Sequential Therapy for Multiple Myeloma

(MASTER-2 Trial)

Recruiting at 10 trial locations

Overseen By Margaret A Thomas, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alabama at Birmingham

Must not be taking: Anti-BCMA, Anti-CD38, others

Disqualifiers: Plasma cell leukemia, Active CNS involvement, 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

300 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment options for people with multiple myeloma, a type of blood cancer, to determine if they can reduce cancer cells in the bone marrow. The study tests different combinations of medications, such as bortezomib (Velcade), daratumumab (Darzalex), and lenalidomide (Revlimid), to identify the best way to maintain a low level of cancer cells. Individuals recently diagnosed with multiple myeloma who have not undergone extensive treatment might be suitable for this trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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, if you have been on certain therapies like targeted therapy, epigenetic therapy, or investigational drugs, you may need to stop them at least 21 days before starting the trial.

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

Research has shown that the combination of teclistamab and daratumumab is generally manageable for patients. Studies found that this combination produced side effects similar to each drug when used alone, with no unexpected side effects.

For the combination of daratumumab, lenalidomide, and bortezomib, studies found it effective and safe for newly diagnosed patients. These treatments help patients live longer and are considered a strong option for treating multiple myeloma.

Both combinations have shown promising results without new safety concerns, suggesting they are manageable for patients. However, discussing potential side effects and other concerns with a healthcare provider remains important. ^{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 explore a sequential therapy approach that could enhance effectiveness by tailoring to patients' specific responses. Unlike traditional treatments, which often follow a one-size-fits-all regimen, this approach offers a dynamic treatment plan. For example, in MRD (minimal residual disease) positive patients, the trial explores intensification with AHCT (Autologous Hematopoietic Cell Transplant) and maintenance with drugs like Daratumumab combined with either Lenalidomide or Bortezomib. This personalized strategy aims to better address the disease's complexity and potentially improve outcomes by adapting to each patient’s unique disease progression.

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

Research has shown that combining daratumumab with bortezomib and lenalidomide is promising for treating multiple myeloma. Participants in Arm M of this trial will receive this combination during induction, which has helped patients live longer without their cancer worsening, thereby improving progression-free survival. In Arm A and Arm B, participants will receive daratumumab with lenalidomide, increasing the chances of achieving minimal residual disease (MRD) negativity, defined as having fewer than 1 cancer cell out of 100,000 in the bone marrow. Additionally, the combination of teclistamab and daratumumab, part of Arm C, has shown strong results, with many patients experiencing a complete response, meaning no signs of cancer can be detected. Together, these treatments offer hope for reducing cancer cells in multiple myeloma. ^{1 2 3 6 7}

Who Is on the Research Team?

Luciano Costa, MD

Principal Investigator

University of Alabama at Birmingham

Are You a Good Fit for This Trial?

This trial is for adults over 18 with newly diagnosed multiple myeloma needing treatment. They should be fairly active (ECOG 0-2) and can have had limited prior treatments like dexamethasone or bortezomib. Their blood work must show certain levels of monoclonal protein, and they need specific lab values for hemoglobin and platelets.

Inclusion Criteria

You have more than 200 milligrams of M protein in your urine in a 24-hour period.

You have a high level of a specific type of protein in your blood.

My hemoglobin level is at least 7 g/dL without recent blood transfusions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive 6 cycles of Dara-VRd to assess depth of response and MRD negativity

6 months

Consolidation Treatment

MRD negative patients receive 3 additional cycles of treatment; MRD positive patients undergo AHCT and further treatment

3 months

Maintenance Treatment

Participants receive 13 cycles of maintenance therapy with either Dara-Tec or Dara-R based on MRD status

13 months

Follow-up

Participants are monitored for progression-free survival and overall survival

60 months

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Daratumumab
• Lenalidomide
• Tecistamab

Trial Overview

The study tests if patients who reach very low levels of cancer cells after 6 cycles of therapy can maintain this with more treatment instead of a stem cell transplant. It also checks if adding teclistamab to the transplant process helps those not yet at low cancer cell levels achieve it better than standard drugs plus daratumumab.

How Is the Trial Designed?

Group I: Arm M Experimental Treatment 1 Intervention

Induction - 6 cycles of Dara-VRd in all participants

Group II: Arm C Experimental Treatment 1 Intervention

AHCT intensification, 3 cycles of Dara-Tec consolidation and 13 cycles of Dara-Tec maintenance in MRD positive patients

Group III: Arm A Experimental Treatment 1 Intervention

3 cycles of Dara-VRd intensification followed by 13 cycles of Dara-R maintenance in MRD negative patients

Group IV: Arm B Active Control 1 Intervention

AHCT intensification followed by 13 cycles of Dara-R maintenance in MRD negative patients

Group V: Arm D Active Control 1 Intervention

AHCT intensification, 3 cycles of Dara-R consolidation and 13 cycles of Dara-R maintenance in MRD positive patients

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?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Sarah Cannon

Industry Sponsor

Trials

3

Recruited

950+

coMMit, Myeloma Trials, Innovated

Collaborator

Trials

2

Recruited

380+

Janssen Scientific Affairs, LLC

Industry Sponsor

Trials

165

Recruited

579,000+

Joaquin Duato

Janssen Scientific Affairs, LLC

Chief Executive Officer since 2022

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

Dr. Jijo James, MD

Janssen Scientific Affairs, 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 a phase 3 trial involving 559 patients with relapsed or refractory multiple myeloma who had previously received lenalidomide, the combination of pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared to bortezomib and dexamethasone alone, with a median survival of 11.20 months versus 7.10 months.

While the combination treatment showed better efficacy, it also resulted in higher rates of serious adverse events, particularly neutropenia and infections, indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Richardson, PG., Oriol, A., Beksac, M., et al.[2020]

The introduction of bortezomib and lenalidomide, especially in combination with dexamethasone, has significantly improved treatment outcomes for multiple myeloma, leading to better response rates and longer durations of response compared to older therapies.

Triplet regimens like lenalidomide, bortezomib, and dexamethasone (RVD) have shown enhanced efficacy and good tolerability in both newly diagnosed and relapsed/refractory multiple myeloma patients, indicating a promising approach for improving patient survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of multiple myeloma with lenalidomide and bortezomib combination therapy]. Takeda, Y., Sakaida, E., Nakaseko, C.[2018]

The addition of daratumumab to bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) for treating relapsed or refractory multiple myeloma was shown to be effective, but the cost-effectiveness of these combinations is questionable due to high costs.

The incremental cost-effectiveness ratio (ICER) for DVd was $284,180 per quality-adjusted life year (QALY) and for DRd was $1,369,062 per QALY, indicating that significant price reductions for daratumumab would be necessary for these treatments to be considered cost-effective in the US healthcare system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Daratumumab-based Triplet Therapies in Patients With Relapsed or Refractory Multiple Myeloma. Zhang, TT., Wang, S., Wan, N., et al.[2019]

In a study involving elderly myeloma patients, both treatment regimens—bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd)—showed similar effectiveness in managing the disease.

The two treatment approaches also resulted in comparable levels of toxicity, suggesting that either regimen can be safely used for elderly patients with myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Together for better? Cavo, M.[2021]

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 human CD38 monoclonal antibody, shows significant effectiveness in killing multiple myeloma cells that are resistant to lenalidomide and bortezomib, as demonstrated in both ex vivo assays and in vivo mouse models.

The combination of daratumumab with lenalidomide enhances the lysis of resistant myeloma cells and effectively reduces tumor growth in a xenograft model, suggesting a promising new treatment option for patients who do not respond to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib. Nijhof, IS., Groen, RW., Noort, WA., et al.[2020]

In a study of 1,000 newly diagnosed myeloma patients treated with the RVD induction regimen, an impressive overall response rate of 97.1% was observed, with 89.9% achieving a very good partial response or better after transplantation.

The median overall survival for the entire cohort was 126.6 months, with 10-year survival rates of 29% for high-risk patients and 58% for standard-risk patients, highlighting the long-term benefits of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Follow-Up Results of Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy and Risk-Adapted Maintenance Approach in Newly Diagnosed Multiple Myeloma. Joseph, NS., Kaufman, JL., Dhodapkar, MV., et al.[2021]

New therapies like thalidomide, lenalidomide, and bortezomib have emerged in the last 6 years, offering promising treatment options for multiple myeloma, which is currently incurable and has a median survival of 3-4 years.

The review highlights the importance of combining these new agents with traditional treatments to potentially improve patient outcomes in managing multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of new drugs for the treatment of patients with multiple myeloma. Kenealy, M., Prince, HM.[2018]

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]

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]

Recent advancements in treating relapsed multiple myeloma include new agents like pomalidomide, carfilzomib, and daratumumab, which, when combined with standard treatments (lenalidomide-dexamethasone or bortezomib-dexamethasone), have shown improved response rates and progression-free survival in randomized studies.

Daratumumab is highlighted as a breakthrough treatment, and its combinations may soon become the preferred option for patients, although the high cost and availability of these therapies remain significant barriers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How I treat first relapse of myeloma. Harousseau, JL., Attal, M.[2021]

Lenalidomide has significantly improved treatment outcomes for patients with multiple myeloma, but it is associated with predictable adverse events such as neutropenia, venous thromboembolism, and gastrointestinal disturbances.

The adverse events linked to lenalidomide can be effectively managed through patient monitoring, supportive care, and dose adjustments, ensuring that patients can continue their treatment safely.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide treatment for patients with multiple myeloma: diagnosis and management of most frequent adverse events. Pérez Persona, E., Mesa, MG., García Sánchez, PJ., et al.[2018]

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D-VRd with daratumumab/lenalidomide maintenance led to sustained PFS and MRD negativity across high-risk subgroups of newly diagnosed multiple myeloma.

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Results showed significant improvements in PFS with the daratumumab-based regimen vs. standard of care (84.3% vs. 67.7%; HR = 0.42; 95% CI, 0.3- ...