SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024 and 12,540 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2024 remains an incurable disease.
Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median Progression-Free Survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with relapsed or refractory myeloma often have disease that is refractory to multiple drugs.
Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase III studies involving patients with relapsed or refractory myeloma.
The researchers conducted an insightful study aimed at identifying predictive biomarkers to enhance the efficacy of CAR T-cell therapy for patients with relapsed or refractory multiple myeloma (MM). While CAR T-cell therapy has revolutionized treatment for B-cell malignancies and other blood cancers, the high cost of therapy and variability in patient response highlight the need for precise biomarkers that could guide clinicians in selecting the best candidates for this therapy. This research delves into the factors that affect patient response, specifically focusing on the role of the Absolute Lymphocyte Count (ALC) in predicting treatment success and disease progression.
The researchers analyzed data from 156 patients with relapsed or refractory multiple myeloma, treated with two BCMA-targeting CAR T-cell therapies: Ciltacabtagene autoleucel (CARVYKTI®) and Idecabtagene vicleucel (ABECMA®). These patients, who were treated between 2017 and 2023, had previously undergone several lines of therapy, rendering them refractory to conventional treatments. The research team collected and analyzed Absolute Lymphocyte Counts (ALC), a key immune marker, from 5 days before the CAR-T infusion for up to 15 days post-infusion, to determine if ALC could be used as a predictive biomarker for patient outcomes. The focus on this early post-infusion window was based on the hypothesis that the expansion of T cells, which is critical for the effectiveness of CAR T-cell therapy, would be reflected in the ALC levels. This study sought to correlate early ALC levels with long-term outcomes such as depth of response, Progression-Free Survival (PFS), and overall Duration of Response (DoR).
The findings demonstrated that ALC is a strong predictor of response to CAR T-cell therapy, with higher ALC values correlating with deeper responses and longer PFS. Specifically, patients who had an ALC maximum (ALCmax) above 1.0 x 103/µL during the first 15 days after infusion experienced a significant improvement in PFS, more than five times greater, compared to those with lower ALC counts. Patients with ALCmax above 1.0 x 103/µL had a median PFS of 33.1 months, while those with counts at or below 0.5 x 103/µL had a significantly shorter PFS of 6 months. The high-risk group, with an ALCmax of 0.5 or less x 103/µL, showed over three times the likelihood of early disease progression compared to their counterparts with higher ALC counts, making them a vulnerable population within the study cohort. The analysis also took into account a variety of potential confounding factors, such as patient age, previous therapies, high-risk cytogenetics, and the specific CAR T-cell product used. Even when these factors were considered, ALC remained an independent prognostic indicator, making it a reliable marker for predicting the depth and duration of response in this setting.
The researchers also explored the biological mechanisms underlying this phenomenon. CAR T-cell therapy relies heavily on the expansion of the infused T cells within the patient’s body. ALC, which includes a count of lymphocytes such as T cells, may serve as a surrogate marker for this expansion. Patients with higher ALC are likely to experience more robust CAR T-cell proliferation, leading to deeper and more durable anti-tumor responses. This aligns with previous findings that T-cell expansion after infusion is closely linked to treatment success. Additionally, the study noted that patients with higher ALC levels were also more likely to experience Cytokine Release Syndrome (CRS), a common side effect of CAR T-cell therapy that results from the rapid activation and expansion of T cells. While CRS can be a challenging complication to manage, its occurrence might also be a marker of effective CAR T-cell therapy.
The identification of ALC as a biomarker has significant implications for clinical practice. Physicians can now use ALC levels measured within the first 15 days post-infusion to guide treatment decisions. For patients with low ALC counts, this early biomarker could signal the need for alternative treatment approaches or additional therapeutic interventions to manage potential relapse. Given the limited options for patients who relapse after CAR T-cell therapy, having this early warning could be vital for planning the next steps in their treatment journey. Conversely, patients with high ALC levels can be reassured that they are more likely to achieve a deep and sustained response, allowing clinicians to optimize follow-up care and monitoring accordingly.
The researchers are further investigating the biological factors that influence ALC levels after CAR T-cell infusion. By analyzing patient samples and conducting deeper biological studies, they aim to uncover why some patients experience robust lymphocyte expansion while others do not. Understanding these underlying mechanisms could lead to new interventions that enhance CAR T-cell expansion, ultimately improving outcomes for a broader range of patients. Identifying potential pre-infusion markers that could predict whether a patient will have a favorable ALC response may be relevant. If such biomarkers can be identified, clinicians might be able to intervene even earlier, adjusting treatment plans before CAR T-cell therapy begins.
Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma. Saldarriaga MM, Pan D, Unkenholz C, et al. Blood Adv (2024) 8 (15): 3859–3869. https://doi.org/10.1182/bloodadvances.2023012470
