Early Post-Infusion Absolute Lymphocyte Count as a Prognostic Marker in BCMA-Targeting CAR-T Therapy for Relapsed Multiple Myeloma

The chimeric antigen receptor T-cell (CAR-T) therapy has made significant success in the treatment of various hematological malignancies. Particularly, in multiple myeloma (MM), relapsed/refractory (R/R) disease poses a considerable therapeutic challenge due to its aggressive nature and poor prognosis after conventional treatments. BCMA-targeting CAR-T cells, specifically ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), have shown promising results, achieving high overall response rates in patients who have exhausted other therapeutic options. Despite these encouraging outcomes, the durability of response varies widely among patients, necessitating a deeper understanding of factors that influence long-term efficacy. One of the main challenges in CAR-T therapy is predicting which patients will experience prolonged progression-free survival (PFS) and duration of response (DoR) following treatment. While the in vivo expansion of CAR-T cells post-infusion is known to correlate with treatment efficacy, the methods to measure this expansion are predominantly confined to research settings and are not routinely available in clinical practice. Consequently, there is a pressing need for accessible, reliable prognostic markers that can predict treatment outcomes and guide therapeutic decisions. The study conducted by Professors Ruben Niesvizky and Mark Bustoros at Weill Cornell Medicine addresses this critical gap by investigating the kinetics and prognostic impact of absolute lymphocyte count (ALC) in the early post-infusion period. Given that lymphocyte expansion is an indirect measure of CAR-T cell proliferation, the researchers hypothesized that ALC could serve as a surrogate marker for CAR-T cell expansion and, by extension, predict clinical outcomes in patients with R/R MM. This multicenter study aimed to elucidate the relationship between ALC dynamics within the first 15 days post-CAR-T infusion and key clinical outcomes, such as depth of response, PFS, and DoR, thereby providing a practical and scalable prognostic tool for use in routine clinical practice.

The study included 156 patients with relapsed/refractory multiple myeloma (R/R MM) treated with either ciltacabtagene autoleucel (cilta-cel) or idecabtagene vicleucel (ide-cel) at Weill Cornell Medicine, Columbia University Irving Medical Center, and Mount Sinai Hospital. The researchers collected baseline demographics, clinical characteristics, and ALC measurements from preconditioning through the first 15 days post-infusion. The overall response rate was 89%, with 65% achieving complete response (CR). Importantly, the study observed that patients treated with cilta-cel had a higher median ALCmax (2 × 10^3/μL) compared to those treated with ide-cel (0.8 × 10^3/μL). This difference highlighted product-specific variations in immune response and underscored the necessity of considering these differences when interpreting clinical outcomes. The researchers focused on the kinetics of ALC post-CAR-T infusion and its correlation with clinical outcomes. They found that higher ALCmax was associated with improved PFS and duration of response (DoR). Specifically, patients with ALCmax >1.0 × 10^3/μL had significantly better PFS (30.5 months vs. 6 months) and DoR compared to those with ALCmax ≤1.0 × 10^3/μL. This association remained significant even after adjusting for other prognostic factors such as age, presence of high-risk cytogenetics, and the type of CAR-T product used. These findings suggest that ALCmax could serve as a robust prognostic marker for clinical outcomes in R/R MM patients treated with BCMA-targeting CAR-T cells. The study also examined the relationship between ALCmax and immune-related toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). They found that the presence of CRS was associated with higher ALCmax, with patients experiencing CRS showing a significantly higher median ALCmax compared to those who did not develop CRS. This correlation was observed in both cilta-cel and ide-cel recipients, indicating that higher lymphocyte counts might be linked to a more robust immune response, which in turn could result in higher rates of immune-related toxicities. The presence of ICANS also showed a similar trend, further supporting the potential of ALC as a surrogate marker for CAR-T cell expansion and associated immune activation.  To further validate the hypothesis that ALC is an indicator of CAR-T cell expansion, the researchers conducted flow cytometry on peripheral blood samples from four patients. They observed significant expansion of BCMA CAR-T cells, which correlated strongly with increases in ALC. For instance, at day 14 post-infusion, BCMA CAR-T cells constituted a significant proportion of the total T lymphocyte population in patients with higher ALCmax. This finding provided direct evidence that the observed increases in ALC were driven by the expansion of CAR-T cells, reinforcing the utility of ALC as a practical and accessible marker for CAR-T cell proliferation.  The researchers extended their analysis by comparing ALC dynamics in patients treated with BCMA-targeting CAR-T cells for MM with those treated with CD19-targeting CAR-T cells for non-Hodgkin lymphoma (NHL). They found distinct differences in ALC kinetics between the two groups. The median ALCmax for BCMA CAR-T was significantly higher than that for CD19 CAR-T (1.3 × 10^3/μL vs. 0.47 × 10^3/μL). Additionally, the time to ALCmax was longer in BCMA CAR-T recipients. These differences highlighted the influence of disease-specific factors on CAR-T cell expansion and the potential variability in immune response across different CAR-T constructs. Importantly, the study identified specific ALCmax cutoffs that could stratify patients based on their risk of disease progression. An ALCmax ≤0.5 × 10^3/μL was associated with poor outcomes, with a median PFS of less than 4 months, regardless of the CAR-T product used. Conversely, an ALCmax >1.0 × 10^3/μL indicated a favorable prognosis, with a median PFS of 30 months. These cutoffs provide clinicians with practical thresholds to identify high-risk patients early in the treatment course and potentially adjust therapeutic strategies accordingly.

The study by Professors Ruben Niesvizky and Mark Bustoros represents a pivotal advancement in understanding the prognostic factors influencing outcomes in patients with relapsed/refractory multiple myeloma (R/R MM) treated with BCMA-targeting CAR-T cells. The identification of ALC kinetics as a surrogate marker for CAR-T cell expansion and a predictor of clinical outcomes addresses a critical gap in the management of CAR-T therapy. Specifically, the study elucidates the relationship between early post-infusion ALC dynamics and key clinical endpoints such as PFS and duration of response (DoR). This contributes significantly to the field of immunotherapy by offering a novel, easily accessible biomarker that can be used to predict treatment efficacy and guide clinical decision-making.

The study establishes ALCmax as a reliable early prognostic marker. Clinicians can measure ALC within the first 15 days post-CAR-T infusion to predict which patients are likely to have better outcomes. This enables early identification of high-risk patients who may benefit from additional or alternative therapeutic interventions. Moreover, by identifying specific ALCmax cutoffs (e.g., ≤0.5 × 10^3/μL and >1.0 × 10^3/μL), the study provides practical thresholds for stratifying patients based on their risk of disease progression. Patients with ALCmax ≤0.5 × 10^3/μL, who are at higher risk of early disease progression, can be closely monitored and potentially offered more aggressive or adjunctive treatments to improve their prognosis. Furthermore, ALC measurement is a routine laboratory test that is widely available and cost-effective. Integrating ALC monitoring into clinical practice does not require sophisticated or specialized equipment, making it feasible for widespread adoption in both academic and community healthcare settings. In addition, understanding the correlation between ALC kinetics and CAR-T cell expansion helps clinicians tailor CAR-T therapy more effectively. For instance, interventions that enhance CAR-T cell expansion could be prioritized for patients with low ALCmax, potentially improving their response to treatment.  The association of ALCmax with immune-related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) underscores the need for enhanced monitoring of patients with high ALCmax. This can help mitigate the risks of severe toxicities and manage side effects more proactively.

In conclusion, the study conducted by Professors Ruben Niesvizky and Mark Bustoros presents compelling evidence that ALC kinetics, particularly ALCmax, serve as a valuable prognostic marker in patients with R/R MM treated with BCMA-targeting CAR-T cells. By demonstrating the association between higher ALCmax and improved clinical outcomes, as well as validating ALC as a surrogate marker for CAR-T cell expansion through flow cytometry, the researchers provide a robust framework for integrating ALC measurements into clinical practice. This approach offers a practical, accessible tool for predicting treatment response and guiding therapeutic decisions, ultimately aiming to optimize outcomes for patients with relapsed multiple myeloma.