CAR-T Therapy for Multiple Myeloma

Overseen By Armin Ghobadi, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must not be taking: Investigational agents

Disqualifiers: Other malignancy, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

25 Participants Needed

Trial Summary

What is the purpose of this trial?

Despite recent therapeutic advances, multiple myeloma (MM) remains an incurable disease. Although survival has improved, there are nevertheless diminishing durations of response to each subsequent line of therapy. This highlights the need for further therapeutic innovation. BCMA-targeting CAR-T cells show impressive response rates; however, their median duration of response is disappointing. The investigators propose that CS1(SLAMF7)-targeting CAR-T cells will fill a gap in the MM armamentarium. CS1 is an attractive target in MM because it is expressed in most patients. Elotuzumab (Empliciti®), an approved anti-CS1 antibody, has proven the clinical efficacy of this target. CAR-T cells are an ideal modality to target CS1, given that two approved treatments, ide-cel (idecabtagene vicleucel, AbecmaTM) and cilta-cel (ciltacabtagene autoleucel, Carvykti™), have proven the potential for cellular immunotherapy in MM. The investigators are testing the safety and preliminary anti-myeloma efficacy of WS-CART-CS1, a CAR-T cell therapy targeting CS1.

Will I have to stop taking my current medications?

The trial requires that you stop any systemic therapy for multiple myeloma at least 14 days before a specific procedure called leukapheresis. If you are on other investigational agents or have received cellular therapy recently, you may also need to stop those.

What data supports the effectiveness of the treatment WS-CART-CS1 for multiple myeloma?

Research shows that CAR-T cell therapies targeting CS1 and BCMA antigens are effective in treating multiple myeloma by specifically killing cancer cells and blocking tumor growth. These therapies have shown promise in both laboratory and animal studies, indicating potential for successful treatment in humans. ^{1 2 3 4 5}

Is CAR-T therapy safe for treating multiple myeloma?

CAR-T therapy for multiple myeloma has shown a good safety profile in clinical trials, with some patients experiencing mild to moderate side effects like cytokine release syndrome (a reaction that can cause fever and low blood pressure) and blood-related issues such as low white blood cell counts. No severe neurological side effects were observed. ^{2 4 6 7 8}

How is the WS-CART-CS1 treatment different from other treatments for multiple myeloma?

WS-CART-CS1 is a unique CAR-T cell therapy that targets the CS1 protein on myeloma cells, which is highly expressed on these cancer cells but limited on normal cells, making it a promising target. This approach is different from other treatments as it specifically modifies T cells to attack myeloma cells, potentially offering a more targeted and effective treatment option. ^{2 3 4 7 9}

Research Team

Armin Ghobadi, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for individuals with multiple myeloma, a type of blood cancer. Participants should have tried other treatments that didn't work well enough. They must be healthy enough to undergo the procedure and not have any infections or immune system problems that could make it unsafe.

Inclusion Criteria

Measurable disease meeting specific criteria such as Serum M-protein, Urine M-protein, Serum FLC assay, biopsy-proven plasmacytoma, or Bone marrow plasma cells

My kidney, liver, lungs, and heart are all working well.

Agreement to use adequate contraception for women of childbearing potential and men

Exclusion Criteria

I have been treated with CS1-targeted therapies before.

I do not have any infections or serious conditions that would stop me from receiving treatment.

I received treatment for multiple myeloma less than 14 days before my planned leukapheresis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Apheresis and Pre-treatment

Participants undergo apheresis for WS-CART-CS1 manufacturing and may receive anti-multiple myeloma therapy before lymphodepleting chemotherapy

1-2 weeks

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy on days -5, -4, and -3

1 week

Treatment

WS-CART-CS1 infusion occurs three days after the last dose of lymphodepleting chemotherapy

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Long-term Follow-up

Participants are monitored for overall survival and progression-free survival

15 years

Treatment Details

Interventions

• WS-CART-CS1

Trial Overview The trial is testing WS-CART-CS1, a new CAR-T cell therapy targeting CS1 on cancer cells, combined with lymphodepleting chemotherapy which prepares the body for the CAR-T treatment by lowering immune cells.

Participant Groups

Group I: Part B Dose Expansion: WS-CART-CS1 Experimental Treatment 2 Interventions

* Undergo apheresis procedure for WS-CART-CS1 manufacturing. * Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician. * Lymphodepleting chemotherapy on days -5, -4, and -3. * Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused. * Part B is the dose expansion portion of the study. The dose of WS-CART-CS1 will be determined in Part A of the study.

Group II: Part A Dose Escalation: WS-CART-CS1 Experimental Treatment 2 Interventions

* Undergo apheresis procedure for WS-CART-CS1 manufacturing. * Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician. * Lymphodepleting chemotherapy on days -5, -4, and -3. * Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused. * Part A is the dose escalation portion of the study with the starting dose of 0.5 x 10\^6 cells/kg of WS-CART-CS1.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Paula C. & Rodger O. Riney Blood Cancer Research

Collaborator

Trials

1

Recruited

30+

Findings from Research

In a study involving 113 patients with relapsed or refractory multiple myeloma, a single infusion of cilta-cel resulted in a remarkable overall response rate of 97%, with 67% achieving a stringent complete response, indicating its high efficacy in this challenging patient population.

While cilta-cel demonstrated significant therapeutic benefits, it was associated with common hematological adverse events and cytokine release syndrome in 95% of patients, though most cases were manageable, highlighting the importance of monitoring for these effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Berdeja, JG., Madduri, D., Usmani, SZ., et al.[2021]

In a phase I clinical trial involving 30 multiple myeloma patients, anti-BCMA CAR T cells showed favorable safety with no high-grade cytokine release syndrome and only one case of low-grade neurologic toxicity.

The treatment demonstrated significant efficacy, with 10 out of 15 patients with measurable disease achieving a partial response or better, and 4 patients converting to minimal residual disease-negative complete response, indicating strong antimyeloma activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy. Garfall, AL., Cohen, AD., Susanibar-Adaniya, SP., et al.[2023]

The study introduces a novel CAR T-cell design that targets two different antigens, BCMA and CS1, on multiple myeloma cells, showing consistent and potent anti-tumor activity in mouse models.

This dual-targeting approach resulted in superior survival rates in treated mice compared to traditional CAR T-cells that only target a single antigen, suggesting it could help overcome the issue of relapse due to antigen loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A compound chimeric antigen receptor strategy for targeting multiple myeloma. Chen, KH., Wada, M., Pinz, KG., et al.[2019]

CS1-targeted CAR T cells demonstrated enhanced activation and cytotoxicity against multiple myeloma (MM) cells in vitro and ex vivo, indicating their potential effectiveness in treating this cancer.

In mouse models, the use of CS1-CAR T cells significantly suppressed the growth of human MM cells and improved survival, suggesting that targeting CS1 could be a promising therapeutic strategy for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells. Chu, J., He, S., Deng, Y., et al.[2021]

The study developed novel CS1 CAR-T cells and bispecific CS1-BCMA CAR-T cells that specifically target multiple myeloma cells, showing effective tumor cell killing in laboratory tests and in live models.

These CAR-T cells not only killed multiple myeloma cells but also secreted IFN-gamma, indicating a strong immune response, and they successfully inhibited tumor growth in vivo, paving the way for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel CS1 CAR-T Cells and Bispecific CS1-BCMA CAR-T Cells Effectively Target Multiple Myeloma. Golubovskaya, V., Zhou, H., Li, F., et al.[2021]

In a study of 21 patients with relapsed and refractory multiple myeloma treated with BCMA-chimeric antigen receptor T cells (CART), 17 patients showed effective responses, including 10 achieving complete remission, indicating a promising efficacy of this treatment.

The treatment was associated with manageable adverse reactions, primarily cytokine release syndrome (CRS), which occurred in 20 patients but was mostly mild (Grade 1 or 2), demonstrating that BCMA-CART can be safely administered with proper monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Toxicity Management and Efficacy Evaluation of BCMA-CART in the Treatment of Relapsed and Refractory Multiple Myeloma]. Zhang, XY., Ding, HY., Gang, DX., et al.[2022]

Targeting the distal V domain of the CS1 protein with CAR-T therapy shows promise for effectively killing myeloma cells in both laboratory and mouse model studies.

Creating a fratricide-resistant version of CAR-T cells by deleting CS1 did not enhance the treatment's effectiveness, indicating that the original CAR-T design remains optimal for targeting myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells. O'Neal, J., Ritchey, JK., Cooper, ML., et al.[2023]

In a study involving 16 patients with relapsed or refractory multiple myeloma, the bispecific CS1-BCMA CAR-T cells showed a high overall response rate of 81%, with 38% achieving a stringent complete response, indicating strong efficacy in targeting this challenging cancer.

The treatment had a manageable safety profile, with 38% of patients experiencing mild cytokine release syndrome and significant hematological adverse events, but no neurological toxicities were reported, suggesting a favorable safety outcome for this innovative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma. Li, C., Xu, J., Luo, W., et al.[2023]

Chimeric antigen receptor (CAR)-modified T cell therapy has shown promising efficacy in treating refractory or relapsed multiple myeloma (MM) in both preclinical and clinical studies, indicating a potential new treatment avenue for this incurable disease.

The toxicities associated with CAR-T cell therapy are manageable, suggesting that this innovative approach could be a safe option for patients with MM, especially as research continues to identify effective targets and improve technologies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapies for multiple myeloma. Wu, C., Zhang, L., Brockman, QR., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy. [2023]

3. England pubmed.ncbi.nlm.nih.gov

A compound chimeric antigen receptor strategy for targeting multiple myeloma. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Novel CS1 CAR-T Cells and Bispecific CS1-BCMA CAR-T Cells Effectively Target Multiple Myeloma. [2021]

6. China pubmed.ncbi.nlm.nih.gov

[Toxicity Management and Efficacy Evaluation of BCMA-CART in the Treatment of Relapsed and Refractory Multiple Myeloma]. [2022]

7. England pubmed.ncbi.nlm.nih.gov

CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapies for multiple myeloma. [2020]