CAR-T Therapy for Multiple Myeloma

(CARTITUDE-4 Trial)

Not currently recruiting at 141 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Janssen Research & Development, LLC

Must not be taking: Monoclonal antibodies, Cytotoxic therapy

Disqualifiers: CAR-T therapy, BCMA therapy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Until confirmed PD, death, intolerable toxicity, withdrawal of consent, or end of the study

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment option called ciltacabtagene autoleucel (cilta-cel), a type of CAR-T therapy, for individuals with multiple myeloma, a type of blood cancer. The study aims to evaluate how well this new therapy works compared to standard treatments, which include medications like Pomalidomide, Bortezomib, Dexamethasone, and Daratumumab. Participants should have multiple myeloma that remains active or is progressing despite previous treatments, and they should have previously tried a therapy that includes a proteasome inhibitor and an immunomodulatory drug. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that certain treatments like monoclonal antibodies, cytotoxic therapy, proteasome inhibitors, and immunomodulatory drugs should not be taken within a specific period before starting the trial. It's best to discuss your current medications with the trial team.

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

Research has shown that ciltacabtagene autoleucel, or cilta-cel, has been studied for its safety and effectiveness. Previous studies found that cilta-cel, already approved for treating certain types of relapsed or hard-to-treat multiple myeloma, can be effective with long-lasting benefits. However, like many treatments, it can have side effects.

Common side effects include low blood cell counts, fatigue, and infections, which are usually manageable with proper care. More serious side effects, such as cytokine release syndrome (CRS), an immune reaction, have also been noted but are less common. Doctors are aware of these risks and have ways to manage them.

Clinical trials are designed to carefully monitor and manage these risks, ensuring patient safety remains a top priority. Those considering joining a trial should discuss it with their healthcare provider to make an informed decision. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for multiple myeloma?

Researchers are excited about Ciltacabtagene Autoleucel (Cilta-cel) for multiple myeloma because it takes a groundbreaking approach by using CAR-T cell therapy. Unlike traditional treatments like bortezomib, daratumumab, dexamethasone, and pomalidomide, which target the cancer cells directly, Cilta-cel modifies a patient’s own T cells to recognize and attack the cancer cells more effectively. This personalized treatment harnesses the immune system's power, potentially leading to more durable responses and fewer relapses. Additionally, Cilta-cel is administered as a single infusion, which could be more convenient compared to the ongoing dosing schedules of current therapies.

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

Research shows that a treatment called ciltacabtagene autoleucel (cilta-cel), which participants in this trial may receive, holds promise for multiple myeloma, a type of blood cancer. In earlier studies, cilta-cel performed as well as current treatments for patients whose cancer returned or didn't respond to other therapies. Notably, one study found that just one dose of cilta-cel led to long-lasting remission, with one-third of patients experiencing no cancer progression for at least five years. This trial will compare cilta-cel to standard therapies, including PVd or DPd, to evaluate its effectiveness as a strong alternative for multiple myeloma. ^{1 6 7 8 9}

Who Is on the Research Team?

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Are You a Good Fit for This Trial?

This trial is for people with multiple myeloma who've had 1-3 prior treatments including specific drugs, are lenalidomide-refractory, and meet certain lab value criteria. Not eligible if they've had CAR-T or BCMA-targeted therapies, recent high-dose steroids, antibody treatment within 21 days, chemotherapy within 14 days, or have unresolved severe side effects from past cancer therapy.

Inclusion Criteria

My myeloma has worsened within 6 months after my last treatment.

My condition did not improve after taking lenalidomide.

Your recent medical tests must show specific results.

Exclusion Criteria

I have taken a lot of steroids, like prednisone, recently.

I do not have severe nerve pain or damage.

I have not received monoclonal antibody treatment in the last 21 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Ciltacabtagene Autoleucel (Cilta-cel) or standard therapy (PVd or DPd). Cilta-cel involves a conditioning regimen and CAR-T cell infusion. PVd and DPd involve cycles of pomalidomide, bortezomib, dexamethasone, and daratumumab.

Until confirmed PD, death, intolerable toxicity, withdrawal of consent, or end of the study

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 years

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Daratumumab
• Dexamethasone
• JNJ-68284528
• Pomalidomide

Trial Overview

The study compares JNJ-68284528 (a CAR-T cell therapy targeting BCMA) against standard therapies: PVd (Pomalidomide with Bortezomib and Dexamethasone) or DPd (Daratumumab with Pomalidomide and Dexamethasone), to see which is more effective for relapsed multiple myeloma patients.

How Is the Trial Designed?

Group I: Arm B: (Ciltacabtagene Autoleucel [Cilta-cel]) Experimental Treatment 1 Intervention

Participants will receive at least one cycle of bridging therapy (PVd or DPd) and additional cycles of bridging therapy may be considered based on participant's clinical status and timing of availability of cilta-cel along with conditioning regimen (cyclophosphamide 300 milligram \[mg\]/m\^2 intravenous \[IV\] and fludarabine 30 mg/m\^2 IV daily, for 3 days), and cilta-cel infusion 0.75 \* 10\^6 chimeric antigen receptor (CAR)-positive viable T cells/ kilogram (kg).

Group II: Arm A: PVd or DPd (Standard Therapy) Experimental Treatment 4 Interventions

Participants will receive either PVd or DPd as a standard therapy. In PVd treatment, participants will receive oral pomalidomide 4 mg on Days 1 to 14 in each cycle; bortezomib 1.3 mg/meter square (m\^2) SC on Days 1, 4, 8 and 11 (Cycles 1 to 8) and on Days 1 and 8 (Cycle 9 onwards) and oral dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11 and 12 (Cycles 1 to 8) and Days 1, 2, 8 and 9 (Cycle 9 onwards). Each cycle will consist of 21 days. In DPd treatment, participants will receive daratumumab SC 1800 mg weekly on Days 1, 8, 15, and 22 (Cycles 1 and 2), every 2 weeks on Days 1 and 15 (Cycles 3 to 6) and every 4 weeks on Day 1 (Cycle 7 onwards); oral pomalidomide 4 mg on Days 1 to 21 (Cycle 1 onwards); dexamethasone 40 mg oral or IV weekly on Days 1, 8, 15, and 22 (Cycle 1 onwards). Each cycle will consist of 28 days. Participants will continue to receive PVd or DPd until confirmed PD, death, intolerable toxicity, withdrawal of consent, or end of the study, whichever occurs earlier.

Bortezomib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Janssen Research & Development, LLC

Lead 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

Daratumumab, a monoclonal antibody targeting CD38, has shown significant efficacy as a monotherapy in relapsed/refractory multiple myeloma, achieving an overall response in about one-third of patients, with rapid and durable effects.

In combination with other treatments like bortezomib or lenalidomide, daratumumab significantly prolonged progression-free survival, although the overall survival benefit is still being evaluated, and it was generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. Blair, HA.[2018]

In the phase 3 LEPUS study involving 211 Chinese patients with relapsed or refractory multiple myeloma, the combination of daratumumab, bortezomib, and dexamethasone (D-Vd) significantly prolonged progression-free survival (PFS) compared to bortezomib and dexamethasone alone (median PFS of 14.8 months vs. 6.3 months).

D-Vd also showed higher overall response rates and better response quality, with 84.7% of patients achieving an overall response compared to 66.7% with Vd, and no new safety concerns were identified, supporting D-Vd as a standard treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab, Bortezomib, and Dexamethasone versus Bortezomib and Dexamethasone in Chinese Patients With Relapsed or Refractory Multiple Myeloma: Updated Analysis of LEPUS. Fu, W., Li, W., Hu, J., et al.[2023]

Four new agents have been approved for treating relapsed/refractory multiple myeloma, including bortezomib, lenalidomide, thalidomide, and liposomal doxorubicin, but there is no standard treatment, making personalized therapy essential.

New agents like carfilzomib and pomalidomide are being studied for their effectiveness and side effects, highlighting the importance of understanding treatment-related adverse events in choosing the best therapy for individual patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-related adverse events in patients with relapsed/refractory multiple myeloma. Vij, R.[2017]

Daratumumab, when combined with lenalidomide and dexamethasone (DRd) or bortezomib and dexamethasone (DVd), showed an overall response rate of 80% in 171 heavily treated patients with relapsed/refractory multiple myeloma, indicating its efficacy in this challenging patient population.

Patients receiving the DRd combination experienced better progression-free survival (PFS) compared to those on DVd, with PFS rates of 84% and 77%, respectively, while the treatment was generally safe, with common side effects including neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group. Fazio, F., Franceschini, L., Tomarchio, V., et al.[2022]

In a phase 3 study (CASTOR) with a median follow-up of 19.4 months, the combination of daratumumab, bortezomib, and dexamethasone significantly improved progression-free survival (16.7 months) compared to bortezomib and dexamethasone alone (7.1 months), indicating its efficacy in treating relapsed/refractory multiple myeloma.

Daratumumab plus bortezomib and dexamethasone also showed a higher overall response rate (83.8% vs. 63.2%) and was particularly beneficial for patients with one prior line of therapy, demonstrating a favorable safety profile consistent over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Spencer, A., Lentzsch, S., Weisel, K., et al.[2019]

In a subgroup analysis of the CASTOR trial involving 498 patients, daratumumab combined with bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival (PFS) in patients with high cytogenetic risk (12.6 months) compared to bortezomib and dexamethasone alone (6.2 months).

D-Vd also demonstrated a higher rate of minimal residual disease (MRD) negativity, indicating deeper responses in treatment effectiveness, while maintaining a safety profile consistent with the overall study population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. Weisel, K., Spencer, A., Lentzsch, S., et al.[2021]

In a study of 85 newly diagnosed multiple myeloma patients, a high-dose bortezomib regimen (1.6 mg/m2) resulted in a significantly higher complete response rate (43.6%) compared to a low-dose regimen (1.3 mg/m2) which had a response rate of only 12.8%.

While the high-dose regimen showed improved efficacy, particularly in younger patients and those with advanced disease, it was associated with a higher incidence of severe diarrhea, leading to more dose reductions in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II, open-label and multicenter study of combination regimens of bortezomib at two doses by subcutaneous injection for newly diagnosed multiple myeloma patients. Li, F., Yao, FS., Zhu, XJ., et al.[2021]

In the final analysis of the CASTOR study, daratumumab combined with bortezomib and dexamethasone (D-Vd) significantly improved overall survival (OS) in patients with relapsed or refractory multiple myeloma, with a median OS of 49.6 months compared to 38.5 months for bortezomib and dexamethasone alone (Vd).

The study, which followed patients for a median of 72.6 months, found that D-Vd provided OS benefits across various subgroups, including older patients and those with high-risk disease, although it was associated with higher rates of certain adverse events like thrombocytopenia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial. Sonneveld, P., Chanan-Khan, A., Weisel, K., et al.[2023]

In a study of 103 patients with relapsed/refractory multiple myeloma, the combination of daratumumab, pomalidomide, and dexamethasone showed an overall response rate of 60%, indicating significant efficacy even in patients with a history of multiple prior therapies.

The safety profile of this combination treatment was similar to pomalidomide and dexamethasone alone, with the main exception being a higher incidence of neutropenia and infusion-related reactions, but without an increase in infection rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Chari, A., Suvannasankha, A., Fay, JW., et al.[2022]

Intravenous daratumumab, when combined with bortezomib, thalidomide, and dexamethasone, significantly improves treatment outcomes for adults with newly diagnosed multiple myeloma, leading to higher rates of stringent complete response and prolonged progression-free survival, as shown in the phase III CASSIOPEIA trial.

The addition of daratumumab has a minimal impact on overall toxicity, with the most common serious side effects being blood-related issues, indicating it is a relatively safe option for patients undergoing treatment for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma. Lamb, YN.[2021]

Intravenous daratumumab, when combined with bortezomib, melphalan, and prednisone, significantly improves progression-free survival in patients with newly diagnosed multiple myeloma who cannot undergo autologous stem cell transplantation, as shown in the phase 3 ALCYONE trial.

The addition of daratumumab does not increase overall toxicity compared to the standard treatment, although it may lead to more infusion-related reactions and infections, making it a promising and relatively safe treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Ineligible Newly Diagnosed Multiple Myeloma. Syed, YY.[2021]

In a phase 3 trial involving 304 patients with relapsed or refractory multiple myeloma, the combination of daratumumab with pomalidomide and dexamethasone significantly improved progression-free survival compared to pomalidomide and dexamethasone alone, with a median of 12.4 months versus 6.9 months.

While the combination treatment was effective, it was associated with a higher incidence of grade 3 or 4 adverse events, particularly neutropenia, indicating that while daratumumab enhances treatment efficacy, it may also increase the risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Dimopoulos, MA., Terpos, E., Boccadoro, M., et al.[2021]

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