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Although multiple myeloma is an incurable disease, the past decade has witnessed significant improvement in patient outcomes. This was brought about by the development of T-cell redirection therapies such as chimeric antigen receptor (CAR) T-cells, which can leverage the natural ability of the immune system to fight myeloma cells. The approval of the B-cell maturation antigen (BCMA)-directed CAR T, idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel) has resulted in a paradigm shift in the treatment of relapsed/refractory multiple myeloma. Overall response rates ranging from 73 to 97% are currently achievable. However, the limitations of KarMMa-1 and CARTITUDE-1 studies spurred the generation of real-world data to provide some insights into the effectiveness of ide-cel and cilta-cel among patients who were excluded from clinical trials, particularly those who received prior BCMA-targeted or other T-cell redirection therapies. Despite their unprecedented clinical efficacy in heavily pretreated patients, responses to CAR T remain non-durable. Although the underlying mechanisms of resistance to these agents haven't been fully elucidated, studies have suggested that resistance patterns could be multifaceted, implicating T-cell exhaustion and tumor intrinsic mechanisms such as BCMA target loss, upregulation of gammasecretase, and others. Herein, we provide a succinct overview of the development of CAR T-cells, manufacturing process, and associated toxicities/complications. In this review, we also recapitulate the existing literature pertaining MM CAR-T as well as emerging data from some of the ongoing clinical trials designed to mitigate the shortcomings of these agents, and improve the clinical efficacy of CAR T, especially in the relapsed/refractory setting. [ABSTRACT FROM AUTHOR]

In newly diagnosed multiple myeloma (NDMM), measurable residual disease (MRD) status is prognostically important, but its role in treatment-decisions remains unclear. In a phase II trial (NCT04113018), we assessed daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction followed by a next generation sequencing (NGS) based MRD-adapted strategy. The primary endpoint was rate of complete response and stringent complete response (≥CR) after induction. Flow cytometry was used to profile T cells. Among 39 patients, 21 (54%) achieved ≥CR post-induction (P=0.375) with MRD-negative rates of 59% (10-5) and 41% (10-6). MRD-negative patients (n=24, group A) received lenalidomide maintenance, showing sustained MRD-negativity in 14/18 (77.8%) for ≥12 cycles. MRD-positive transplant-eligible patients (n=8, group B) underwent ASCT, with 5 (62.5%) converting to MRD-negative (10-5) and 3 (37.5%) at 10-6. MRD-positive transplant-ineligible patients (n=4, group C) received KRd consolidation. MRD-negative rates improved to 77% (10-5) and 72% (10-6) at any time. No additional safety concerns were identified beyond those already known for Dara-KRd. With a median follow-up of 30.1 months, three, two and one patient(s) in groups A, B, and C have experienced disease progression or death. The 2-year PFS rate was 82.5%. We observed that the Dara-KRd regimen strongly activated memory T cells, which was associated with an MRD-negative state after induction. Although the primary endpoint was not met, Dara-KRd induction in NDMM achieved high rates of ≥CR and MRD-negativity without new safety concerns. The post-induction MRD-adapted strategy deepened responses in the MRD-positive group while maintaining durable MRD control in the negative group., (Copyright © 2024 American Society of Hematology.)