Homing in on Currently Recruiting Clinical Trials With Practice Changing Implications in Lymphoma and Myeloma

Leland Metheny, MD

New treatment innovations centering around CAR T-cell therapy, including the development of a rapid CAR T-cell product are underway, aiming to not just extend progression-free survival (PFS) but to work towards a cure for patients with non-Hodgkin lymphoma (NHL) and multiple myeloma, according to Leland Metheny, MD.

Currently recruiting clinical trials are examining approaches with CAR T-cell therapy including the multicenter phase 2S2114 study (NCT05633615) which is examining maintenance therapy with mosunetuzumab-axgb (Lunsumio), polatuzumab vedotin-piiq (Polivy), or both agents, following chemotherapy and then CAR T-cell therapy for types of NHL including diffuse large B-cell lymphoma (DLBCL).¹ Additionally, the phase 1 CASE2422 study (NCT05400109) is examining a rapid CAR T-cell product in NHL, looking to establish safety with the shorter manufacturing process of UF-KURE19 CAR T cells, which are reinfused into the body using a lentivirus that is no longer active.²

“There are multiple investigator-initiated clinical trials specific to our cancer center Seidman Cancer Center as well as multi-institutional clinical trials that could result in practice-changing [findings],” Metheny said in an interview with OncLive^®, following a State of the Science Summit™ he presented at. “I focused on the cellular therapy aspect of clinical trials because that seems to be, at least for right now, where a lot of cancer therapy is heading towards—curative cellular therapies for hematologic malignancies and possibly cellular therapies for solid tumors as well.”

In multiple myeloma, the phase 1 LMY-920-001 study (NCT05312801) examining BAFF-directed CAR T cells with LMY-920 is open and enrolling at University Hospitals Seidman Cancer Center with point of care manufacturing at UH Wesley Center; the trial is looking to establish the recommended phase 2 dose of LMY-920. Metheny noted that the agent is promising as it has 3 targets rather than 1 or 2.³ Additionally, the phase 3 DRAMMATIC trial (S1803; NCT04071457) is examining post-autologous stem cell transplant (ASCT) maintenance with the addition of daratumumab (Darzalex) to lenalidomide (Revlimid).⁴

In the interview, Metheny, an assistant professor of medicine at Case Western Reserve University School of Medicine and member of the Immune Oncology Program at Case Comprehensive Cancer Center, as well as a hematologist/oncologist at University Hospitals Cleveland Medical Center in Ohio, detailed these ongoing trials and their implications for the field of hematologic oncology.

OncLive: What ongoing NHL studies could be practice changing?

Metheny: Focusing on cellular or immunotherapies for NHL, [CASE2422 is] a homegrown investigator-initiated clinical trial here at Seidman Cancer Center [examining] a rapid CAR T-cell product that is directed against lymphoma cells. It’s manufactured to kill lymphoma cells from the patient’s immune cells. Traditionally the time for manufacture has been a few weeks to maybe a month and requires a specialized site for manufacturing. [But] this rapid CAR [T-cell product] in general does 2 things that are novel and practice changing.

First, it shortens the time of manufacture so that a patient can have their immune cells taken from them, manufactured, and received within 7 days, which is an incredibly short window compared with the standard practice for the FDA-approved CAR T-cell therapies.

Second, it would show that rapid point of care manufacturing is possible, meaning point of care can be done at the site where the patient gets their cells taken from. It’s a very simple process and instead of having to collect the cells from the patient and ship them to a site many miles away, the cells can be manufactured locally and given within 7 days. This could be done in places that don’t have access to funds or the logistics that are required for standard of care CAR T-cell therapy. It could be done in third world countries very quickly and easily to provide care and curative therapy.

Which multicenter NHL trial has the most practice-changing potential?

[S2114] is a multi-institutional study that’s part of [the SWOG] consortium that involves giving immunotherapy after CAR T-cell therapy for types of NHLs [including DLBCL]. There’s a certain percentage of patients who get CAR T-cell therapy and don’t immediately go into remission. For those patients, there’s a percentage who will naturally convert to complete remission [CR] and there’s a certain percentage who will not.

This study is trying to find out if we add on a maintenance therapy that’s targeted against lymphoma cells after the CAR T-cell therapy, can we change those percentages so that a larger percentage of patients will convert to CR and therefore be potentially cured? Both this [study and CASE2422] have practice-changing implications.

Are there any key local clinical trials in Ohio for patients with multiple myeloma?

Our local trial involves a CAR T-cell product [called LMY-920]; the SOC CAR T-cell therapies for multiple myeloma are not intended to be curative and have a PFS that ranges between 9 months to somewhat over a year. There’s an opportunity to potentially develop a more effective CAR T-cell product that results in a longer [progression]-free state. This CAR T-cell product is a BAFF CAR T-cell developed at Case Western Reserve University and Seidman Cancer Center. It’s unique in that it attaches to 3 potential targets on myeloma cells, whereas the standard CAR T-cell [therapies] do not attach to 3 targets—usually they attach to 1 or 2.

The myeloma cell can sometimes downregulate or hide that target on the cell surface, and therefore it can escape the effectiveness of CAR T-cell therapy. With this product, given that it has 3 targets, it’s much more unlikely that a myeloma cell will be able to downregulate or hide 3 targets on its cell surface [vs] 1 or 2. The idea is that the immune escape mechanism that myeloma can develop will be significantly lessened, and therefore the PFS in those patients will be longer as [still prove] safe. That’s the first step, [proving] safe.

What multicenter clinical trials are ongoing in multiple myeloma?

The multi-institutional [DRAMMATIC] clinical trial, which is also part of a consortium, focuses on maintenance therapy after autologous transplant for multiple myeloma. The standard practice is autologous transplant and maintenance lenalidomide afterwards; that is wildly successful and is a clear SOC for patients with multiple myeloma that has resulted in much longer PFS periods for many patients than [what] SOC chemotherapy can give.

The idea with this clinical trial is if we add the antibody daratumumab to that maintenance lenalidomide, can we lengthen that period of [PFS] even longer than [what was] seen with maintenance lenalidomide alone? If that is a positive study, then the new standard practice would be an autologous transplant followed by lenalidomide/daratumumab maintenance.

References

1. Testing drug treatments after CAR T-cell therapy in patients with relapsed/refractory diffuse large B-cell lymphoma. ClinicalTrials.gov. Updated April 4, 2024. Accessed May 1, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05633615
2. Evaluate the safety of UF-KURE19 cells in non-Hodgkin lymphomas. ClinicalTrials.gov. Updated March 29, 2024. Accessed May 1, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05400109
3. Phase 1 study of BAFF CAR-T cells (LMY-920) for non-Hodgkin lymphoma. ClinicalTrials.gov. Updated December 4, 2023. Accessed May 1, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05312801
4. S1803, lenalidomide +/- daratumumab/rHuPh20 as post-ASCT maintenance for MM w/MRD to direct therapy duration (DRAMMATIC). ClinicalTrials.gov. Updated August 14, 2023. Accessed May 1, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04071457