Allo CAR-T: A Glimmer of Hope for Relapsed Plasma Cell Leukemia Patients

A new investigational treatment is being researched for relapsed plasma cell leukemia. In this article, you will learn more about what plasma cell leukemia is, how it develops, and what treatments are being tested.

What is plasma cell leukemia?

Plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma. There are two types of PCL: 

• Primary PCL or pPCL is when a new patient is diagnosed with PCL.
• Secondary PCL or sPCL is when a multiple myeloma patient relapses with PCL characteristics.

About 200 patients are diagnosed with PCL per year in the United States. Even with advances made in treating multiple myeloma over the past ten years, people with PCL face a difficult prognosis. Median overall survival (OS) for pPCL patients is about 3 years. Some treatment advances have improved that outlook. For patients who want and qualify for a tandem auto-stem cell transplant, which is two stem cell transplants back-to-back, the median OS is about 6 years. The median OS for sPCL is about 3 months with only one transplant and 16 months for tandem transplants (auto/allo or allo/allo). Repalsed PCL also has short OS statistics.

People with PCL have not seen the same advances in treatment as people with multiple myeloma. People with PCL are steadily excluded from the overwhelming majority of clinical studies, which often excludes them from accessing novel treatments approved by the U.S. Food and Drug Administration (FDA), because the treatments do not have outcomes for PCL patients.

Are allo-CAR-T treatments on the horizon for PCL?

A recent press release by the Chinese biotech company Carsgen about their investigational product CT0596 is an interesting development. CT0596 is an allo-CAR-T targeting BCMA using healthy donor derived T-cells. This makes the CAR-T cells readily available for use, also called "off-the-shelf." The almost immediate availability of such CAR-T cells is especially important for ultra-high-risk myeloma and PCL where disease progression is extremely rapid.

The challenge with allo-CAR-T cells is that the donor T-cells will be recognized and rapidly eliminated by the host immune system. This impacts CAR-T cell survival and results in limited expansion in vivo. To address this issue, a CAR recognizing NKG2A, a surface protein of NK-cells, was armored into the alogeneic CAR T-cells to hinder the attack of host NK cells. 

Early outcomes for PCL patients treated with allo-CAR-T

The press release from Carsgen mentions the outcomes of the first two PCL patients dosed with CT0596. In a nutshell, both patients had been heavily pretreated with proteasome inhibitor, immunomodulatory agent, and CD38 monoclonal antibody. Patient 1 developed Grade 2 CRS, Grade 4 cytopenia, and a lung infection. Patient 2 developed Grade 1 CRS, Grade 4 neutropenia, and thrombocytopenia following lymphodepletion and CAR-T cell infusion. Both patients recovered after treatment with tocilizumab and other supportive measures.

The press release stated that, "Efficacy assessments [for Patient 1] at both Week 4 and Week 8 post-infusion showed stringent complete response (sCR), and bone marrow minimal residual disease (MRD) was negative (< 10⁻⁶) at Week 4. Patient 2 achieved sCR at the Week 4, Week 8, and Week 12 assessments post-infusion, with bone marrow MRD negative (< 10⁻⁶) at both Week 4 and Week 12.”

Needless to say, to PCL patients, these are sterling results and not something we are not used to reading. Time will tell, however, how long those short-term results will last and whether graft-versus-host disease will show up later. Still, these early results give us, PCL patients, hope with our journey. All of us are gluttons for good news.

Earlier in this post, I mentioned that Carsgen is based in China. I do want to point out that the company has a U.S. FDA-approved manufacturing facility in Durham, NC. In the case of CT0596, the company expects to open a U.S. Investigational New Drug with FDA in the next few months. 

Carsgen also has another investigational drug product for both multiple myeloma and PCL (CT071). This product targets GPRC5D but is an autologous CAR-T and the Phase 1 clinical trials will start in 2026. For more information on this product you can check out NCT06333509. Please note that PCL patients are specifically included in the acceptance criteria. 

Sources:

Optimal Treatment for Newly Diagnosed Primary Plasma Cell Leukemia: A Retrospective Multicenter Analysis

Anti-GPRC5D CAR-T Cells (CT071) in Participants With RRMM or RRpPCL