Results from a new multi-center study, led by oncologists at NewYork-Presbyterian and Weill Cornell Medicine, has described for the first time a key biomarker – absolute lymphocyte count (ALC) – that has the potential to predict therapeutic response to chimeric antigen receptor (CAR) T-cell immunotherapy for patients with relapsed/refractory multiple myeloma. While this FDA-approved treatment is widely used, until now there has not been a way to predict whether B-cell maturation antigen (BCMA) CAR T-cell therapy would elicit a good response.
NewYork-Presbyterian and Weill Cornell Medicine hematologist Mateo Mejia Saldarriaga, MD, served as lead author on the study, which was recently published in Blood Advances. His NewYork-Presbyterian and Weill Cornell Medicine co-senior authors include hematologists Mark Bustoros, MD, and Ruben Niesvizky, MD, director of the Multiple Myeloma Center.
Below, Dr. Mejia Saldarriaga and Dr. Bustoros discuss the origin and scope of their study on the association between ALC and outcomes in patients receiving BCMA CAR T-cell therapy for multiple myeloma.
A Simple Blood Test…A Significant Observation
Dr. Mejia Saldarriaga: Our study grew out of a clinical observation. In taking care of patients undergoing BCMA CAR T-cell immunotherapy, we noticed that the ALC in a routine CBC blood test significantly increased in a patient within 15 days. The following week, another patient presented with the same phenomenon, which we had not seen described in the literature. From that observation, we learned that it is, in fact, a very frequent occurrence. This provoked more questions and prompted us to seek a better understanding of the mechanism behind this rise in white blood cells. What was striking to us is that while this increase in lymphocytes frequently presents in myeloma CAR T-cell therapy, it does not in CAR T-cell therapy for lymphoma.
Dr. Bustoros: This phenomenon became the basis for our study, not just because it was an interesting observation, but for its potential for clinical implications. Notably, in preparation to receive CAR T-cell therapy, patients undergo chemotherapy to deplete their lymphocytes. So seeing a high increase in the ALC, that was surprising.
Dr. Mejia Saldarriaga: The elevation in the white blood cell count is due to the BCMA CAR T-cells thriving in the body – growing and multiplying to keep the cancer in check. We surmised that by identifying patients who had an elevation in ALC in the first 15 days, we could potentially indicate those who were going to have a higher chance of a deeper and more prolonged response.
Dr. Bustoros: Our study analyzed data on 156 patients who had undergone CAR T-cell therapy with BCMA-targeting agents for relapsed multiple myeloma between 2017 and 2023. This was a multicenter collaboration to ensure the diversity of the patient population and to decrease the chance of bias. The baseline ALCs after patients underwent lympho-depleting chemotherapy were similar. Patient ALCs were taken five days before treatment started and during the first 15 days of BCMA CAR T-cell therapy.
A Prognostic Tool Emerges
Dr. Bustoros: We conducted a stepwise approach to analyze all the variables, such as age at time of infusion, previous lines of therapy, and high risk disease in terms of cytogenetics. After accounting for all of these factors, the ALC was a significant predictor independently of the other variables. The other important variable that was a prognostic factor was extramedullary myeloma. These were the two independent risk factors in our analysis. Patients with higher ALC at day 15 had significantly better response to treatment with their cancer under control for an average of 30 months, whereas those who had lower ALC only had six months of progression-free survival on average. We also found that a higher ALC was associated with an increased risk of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), two common, but manageable side effects of CAR T-cell therapy.
We were able to confirm that high ALC is an independent predictive marker of disease progression after accounting for various factors, such as age, previous treatments, and high risk disease features.
— Dr. Mark Bustoros
Dr. Mejia Saldarriaga: Our research progressed from an observation that was not actionable to a prognostic tool for objectively monitoring the therapeutic response and identifying patients who either have a very good chance of responding or those who may not achieve the same benefit. The beauty of this biomarker is that you don't need to wait weeks to know the result. Finding a low ALC suggests we need to be mindful that this patient has a higher chance of early relapse, so we can start thinking about next lines of therapy.
If doctors can identify patients who are more likely to have a poor response to BCMA CAR T-cell, other treatments can be explored or given earlier.
— Dr. Mateo Mejia Saldarriaga
Clinical Implications and Ongoing Investigations
Dr. Bustoros: The importance of this study is that the ALC is a very easy and measurable test to guide oncologists when they are following patients after CAR T-cell therapy. If the ALC is low, the oncologist would know to have other drugs readily available for the potential early relapse of this patient and advise the patient that other therapies may be needed. Having identified this simple biomarker, we are now trying to understand the biological determinants of a low ALC. Our current research goal is to determine why certain patients would have a very low ALC and others a very high ALC with a much better and durable response. We recently received a grant from the International Myeloma Society to take our work into the translational phase. Then the next step would be to design clinical trials using this biomarker as a surrogate to guide our downstream decisions.
Dr. Mejia Saldarriaga: If we are going to make changes to the current standard of care, we will need to conduct prospective trials. Part of what we're developing now is creating trials of therapeutic interventions using the ALC measurement. Another study observation suggests patients who received last line chemotherapy before the CAR T-cell collection tended to have lower ALC counts. This could impact whether we should use chemotherapy as the last line or a different option if available. This will be another avenue of research.
Dr. Bustoros: We also have an ongoing study comparing lymphoma patients to those with multiple myeloma to try to understand the different mechanisms between the ALC in both diseases. It's an important field for a therapy that's now a standard of care in relapse settings of both myeloma and lymphoma. It’s very important to understand how CAR T-cell therapy works and to have easy biomarkers that could predict patient response.
Many NewYork-Presbyterian physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profiles for Drs. Bustoros and Niesvizky.
