Leveraging ctDNA to Predict Response in Patients With Myeloma Receiving CAR T Cells

Hitomi Hosoya, MD

The use of circulating tumor DNA (ctDNA) and its ability to predict response can potentially eliminate the need for invasive tumor sampling via bone marrow exams in patients with multiple myeloma receiving chimeric antigen receptor (CAR) T-cell therapy, according to Hitomi Hosoya, MD.

“We have a lot of goals but our main goal, in terms of patient care, is to hopefully replace the bone marrow exam with the ctDNA so that we can gain the same genomic information through this blood draw. The other goal is to see if we can do the minimal residual disease [MRD] testing from the blood,” Hosoya told Targeted Oncology^TM in an interview.

Using a Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq), investigators, led by Hoyosa, characterized tumors, and quantified treatment responses of patients with multiple myeloma to explore how it works during CAR T-cell therapy.

With CAPP-Seq, samples from patients with relapsed or refractory multiple myeloma were sequenced. ctDNA with a median allele frequency of 0.91% and 3.82 log hGE/mL was detected in pretreatment plasma and ctDNA levels were higher in patients with relapsed/refractory multiple myeloma vs newly diagnosed multiple myeloma (4.26 vs 3.08 log hGE/mL; P = .02).

Additionally, patients with over 90 days of responses had significantly lower levels of ctDNA compared with patients with early progression after 28 days.

Overall, the study concluded that ctDNA testing in patients with multiple myeloma could improve responses and relapse prediction, as well as uncover mechanisms of therapy resistance.

In the interview, Hosoya discussed the potential use of ctDNA in the myeloma space, including its ability to sequence BCMA-targeted therapies and reduce the need for bone marrow exams.

Targeted Oncology: What role does ctDNA play in the myeloma space?

Hosoya: We have been working on circulating tumor DNA studies focusing on multiple myeloma patients. [While] ctDNA has not been studied vigorously in multiple myeloma yet, our group at Stanford has been studying it a lot for lymphoma patients. Since we haven't studied it much in multiple myeloma, we started examining what the role is, whether we can use it to stratify patients’ prognosis, and whether we can kind of predict full response to a certain therapy and if we can elucidate resistant mechanisms to the therapy.

Can you discuss the study you led regarding CAPP-Seq?

We have enrolled 35 patients from Stanford University to this research protocol. Some of them are receiving conventional standard or a conventional chemotherapy regimen. Some of them are receiving CAR T-cell therapy, and we have followed up their ctDNA levels and what mutations we could detect from the blood plasma and follow it up. Because this is a new study, we enrolled almost everybody that had myeloma, initially. Then, we kind of switched our focus to patients undergoing standard of care CAR T-cell therapy. Our results show that we can detect a good amount of ctDNA from these patients and we can track them throughout the disease course. It [also] correlates with treatment response.

What methods were used in the study?

We collected the patient's blood plasma, as well as bone marrow samples, whenever available. Then, we extracted the DNA from them, prepared and performed hybrid capture and next-generation sequencing. For hybrid capture, we designed our own gene-targeted panel so that we could capture the genes of interest. Then after running the sequence, we analyzed the data and examined whether it makes sense with their clinical course and correlated their clinical outcomes.

What findings were notable in the CAR T-cell cohort of the trial?

Interestingly, we found that in the CAR T cohort, the level of ctDNA on day 28, after the CAR infusion, correlated with their time to progression. We can hopefully use this ctDNA to kind of prognosticate patients after CAR T cell therapy. We also found from ctDNA that clonal evolution was detected before the clinical relapse. These patients were responding to the CAR T-cell therapy, but we were able to detect this relapse coming up about a month prior to the clinical relapse. We also saw that this relapse was occurring because they lost the targets, which is the BCMA, which is a target of the CAR T. These patients lost their target as we were able to see in the blood samples.

How do you foresee these findings impacting the treatment of patients moving forward?

This is an early study, and we are not trying to recommend anything based on this study yet. But like other disease areas, such as lymphoma and some of the solid tumors, the ctDNA might be more usable in the future, instead of doing the bone marrow, some biopsies to determine their prognosis, etc.

In terms of future direction, we are trying to see if we can improve the sensitivity of MRD detection from the blood. Right now, we send bone marrow samples for MRD detection, and the sensitivity is 10-6. We are trying to beat this from this ctDNA study. We have a lot of goals but our main goal, in terms of patient care, is to hopefully replace the bone marrow exam with the ctDNA so that we can gain the same genomic information through this blood draw. The other goal is to see if we can do the MRD testing from the blood.

REFERENCE:

Hosoya H, Carleton M, Tanaka K, et al. Circulating Tumor DNA for Disease Characterization and Response Prediction in Myeloma Patients Undergoing Chimeric Antigen Receptor T-Cell Therapy. Presented at: 2023 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.February 15-19, 2023; Orlando, FL. Abstract 1