Sequential Therapy for Multiple Myeloma

(MASTER-2 Trial)

Recruiting at 8 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

Trial Summary

What is the purpose of this trial?

This research study will determine the proportion of patients with lowest minimal residual disease (MRD) response obtainable after receiving 6 cycles of study treatment. Minimal residual disease is multiple myeloma cells below the level of 1 cancer cell out of 100,000 in the bone marrow. For patients who become MRD "negative" (i.e. less than 1 cancer cell out of 100,000) at the end of 6 cycles of therapy, this study will study if that good response can be maintained with 3 additional cycles of treatment instead of use of autologous hematopoietic cell transplantation (AHCT). For patients who are MRD "positive" at the end of 6 cycles of therapy, this study will answer whether more patients can become and remain MRD "negative" with AHCT plus teclistamab in combination with daratumumab when compared with patients who undergo AHCT followed by lenalidomide (an established anti-myeloma drug) plus daratumumab.

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.

What evidence supports the effectiveness of the drugs used in the Sequential Therapy for Multiple Myeloma?

Research shows that combining daratumumab with other drugs like bortezomib and lenalidomide can significantly improve outcomes for patients with multiple myeloma, leading to longer periods without the disease getting worse and deeper responses to treatment. ^{1 2 3 4 5}

What safety data exists for the sequential therapy for multiple myeloma?

The safety data for the sequential therapy involving drugs like bortezomib, lenalidomide, and daratumumab shows that common side effects include blood-related issues like neutropenia (low white blood cell count), thrombocytopenia (low platelet count), and anemia (low red blood cell count), as well as peripheral sensory neuropathy (nerve damage causing tingling or numbness) and infections. These side effects are generally predictable and manageable with proper monitoring and care. ^{4 6 7 8 9}

How is the drug combination of Bortezomib, Daratumumab, and Lenalidomide unique for treating multiple myeloma?

This drug combination is unique because it includes daratumumab, a monoclonal antibody that targets a specific protein on myeloma cells, which can enhance the effectiveness of traditional treatments like bortezomib and lenalidomide. The addition of daratumumab has been shown to improve response rates and prolong the time patients live without their disease getting worse, offering a promising option for both newly diagnosed and relapsed multiple myeloma patients. ^{3 10 11 12 13}

Research Team

Luciano Costa, MD

Principal Investigator

University of Alabama at Birmingham

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Ricardo Attar

Janssen Scientific Affairs, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology, University of Buenos Aires

Dr. Anastasia G. Daifotis

Janssen Scientific Affairs, LLC

Chief Medical Officer since 2023

MD

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2020]

2. United States 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. [2021]

3. Japan pubmed.ncbi.nlm.nih.gov

[Treatment of multiple myeloma with lenalidomide and bortezomib combination therapy]. [2018]

4. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

Together for better? [2021]

7. 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]

8. England 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. [2020]

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

Lenalidomide treatment for patients with multiple myeloma: diagnosis and management of most frequent adverse events. [2018]

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

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

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

Cost-effectiveness of Daratumumab-based Triplet Therapies in Patients With Relapsed or Refractory Multiple Myeloma. [2019]

12. Australia pubmed.ncbi.nlm.nih.gov

Current status of new drugs for the treatment of patients with multiple myeloma. [2018]

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

How I treat first relapse of myeloma. [2021]