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CAR T cell therapy for multiple myeloma: What have we learned?

Leukemia volume 36, pages 1481–1484 (2022)Cite this article

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The prognosis of multiple myeloma (MM) has improved substantially over the last two decades. Treatment with proteasome inhibitors (PI), immunomodulatory agents (IMIDs) and CD38 antibodies induces responses in ≥90% of newly-diagnosed MM patients. However, eventually patients relapse and have shorter remission durations with each subsequent line of therapy. The prognosis for patients with ‘triple-class’ refractory disease to PI, IMID and CD38 antibodies is particularly poor. Recent breakthroughs in the fields of immunology and genetic engineering have resulted in myriad novel immunotherapy approaches to fight cancer, most of which focus on redirecting the endogenous T-cell repertoire against tumor cells. In relapsed and refractory (RR) MM, immunotherapies targeting B-cell maturation antigen (BCMA) have shown remarkably high response rates, with the most mature data coming from studies with BCMA-directed chimeric antigen receptor (CAR) T cells. Here, we will discuss the most recent clinical data and correlative findings, lessons learned from initial studies, and ongoing research efforts in the area.

BCMA (CD269) is an optimal target for MM immunotherapy, based on its near-uniform expression on MM cells, limited expression on other tissues, and role in promoting MM cell proliferation and survival [1]. Four initial phase I studies in advanced RRMM independently validated BCMA as a CAR T cell target, with overall response rates (ORR) of 64–90% at optimal doses, and toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and cytopenias, similar to those seen with CD19-directed T cells [2,3,4,5]. These impressive and previously-unseen responses led to multiple trials exploring the efficacy and safety of BCMA CAR T cells in MM, including 2 registration studies reporting initial results: the phase 2 KarMMa study evaluating idecabtagene vicleucel (ide-cel, bb2121) [6], and the phase 1b/2 CARTITUDE-1 trial evaluating ciltacabtagene autoleucel (cilta-cel, JNJ-68284528, LCAR-B38M) [7]. Key details and results are summarized in Table 1. The efficacy and overall safety observed in these studies made ide-cel the first FDA-approved cellular therapy for RRMM, with cilta-cel currently undergoing FDA evaluation.

Table 1 Registration phase 2 trials of BCMA-directed CAR T cells in RRMM.
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Authors and Affiliations

  1. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    Sandra Susanibar Adaniya, Edward A. Stadtmauer & Adam D. Cohen

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SSA and ADC developed and wrote the manuscript; EAS provided feedback and edited the manuscript.

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Correspondence to Adam D. Cohen.

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Competing interests

SSA: none. EAS: none. ADC has received research support from Novartis and GlaxoSmithKline; has performed consulting/advisory boards for Bristol-Myers Squibb/Celgene, Janssen, GlaxoSmithKline, Takeda, Oncopeptides, AstraZeneca, Roche/Genentech, and Seattle Genetics; and has had intellectual property licensed on behalf of the University of Pennsylvania to Novartis.

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Susanibar Adaniya, S., Stadtmauer, E.A. & Cohen, A.D. CAR T cell therapy for multiple myeloma: What have we learned?. Leukemia 36, 1481–1484 (2022). https://doi.org/10.1038/s41375-022-01539-8

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