Triple Drug Therapy for Multiple Myeloma

(DFCI 10-106 Trial)

Recruiting at 45 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Paul Richardson, MD

Must not be taking: Investigational agents

Disqualifiers: Pregnancy, Brain metastases, Heart failure, 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: 28.2 to 36.1 months

729 Participants Needed

Trial Summary

What is the purpose of this trial?

In this research study, we are looking to explore the drug combination, lenalidomide, bortezomib and dexamethasone alone or when combined with autologous stem cell transplantation to see what side effects it may have and how well it works for treatment of newly diagnosed multiple myeloma. Specifically, the objective of this trial is to determine if, in the era of novel drugs, high dose therapy (HDT) is still necessary in the initial management of multiple myeloma in younger patients. In this study, HDT as compared to conventional dose treatment would be considered superior if it significantly prolongs progression-free survival by at least 9 months or more, recognizing that particular subgroups may benefit more compared to others.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does allow corticosteroids if the dose is low enough. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the triple drug therapy for multiple myeloma?

Research shows that the combination of lenalidomide, bortezomib, and dexamethasone (RVD) is effective in treating multiple myeloma, improving response rates and prolonging response duration compared to older treatments. Studies have demonstrated significant efficacy and favorable tolerability of this combination in both newly diagnosed and relapsed/refractory multiple myeloma patients. ^{1 2 3 4 5}

Is triple drug therapy for multiple myeloma safe for humans?

The combination of lenalidomide, bortezomib, and dexamethasone has been studied for multiple myeloma and is generally considered safe, with common side effects including fatigue, muscle cramps, and risk of blood clots. These drugs have been approved by health authorities for use in multiple myeloma, indicating a recognized safety profile. ^{6 7 8 9 10}

How is the triple drug therapy of Bortezomib, Dexamethasone, and Lenalidomide unique for treating multiple myeloma?

The triple drug therapy of Bortezomib, Dexamethasone, and Lenalidomide is unique because it combines three powerful agents that work together to improve response rates and prolong the duration of response in multiple myeloma patients. This combination has shown significant efficacy and favorable tolerability, making it more effective than older treatments and double-drug regimens. ^{1 2 3 4 11}

Research Team

Paul Richardson

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for individuals up to age 65 with newly diagnosed Multiple Myeloma, who are generally in good health (ECOG </=2) and have not received systemic therapy for MM. They must have a negative HIV test, no severe neuropathy or respiratory issues, not be pregnant or breastfeeding, and their blood counts and organ functions need to meet specific criteria.

Inclusion Criteria

I have been diagnosed with Multiple Myeloma.

Voluntary written informed consent

I can take care of myself and perform daily activities.

Exclusion Criteria

I have cancer that has spread to my brain.

Receiving any other investigational agents

My platelet count is below 50,000.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of Lenalidomide, Bortezomib, and Dexamethasone, with or without autologous stem cell transplantation

28.2 to 36.1 months

Every cycle on treatment

Maintenance

Participants receive daily lenalidomide until disease progression, unacceptable toxicity, or withdrawal

Up to 128 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Long-term follow-up every 2 months until death

Treatment Details

Interventions

• Autologous Stem Cell Transplant
• Bortezomib
• Dexamethasone
• Lenalidomide

Trial Overview The study tests the effectiveness of lenalidomide, bortezomib, dexamethasone alone versus combined with autologous stem cell transplantation in treating Multiple Myeloma. The goal is to see if high-dose treatment extends progression-free survival by at least 9 months compared to conventional doses.

Participant Groups

Group I: RVD Alone Experimental Treatment 3 Interventions

All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12

Group II: RVD plus ASCT Active Control 4 Interventions

All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12

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?

Paul Richardson, MD

Lead Sponsor

Trials

2

Recruited

780+

Paul G. Richardson, MD

Lead Sponsor

Trials

2

Recruited

780+

Beth Israel Deaconess Medical Center

Collaborator

Trials

872

Recruited

12,930,000+

Emory University

Collaborator

Trials

1,735

Recruited

2,605,000+

University of Michigan

Collaborator

Trials

1,891

Recruited

6,458,000+

Millennium Pharmaceuticals, Inc.

Industry Sponsor

Trials

406

Recruited

46,900+

Dr. Christophe Bianchi

Millennium Pharmaceuticals, Inc.

Chief Medical Officer since 2006

MD from University of Geneva

Dr. Deborah Dunsire

Millennium Pharmaceuticals, Inc.

Chief Executive Officer since 2005

MD from University of Witwatersrand

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Celgene Corporation

Industry Sponsor

Trials

446

Recruited

58,500+

Mark Alles

Celgene Corporation

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Sol J. Barer

Celgene Corporation

Chief Medical Officer since 2006

PhD in Organic and Physical Chemistry from Rutgers University

Cape Cod Hospital

Collaborator

Trials

3

Recruited

25,800+

Findings from Research

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 study involving 98 relapsed refractory multiple myeloma patients, treatment with lenalidomide plus dexamethasone resulted in a 52% overall response rate, with 49% achieving partial remission and 3% achieving complete remission, despite patients having undergone a median of 5 prior treatments.

The combination therapy not only provided rapid responses but also extended overall survival by nearly six months, demonstrating its efficacy and safety regardless of previous treatments with thalidomide and bortezomib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium. Delforge, M., Michiels, A., Doyen, C., et al.[2018]

Thalidomide, when used as a first-line treatment combined with conventional chemotherapy, has been shown to improve survival rates in patients over 65, despite its potential toxicity to the peripheral nervous system.

Bortezomib and lenalidomide, both effective in treating myeloma relapse, can be used in combination with dexamethasone and each other, indicating a shift towards using these agents to manage myeloma as a chronic disease rather than relying solely on traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New drugs for myeloma]. Moreau, P.[2019]

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 large observational study of 2150 patients with relapsed/refractory multiple myeloma, lenalidomide plus dexamethasone demonstrated a favorable safety profile, with lower incidence rates of neuropathy and infections compared to other treatments like bortezomib and thalidomide.

The study confirmed that lenalidomide's safety profile in a real-world setting is consistent with previous clinical trial data, with no new safety concerns identified, although it did show a higher incidence of neutropenia compared to bortezomib and thalidomide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Noninterventional, Observational, European Post-Authorization Safety Study of Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide. Gamberi, B., Berthou, C., Hernandez, M., et al.[2021]

Lenalidomide, when combined with dexamethasone, significantly improves time to progression in patients with multiple myeloma compared to placebo, as shown in two randomized, double-blind studies.

However, the treatment is associated with serious side effects, including increased risks of neutropenia, thrombocytopenia, and thromboembolic events, leading to its restricted distribution under the RevAssist program.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of multiple myeloma after one prior therapy. Hazarika, M., Rock, E., Williams, G., et al.[2020]

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]

Lenalidomide combined with dexamethasone has been shown to be effective for treating relapsed/refractory multiple myeloma, and it has received approval from both the FDA and EMA for patients who have undergone at least one prior therapy.

The most common serious side effects include cytopenias and infections, but an expert panel has provided management strategies to minimize these risks, ensuring that patients can receive the full benefits of the treatment without unnecessary dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. Palumbo, A., Dimopoulos, M., San Miguel, J., et al.[2018]

Lenalidomide, when combined with dexamethasone, significantly improves response rates and survival in patients with relapsed/refractory multiple myeloma, showing a response rate of 60% compared to 20% with placebo in Phase III trials.

While lenalidomide is effective, it is associated with common adverse events such as hematologic toxicity and venous thromboembolism, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current treatment strategies with lenalidomide in multiple myeloma and future perspectives. Larocca, A., Cavallo, F., Mina, R., et al.[2018]

References

1. Japan pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium. [2018]

3. France pubmed.ncbi.nlm.nih.gov

[New drugs for myeloma]. [2019]

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. Turkey pubmed.ncbi.nlm.nih.gov

Efficacy and safety of lenalidomide and dexamethasone in patients with relapsed/ refractory multiple myeloma: a real-life experience [2018]

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

A Noninterventional, Observational, European Post-Authorization Safety Study of Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of multiple myeloma after one prior therapy. [2020]

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

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

9. England pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Current treatment strategies with lenalidomide in multiple myeloma and future perspectives. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. [2022]