DVRd + Ciltacabtagene Autoleucel / ASCT for Multiple Myeloma

(CARTITUDE-6 Trial)

Recruiting at157 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Stichting European Myeloma Network

Must not be taking: Strong CYP3A4 inducers

Disqualifiers: Prior CAR-T, BCMA therapy, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of four drugs followed by either a special cell therapy or a stem cell transplant in newly diagnosed multiple myeloma patients who can have a transplant. The drugs fight cancer and boost immunity, while the cell therapy reprograms immune cells to attack cancer, and the stem cell transplant rebuilds bone marrow.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have received a strong cytochrome P450 (CYP)3A4 inducer recently. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment DVRd + Ciltacabtagene Autoleucel / ASCT for Multiple Myeloma?

Research shows that combinations including lenalidomide, bortezomib, and dexamethasone (RVD) are effective in treating multiple myeloma, with significant improvements in patient outcomes. Additionally, adding daratumumab to similar drug combinations has been shown to enhance the depth of response and progression-free survival in patients. ^{1 2 3 4 5}

What makes the DVRd + Ciltacabtagene Autoleucel / ASCT treatment unique for multiple myeloma?

This treatment combines a four-drug regimen (Bortezomib, Daratumumab, Dexamethasone, Lenalidomide) with a novel CAR-T cell therapy (Ciltacabtagene Autoleucel) and autologous stem cell transplantation (ASCT), offering a comprehensive approach that targets multiple pathways in multiple myeloma, potentially improving outcomes for patients who have been exposed to other treatments. ^{2 6 7 8 9}

Research Team

Eligibility Criteria

This trial is for newly diagnosed multiple myeloma patients who have measurable disease, are in good physical condition (ECOG grade 0 or 1), and have normal lab values. It's not open to those who've had CAR-T therapy, BCMA target therapy, other MM treatments except corticosteroids, strong CYP3A4 inducers recently, live vaccines within a month (except COVID-19 vaccine), or CNS involvement by MM.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

Your test results need to be within a certain range.

I have newly diagnosed multiple myeloma and plan to undergo high-dose therapy and stem cell transplant.

Exclusion Criteria

My cancer has affected or previously affected my brain or spinal cord.

I have not had any live vaccines (other than COVID-19) in the last 4 weeks.

I have not taken strong CYP3A4 inducers recently.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) for 6 cycles in Arm B and 4 cycles in Arm A

24 weeks for Arm B, 16 weeks for Arm A

Weekly visits for drug administration

Conditioning and CAR-T Cell Therapy

Participants in Arm B receive a conditioning regimen followed by Cilta-cel infusion

1 week

Autologous Stem Cell Transplant (ASCT)

Participants in Arm A undergo ASCT followed by DVRd consolidation

4 weeks

Maintenance Therapy

Lenalidomide maintenance therapy is administered until confirmed progressive disease or unacceptable toxicity, for a maximum of 2 years

up to 104 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 24 months

Treatment Details

Interventions

• Bortezomib (Protein Degradation Enhancer)
• Ciltacabtagene Autoleucel (CAR T-cell Therapy)
• Daratumumab (Monoclonal Antibodies)
• Dexamethasone (Corticosteroid)
• Lenalidomide (Immunomodulatory Agent)

Trial Overview The study compares two approaches: one group receives Daratumumab with Bortezomib, Lenalidomide and Dexamethasone followed by a cell-based gene therapy called Ciltacabtagene Autoleucel; the other follows the same initial treatment but then has an Autologous Stem Cell Transplant instead.

Participant Groups

Group I: Arm B: DVRd followed by Ciltacabtagene Autoleucel Experimental Treatment 7 Interventions

Participants will receive daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) for 6 induction cycles. Participants will receive a conditioning regimen (cyclophosphamide 300 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), followed by lenalidomide post CAR-T cell therapy for 2 years Daratumumab subcutaneously (SC), 1800 mg on days 1, 8, 15 and 22 of cycle 1 and 2, on days 1 and 15 of cycle 3-6. Bortezomib SC 1.3 mg/m\^2 on days 1, 4, 8, and 11 of each cycle 1-6. Lenalidomide orally, 25 mg on days 1 to 21 of each cycle 1-6. Dexamethasone orally, 40 mg once a week on days 1, 8, 15 and 22 of each cycle 1-6. Each cycle will consist of 28 days. Lenalidomide maintenance orally 10 to 15 mg on days 1 to 28 (continuously) until confirmed progressive disease or unacceptable toxicity or for a maximum of 2 years

Group II: Arm A: DVRd + ASCT+DVRd (Standard Therapy) Active Control 4 Interventions

Participants will receive daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) for 4 induction cycles. Followed by ASCT and 2 cycles of DVRd consolidation, and lenalidomide maintenance therapy for 2 years Daratumumab subcutaneously (SC), 1800 mg on days 1, 8, 15 and 22 of cycle 1 and 2, on days 1 and 15 of cycle 3-6. Bortezomib SC 1.3 mg/m\^2 on days 1, 4, 8, and 11 of each cycle 1-6. Lenalidomide orally, 25 mg on days 1 to 21 of each cycle 1-6. Dexamethasone orally, 40 mg once a week on days 1, 8, 15 and 22 of each cycle 1-6. Each cycle will consist 28 days. Lenalidomide maintenance orally 10 to 15 mg on days 1 to 28 (continuously) until confirmed progressive disease or unacceptable toxicity or for a maximum of 2 years

Bortezomib is already approved in Canada, Japan for the following indications:

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?

Stichting European Myeloma Network

Lead Sponsor

Trials

28

Recruited

18,600+

European Myeloma Network B.V.

Lead Sponsor

Trials

17

Recruited

7,300+

European Myeloma Network

Lead Sponsor

Trials

27

Recruited

12,600+

Janssen Research & Development, LLC

Industry 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

In the CASSIOPEIA trial, daratumumab maintenance therapy significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared to observation only, with a hazard ratio of 0.53, indicating a 47% reduction in the risk of disease progression or death.

The study involved 886 patients and showed that while daratumumab was effective, it also had some associated risks, including serious adverse events in 23% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Moreau, P., Hulin, C., Perrot, A., et al.[2021]

In a phase 3 trial involving 722 adults with newly diagnosed multiple myeloma, adding autologous stem-cell transplantation (ASCT) to triplet therapy (RVD) significantly improved progression-free survival, with a median of 67.5 months for the transplantation group compared to 46.2 months for the RVD-alone group.

Despite the improved progression-free survival, there was no overall survival benefit between the two groups, indicating that while ASCT may delay disease progression, it does not necessarily extend life expectancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. Richardson, PG., Jacobus, SJ., Weller, EA., et al.[2023]

The combination therapy of carfilzomib, lenalidomide, dexamethasone, and daratumumab achieved a high minimal residual disease (MRD) negativity rate of 71% in newly diagnosed multiple myeloma patients, indicating effective treatment without the need for high-dose melphalan chemotherapy or autologous transplant.

The treatment demonstrated excellent safety and tolerability, with a 1-year progression-free survival rate of 98% and no reported deaths, although some patients experienced grade 3 or 4 adverse events like neutropenia and rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial. Landgren, O., Hultcrantz, M., Diamond, B., et al.[2022]

In a phase II study involving 31 patients under 65 years old with newly diagnosed multiple myeloma, the combination therapy of lenalidomide, bortezomib, and dexamethasone (RVD) led to high response rates, with 87% of patients achieving a very good partial response or better after consolidation therapy.

The treatment showed favorable safety, with no treatment-related mortality and a 100% overall survival rate at 3 years; importantly, 68% of patients achieved minimal residual disease (MRD) negativity, and none of these patients relapsed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. Roussel, M., Lauwers-Cances, V., Robillard, N., et al.[2022]

In a phase III study involving 155 multiple myeloma patients, bortezomib and lenalidomide treatments showed similar effectiveness, with 15% and 18% of patients achieving a very good partial response (VGPR) respectively, indicating comparable efficacy.

Both treatment regimens resulted in similar median progression-free survival (PFS) of 16.3 months for bortezomib and 18.6 months for lenalidomide, along with comparable two-year overall survival rates of 75% and 74%, confirming their safety and effectiveness in managing multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib, cyclophosphamide, dexamethasone versus lenalidomide, cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse. Montefusco, V., Corso, A., Galli, M., et al.[2020]

Ciltacabtagene autoleucel (cilta-cel) showed significantly better overall response rates and complete response rates compared to idecabtagene vicleucel (ide-cel) in patients with relapsed or refractory multiple myeloma, based on data from the CARTITUDE-1 and KarMMa trials involving patients previously treated with multiple therapies.

Cilta-cel also demonstrated improved duration of response, progression-free survival, and overall survival compared to ide-cel, indicating its potential as a more effective treatment option for patients with triple-class exposed multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated results from a matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma. Martin, T., Usmani, SZ., Schecter, JM., et al.[2023]

The addition of daratumumab to the standard RVd therapy for newly diagnosed multiple myeloma significantly improved the stringent complete response (sCR) rates from 32.0% to 42.4% after autologous stem cell transplantation, with further improvement to 62.6% after longer follow-up.

While daratumumab (D-RVd) showed better efficacy in achieving deeper responses and higher rates of minimal residual disease negativity, it was associated with a higher incidence of grade 3/4 hematologic adverse events and infections, although the rates of severe infections were similar to the RVd group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Voorhees, PM., Kaufman, JL., Laubach, J., et al.[2021]

Ciltacabtagene autoleucel (cilta-cel) showed significantly better overall response rates and complete response rates compared to idecabtagene vicleucel (ide-cel) in patients with relapsed or refractory multiple myeloma, based on a comparative analysis of individual patient data from 1 trial and published data from another.

Cilta-cel also demonstrated improved duration of response and progression-free survival, indicating its potential as a more effective treatment option for patients previously treated with multiple therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma. Martin, T., Usmani, SZ., Schecter, JM., et al.[2022]

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]

References

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

Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. [2021]

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

Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. [2023]

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

Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial. [2022]

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

Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Bortezomib, cyclophosphamide, dexamethasone versus lenalidomide, cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Updated results from a matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma. [2023]

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

Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. [2021]

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

Matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma. [2022]

9. 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]