Daratumumab-Based Regimens for Multiple Myeloma

(DeRIVE Trial)

Overseen By Ajay Nooka, MD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Strong CYP3A inducers

Disqualifiers: Smoldering MM, Hepatitis B, HIV, 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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests different drug combinations to treat multiple myeloma, a type of blood cancer. The study focuses on daratumumab, an immunotherapy that helps the immune system target cancer cells, combined with chemotherapy drugs like ixazomib, dexamethasone, and sometimes bortezomib (also known as Velcade). Participants will receive various combinations to identify the most effective treatment. This trial suits individuals recently diagnosed with multiple myeloma who experience symptoms like bone pain or fatigue. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take certain medications like strong CYP3A inducers (e.g., rifampin, carbamazepine) within 14 days 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 shows that the combination of daratumumab, ixazomib, and dexamethasone is generally safe for patients with multiple myeloma. Studies have found that this treatment mix is well-tolerated and can improve patients' quality of life. Participants in these studies received up to 16 cycles and responded well to the treatment.

Similarly, researchers have thoroughly studied the combination of daratumumab with bortezomib and dexamethasone. Long-term results indicate a consistent safety profile, with manageable and expected side effects. This combination has also provided significant benefits for patients.

Overall, past research has shown both treatment groups in the trial to be safe. However, like any treatment, some side effects may occur. Discuss potential risks with a healthcare professional before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for multiple myeloma because they incorporate daratumumab, a monoclonal antibody that targets CD38 on myeloma cells, enhancing the immune system's ability to attack the cancer. Unlike traditional treatments like lenalidomide or melphalan, these regimens explore combinations with daratumumab and proteasome inhibitors like ixazomib and bortezomib, which may offer a more targeted approach and potentially improve outcomes. Additionally, the inclusion of ixazomib, an oral proteasome inhibitor, offers a more convenient administration route compared to injectable options, possibly improving patient convenience and adherence. By combining these innovative agents, researchers hope to enhance the efficacy and tolerability of multiple myeloma treatment.

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

In this trial, participants will receive different daratumumab-based regimens. Studies have shown that combining daratumumab with ixazomib and dexamethasone, which participants in Arm I (DId) may receive, effectively treats multiple myeloma. One study found that 92.4% of patients responded well to this combination, indicating positive results for most patients. Meanwhile, participants in Arm II (DVd, DId) will initially receive a combination of daratumumab, bortezomib, and dexamethasone. Another study found that adding daratumumab to bortezomib and dexamethasone helped patients live longer without their cancer worsening, significantly improving survival rates. Both treatments use daratumumab, which helps the immune system attack cancer cells. These findings suggest these combinations could be effective options for treating newly diagnosed multiple myeloma. ^{6 7 8 9 10}

Who Is on the Research Team?

Ajay K. Nooka, MD,MPH,FACP

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed multiple myeloma who are in good physical condition (ECOG PS 0-1) and have measurable disease. They can't have had certain other conditions or treatments, must agree to contraception if applicable, and be willing to follow the study rules. Pregnant women, those with allergies to study drugs, or patients treated previously with similar drugs are excluded.

Inclusion Criteria

I agree to use contraception as required.

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

You have a certain level of M-protein in your blood or urine that can be measured.

Exclusion Criteria

I haven't taken strong CYP3A inducers or St. John's wort recently.

I am allergic or react badly to dexamethasone, boron, mannitol, or similar drugs.

I have been treated with anti-CD38 therapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive dexamethasone, daratumumab, and either ixazomib or bortezomib in cycles to treat multiple myeloma

24 weeks

Weekly visits for drug administration

Stem Cell Transplant

Eligible patients undergo stem cell transplant per standard of care

4 weeks

Maintenance

Patients continue treatment with dexamethasone, daratumumab, and ixazomib for up to 24 months

24 months

Monthly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3 months for up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Daratumumab
• Dexamethasone
• Ixazomib

Trial Overview

The trial is testing a combination of daratumumab, ixazomib, and dexamethasone against the same combo plus bortezomib in treating new multiple myeloma cases. It aims to see which regimen is more effective at stopping cancer growth by comparing these two treatment groups.

How Is the Trial Designed?

Group I: Arm II (DVd, DId) Experimental Treatment 4 Interventions

INDUCTION CYCLES 1-3: Patients receive dexamethasone IV and PO on days 1, 8, and 15, daratumumab IV on days 1, 8, and 15, and bortezomib subcutaneously (SC) on days 1, 4, 8, and 11. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. INDUCTION CYCLES 4-8: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22, daratumumab IV on days 1 and 15, and ixazomib PO on days 1, 8, and 15. Treatment repeats every 28 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Eligible patients then undergo stem cell transplant per standard of care. Patients who have at least stable disease after induction and patients who have undergone transplant continue to Maintenance. MAINTENANCE: Patients receive dexamethasone IV on day 1, daratumumab IV on day 1, and ixazomib PO on days 1, 8, and 15. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (DId) Experimental Treatment 3 Interventions

INDUCTION: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22, daratumumab IV on days 1, 8, 15, and 22 of cycles 1-2 and on days 1 and 15 of cycles 3-8, and ixazomib PO on days 1, 8, and 15. Treatment repeats every 28 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Eligible patients then undergo stem cell transplant per standard of care. Patients who have at least stable disease after induction and patients who have undergone transplant continue to Maintenance. MAINTENANCE: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22, daratumumab IV on day 1, and ixazomib PO on days 1, 8, and 15. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

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?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Takeda

Industry Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Janssen, LP

Industry Sponsor

Trials

169

Recruited

329,000+

Founded

1953

Headquarters

Beerse, Belgium

Known For

Mental Health Therapies

Top Products

Imodium, Remicade, Invega, Procrit

Joaquin Duato

Janssen, LP

Chief Executive Officer since 2022

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

Dr. Jijo James, MD

Janssen, LP

Chief Medical Officer since 2014

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

Published Research Related to This Trial

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 the POLLUX study, after 25.4 months of follow-up, the combination of daratumumab with lenalidomide and dexamethasone significantly improved progression-free survival in patients with relapsed/refractory multiple myeloma, with a hazard ratio of 0.41 compared to lenalidomide/dexamethasone alone.

The overall response rate was notably higher with the daratumumab combination (92.9%) compared to the control (76.4%), and a significant proportion of patients achieved minimal residual disease negativity (26.2% vs 6.4%), indicating a deeper response without new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Dimopoulos, MA., San-Miguel, J., Belch, A., et al.[2019]

Daratumumab is a first-in-class monoclonal antibody that targets CD38 and is approved for treating relapsed or refractory multiple myeloma, highlighting its role as a new therapeutic option for this challenging disease.

Determining the right dosage regimen for daratumumab is complex due to its unique pharmacokinetics, which are influenced by the drug's target-mediated disposition, necessitating careful evaluation in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma. Xu, XS., Yan, X., Puchalski, T., et al.[2023]

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]

Daratumumab, a CD38-targeted monoclonal antibody, has been shown to be effective for treating relapsed multiple myeloma, particularly in patients who have undergone at least three prior therapies, including bortezomib and lenalidomide.

The drug has an excellent safety profile, with moderate-grade infusion-related reactions being the most common side effect, primarily occurring during the first infusion, highlighting its tolerability in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab for the treatment of multiple myeloma. Touzeau, C., Moreau, P.[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]

In a phase 1/2 trial involving 65 patients with newly diagnosed multiple myeloma, the combination of oral ixazomib, lenalidomide, and dexamethasone was found to be generally well tolerated, with a maximum tolerated dose of ixazomib established at 2.97 mg/m².

The treatment resulted in a very good partial response or better in 58% of patients, indicating significant efficacy and supporting further phase 3 trials for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Kumar, SK., Berdeja, JG., Niesvizky, R., et al.[2019]

Daratumumab is a monoclonal antibody that effectively targets CD38 on multiple myeloma cells, leading to cell death through various mechanisms such as complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.

It has shown a favorable safety profile and significant clinical activity as both a standalone treatment and in combination with lenalidomide for patients with relapsed multiple myeloma who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: monoclonal antibody therapy to treat multiple myeloma. Xia, C., Ribeiro, M., Scott, S., et al.[2018]

Daratumumab, a monoclonal antibody targeting CD38, has been approved in the USA for treating multiple myeloma in patients who have undergone at least three prior therapies, demonstrating its role as a treatment option for difficult-to-treat cases.

In a phase II trial, daratumumab monotherapy showed an overall response rate of about 30% in patients with relapsed or refractory multiple myeloma, indicating its efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: First Global Approval. McKeage, K.[2018]

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]

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