Quadruple Therapy for Multiple Myeloma

Overseen By Jacob Laubach, MD

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jacob Laubach, MD

Must not be taking: Corticosteroids, Investigational agents

Disqualifiers: Other malignancy, 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: 1

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This research is testing whether the investigational drug isatuximab is safe and effective when used in combination with standard agents for the treatment of newly diagnosed multiple myeloma.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on corticosteroids or have certain medical conditions, it might affect your eligibility. It's best to discuss your current medications with the trial team.

What evidence supports the effectiveness of the drug combination used in the Quadruple Therapy for Multiple Myeloma?

Research shows that bortezomib and dexamethasone are effective in treating relapsed or refractory multiple myeloma, with 55% of patients achieving at least a partial response. Additionally, bortezomib and lenalidomide are well-established therapies for multiple myeloma, with studies indicating they are equally effective in terms of response and survival rates. ^{1 2 3 4 5}

Is the quadruple therapy for multiple myeloma safe for humans?

The combination of bortezomib, lenalidomide, and dexamethasone has been studied and approved for multiple myeloma, showing it is generally safe for humans. Common side effects include neutropenia (low white blood cell count) and thrombocytopenia (low platelet count), but serious side effects like peripheral neuropathy (nerve damage) and deep vein thrombosis (blood clots) were not common. The treatment was well tolerated in studies, even in patients who had been previously treated with similar drugs. ^{6 7 8 9 10}

What makes the quadruple drug therapy for multiple myeloma unique?

The quadruple drug therapy for multiple myeloma is unique because it combines four drugs—Bortezomib, Dexamethasone, Isatuximab, and Lenalidomide—to target the cancer in different ways, potentially improving effectiveness. Bortezomib is a proteasome inhibitor that can be administered subcutaneously to reduce side effects, while Lenalidomide and Isatuximab work through different mechanisms to prevent cancer cell growth, making this combination a comprehensive approach to treatment. ^{1 3 6 7 11}

Research Team

Jacob Laubach, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for people up to 75 years old with newly diagnosed multiple myeloma who need treatment and are eligible for stem cell transplant. They must have measurable disease, acceptable blood counts, organ function within certain limits, and agree to follow specific safety programs. Pregnant or breastfeeding women, those unwilling to use contraception, or anyone treated for another cancer in the last 3 years cannot join.

Inclusion Criteria

Your blood platelet count is at least 75,000 cells/dL if less than half of your bone marrow cells are plasma cells, or at least 30,000 cells/dL if half or more of your bone marrow cells are plasma cells, without needing a blood transfusion in the 3 days before the screening test.

You have a high level of M protein in your blood.

I have been diagnosed with multiple myeloma and need treatment now.

Exclusion Criteria

I cannot tolerate blood clot prevention treatments.

Receiving any other investigational agents

Any medical or psychiatric illness that in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Induction

Participants receive two 42-day cycles of the 4-drug regimen: Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone

12 weeks

Multiple visits (in-person)

Stem Cell Mobilization

Stem cell mobilization at the discretion of the Principal Investigator

Maintenance

Participants continue treatment until disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

42 months

Treatment Details

Interventions

• Bortezomib Injection
• Dexamethasone
• Isatuximab
• Lenalidomide

Trial Overview The study tests if isatuximab combined with standard drugs (lenalidomide, bortezomib injection, dexamethasone) is safe and effective for treating new cases of multiple myeloma. Participants will receive this combination therapy before potentially undergoing a stem cell transplant.

Participant Groups

Group I: Isa-RVD Experimental Treatment 4 Interventions

The main study consists of 4 phases a) 28-day screening phase; b) an induction phase inclusive of two 42-day induction treatment cycles: Isatuximab (IV), Bortezomib (SQ). Lenalidomide (PO), Dexamethasone; c) Followed by stem cell mobilization (at the discretion of the Principal Investigator \[PI\]);d) Participants will proceed with either autologous stem cell transplant or two additional induction cycles. - Induction will be followed by a maintenance phase that continues until disease progression.

Bortezomib Injection is already approved in European Union, United States 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

Who Is Running the Clinical Trial?

Jacob Laubach, MD

Lead Sponsor

Trials

1

Recruited

50+

Jacob Laubach

Lead Sponsor

Trials

1

Recruited

50+

Sanofi

Industry Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

Findings from Research

Bortezomib is the first proteasome inhibitor approved for treating multiple myeloma (MM), showing significant survival benefits as a mono-therapy and in combination with other drugs.

The neurotoxicity associated with bortezomib has been reduced through subcutaneous administration and weekly dosing, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib for the treatment of multiple myeloma. Grosicki, S., Barchnicka, A., Jurczyszyn, A., et al.[2015]

Novel therapies targeting multiple myeloma (MM) cells and their interaction with the bone marrow show promise in overcoming resistance to traditional treatments, as demonstrated in preclinical models and clinical trials.

Proteasome inhibitors like bortezomib and immunomodulatory drugs such as Revimid have rapidly progressed from laboratory research to clinical use, showing effectiveness in patients with relapsed refractory MM and are now being evaluated for earlier treatment stages to enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical update: novel targets in multiple myeloma. Anderson, KC.[2019]

In a study of 85 patients with relapsed/refractory multiple myeloma, the combination of bortezomib and dexamethasone resulted in a 55% overall response rate, with 19% achieving complete response and 35% achieving very good partial response after a median of 6 treatment cycles.

While bortezomib-dexamethasone was effective, with a median overall survival of 22 months, 78% of patients experienced peripheral neuropathy, highlighting the need for monitoring and management of this adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes. Pantani, L., Zamagni, E., Zannetti, BA., et al.[2015]

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]

Bortezomib, approved for multiple myeloma treatment in 2003, has shown high response rates when combined with other agents like corticosteroids and thalidomide, but overall survival benefits compared to sequential treatments are not consistently demonstrated, especially in patients under 65 with newly diagnosed myeloma.

Specific bortezomib combinations, such as VTD (bortezomib, thalidomide, dexamethasone), are particularly useful in patients with renal failure, while VDT-PACE is beneficial for aggressive disease presentations, highlighting the importance of tailoring treatment regimens to individual patient scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib combination therapy in multiple myeloma. Kapoor, P., Ramakrishnan, V., Rajkumar, SV.[2021]

The combination of bortezomib and lenalidomide is an FDA-approved treatment for multiple myeloma, with lenalidomide working by promoting the degradation of specific proteins that help myeloma cells grow.

Despite bortezomib inhibiting the same protein degradation process that lenalidomide relies on, the two drugs can still work effectively together, highlighting a complex interaction in their mechanisms of action against multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The paradoxical pharmacological mechanisms of lenalidomide and bortezomib in the treatment of multiple myeloma. Wang, B., Duan, J., Zhou, L.[2022]

Bortezomib (Velcade) is an FDA-approved treatment for multiple myeloma and mantle cell lymphoma, available via both intravenous (IV) and subcutaneous (SC) injection, providing an option for patients with difficult IV access.

Strategies to minimize injection site reactions with SC administration are important for improving patient comfort and treatment adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous administration of bortezomib: strategies to reduce injection site reactions. Kurtin, S., Knop, CS., Milliron, T.[2021]

In a study of elderly multiple myeloma patients who are typically ineligible for transplantation, an alternating treatment regimen of bortezomib-dexamethasone and lenalidomide-dexamethasone was evaluated over a 63-day cycle, focusing on balancing safety and efficacy.

The treatment regimen aimed to improve overall response rates in newly diagnosed patients, highlighting the need for effective therapies that can be tolerated by this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Over 75 Years Old with Alternating Bortezomib/dexamethasone and Lenalidomide/dexamethasone: the MARBLE Trial. Yokoyama, A., Kada, A., Saito, AM., et al.[2020]

In a phase 1 study involving 34 patients with relapsed or refractory multiple myeloma, the combination of pomalidomide, bortezomib, and low-dose dexamethasone was found to be well tolerated, with no dose-limiting toxicities and a maximum tolerated dose established at pomalidomide 4 mg and bortezomib 1.3 mg/m2.

The treatment showed an overall response rate of 65% and a median duration of response of 7.4 months, indicating its efficacy in patients who had previously been treated with lenalidomide and bortezomib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma. Richardson, PG., Hofmeister, CC., Raje, NS., et al.[2018]

Bortezomib significantly prolongs time to disease progression in multiple myeloma patients compared to high-dose dexamethasone, with a median progression time of 6.2 months versus 3.5 months, based on a phase 3 trial involving 669 patients.

The treatment with bortezomib also showed a higher response rate (38% complete plus partial response) compared to dexamethasone (18%), while the adverse events were consistent with previous studies, including issues like peripheral neuropathy and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Kane, RC., Farrell, AT., Sridhara, R., et al.[2015]

In a study comparing two induction therapies for newly diagnosed multiple myeloma, the quadruplet regimen (D-VTd) showed significantly better response rates after treatment, with 90.5% achieving complete remission (CR) or stringent complete remission (sCR) compared to 68.6% in the triplet regimen (VRd).

The quadruplet regimen (D-VTd) also resulted in a higher rate of very good partial response (VGPR or better) at 93%, compared to 67.6% in the triplet regimen (VRd), although VRd was associated with a higher incidence of skin rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study. Byun, JM., Park, SS., Yoon, SS., et al.[2023]

References

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

Bortezomib for the treatment of multiple myeloma. [2015]

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

Clinical update: novel targets in multiple myeloma. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes. [2015]

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

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

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

Bortezomib combination therapy in multiple myeloma. [2021]

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

The paradoxical pharmacological mechanisms of lenalidomide and bortezomib in the treatment of multiple myeloma. [2022]

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

Subcutaneous administration of bortezomib: strategies to reduce injection site reactions. [2021]

8. Japan pubmed.ncbi.nlm.nih.gov

Phase II Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Over 75 Years Old with Alternating Bortezomib/dexamethasone and Lenalidomide/dexamethasone: the MARBLE Trial. [2020]

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

Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma. [2018]

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

United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. [2015]

11. Korea (South) pubmed.ncbi.nlm.nih.gov

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study. [2023]