Linvoseltamab vs EPd for Multiple Myeloma

(LINKER-MM3 Trial)

Recruiting at 256 trial locations

Overseen By Clinical Trials Administrator

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Regeneron Pharmaceuticals

Must not be taking: Elotuzumab, Pomalidomide, BCMA immunotherapies

Disqualifiers: Plasma cell leukemia, Amyloidosis, Waldenström macroglobulinemia, 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: 12 weeks

380 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is researching an experimental drug called linvoseltamab, also called REGN5458. Linvoseltamab has previously been studied by itself (without other cancer drugs) in participants who had advanced multiple myeloma that returned and needed to be treated again after many other therapies had failed. These participants were no longer benefiting from standard medications and had no good treatment options. In that study, some participants who were treated with linvoseltamab had improvement of their myeloma (shrinkage of their tumors), including some participants who had complete responses (that is, the treatment got rid of all evidence of myeloma in their bodies). This study is focused on participants who have multiple myeloma that has returned or needs to be treated again after one to four prior treatments and have standard cancer treatment options available to them. The aim of this study is to see how safe and effective linvoseltamab is compared to a combination of three cancer drugs: elotuzumab, pomalidomide and dexamethasone, (called EPd) in participants who have returned after having received prior treatment that included lenalidomide, a proteosome inhibitor, and (for participants in some countries) a cluster of differentiation 38 (CD38) antibody. Half of the participants in this study will get linvoseltamab, and the other half will get EPd. This study is looking at several other research questions, including: * How long participants benefit from receiving linvoseltamab compared with EPd * How many participants treated with linvoseltamab or EPd have improvement of their multiple myeloma and by how much * What side effects happen from taking linvoseltamab compared to EPd * How long participants live while receiving treatment or after treatment with linvoseltamab compared to EPd * If there is any improvement in pain after treatment with linvoseltamab compared to EPd

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that you cannot have had any systemic anti-cancer therapy within 28 days before starting the study drug. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination of Linvoseltamab, Elotuzumab, Pomalidomide, and Dexamethasone for treating multiple myeloma?

Research shows that the combination of elotuzumab, pomalidomide, and dexamethasone is effective in treating multiple myeloma, especially in patients who have not responded to other treatments. This combination has been shown to improve progression-free survival, meaning patients live longer without the disease getting worse. ^{1 2 3 4 5}

Is Linvoseltamab vs EPd safe for humans?

The combination of elotuzumab, pomalidomide, and dexamethasone (EPd) has been shown to be generally safe in patients with relapsed and refractory multiple myeloma, with common side effects including neutropenia (low white blood cell count), anemia (low red blood cell count), and infections. Pomalidomide and dexamethasone have a manageable safety profile, but they can cause side effects like neutropenia, anemia, and thrombocytopenia (low platelet count). ^{1 5 6 7 8}

What makes the Linvoseltamab vs EPd treatment for multiple myeloma unique?

The Linvoseltamab vs EPd treatment is unique because it includes Linvoseltamab, a novel BCMAxCD3 antibody, which targets specific proteins on cancer cells to enhance the immune system's ability to fight multiple myeloma. This approach is different from traditional treatments that primarily rely on chemotherapy or other monoclonal antibodies like elotuzumab, which targets the SLAMF7 receptor. ^{1 2 4 5 9}

Research Team

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Eligibility Criteria

This trial is for people with multiple myeloma that's come back or needs more treatment after 1-4 previous therapies. They must have measurable disease, be mostly active (ECOG ≤1), and have used lenalidomide and a proteasome inhibitor before. Their blood, liver, kidneys, heart, and bone marrow should work well enough to handle the treatments.

Inclusion Criteria

I've had 1-4 treatments for my MM, including specific drugs, and my disease has progressed.

My blood, liver, kidneys, heart, and bone marrow are functioning well.

Life expectancy of at least 6 months

Exclusion Criteria

I have had BCMA-targeted therapy, but BCMA antibody-drug conjugates are okay.

I had a stem cell transplant recently and am not on strong immune-suppressing drugs.

I do not have an uncontrolled infection like HIV, HBV, or HCV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either linvoseltamab or the combination of elotuzumab, pomalidomide, and dexamethasone (EPd)

12 weeks

Regular visits as per treatment protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dexamethasone
• Elotuzumab
• Linvoseltamab
• Pomalidomide

Trial Overview The study compares linvoseltamab (REGN5458) with a standard combo of cancer drugs: elotuzumab, pomalidomide & dexamethasone (EPd). Participants are split into two groups; one gets linvoseltamab while the other receives EPd. The goal is to see which group does better in terms of safety, effectiveness, side effects duration of benefit and overall survival.

Participant Groups

Group I: Linvoseltamab Experimental Treatment 1 Intervention

Randomization 1:1

Group II: Elotuzumab/Pomalidomide/Dexamethasone (EPd) Active Control 3 Interventions

Randomization 1:1

Dexamethasone is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Findings from Research

In a study of 117 patients with relapsed or refractory multiple myeloma, those treated with elotuzumab plus pomalidomide and dexamethasone experienced a median progression-free survival of 10.3 months, compared to 4.7 months for those receiving pomalidomide and dexamethasone alone, indicating a significant improvement in treatment efficacy.

The overall response rate was also higher in the elotuzumab group at 53% versus 26% in the control group, with fewer severe adverse events like neutropenia and anemia, suggesting that elotuzumab may enhance treatment outcomes while maintaining a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. Dimopoulos, MA., Dytfeld, D., Grosicki, S., et al.[2019]

In the phase II ELOQUENT-3 trial, the combination of elotuzumab with pomalidomide and dexamethasone (EPd) significantly improved overall survival (OS) in patients with relapsed/refractory multiple myeloma, with a median OS of 29.8 months compared to 17.4 months for the pomalidomide/dexamethasone (Pd) group.

The safety profile of EPd was consistent with previous studies, showing no new safety concerns, indicating that this treatment is both effective and safe for patients who have already undergone multiple lines of therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial. Dimopoulos, MA., Dytfeld, D., Grosicki, S., et al.[2023]

In the phase III ELOQUENT-2 trial involving adults with relapsed multiple myeloma, elotuzumab combined with lenalidomide and dexamethasone significantly improved progression-free survival and overall response rates compared to the standard treatment alone.

The addition of elotuzumab did not negatively affect health-related quality of life and had a manageable safety profile, with the most common serious side effects being blood-related issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elotuzumab: A Review in Relapsed and/or Refractory Multiple Myeloma. Lamb, YN.[2019]

The combination of elotuzumab with pomalidomide and dexamethasone has shown promising efficacy in treating refractory or relapsed multiple myeloma, suggesting it may be more effective than the standard pomalidomide and dexamethasone regimen alone.

As most multiple myeloma patients will likely receive initial treatments with proteasome inhibitors and lenalidomide, the elotuzumab-pomalidomide-dexamethasone combination is expected to become the standard second-line therapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elotuzumab in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma. Eleutherakis-Papaiakovou, E., Gavriatopoulou, M., Ntanasis-Stathopoulos, I., et al.[2020]

Elotuzumab combined with pomalidomide and dexamethasone (E-Pd) was shown to effectively prolong progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma (RRMM), based on data from 440 patients in the ELOQUENT-3 study.

The pharmacokinetics of elotuzumab were well-characterized, revealing that its exposure did not lead to an increase in severe adverse events (grade 3+ AEs), indicating a favorable safety profile when used with the Pd regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic and exposure-response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma. Ide, T., Osawa, M., Sanghavi, K., et al.[2022]

In a study of 103 patients with relapsed/refractory multiple myeloma, the combination of daratumumab, pomalidomide, and dexamethasone showed an overall response rate of 60%, indicating significant efficacy even in patients with a history of multiple prior therapies.

The safety profile of this combination treatment was similar to pomalidomide and dexamethasone alone, with the main exception being a higher incidence of neutropenia and infusion-related reactions, but without an increase in infection rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Chari, A., Suvannasankha, A., Fay, JW., et al.[2022]

Pomalidomide, when combined with low-dose dexamethasone, significantly improves progression-free survival and overall survival in adults with relapsed and refractory multiple myeloma, based on results from multinational phase II and III studies involving patients who had undergone at least two prior treatments.

The treatment has a manageable safety profile, with the most common serious side effects being neutropenia, infections, anemia, and thrombocytopenia, making it a viable option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pomalidomide: A Review in Relapsed and Refractory Multiple Myeloma. Hoy, SM.[2018]

In a myeloma mouse model, combining tumor antigen-loaded dendritic cells with pomalidomide and dexamethasone significantly inhibited tumor growth compared to other treatment groups, indicating enhanced antitumor immunity.

This combination therapy reduced immune suppressor cells and increased immune effector cells, suggesting a shift from an immune-suppressive to an immune-supportive environment, which could improve treatment outcomes in myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic Antimyeloma Activity of Dendritic Cells and Pomalidomide in a Murine Myeloma Model. Vo, MC., Yang, S., Jung, SH., et al.[2019]

Elotuzumab, a monoclonal antibody targeting the SLAMF7 receptor, shows no significant activity as a standalone treatment for relapsed or refractory multiple myeloma, but improves outcomes when combined with other therapies like lenalidomide and dexamethasone.

The FDA approved elotuzumab in November 2015 for multiple myeloma patients who have undergone one to three prior treatments, based on positive results from the ELOQUENT-2 phase III clinical trial, highlighting its efficacy in combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elotuzumab: the first approved monoclonal antibody for multiple myeloma treatment. Magen, H., Muchtar, E.[2020]

References

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

Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. [2019]

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

Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial. [2023]

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

Elotuzumab: A Review in Relapsed and/or Refractory Multiple Myeloma. [2019]

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

Elotuzumab in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic and exposure-response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma. [2022]

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

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. [2022]

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

Pomalidomide: A Review in Relapsed and Refractory Multiple Myeloma. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Synergistic Antimyeloma Activity of Dendritic Cells and Pomalidomide in a Murine Myeloma Model. [2019]

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

Elotuzumab: the first approved monoclonal antibody for multiple myeloma treatment. [2020]