Joshua P. Sasine, MD, PhD, hematologist/oncologist, assistant professor, Cedars-Sinai Medical Center, discusses the potential role of ciltacabtagene autoleucel (cilta-cel; Carvykti) in earlier lines of therapy for patients with multiple myeloma.

The phase 3 CARTITUDE-4 trial (NCT04181827) evaluated the use of cilta-cel vs standard-of-care (SOC) pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd) in patients with lenalidomide (Revlimid)-refractory multiple myeloma who had previously received 1 to 3 prior lines of therapy. In the trial, cilta-cel provided a significant progression-free survival advantage to patients across all prespecified groups vs SOC regimens. Overall, results from the trial indicated that cilta-cel in earlier lines could not only improve tolerability but could become new standard of care for patients with lenalidomide-refractory myeloma.

Based on this trial, cilta-cel continues to be the focus on ongoing efforts to move CAR T-cell therapy into earlier lines in myeloma. Several ongoing trials are also comparing the agent's efficacy with that of autologous stem cell transplant (ASCT) in this disease space, Sasine remarks. Previously reported data has shown that ASCT also provides a substantial, consistent PFS benefit for patients with multiple myeloma. However, it is historically difficult to demonstrate an overall survival (OS) advantage with ASCT in this setting, and research on cilta-cel may encounter a similar problem, Sasine states. Additionally, OS results may lead to discussion regarding whether the lack of a true crossover trial design influenced results, he notes.

With potential uncertainty surrounding OS results, PFS and toxicity profiles will be the most important measures to consider when determining if cilta-cel should be used in earlier lines, and if it should be used before ASCT, Sasine asserts. Patients who are elderly or have high-risk disease may benefit from earlier utilization of CAR T-cell therapy due to its superior tolerability vs ASCT, he says. However, more data are needed to determine if this approach should consistently replace ASCT in the frontline for standard-risk patients, Sasine concludes.

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Joshua P. Sasine, MD, PhD,  discusses the potential role of cilta-cel in earlier lines of therapy for patients with multiple myeloma.

Dr Sasine on the Potential Use of Cilta-Cel in Earlier Lines for Multiple Myeloma

Joshua P. Sasine, MD, PhD, clinical instructor of medicine, hematologist, and oncologist, University of California, Los Angeles, discusses the challenges in predicting a patient’s individual benefit with CAR T-cell therapy in hematologic malignancies. 

Though it is difficult to pinpoint predictive patient characteristics to CAR T-cell therapy, it is getting easier, Sasine says. Both before and after CAR T-cell treatment, certain cytokine profiles appear to be associated with long-term, durable remissions.  

Also, characteristics of the treatment, such as the depth of lymphodepletion, could potentially indicate a patient’s prognosis. Importantly, this can be modified and controlled in the clinic, concludes Sasine. 

Joshua P. Sasine, MD, PhD, discusses the challenges in predicting a patient’s individual benefit with CAR T-cell therapy in hematologic malignancies. 
 

Dr. Sasine on Predicting Individual Benefit with CAR T Cells 

Joshua P. Sasine, MD, PhD, clinical instructor of medicine, hematologist, and oncologist, University of California, Los Angeles, discusses new developments with CAR T-cell therapy.

Follow-up data from the initial trials of CAR T-cell therapy continue to show benefit with this approach. Moreover, providers have become more accustomed to how to use these therapies. In doing so, they have learned how to make these products safer and predict which patients are most likely to benefit from them. Such strategies include inhibiting cytokines that have a direct implication on the neurotoxicity of the CAR T cells, says Sasine. Another approach is bispecific CAR T cells, which are designed to eradicate one of the escape mechanisms that cancer cells have to avoid CAR T cell recognition.

It’s difficult to predict the likelihood of response to CAR T-cell therapy on an individualized level. However, the field is beginning to understand that there are certain cytokine profiles both before and after CAR T cells are administered that are associated with durable remissions. Moreover, there are certain pre-therapeutic indicators of response, including the depth of conditioning for CAR T cells. Notably, the depth of lymphodepletion can be modified, whereas other factors are merely predictive, concludes Sasine.

Dr. Sasine on New Developments With CAR T-Cell Therapy

Joshua P. Sasine, MD, PhD, clinical instructor of medicine, University of California, Los Angeles, discusses how to determine if a patient will have a response to CAR T-cell therapy.

Currently, it is difficult to determine who is going to benefit the most from CAR T-cell therapy, according to Sasine. However, researchers are getting closer to that because there are certain cytokine profiles now known, both before and after CAR T cells are given, that are associated with long-term, durable remissions, explains Sasine.

Lymphodepletion can also be a signal to determine response to CAR T cell therapy. This is something that can be modified within a physician's control, whereas other aspects are unmodifiable but can be helpful for predicting response.

Joshua P. Sasine, MD, PhD

Articles

Dr Sasine on the Potential Use of Cilta-Cel in Earlier Lines for Multiple Myeloma

Dr. Sasine on Predicting Individual Benefit with CAR T Cells

Dr. Sasine on New Developments With CAR T-Cell Therapy

Dr. Sasine on Determining Outlook With CAR T-Cell Therapy in Hematologic Cancers