Linvoseltamab for Multiple Myeloma

(LINKER-MGUS1 Trial)

Recruiting at 14 trial locations

Overseen By Clinical Trials Administrator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Regeneron Pharmaceuticals

Disqualifiers: High-risk SMM, Myeloma-defining events, Amyloidosis, 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

116 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how well an experimental drug, linvoseltamab (a BCMAxCD3 antibody), can help individuals at moderate risk of developing multiple myeloma, a type of blood cancer. The trial targets participants with specific pre-cancer conditions that could lead to multiple myeloma. Researchers aim to determine if linvoseltamab can reduce abnormal cells and improve conditions like HR-MGUS and NHR-SMM. They also study the side effects and the body's reaction to the drug. Individuals diagnosed with conditions like HR-MGUS or NHR-SMM, who are concerned about progressing to multiple myeloma, might be suitable for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that linvoseltamab is likely to be safe for humans?

Research has shown that linvoseltamab generally has a manageable safety profile for patients with multiple myeloma. In these studies, some patients experienced side effects, but they were usually manageable. Common side effects included low blood cell counts and reactions related to the drug infusion, which were mostly mild to moderate and often occurred during or shortly after treatment.

While the treatment appears promising, it remains under study. Researchers continue to explore its safety in different patient groups. The trial's later stage indicates that earlier studies found the drug to be relatively well-tolerated. However, ongoing research is crucial to understanding how different doses affect safety and effectiveness. Always consult a healthcare professional to understand what participating in a trial might mean. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for multiple myeloma?

Linvoseltamab is unique because it targets BCMA, a protein found on the surface of multiple myeloma cells, offering a new mechanism of action compared to standard treatments like proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies targeting different proteins. This targeted approach could potentially lead to more effective and specific destruction of cancer cells with fewer side effects. Researchers are excited about linvoseltamab because it represents a shift towards more personalized and precise cancer therapies, which could significantly improve treatment outcomes for patients with multiple myeloma.

What evidence suggests that linvoseltamab might be an effective treatment for multiple myeloma?

Research shows that linvoseltamab has promising results in treating multiple myeloma, a type of cancer affecting plasma cells. In earlier studies, patients with relapsed or hard-to-treat multiple myeloma who took 200 mg of linvoseltamab experienced strong and lasting improvements. On average, these improvements lasted about 29.4 months, indicating the treatment's long-term effectiveness. This trial will randomize participants across different dosing regimens of linvoseltamab to further assess its efficacy and safety. Even patients in high-risk groups responded well in previous studies, suggesting linvoseltamab could also help those with precancerous conditions like HR-MGUS and NHR-SMM by targeting and eliminating abnormal plasma cells. ^{5 6 7 8 9}

Who Is on the Research Team?

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Are You a Good Fit for This Trial?

Adults with high-risk monoclonal gammopathy (HR-MGUS) or non-high-risk smoldering multiple myeloma (NHR-SMM) can join this study. They should be relatively healthy, able to perform daily activities with ease (ECOG ≤1), and have good blood and liver function. Their kidneys must also work well enough to filter waste from the blood.

Inclusion Criteria

My condition is either high-risk MGUS or smoldering myeloma.

I am fully active and can carry on all pre-disease activities without restriction.

My kidney function, measured by GFR, is adequate.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-In (Part 1)

Sequential groups of participants will be enrolled to assess the initial safety and tolerability of the step-up regimen leading up to the start of different full doses of linvoseltamab.

5 weeks

Expansion (Part 2)

Participants will be randomized to different dosing regimens to further assess the side effects of linvoseltamab and evaluate its ability to eliminate abnormal plasma cells.

Up to 5.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Linvoseltamab

Trial Overview The trial is testing Linvoseltamab's ability to eliminate abnormal plasma cells in patients with HR-MGUS or NHR-SMM. It starts with increasing doses of Linvoseltamab, followed by a full dose. The first part checks safety at different doses; the second part compares dosing regimens for effectiveness and side effects.

How Is the Trial Designed?

Group I: Safety Run-In (Part 1) Experimental Treatment 1 Intervention

Sequential groups of participants will be enrolled to assess the initial safety and tolerability of the step-up regimen leading up to the start of different full doses of linvoseltamab.

Group II: Expansion (Part 2) - Dose regimen 4 Experimental Treatment 1 Intervention

Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens

Group III: Expansion (Part 2) - Dose regimen 3 Experimental Treatment 1 Intervention

Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens

Group IV: Expansion (Part 2) - Dose regimen 2 Experimental Treatment 1 Intervention

Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens

Group V: Expansion (Part 2) - Dose regimen 1 Experimental Treatment 1 Intervention

Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens

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

Published Research Related to This Trial

Monoclonal antibodies, such as daratumumab and isatuximab, have significantly improved treatment outcomes for multiple myeloma patients, being effective from first-line therapy to cases of refractory disease.

Belantamab mafodotin, the first antibody drug conjugate targeting B cell maturation antigen, is now approved for use as a monotherapy in advanced multiple myeloma, showcasing the potential of novel agents in enhancing patient prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma. Radocha, J., van de Donk, NWCJ., Weisel, K.[2023]

Monoclonal antibodies (mAbs) are a promising new treatment for multiple myeloma (MM), with two already approved: daratumumab for newly diagnosed and relapsed patients, and elotuzumab for relapsed cases.

mAbs work by targeting specific antigens on MM cells to induce cell death, enhance immune response, or deliver cytotoxic drugs, and ongoing clinical trials are exploring their effectiveness in combination with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma. Bonello, F., Mina, R., Boccadoro, M., et al.[2020]

Monoclonal antibodies, such as daratumumab and isatuximab targeting CD38, and elotuzumab targeting SLAMF7, are emerging as effective salvage therapies for patients with relapsed or refractory multiple myeloma, based on recent literature up to March 2020.

These therapies are expected to significantly change treatment strategies for myeloma, but careful consideration of their combinations and potential new toxicities will be crucial for future patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses. Musto, P., La Rocca, F.[2021]

Anti-CD38 monoclonal antibodies have become a standard treatment for multiple myeloma, significantly enhancing patient response when used alongside traditional therapies.

New therapies targeting BCMA, including drug conjugates and bispecific T-cell engagers, show promise as effective options for treating multiple myeloma, particularly in patients who have become resistant to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal antibodies as an addition to current myeloma therapy strategies. Jullien, M., Touzeau, C., Moreau, P.[2021]

Anti-B-cell maturation antigen (BCMA) therapies, including bispecific antibodies and CAR T cells, have shown effectiveness in treating relapsed refractory multiple myeloma, with all four reviewed agents receiving FDA approval for adult patients.

However, these therapies can lead to severe side effects such as cytokine release syndrome and neurotoxicity, which can be life-threatening; the review emphasizes the importance of understanding these complications and outlines management strategies to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Adverse Reactions for BCMA-Directed Therapy in Relapsed Multiple Myeloma: A Focused Review. Khanam, R., Faiman, B., Batool, S., et al.[2023]

Elotuzumab, an antibody targeting SLAMF7, has been shown to reduce the risk of disease progression or death by 30% when combined with lenalidomide and dexamethasone in patients with relapse/refractory multiple myeloma, based on the ELOQUENT-2 trial.

Daratumumab, targeting CD38, demonstrated significantly improved complete response rates and progression-free survival in multiple myeloma patients when combined with bortezomib and dexamethasone, as well as with lenalidomide and dexamethasone, in the CASTOR and POLLUX trials, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic antibodies for multiple myeloma. Ishida, T.[2018]

Emerging bispecific antibody therapies targeting proteins like BCMA and GPRC5D show promising efficacy in treating relapsed/refractory multiple myeloma, with response rates between 50-80% in heavily pretreated patients.

While these therapies offer a more readily available option compared to CAR-T cell therapy, they also carry risks of adverse events such as cytokine release syndrome (40-90% incidence) and neurotoxicity (3-20% incidence), highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell redirecting bispecific antibodies for multiple myeloma: emerging therapeutic strategies in a changing treatment landscape. Kazandjian, D., Kowalski, A., Landgren, O.[2023]

Ciltacabtagene autoleucel (cilta-cel) demonstrated significantly improved efficacy compared to three non-CAR-T therapies for treating relapsed or refractory multiple myeloma, with at least a 3.1-fold increase in overall response rates and a 10.3-fold increase in complete response rates.

Patients receiving cilta-cel experienced at least a 74% reduction in the risk of disease progression or death and a 47% reduction in the risk of death, indicating its strong potential as a treatment option for patients who have been previously treated with multiple therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-Adjusted Indirect Treatment Comparison to Assess the Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 Versus Belantamab Mafodotin in DREAMM-2, Selinexor-Dexamethasone in STORM Part 2, and Melphalan Flufenamide-Dexamethasone in HORIZON for the Treatment of Patients With Triple-Class Exposed Relapsed or Refractory Multiple Myeloma. Weisel, K., Krishnan, A., Schecter, JM., et al.[2022]

Isatuximab (anti-CD38) and F50067 (anti-CXCR4) showed promising results as monotherapies in treating multiple myeloma, with overall response rates of 66.7% and 32%, respectively, based on a review of 39 studies involving 1906 patients.

Combination therapies using Isatuximab with lenalidomide and dexamethasone achieved a clinical benefit rate of 83%, while Indatuximab Ravtansine showed response rates of 78% and 79% when combined with these agents, indicating that mAbs can enhance treatment efficacy when used alongside traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development. Iftikhar, A., Hassan, H., Iftikhar, N., et al.[2023]

Isatuximab, an anti-CD38 monoclonal antibody, was found to be well tolerated and effective in treating heavily pretreated relapsed/refractory multiple myeloma, with an overall response rate of 36.4% in a phase 2 trial involving 28 patients.

The most common side effects were mild infusion reactions occurring in 42.9% of patients, indicating a manageable safety profile, while the median progression-free survival was 4.7 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study. Sunami, K., Suzuki, K., Ri, M., et al.[2020]

In a study of 14 patients with newly diagnosed multiple myeloma, the combination of siltuximab with lenalidomide, bortezomib, and dexamethasone showed a high overall response rate of 90.9%, indicating strong efficacy in treating this condition.

The maximum tolerated dose of siltuximab was determined to be 8.3 mg/kg, with serious adverse events including grade 3 pneumonia and grade 4 thrombocytopenia, but no deaths occurred during the study, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Siltuximab (CNTO 328) with lenalidomide, bortezomib and dexamethasone in newly-diagnosed, previously untreated multiple myeloma: an open-label phase I trial. Shah, JJ., Feng, L., Thomas, SK., et al.[2018]

In a real-world study involving four patients with relapsed/refractory multiple myeloma (RRMM), isatuximab-based therapy showed clinical benefits, even in patients previously treated with daratumumab, indicating that prior anti-CD38 therapy does not prevent a positive response to isatuximab.

The findings also suggest that isatuximab can be safely used in patients with renal insufficiency, further supporting its potential as a treatment option for diverse patient profiles in RRMM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with isatuximab in the treatment of relapsed-refractory multiple myeloma: a case series from the Grand Duchy of Luxembourg. De Wilde, S., Plawny, L., Berchem, G.[2023]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/7012/527741/Comparative-Effectiveness-of-Linvoseltamab-Versus

Comparative Effectiveness of Linvoseltamab Versus Current ... High objective response rates (ORR) to linvoseltamab 200 mg in the LINKER-MM1 trial (NCT03761108) were demonstrated across high-risk subgroups, ...

2. onclive.com onclive.com/view/linvoseltamab-adds-highly-effective-option-in-later-line-multiple-myeloma

Linvoseltamab Adds Highly Effective Option in Later-Line ... Data from LINKER-MM1 revealed that patients who received the BCMA-directed CD3 T-cell engager (n = 80) experienced an objective response rate ( ...

3. investor.regeneron.com investor.regeneron.com/news-releases/news-release-details/new-regn5458-bcmaxcd3-phase-1-data-show-75-response-rate-highest/

New REGN5458 (BCMAxCD3) Phase 1 Data Show 75% ... The new results from the Phase 1 portion of the Phase 1/2 trial in patients with relapsed/refractory multiple myeloma found a 51% overall response rate (ORR) ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38879802/

Linvoseltamab for Treatment of Relapsed/Refractory ... Conclusion: Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.01008

Linvoseltamab for Treatment of Relapsed/Refractory ... Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11272139/

Linvoseltamab for Treatment of Relapsed/Refractory ... Here we present the efficacy, safety, and clinical pharmacology data from the phase I and phase II portions of LINKER-MM1, with a focus on ...

7. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/7056/527036/Exposure-Response-Analyses-of-Various-Efficacy-and

Exposure-Response Analyses of Various Efficacy and Safety ... Linvoseltamab, an investigational BCMAxCD3 bispecific antibody, for the treatment of patients with relapsed or refractory multiple myeloma.

8. ajmc.com ajmc.com/view/linvoseltamab-shows-durable-efficacy-manageable-safety-in-r-r-multiple-myeloma

Linvoseltamab Shows Durable Efficacy, Manageable ... Linvoseltamab is a BCMA [B-cell maturation antigen] and CD3 bispecific antibody that was studied in patients with relapsed, refractory multiple myeloma.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03761108

NCT03761108 | Phase 1/2 Study of Linvoseltamab in Adult ... The main purpose of this study is to learn about the safety of linvoseltamab and to find out what is the best dose of linvoseltamab to give to patients with ...