CAR-T Therapy for Multiple Myeloma

(CARTITUDE-4 Trial)

Recruiting at 123 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

419 Participants Needed

Trial Summary

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.

What data supports the effectiveness of this treatment for multiple myeloma?

Research shows that adding daratumumab to other drugs like bortezomib and dexamethasone significantly improves the time patients live without their disease getting worse in multiple myeloma. This combination has been effective in both newly diagnosed and previously treated patients, suggesting it could be a promising option for multiple myeloma treatment. ^{1 2 3 4 5}

What safety data exists for CAR-T Therapy and related treatments for multiple myeloma?

The safety profile of treatments like daratumumab, bortezomib, and dexamethasone, which are used in multiple myeloma, shows that common side effects include infusion-related reactions and blood-related issues like neutropenia (low white blood cell count), anemia (low red blood cell count), and leukopenia (low white blood cell count). These treatments have been generally well-tolerated, with side effects consistent with individual therapies. ^{5 6 7 8 9}

What makes CAR-T Therapy for Multiple Myeloma unique compared to other treatments?

CAR-T Therapy for Multiple Myeloma is unique because it involves genetically modifying a patient's own immune cells to better recognize and attack cancer cells, which is different from traditional treatments that use drugs to target cancer cells directly. This personalized approach can potentially lead to more effective and long-lasting responses in patients. ^{1 9 10 11 12}

What is the purpose of this trial?

This trial is testing a new treatment called JNJ-68284528 (cilta-cel) for patients with multiple myeloma who haven't responded to other treatments. The treatment uses modified immune cells to better recognize and attack cancer cells. The goal is to see if this new treatment works better than standard therapies. Cilta-cel was approved earlier this year.

Research Team

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Giacomo Salvadore

Janssen Research & Development, LLC

Chief Medical Officer since 2023

MD from the University of Rome, Tor Vergata

Ricardo Attar

Janssen Research & Development, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology from the University of Buenos Aires

Findings from Research

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]

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]

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 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]

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]

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]

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 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]

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]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

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

2. England 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. [2021]

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

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. [2021]

4. United States 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. [2023]

5. United States 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. [2023]

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

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. [2022]

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

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

8. Germany 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. [2021]

9. Italy pubmed.ncbi.nlm.nih.gov

Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. [2019]

10. United States 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. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

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

12. New Zealand pubmed.ncbi.nlm.nih.gov

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