Chimeric Antigen Receptor T Cell Therapy for Myeloma: Where Are We Now and What Is Needed to Move Chimeric Antigen Receptor T Cells Forward to Earlier Lines of Therapy? Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy

Anderson, Larry D.; Dhakal, Binod; Jain, Tania; Oluwole, Olalekan O.; Shah, Gunjan L.; Sidana, Surbhi; Perales, Miguel-Angel; Pasquini, Marcelo C.

doi:10.1016/j.jtct.2023.10.022

Cited by 18 publications

(10 citation statements)

References 106 publications

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“…It remains very difficult to show OS benefit in any modern comparative trial for MM given the median 7-10 year survival quoted for standard risk patients and significant crossover that occurs in many trials. Increasingly, patients’ OS is based on sequential progression free intervals in which the optimal sequence is unclear and ever changing due to newer data, approvals, and guidelines ( 97 – 99 ). The considerations we present in this section presume the indications approved in the United States in early 2024, and we acknowledge that in other parts of the world, these discussions differ based on availability and cost ( 100 – 102 ).…”

Section: Discussion: Car T or Ahct Or Both?mentioning

confidence: 99%

“…This will be especially important as CAR T migrates into less academic institutions where the systems to ensure adequate supportive care may need to be optimized. Additionally, when considering the prospect of bringing CAR T therapy to earlier lines of treatment, we will need to understand the value beyond traditional efficacy alone, with demonstration of quality-adjusted life years and other patient-reported outcomes, and the cost (both short- and long-term) to the healthcare system ( 97 ).…”

Section: Discussion: Car T or Ahct Or Both?mentioning

confidence: 99%

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Autologous hematopoietic stem cell transplantation for multiple myeloma in the age of CAR T cell therapy

Hughes,

Shah,

Paul

2024

Front. Oncol.

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Chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of relapsed and refractory myeloma, with excellent outcomes and a tolerable safety profile. High dose chemotherapy with autologous hematopoietic stem cell transplantation (AHCT) is established as a mainstream of newly diagnosed multiple myeloma (NDMM) management in patients who are young and fit enough to tolerate such intensity. This standard was developed based on randomized trials comparing AHCT to chemotherapy in the era prior to novel agents. More recently, larger studies have primarily shown a progression free survival (PFS) benefit of upfront AHCT, rather than overall survival (OS) benefit. There is debate about the significance of this lack of OS, acknowledging the potential confounders of the chronic nature of the disease, study design and competing harms and benefits of exposure to AHCT. Indeed upfront AHCT may not be as uniquely beneficial as we once thought, and is not without risk. New quadruple-agent regimens are highly active and effective in achieving a deep response as quantified by measurable residual disease (MRD). The high dose chemotherapy administered with AHCT imposes a burden of short and long-term adverse effects, which may alter the disease course and patient’s ability to tolerate future therapies. Some high-risk subgroups may have a more valuable benefit from AHCT, though still ultimately suffer poor outcomes. When compared to the outcomes of CAR T cell therapy, the question of whether AHCT can or indeed should be deferred has become an important topic in the field. Deferring AHCT may be a personalized decision in patients who achieve MRD negativity, which is now well established as a key prognostic factor for PFS and OS. Reserving or re-administering AHCT at relapse is feasible in many cases and holds the promise of resetting the T cell compartment and opening up options for immune reengagement. It is likely that personalized MRD-guided decision making will shape how we sequence in the future, though more studies are required to delineate when this is safe and appropriate.

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Section: Discussion: Car T or Ahct Or Both?mentioning

confidence: 99%

Section: Discussion: Car T or Ahct Or Both?mentioning

confidence: 99%

Autologous hematopoietic stem cell transplantation for multiple myeloma in the age of CAR T cell therapy

Hughes,

Shah,

Paul

2024

Front. Oncol.

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“…Also, in cases where ASCT is not intended to be the initial therapeutic approach, the CARTITUDE-5 study [62], a randomized phase 3 trial will compare the efficacy of Bortezomib, Lenalidomide, and Dexamethasone (VRd) induction followed by cilta-cel versus VRd induction followed by Lenalidomide and Dexamethasone (Rd) maintenance therapy. The results of these ongoing studies are eagerly awaited to evaluate the true potential of CAR-T therapy in the initial treatment of multiple myeloma [63].…”

Section: Discussionmentioning

confidence: 99%

An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis

Pereira,

Bergantim

2024

IJMS

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Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy’s efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy.

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“…Between 2020 and 2023, the US Food and Drug Administration (FDA) has approved one antibody‐drug conjugate (ADC; belantamab mafodotin), two chimeric antigen receptor T‐cell (CAR‐T) products (idecabtagene vicleucel [ide‐cel] and ciltacabtagene autoleucel [cilta‐cel]), and two bispecific antibodies (BsAbs; teclistamab and elranatamab) targeting BCMA for adults with relapsed and/or refractory MM (RRMM) who received at least four prior lines of therapy (including a proteasome inhibitor, an immunomodulatory drug, and an anti‐CD38 monoclonal antibody) 3,4 . Despite belantamab's withdrawal from the US market due to a lack of progression‐free survival (PFS) improvement in the DREAMM‐3 trial, the practical significance of other BCMA‐directed agents has continued to rise 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Recent results from the KarMMa‐3 and CARTITUDE‐4 trials indicate that BCMA‐targeting therapies might soon be applicable during the initial stages of the disease 6,7 . Several ongoing trials are further investigating the use of these agents earlier in MM natural history (NCT04196491; NCT04923893; NCT05243797; NCT05317416; NCT05623020) 3,4,8 …”

Section: Introductionmentioning

confidence: 99%

Soluble B‐cell maturation antigen in multiple myeloma

Costa,

Ortiz,

Lesokhin

et al. 2024

American J Hematol

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B‐cell maturation antigen (BCMA) has emerged as a promising immunotherapeutic target in multiple myeloma (MM) management, with the successive approval of antibody‐drug conjugates, bispecific antibodies, and chimeric antigen receptor T‐cell therapies directed to this membrane receptor. Soluble BCMA (sBCMA), a truncated version produced through gamma‐secretase cleavage, can be quantified in serum/plasma samples from patients with MM via electrochemiluminescence, fluorescence, or enzyme‐linked immunosorbent assays, as well as through mass spectrometry‐based proteomics. Besides its short serum half‐life and independence from kidney function, sBCMA represents a reliable and convenient tool for MM monitoring in patients with nonsecretory or oligosecretory disease. Numerous studies have suggested a potential utility of this bioanalyte in the risk stratification of premalignant plasma cell disorders, diagnosis and prognostication of MM, and response evaluation following anti‐myeloma therapies. In short, sBCMA might be the “Swiss army knife” of MM laboratory testing, but is it ready for prime time?

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Chimeric Antigen Receptor T Cell Therapy for Myeloma: Where Are We Now and What Is Needed to Move Chimeric Antigen Receptor T Cells Forward to Earlier Lines of Therapy? Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy

Cited by 18 publications

References 106 publications

Autologous hematopoietic stem cell transplantation for multiple myeloma in the age of CAR T cell therapy

Autologous hematopoietic stem cell transplantation for multiple myeloma in the age of CAR T cell therapy

An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis

Soluble B‐cell maturation antigen in multiple myeloma

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