Editorial: Advances and new horizons in cellular therapies for leukemia and myeloma

The expanding role of cellular therapies in hematologic malignancies has fundamentally reshaped patient outcomes while reducing dependence on highly toxic cytotoxic chemotherapy. Within this framework, our Research Topic aims to underscore the evolving integration of immune and cellular therapy approaches into contemporary multiple myeloma (MM) management.

CAR-T cell therapy has emerged as one of the most effective and promising therapies for patients with MM. Yu et al. provide a comprehensive overview of CAR-T in MM including the major target antigens, key challenges, and strategies to overcome CAR-T failure. CAR-T cells directed against the B-cell maturation antigen (BCMA) have been the most successful so far in MM with two products, ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) approved by the United States Food and Drug Administration (FDA) in relapsed and refractory myeloma (RRMM) based on their unprecedented responses even in refractory cases. However, CAR-T is not curative and many patients still relapse following the treatment. Antigen escape, immunosuppressive marrow microenvironment, and T-cell exhaustion have been implicated in the failure of this treatment. Advancements in CAR-T engineering to optimize CAR-T structure including multi-antigen CARs, armored and gated CARs, and efforts to improve T-cell persistence and safety are being investigated and appear promising. Given the long vein-to-vein time, off-the-shelf products that could be used for rapidly progressive disease such as allogeneic CAR-T/NK cell are desirable and currently being investigated. What follows CAR-T therapy may ultimately determine its success apart from appropriate patient selection; optimizing post–CAR-T interventions to sustain efficacy and mitigate relapse is now an urgent priority. Along with that, expanding patient access to durable CAR-T therapies via scalable production strategies is equally important, as innovation without accessibility will only widen existing disparities in cancer care.

As the role of cellular therapies in myeloma evolves and their utilization expands, several alternative CAR-T targets, beyond BCMA, are being explored. G protein-coupled receptor class C group 5 (GPRC5D) is the foremost CAR-T target among the emerging options with efficacy even after BCMA failure. In their meta-analysis of eighteen early-phase clinical trials investigating CAR-T targeting BCMA or GPRC5D, Yang et al. offer valuable insights into their safety and efficacy in RRMM. This analysis reports a clear efficacy advantage of GPRC5D CAR-T with a higher overall response rate, complete response rate, with similar MRD negativity rate compared to BCMA CAR-T. It is of note that both products seem to be equally efficacious in patients with traditional high-risk features such as extramedullary disease and adverse cytogenetics. However, significantly fewer patients treated with GPRC5D CAR-T cell therapy relapsed, likely due to the receptor’s expression being independent of BCMA and its non-shedding pattern that could lead to stronger CAR-T engagement, even with BCMA-low or -negative disease. Both therapies showed favorable toxicity profiles; however, rates of high-grade cytokine release syndrome (CRS) were higher with BCMA CAR. Given these findings and the recognition of antigen escape as a well-known mechanism of treatment failure, GPRC5D stands as a viable option for patients relapsing after BCMA CAR. While being a promising option in RRMM, the superior efficacy and safety of GPRC5D CAR-T reported in this analysis needs to be validated in phase II and III trials, before changing the treatment paradigm.

While advances in CAR-T therapy have undoubtedly shaped the treatment landscape in MM, other plausible cellular therapy options continue to be explored. In a notable retrospective analysis, Lei et al. report outcomes in 20 patients with multiple myeloma treated with HLA-mismatched peripheral blood stem cell microtransplant over a 16-year period. Although microtransplants have been previously explored in acute leukemia and non-Hodgkin lymphoma, this study represents the first report of its application in myeloma. Despite the modest cohort size, the study introduces a novel, low-intensity therapeutic strategy that appears well tolerated, with lower toxicity compared with high-dose chemotherapy followed by autologous stem cell rescue or CAR-T cell therapy, and with the potential for broader clinical accessibility.

The reported overall response rate was 85% (17 of 20 patients). Six-year overall survival approached 65%, and six-year progression-free survival was 35%—notable outcomes given that nearly half of the cohort harbored high-risk cytogenetic abnormalities, including 1q gain, t(4;14), and del(17p). Importantly, in a subset of patients, the authors observed evidence of immune reconstitution, reflected by improvements in T-cell and natural killer cell function following microtransplantation.

While limited by its retrospective design and small sample size, this analysis is both provocative and hypothesis-generating. It provides a foundation for prospective evaluation of HLA mismatched peripheral blood microtransplantation as a potential therapeutic strategy in MM.

Lastly, the role of targeted immune therapy, specifically, the CD38 monoclonal antibody, daratumumab is highlighted by Garg and Devarakonda in their comprehensive review of smoldering myeloma—a condition historically managed with observation rather than intervention in the pre–FDA approval era. The authors describe the evolving landscape of management options, particularly for patients with high-risk smoldering disease. Smoldering multiple myeloma is generally considered to be a “gray zone” plasma cell disorder situated between monoclonal gammopathy of undetermined significance and overt MM, for which most patients have traditionally been monitored without therapy.

This concise and highly informative review addresses the contemporary complexities surrounding smoldering myeloma, including variability in diagnostic definitions, challenges in disease classification, and the long-standing controversy regarding the timing of therapeutic intervention. With the recent approval of daratumumab for patients with high-risk smoldering myeloma, the decision of whom to treat has become increasingly nuanced. The authors provide a systematic framework for approaching these patients, highlighting emerging data demonstrating survival benefit and delayed progression to overt myeloma. The insights offered in this review equip clinicians with a modern understanding of management strategies in the post-daratumumab approval era and contribute meaningfully to ongoing discussions regarding optimal care for patients with this complex and evolving entity.

Over the past decade, drug development in MM has undergone a transformative evolution, yielding unprecedented depths of response and meaningful gains in survival. Advances in cellular and immune-based therapies have been central to these improvements. Yet, despite this progress, the challenges of clonal evolution and therapeutic resistance remain. Most patients ultimately experience relapse and continue to succumb to the disease, underscoring the urgent need for ongoing investigation and innovation.

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Footnotes

Edited and reviewed by: Savita Rangarajan, University of Southampton, United Kingdom