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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the investigational drug isatuximab, combined with standard treatments, is safe and effective for people newly diagnosed with multiple myeloma (a type of blood cancer). It involves a combination of four drugs: bortezomib injection, dexamethasone, isatuximab, and lenalidomide. Participants will undergo different phases, including treatment cycles and possibly a stem cell transplant. This trial may suit individuals diagnosed with multiple myeloma who need treatment. As a Phase 2 trial, the research focuses on measuring how well the treatment works in an initial, smaller group of people.

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.

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

Research shows that the drugs in this trial have different safety profiles.

**Isatuximab**: Studies indicate that isatuximab is usually well-tolerated, though it can cause serious side effects like infections and low white blood cell counts. Some patients have experienced reactions during or after intravenous administration.

**Bortezomib**: Bortezomib is commonly used to treat multiple myeloma, with manageable side effects. Its FDA approval and widespread use suggest it is generally safe.

**Dexamethasone**: This drug is among the most commonly used for treating multiple myeloma. While it can cause side effects, management strategies allow for long-term use.

**Lenalidomide**: Lenalidomide is FDA-approved for multiple myeloma but carries risks like blood clots and increased infection susceptibility.

Overall, these drugs are generally well-tolerated, especially when used together in this study. However, each has potential side effects that participants should consider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the quadruple therapy for multiple myeloma because it combines four powerful drugs: Bortezomib, Dexamethasone, Isatuximab, and Lenalidomide. This combination is unique because it integrates Isatuximab, a monoclonal antibody, which specifically targets and kills myeloma cells, offering a novel mechanism compared to standard treatments. Additionally, this regimen is designed to be more comprehensive, addressing multiple aspects of the disease simultaneously, which could potentially improve outcomes and extend remission periods for patients. By enhancing the body's immune response and directly attacking cancer cells, this approach may offer a more effective alternative to existing therapies.

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

Research has shown that adding isatuximab to the treatment of newly diagnosed multiple myeloma may be promising. In this trial, participants will receive the combination known as Isa-RVD, which includes isatuximab, bortezomib, lenalidomide, and dexamethasone. Studies have found that Isa-RVD is more effective than the standard treatment of bortezomib, lenalidomide, and dexamethasone (VRd) alone. Specifically, patients who received Isa-RVD experienced longer periods without disease progression compared to those who did not receive isatuximab. These findings suggest that Isa-RVD could better control the disease, supporting the potential benefit of adding isatuximab to the treatment. ^{6 7 8 9 10}

Who Is on the Research Team?

Jacob Laubach, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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 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]

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]

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]

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]

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]

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 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]

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]

Citations

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FDA approves isatuximab-irfc with bortezomib ... A total of 446 patients were randomized (3:2) to receive either isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) or ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38832972/

Isatuximab, Bortezomib, Lenalidomide, and ... Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to ...

3. sarclisa.com sarclisa.com/newly-diagnosed-trial-results

Newly Diagnosed Trial Results Trial 3: SARCLISA + Velcade®, Revlimid®, and dexamethasone (VRd) helped more patients live progression free vs VRd alone.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04653246

Study Details | NCT04653246 | Isatuximab, Lenalidomide, ... In this research study, investigators are evaluating whether isatuximab is safe and effective in participants with newly diagnosed multiple myeloma when given ...

5. nejm.org nejm.org/doi/10.1056/NEJMoa2400712

Isatuximab, Bortezomib, Lenalidomide, and ... Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/212782s000lbl.pdf

BORTEZOMIB INJECTION - accessdata.fda.gov Safety data from Phase 2 and 3 studies of single agent bortezomib 1.3 mg/m2/dose twice weekly for two weeks followed by a ten day rest period in 1163 patients ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30118610/

The safety of bortezomib for the treatment of multiple ... Bortezomib is an important part of current anti-myeloma therapy with a good clinical efficacy and manageable side effects.

8. myeloma.org myeloma.org/velcade-bortezomib

Velcade (Bortezomib) & Multiple Myeloma Treatment | IMF Velcade (bortezomib) is approved by the FDA for use throughout the myeloma disease course, in combination with nearly all other FDA-approved anti-myeloma ...

9. ema.europa.eu ema.europa.eu/en/documents/product-information/velcade-epar-product-information_en.pdf

Velcade, INN-bortezomib - EMA These adverse reactions are based on an integrated data set of 5,476 patients of whom 3,996 were treated with VELCADE at 1.3 mg/m2 and included in Table 7.

10. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/6713/506264/Safety-and-Efficacy-of-Bortezomib-Pomalidomide

Safety and Efficacy of Bortezomib-Pomalidomide ... Introduction: Pomalidomide is a third-generation immunomodulatory drug approved for relapsed and/or refractory Multiple Myeloma (RRMM).