CAR T cell therapy in multiple myeloma, where are we now and where are we heading for?

Abstract

The introduction of chimeric antigen receptor (CAR) T cells revolutionized treatment of relapsed and refractory multiple myeloma (RRMM) in recent years. Currently, two CAR T cell products—idecabtagene vicleucel and ciltacabtagene autoleucel—are approved in the United States and the European Union to treat patients with three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti‐CD38 antibody. Moreover, seminal phase III trials of both agents in earlier lines of therapy have been published recently. Despite unprecedented rates of deep and lasting remissions in RRMM, there are still areas of uncertainty regarding the optimal use and distribution of CAR T cells in multiple myeloma. In the current review, we discuss the available data on approved CAR T cell products as well as unmet clinical needs and ongoing developments to optimize usage of this promising treatment modality in multiple myeloma.

Anti-Idiotypic VHHs and VHH-CAR-T Cells to Tackle Multiple Myeloma: Different Applications Call for Different Antigen-Binding Moieties

“…More recently, thriving on the successes in other hematologic cancers (namely, lymphomas and leukemias), important progress has been made in the field of chimeric antigen receptor (CAR)-T cell therapy. In 2021 and 2022, two CAR-T cell products were FDA- and EMA-approved for MM after at least three prior lines of treatment [ 10 ]. Both Abecma ® (idecabtagene vicleucel) and Carvykti ® (ciltacabtagene autoleucel) are second-generation CAR-T cells directed against BCMA and show impressive results in heavily pre-treated patients.…”

“…Both Abecma ® (idecabtagene vicleucel) and Carvykti ® (ciltacabtagene autoleucel) are second-generation CAR-T cells directed against BCMA and show impressive results in heavily pre-treated patients. However, the success of these novel therapy approaches is, again, limited in time, and patient relapse is still frequently reported [ 10 , 11 , 12 ]. The reasons for relapse are multifold.…”

“…Firstly, BCMA-specific CAR-T cell therapy relapse is observed when an anti-CAR immune response occurs. In many cases, including in MM, anti-murine single-chain variable fragment (scFv) antibodies are reported to be responsible for neutralizing the therapeutic cells [ 10 , 11 , 13 ]. Furthermore, the intrinsically unstable nature of the scFv format renders these CARs susceptible to antigen-independent membrane aggregation [ 14 , 15 , 16 ].…”

“…These two findings highlight the notion that the classical scFv-based CAR format may not be ideal [ 18 ]. Thirdly, the use of BCMA as a drug target has also been questioned [ 10 , 11 , 12 ], as it is sensitive to γ-secretase-mediated shedding [ 19 , 20 , 21 ], and (in fewer cases) antigen loss has also been observed [ 11 , 22 ]. Finally, patient relapse may also be linked to an enhanced immunosuppressive bone marrow micro-environment [ 11 ].…”

Chimeric antigen receptor T‐cell therapy, where are we now and where are we heading for

“…The first part of this special issue contained five reviews, which comprehensively elucidated “CAR‐T‐cell therapy, where are we now and where are we heading for” in hematological malignancies 1 and specifically focused on MM 2 . Although great success has been achieved in treating ALL, CAR‐T‐cell therapy has not yet become a routine treatment for acute myeloid leukemia (AML).…”