On March 26, 2021, idecabtagene vicleucel was approved for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.1,2 Idecabtagene vicleucel is the first U.S. Food and Drug Administration–approved cell-based gene therapy for multiple myeloma.
Idecabtagene vicleucel is a B-cell maturation antigen–directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. Each dose is customized using an individual’s own T cells, which are collected, genetically modified, and infused back into the patient.
Supporting Efficacy Data
Approval was based on findings in the multicenter, phase II KarMMa study (ClinicalTrials.gov identifier NCT03361748).2,3 The trial enrolled 127 patients with relapsed and refractory multiple myeloma who received at least three prior lines of antimyeloma therapies (≥ 4 prior lines in 88%). Patients with a history of central nervous system disease (such as seizure or cerebrovascular ischemia) or requiring ongoing treatment with chronic immunosuppression were excluded. Efficacy was evaluated in 100 patients who received idecabtagene vicleucel in the dose range of 300 to 460 × 106 CAR-positive T cells. Efficacy was established based on overall response rate, complete response rate, and duration of response, as evaluated by an Independent Response Committee using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.
The median duration of follow-up was 11.4 months. An objective response was observed in 72 patients (72.0%, 95% confidence interval [CI] = 62%–81%), with a stringent complete response in 28 (28%, 95% CI = 19%–38%). A very good partial response was observed in 25 patients (25.0%) and a partial response in 19 (19.0%). The median duration of response was 11.0 months (95% CI = 10.3–11.4 months) among all responders and 19.0 months (95% CI = 11.4 months to not estimable) among those with a stringent complete response; 65% of patients with a complete response remained in complete response for at least 12 months.
How It Works
Idecabtagene vicleucel is a CAR-positive T-cell therapy targeting B-cell maturation antigen, which is expressed on the surface of normal and malignant plasma cells. The CAR construct includes an anti–B-cell maturation antigen scFv-targeting domain for antigen specificity, a transmembrane domain, a CD3-zeta T-cell activation domain, and a 4-1BB costimulatory domain. Antigen-specific activation of idecabtagene vicleucel results in CAR-positive T-cell proliferation, cytokine secretion, and subsequent cytolytic killing of B-cell maturation antigen–expressing cells.
How It Is Used
Idecabtagene vicleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. It is provided as a single dose for infusion containing a suspension of CAR-positive T cells in one or more infusion bags. The recommended dose range is 300 to 460 × 106 CAR-positive T cells. Idecabtagene vicleucel is for autologous use only.
The lymphodepleting chemotherapy regimen consists of cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 for 3 days, with idecabtagene vicleucel given 2 days after completion of lymphodepleting therapy.
Patients should be premedicated with acetaminophen (650 mg orally) and diphenhydramine (12.5 mg intravenously or 25 to 50 mg orally, or another H1 antihistamine) approximately 30 to 60 minutes before infusion. Prophylactic use of dexamethasone or other systemic corticosteroids should be avoided, since they may interfere with the activity of idecabtagene vicleucel.
Idecabtagene vicleucel infusion carries a risk of cytokine-release syndrome and neurologic toxicities. A minimum of two doses of tocilizumab and emergency equipment must be available prior to infusion and during the recovery period. The agent must be administered at a REMS-certified health-care facility. Patients should be monitored at least daily for 7 days at the certified health-care facility following infusion for signs and symptoms of cytokine-release syndrome and neurologic toxicities. They should be instructed to remain within proximity of the facility for at least 4 weeks following infusion. Patients should be advised to refrain from driving or engaging in hazardous activities for at least 8 weeks following infusion.
Product labeling provides detailed instructions on the management of cytokine-release syndrome and neurologic toxicities, including the use of tocilizumab and corticosteroid treatment for grades 1 to 4 cytokine-release syndrome and of corticosteroid treatment and nonsedating antiseizure medication for grades 1 to 4 neurologic toxicity.
Safety data are from a total of 127 patients receiving idecabtagene vicleucel in the KarMMa trial. The most common adverse events of any grade (≥ 20%) were cytokine-release syndrome (85%), infection-pathogen unspecified (51%), fatigue (45%), musculoskeletal pain (45%), hypogammaglobulinemia (41%), diarrhea (35%), upper respiratory tract infection (34%), nausea (29%), viral infection (27%), encephalopathy (26%), edema (25%), pyrexia (25%), cough (23%), headache (23%), and decreased appetite (22%). Serious adverse events occurred in 67% of patients, and fatal adverse events occurred in 6% of patients.
Idecabtagene vicleucel label has a boxed warning for cytokine-release syndrome; neurologic toxicities; hemophagocytic lymphohistiocytosis/macrophage activation syndrome; and prolonged cytopenias, which can include bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery. The product also has warnings/precautions for hypersensitivity reactions, infections, prolonged cytopenias, hypogammaglobulinemia, secondary malignancies, and effects on the ability to drive and use machines. Patients may exhibit prolonged grade ≥ 3 cytopenias following infusion; blood cell counts should be monitored prior to and after infusion. Patients should be monitored for hypogammaglobulinemia, and immunoglobulin replacement therapy should be considered.
1. U.S. Food and Drug Administration: FDA approves idecabtagene vicleucel for multiple myeloma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-idecabtagene-vicleucel-multiple-myeloma. Accessed April 12, 2021.
2. Abecma (idecabtagene vicleucel), suspension for intravenous infusion, prescribing information, Celgene Corporation, a Bristol Myers Squibb Company, March 2021. Available at https://www.fda.gov/vaccines-blood-biologics/abecma-idecabtagene-vicleucel. Accessed April 12, 2021.
3. Munshi NC, Anderson LD Jr, Shah N, et al: Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 384:705-716, 2021.