In this issue of Blood, Sidana et al report the largest real-world analysis of chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma (MM), confirming the efficacy and safety of idecabtagene vicleucel (ide-cel) in the late relapse setting.1
In March 2021, idecabtagene vicleucel, which targets B-cell maturation antigen (BCMA) on the cell surface of MM cells, became the first CAR-T therapy approved for relapsed/refractory MM. This was based on the impressive efficacy seen in the KarMMa trial, which showed an overall response rate of 73% and median progression-free survival (PFS) of 8.8 months in a heavily pretreated population.2
Although the approval of ide-cel was widely celebrated, a major question was whether similar efficacy would be seen among patients outside of the clinical trial setting. The United States Myeloma CAR-T Consortium (now renamed as the US Myeloma Immunotherapy Consortium) and the French DESCAR-T registry retrospectively analyzed outcomes with ide-cel among selected cellular therapy centers, each of which suggested that patients outside of clinical trials may experience similar benefit to those enrolled in KarMMa.3,4 In their article, Sidana et al complement and expand on these real-world data (RWD) findings.
The Center for International Blood and Marrow Transplant Research (CIBMTR) registry prospectively collects data for all patients in the United States who undergo transplant and/or cellular therapy, including CAR-T therapy. In their study, the authors report outcomes for 821 patients who were infused with ide-cel between May 2021 and June 2023 after having received at least 4 prior lines of therapy. Notably, the study excluded patients who had a nonconforming CAR-T product and did not capture outcomes of patients who underwent apheresis but who were not infused. Ide-cel led to an overall response rate of 73% and median PFS of 8.8 months, each identical to KarMMa trial findings, and remarkably similar to the other real-world analyses. Rates of cytokine release syndrome, infections, and nonrelapse mortality were also similar to those of the CIBMTR analysis, US CAR-T consortium, FENIX, and KarMMa studies. A detailed comparison of these analyses is provided in the table.
The CIBMTR analysis provides a plethora of supplementary figures and tables for subgroups of interest, providing ample context for clinicians considering use of ide-cel for individual patients in the clinic. On review of the available RWD, several themes regarding anti-BCMA CAR-T therapy in myeloma are beginning to solidify.
First, the underlying biology of myeloma and disease status at the time of CAR-T infusion are important variables that affect the likelihood of deep response and long-term disease control after ide-cel. Bridging therapy (BT, defined as antimyeloma therapy given between leukapheresis and CAR-T infusion) was administered in 54% of patients, and its use was associated with inferior PFS compared with patients who did not receive bridging. However, patients whose disease was responding to therapy (≥very good partial response) at the time of cell infusion had the best long-term outcomes, regardless of BT use. At first glance, this seems like a contradiction. However, patients who received BT had higher rates of ISS stage II or III disease, high-risk cytogenetics, extramedullary disease, prior drug exposure, and baseline cytopenias, despite a shorter time from diagnosis. Therefore, the logical conclusion is that BT itself does not lead to worse outcomes, but its administration in observational studies is associated with more aggressive underlying disease biology. Clinicians should not hesitate to use BT to deepen response prior to ide-cel infusion, as patients who are responding to therapy may have a higher likelihood of long-term benefit and perhaps an improved safety profile as well.
Second, lymphodepletion (LD) quality is critically important. Although fludarabine and cyclophosphamide (Flu/Cy) treatment is the standard of care for most patients, bendamustine is sometimes used as an alternative LD chemotherapy for patients with underlying renal dysfunction. In late 2021, a worldwide fludarabine shortage resulted in many centers having no choice but to use alternative LD regimens, and bendamustine was a common choice. In the current analysis, LD bendamustine resulted in significantly worse PFS compared with Flu/Cy, and this could not be accounted for by disease biology or underlying renal dysfunction.
Third, prior therapy targeting BCMA has a profound impact on the efficacy of anti-BCMA CAR-T therapy. Aside from ide-cel, the CAR-T product ciltacabtagene autoleucel (cilta-cel), as well as 2 CD3xBCMA bispecific antibodies, teclistamab and elranatamab, are approved for use in the United States, and the antibody-drug conjugate (ADC), belantamab mafodotin, was available between August 2020 to February 2023. Although it was previously believed that the type of anti-BCMA therapy and time since prior exposure may be mitigating factors, this analysis suggests that even distant prior use of anti-BCMA ADC therapy retains a negative impact on ide-cel efficacy.
Despite the RWD clarity provided by this study, many questions remain. Most pertinently, how do these data help clinicians to decide between various BCMA therapies within a dynamic treatment landscape with many available anti-BCMA options? Cilta-cel, teclistamab, and elranatamab all have impressive data that compare either similarly or favorably to ide-cel in the late relapse setting,5-8 and several other similar therapies are in various stages of development. In addition, both ide-cel and cilta-cel have been approved in the early relapse setting, based on the KarMMa-3 and CARTITUDE-4 trials,9,10 and anti-BCMA therapies are currently being extensively studied in the newly diagnosed setting.
Ultimately, the decision of when and how to implement anti-BCMA therapy is highly individualized, based on patient preference, fitness, toxicity concerns, and availability/logistics. Although the data in this CIBMTR analysis cannot distinguish the relative benefit of ide-cel compared with alternative therapies, clinicians now have a robust data set from a large cohort of patients confirming that ide-cel is an effective and relatively well-tolerated CAR-T therapy, even in the setting of significant comorbidities that may preclude clinical trial enrollment. Furthermore, ide-cel is optimally used when patients have adequate LD, no prior BCMA exposure, and good disease control at the time of CAR-T infusion. RWD is increasingly incorporated into clinical decision-making, so the study by Sidana and colleagues should be celebrated as a prime example of how such data sets can complement clinical trials.
Conflict-of-interest disclosure: T.S. has served as a consultant for BiolineRx, Janssen, Pfizer, and Sanofi and has received institutional research funding for clinical trials from Alexion Pharmaceuticals, Bristol-Myers Squibb, and Janssen.
