The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

Abstract

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

Ciltacabtagene Autoleucel, an Anti–B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up

“…As of the January 11, 2022, data cutoff, 66 of the 97 patients who received cilta-cel infusion remained on study (Fig 1). As previously reported, the median time from receipt of the apheresis material to release of cilta-cel was 29 days (interquartile range [28][29][30][31][32][33]; no patient discontinued the study because of manufacturing failure. 14 All patients treated with cilta-cel received a dose within the target range (median, 0.71 3 10 6 cells/kg; range, 0.51-0.95 3 10 6 ).…”

“…The ciltacel CAR features two BCMA-targeting, single-domain antibodies comprising two variable regions of heavy chains designed to confer avidity 14 while ide-cel comprises an extracellular single-chain variable fragment with one heavy and one light chain targeting a single epitope of BCMA. [28][29][30] Other recently approved agents for treating triple-class refractory RRMM, selinexor 5 and belantamab mafodotin, 6 have demonstrated limited clinical benefit in heavily pretreated patients with RRMM. ORR with selinexor was 26%, and the median PFS was 3.7 months.…”

“…The cilta-cel CAR features two BCMA-targeting, single-domain antibodies comprising two variable regions of heavy chains designed to confer avidity 14 while ide-cel comprises an extracellular single-chain variable fragment with one heavy and one light chain targeting a single epitope of BCMA. 28-30…”

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

“…At present, anti-BCMA CAR-T cell therapy has been demonstrated to be effective in R/R MM and achieved unprecedented responses (7,8,(67)(68)(69), and two anti-BCMA CAR-T cell products, idecabtagene vicleucel and ciltacabtagene autoleucel, have been approved by the FDA for the treatment of R/R MM (7,70). Furthermore, the anti-BCMA CAR-T cell therapy is effective in R/R MM patients with extramedullary disease (71)(72)(73). However, some MM patients still relapse after anti-BCMA CAR-T therapy, and BCMA expression is downregulated under therapeutic pressure.…”

Anti-ROR1 CAR-T cells: Architecture and performance

“…Subsequently, the interaction between the CAR on T-cells and the tumor antigen on cancer cells triggers an immune response resulting in neoplastic cell death (53). The United States Food and Drug Administration (FDA) has approved the use of CAR-T cells targeting the cluster of differentiation 19 (CD19) (54)(55)(56) and the B-cell maturation antigen (BCMA) (57,58) for the treatment of hematological malignancies. CD19 CAR-T cells and BCMA CAR-T cells were safe and effective in patients with refractory B-cell acute lymphoblastic leukemia (B-cell ALL) and multiple myeloma (MM), respectively.…”