN, unless on a stable dose of anticoagulant
  • Inadequate bone marrow function defined by absolute neutrophil count(ANC)<1000 cells/mm3, platelet count <50,000 mm3, or hemoglobin <9 g/dL
  • Left ventricular ejection fraction < 50%
  • Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine o r systemicsteroids at any dose)
  • Active infection within 72 hours prior to lymphodepletion
  • Previous history of an allogeneic bone marrow transplantation or treatment with any gene therapy-based therapeutic for cancer
  • Significant co-morbid condition or disease which in the judgment of the Investigatorwould place the subject at undue risk or interfere with the study
  • Known HIV positivity
  • History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control
  • Second malignancies in addition to myeloma, if the second malignancy hasrequired therapy in the last 3 years or is not in complte remission
  • Pregnant or lactating women
  • Venous thromboembolic event requiring anticoagulation and who meet any of the following criteria:
    • On a stable dose of anticoagulation for < 1 month
    • Grade 2, 3, or 4 hemorrhage in the last 30 days
    • Experiencing continued symptoms from the VTE event (eg, continued dyspnea or oxygen requirement)

Baseline Characteristics

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

Interventions

  • Randomized to intensive (targeting HbA1c <6%) or standard (HbA1c 7-7.9%) glycemic therapy

    • Then 46% were randomized to intensive (SBP <120) vs. standard (SBP <140) blood pressure therapy
    • Remaining 54% randomized to fenofibrate vs. placebo; all received statin
  • Intensive glycemic control group attended monthly visits for 4 months, then every 2 months, with additional visits and telephone calls as needed
  • Standard therapy group had glycemic control visits every 4 months

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Annual rate of nonfatal MI or nonfatal stroke or cardiovascular death
2.11% vs. 2.29% (HR 0.90; 95% CI 0.78-1.04; P=0.16)

Secondary Outcomes

Annual rate of death from any cause
1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04)
Annual rate of cardiovascular death
0.79% vs. 0.56% (HR 1.35; 95% CI 1.04-1.76; P=0.02)

Subgroup Analysis

Adverse Events

Criticisms

Funding

Further Reading