CAR T-Cell Therapy for Multiple Myeloma

Overseen By Hope Wei

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Antidepressants, Antivirals, Chemotherapy, others

Disqualifiers: Symptomatic multiple myeloma, Active infection, Cardiac conditions, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called ciltacabtagene autoleucel (or cilta-cel) to determine its safety and effectiveness for people with high-risk smoldering multiple myeloma, a type of blood cancer that hasn't yet become active. Participants will also receive two chemotherapy drugs, cyclophosphamide and fludarabine, to prepare their bodies for the main treatment. The trial includes different phases, such as a safety phase and a dose expansion phase, to find the best dose. Suitable candidates for this trial have high-risk smoldering myeloma, which may involve specific protein level patterns or changes in bone marrow. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, certain therapies like chemotherapy, immunotherapy, and radiotherapy are not allowed during the trial, so it's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ciltacabtagene autoleucel (cilta-cel) is safe for people with multiple myeloma. The FDA approved it in 2022 for patients whose multiple myeloma has returned or not responded to other treatments. In studies, cilta-cel demonstrated promising safety results, though some side effects were noted. These include low blood cell counts, fever, and infections, which are common with treatments that reset the immune system.

The chemotherapy drugs cyclophosphamide and fludarabine prepare the body for cilta-cel treatment. They are generally well-tolerated, but like all chemotherapy, they can cause side effects such as nausea, hair loss, and tiredness.

It's important to remember that while cilta-cel shows potential, its use in patients with high-risk, smoldering myeloma is still under study. Safety data is being collected, so participants are closely monitored for any new information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ciltacabtagene autoleucel (cilta-cel) because it offers a new approach for treating multiple myeloma. Unlike standard treatments such as chemotherapy and immunomodulatory drugs, cilta-cel is a CAR T-cell therapy, which means it involves reprogramming a patient's own immune cells to target and destroy cancer cells more effectively. This personalized approach has the potential to provide more durable responses and target the cancer more precisely, which is why it's generating a lot of interest in the medical community.

What evidence suggests that this trial's treatments could be effective for multiple myeloma?

Studies have shown that ciltacabtagene autoleucel, or cilta-cel, can effectively treat multiple myeloma, a type of blood cancer. Research indicates that cilta-cel significantly reduces the risk of disease progression and extends patient survival compared to standard treatments. One study showed that cilta-cel lowered the risk of death by 45%. Other studies have found that patients with relapsed or hard-to-treat multiple myeloma experienced long-term improvement in cancer symptoms and lived longer after receiving cilta-cel. In this trial, participants will receive cilta-cel following a preparatory regimen of Cyclophosphamide and Fludarabine. These findings suggest that cilta-cel could be a promising option for treating high-risk, smoldering myeloma. ^{4 5 6 7 8}

Who Is on the Research Team?

Irene Ghobrial, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults over 18 with high-risk smoldering myeloma, which isn't yet causing symptoms. Participants should have certain blood and bone marrow conditions but no recent other cancers or major illnesses. They must be able to perform daily activities with ease (ECOG PS 0 or 1) and agree to use effective contraception.

Inclusion Criteria

I am a man and will use protection if I have sex with a woman who can have children.

You have a high percentage of certain bone marrow cells and specific changes in their patterns.

My condition is high-risk smoldering multiple myeloma with ≤40% plasma cells.

Exclusion Criteria

I have not had major surgery in the last 2 weeks.

I am not allergic or intolerant to the study drug or its components.

I do not have any unmanaged ongoing illnesses.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-In

Participants undergo apheresis, stem cell collection, and receive cyclophosphamide and fludarabine followed by hospitalization for Cilta-cel administration

3 weeks

Hospitalization for 2 weeks post Cilta-cel infusion

Cilta-Cel Dose Expansion

Expansion cohort participants undergo similar procedures as the safety run-in phase

3 weeks

Hospitalization for 2 weeks post Cilta-cel infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Long-term Follow-up

Extended monitoring for safety and effectiveness up to 15 years

Up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• Ciltacabtagene Autoleucel
• Cyclophosphamide
• Fludarabine Phosphate

Trial Overview The study tests the safety and effectiveness of cilta-cel, a CAR T-cell therapy, along with cyclophosphamide and fludarabine phosphate chemotherapies in treating high-risk smoldering myeloma before it becomes symptomatic.

How Is the Trial Designed?

Group I: Safety Run-In Experimental Treatment 3 Interventions

Participants will be enrolled into each of the 2 safety run-in phases in a standard 3 + 3 design. \- Participants will undergo study procedures as outlined: * Apheresis for collection of peripheral blood mononuclear cells (PBMC) will occur on-site * Stem cell collection on-site post-apheresis per standard care. * Administration of Cyclophosphamide and fludarabine in pre-determined doses 1 x daily for 3 consecutive days. * Hospitalization to receive Cilta-cel in per-determined dose per protocol 1 x daily for 3 consecutive days and will remain in the hospital for 2 weeks post cilta-cell infusion. * Follow-up for 3 years post-treatment and up to 15 years.

Group II: Cilta-Cel Dose Expansion Cohort Experimental Treatment 3 Interventions

Expansion cohort of 14 participants will be enrolled after safety run-in phases, and participants will undergo study procedures as outlined: * Apheresis for collection of peripheral blood mononuclear cells (PBMC) will occur on-site * Stem cell collection on-site post-apheresis per standard care. * Administration of Cyclophosphamide and fludarabine in pre-determined doses 1 x daily for 3 consecutive days. * Hospitalization to receive Cilta-cel in per-determined dose per protocol 1 x daily for 3 consecutive days and will remain in the hospital for 2 weeks post cilta-cell infusion. * Follow-up for 3 years post-treatment and up to 15 years.

Ciltacabtagene Autoleucel is already approved in United States, European Union for the following indications:

Approved in United States as Carvykti for:

• Relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody

Approved in European Union as Carvykti for:

• Relapsed and refractory multiple myeloma after one or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Janssen Research & Development, LLC

Industry Sponsor

Trials

1,022

Recruited

6,408,000+

Joaquin Duato

Janssen Research & Development, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Research & Development, LLC

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Published Research Related to This Trial

Ciltacabtagene autoleucel (cilta-cel) therapy significantly improved health-related quality of life (HRQoL) in patients with relapsed/refractory multiple myeloma, with a notable decrease in reported symptoms such as pain and fatigue from 85.2% at baseline to 22.2% by Day 184.

The majority of patients (70.8%) felt that cilta-cel met or exceeded their treatment expectations, highlighting its efficacy and the positive impact of a long treatment-free period on their overall health perception.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient Perceptions Regarding Ciltacabtagene Autoleucel Treatment: Qualitative Evidence From Interviews With Patients With Relapsed/Refractory Multiple Myeloma in the CARTITUDE-1 Study. Cohen, AD., Hari, P., Htut, M., et al.[2023]

Ciltacabtagene autoleucel (cilta-cel) significantly improved progression-free survival in patients with lenalidomide-refractory multiple myeloma, with a median progression-free survival not reached in the cilta-cel group compared to 11.8 months in the standard-care group, based on a phase 3 trial with 419 participants.

The cilta-cel group also showed higher overall response rates (84.6% vs. 67.3%) and complete response rates (73.1% vs. 21.8%) compared to standard care, although most patients experienced grade 3 or 4 adverse events, including cytokine release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. San-Miguel, J., Dhakal, B., Yong, K., et al.[2023]

Ciltacabtagene autoleucel (cilta-cel) is a CAR T-cell therapy that effectively targets B-cell maturation antigen (BCMA) in patients with relapsed or refractory multiple myeloma, showing early and long-lasting responses based on the Phase 1b/2 CARTITUDE-1 study.

While cilta-cel has a tolerable safety profile with manageable adverse effects, it generally demonstrates better efficacy compared to another CAR T-cell therapy, idecabtagene vicleucel (ide-cel), although both therapies have comparable adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ciltacabtagene autoleucel: The second anti-BCMA CAR T-cell therapeutic armamentarium of relapsed or refractory multiple myeloma. Chekol Abebe, E., Yibeltal Shiferaw, M., Tadele Admasu, F., et al.[2022]

Ciltacabtagene autoleucel (cilta-cel) demonstrated a significantly higher overall response rate (84% vs. 28%) and longer progression-free survival in patients with relapsed/refractory multiple myeloma compared to standard non-CAR-T therapies, based on a comparison of 113 patients in the CARTITUDE-1 study and 190 patients from the MAMMOTH dataset.

In the modified intent-to-treat population, cilta-cel showed an even more impressive overall response rate of 96% compared to 30% in the MAMMOTH cohort, indicating its potential as a highly effective treatment option for patients who have exhausted other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Cilta-cel, an Anti-BCMA CAR-T Cell Therapy, Versus Conventional Treatment in Patients With Relapsed/Refractory Multiple Myeloma. Costa, LJ., Lin, Y., Cornell, RF., et al.[2022]

Ciltacabtagene autoleucel (cilta-cel) showed significantly improved progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) compared to physician's choice of treatment in patients with relapsed or refractory multiple myeloma, with hazard ratios indicating strong benefits (HR: 0.18 for PFS, HR: 0.15 for TTNT, HR: 0.25 for OS).

The study utilized real-world data from the Flatiron Health multiple myeloma cohort to compare cilta-cel's effectiveness, ensuring balanced baseline characteristics through inverse probability of treatment weighting, which supports the robustness of the findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of ciltacabtagene autoleucel in CARTITUDE-1 versus physician's choice of therapy in the Flatiron Health multiple myeloma cohort registry for the treatment of patients with relapsed or refractory multiple myeloma. Martin, T., Krishnan, A., Yong, K., et al.[2023]

Ciltacabtagene autoleucel (cilta-cel) has been approved by the FDA as a fifth-line treatment option for patients with relapsed or refractory multiple myeloma, marking a significant advancement in therapy options for this challenging condition.

Cilta-cel is notable for being the second chimeric antigen receptor T-cell therapy targeting BCMA to receive regulatory approval within a year, highlighting the rapid development of innovative treatments in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cilta-cel OK'd for Multiple Myeloma. [2022]

In a phase 1 study involving 57 patients with relapsed/refractory multiple myeloma, LCAR-B38M chimeric antigen receptor T cells demonstrated an impressive overall response rate of 88%, with a median progression-free survival of 19.9 months and overall survival of 36.1 months.

A specific case of a 56-year-old male patient showed sustained remission for over 5 years after receiving LCAR-B38M treatment, highlighting its potential as a long-term solution for patients with extensive disease who have exhausted other treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year remission without disease progression in a patient with relapsed/refractory multiple myeloma with extramedullary disease treated with LCAR-B38M chimeric antigen receptor T cells in the LEGEND-2 study: a case report. Wang, BY., Zhao, WH., Chen, YX., et al.[2022]

Ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, has shown deep and durable response rates in patients with multiple myeloma who have undergone multiple lines of treatment, indicating its effectiveness even in heavily pretreated cases.

The review highlights the notable adverse events associated with cilta-cel and discusses ongoing studies that may change how multiple myeloma is managed in the future, emphasizing the therapy's potential impact on treatment paradigms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ciltacabtagene autoleucel for the treatment of multiple myeloma. Holstein, SA.[2023]

Ciltacabtagene autoleucel (cilta-cel) is a CAR-T therapy for adult patients with relapsed or refractory multiple myeloma, and the estimated average healthcare costs for administering this therapy in the US are approximately $160,933 per patient over a 12-month period, excluding the cost of the therapy itself.

The analysis highlights various cost components associated with cilta-cel therapy, including apheresis, bridging therapy, and management of adverse events, which can aid healthcare decision-makers in evaluating the economic implications of this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Component Costs of CAR-T Therapy in Addition to Treatment Acquisition Costs in Patients with Multiple Myeloma. Jagannath, S., Joseph, N., Crivera, C., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40768190/

Comparative Effectiveness of Ciltacabtagene Autoleucel in ... Outcomes for comparative effectiveness included progression-free survival (PFS), RW PFS, time to next treatment (TTNT), and overall survival (OS) ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2411.2/532383/Real-World-Efficacy-Outcomes-of-Ciltacabtagene

Real-World Efficacy Outcomes of Ciltacabtagene Autoleucel in ... Real-world efficacy outcomes of Ciltacabtagene Autoleucel in relapsed refractory multiple myeloma: a comparative study with the Cartitude-1 trial.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265025042260

Real-World Efficacy Outcomes of Ciltacabtagene ... Our study demonstrates the comparable efficacy of cilta-cel in patients with RRMM treated in a RW setting. Micro-abstract We retrospectively ...

4. jnj.com jnj.com/innovativemedicine/emea/carvykti-ciltacabtagene-autoleucel-cilta-cel-is-the-first-cell-therapy-to-significantly-extend-overall-survival-versus-standard-therapies-for-patients-with-multiple-myeloma-as-early-as-second-line

CARVYKTI® ▼ (ciltacabtagene autoleucel; cilta-cel) is the ... 45 percent reduction in risk of death achieved with cilta-cel versus standard therapies after three-year follow-up in landmark CARTITUDE-4 study1 Data ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00760

Long-Term (≥5-Year) Remission and Survival After ... CARTITUDE-1 evaluated ciltacabtagene autoleucel (cilta-cel) in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM).

6. ashpublications.org ashpublications.org/blood/article/145/1/85/518044/Safety-and-efficacy-of-standard-of-care

Safety and efficacy of standard-of-care ciltacabtagene ... Ciltacabtagene autoleucel (cilta-cel) was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39365257/

Safety and efficacy of standard-of-care ciltacabtagene ... Ciltacabtagene autoleucel (cilta-cel) was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT07149857

NCT07149857 | A Study to Evaluate Efficacy and Safety of ... The purpose of this study is to evaluate how well (efficacy) cilta-cel works when given with a fludarabine-free lymphodepletion regimen (a process of ...