Biomarkers and Treatment Strategies in CAR T-Cell Therapy for R/R Multiple Myeloma

Doris K. Hansen, MD

Idecabtagene vicleucel (ide-cel; Abecma) has shown promise as a breakthrough therapy in relapsed/refractory (R/R) multiple myeloma. However, understanding the key factors influencing treatment outcomes, particularly regarding toxicity and durable responses, remains a critical focus for researchers and clinicians alike.

In an interview with Targeted Oncology^TM, Doris K. Hansen, MD, Moffitt Cancer Center discussed a comprehensive analysis of pretreatment biomarkers associated with these outcomes in patients receiving ide-cel therapy.¹ The study, which involved a retrospective analysis of 180 patients, uncovered important findings about the relationship between disease characteristics, immune responses, and patient outcomes.

Hansen also touched on her work comparing ide-cel to ciltacabtagene autoleucel (cilta-cel; Carvykti), another promising chimeric antigen receptor (CAR) T-cell therapy, providing valuable insights for the oncology community on how to optimize therapy for patients facing this challenging disease.²

CAR T-cell therapy in multiple myeloma: © Kasloom - stock.adobe.com

Targeted Oncology: What motivated this investigation into pretreatment biomarkers and their potential link to toxicity and lasting responses in ide-cel therapy for R/R multiple myeloma?

Hansen: This study looked at key pretreatment characteristics and biomarkers that may be associated with and predict toxicity, as well as durable responses or disease responses to this product. This was a retrospective analysis performed at Moffitt Cancer Center with a concentrated protocol. A total of 180 patients were included in this analysis. A high proportion of these patients had high-risk disease features. About a third had high plasma cell burden, a third had penta-class refractory disease, and 40% had high-risk genetics.

What were the findings from this analysis?

We identified that patients more likely to experience severe cytokine release syndrome [CRS] received a higher median of T cells. These patients were also more likely to experience greater toxicity, as well as have more advanced disease in terms of ISS staging. They had triple-class refractoriness, high plasma cell burden, and elevated baseline inflammatory markers such as ferritin and C-reactive protein.

We also found associations with certain cytokines and the development of grade 2 or higher cytokine release syndrome. We examined bone marrow immune cell profiling to identify associations with toxicity and response. We found that monocytopenic suppressor cells were associated with reduced T-cell expansion. Conversely, higher proportions of CD4/CD8 ratios and certain central nervous system-positive T cells were associated with responses, as well as cytotoxic natural killer cells.

We identified markers of exposure in patients with high plasma cell burden, including impaired activation, proliferation, and increased expression of inhibitory immune receptors, which contribute to tumor immune tolerance. It is important to note that our study identifies several cytokines, inflammatory markers, and immune cells that are associated with toxicity and response in myeloma patients receiving ide-cel. We hope this provides insight for managing toxicity and potential interventions or therapeutic optimization for high-risk patients, particularly those with non-durable responses.

What are the key takeaways for the community oncology audience?

I think the key takeaway is that while some of these findings are from research labs, there are also clinical biomarkers that can be easily measured in clinical laboratories. If we have patients with significantly high disease burdens based on pre-treatment bone marrow biopsies, we need to consider optimization strategies to reduce their disease burden. This may involve chemotherapy or bridging therapies. If a patient is at high risk for toxicity, we can consider prophylactic interventions or inpatient administration of the product. Additionally, for patients with non-durable responses, maintenance therapies or consolidation therapies may be necessary, particularly for high-risk patients.

Could you delve into the study that evaluated cilta-cel and ide-cel’s safety and efficacy in R/R multiple myeloma?

One of the other abstracts examines the comparative safety and efficacy of standard care and response idecabtagene vicleucel and ciltacabtagene autoleucel. This study addresses a gap due to the lack of prospective randomized controlled trials, as the studies included were single-arm studies with varied responses, toxicities, and survival rates. We used an inverse probability of treatment weighting approach, a form of propensity score matching, to balance confounders across treatment arms while preserving the sample size in this analysis—641 patients were leukapheresis and 586 were infused. We also performed sensitivity analysis.

What are the main take home points from this research?

We found that patients who received cilta-cel were more likely to experience certain toxicities, such as severe CRS, infections, delayed myelotoxicity, and slightly higher non-relapse mortality. However, these findings were not statistically significant. We did observe a trend for more [second primary malignancies], but this was also not significant.

These results should be interpreted with caution. In terms of responses, we identified that cilta-cel was associated with superior responses, particularly in depth of response, and significantly superior overall survival compared to ide-cel. We hope this study provides information for clinical decision-making, patient counseling, and product selection for patients receiving immunotherapies such as ide-cel.

REFERENCES:

1. Comprehensive analysis of pre-treatment biomarkers associated with toxicity and durable responses in idecabtagene vicleucel therapy for relapsed/refractory multiple myeloma. Presented at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10; San Diego, CA; Abstract 896.

2. Comparative safety and efficacy of ciltacabtagene autoleucel and idecabtagene vicleucel CAR T-cell therapies in relapsed or refractory multiple myeloma. Presented at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10; San Diego, CA; Abstract 936.