Linvoseltamab for Multiple Myeloma

(LINKER-MM4 Trial)

Recruiting at 50 trial locations

Overseen By Clinical Trials Administrator

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Regeneron Pharmaceuticals

Must not be taking: Investigational agents

Disqualifiers: CNS involvement, Rapidly progressive disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

132 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, linvoseltamab (a BCMAxCD3 antibody), to determine its effectiveness for people with newly diagnosed multiple myeloma, a type of blood cancer. Researchers aim to assess the drug's safety, potential side effects, and ability to shrink tumors. The study consists of two phases: the first phase explores the appropriate dosing and side effects, while the second phase evaluates the drug's effectiveness in different participant groups. The trial seeks individuals recently diagnosed with multiple myeloma who have not yet received treatment, with some specific exceptions. As a Phase 1/Phase 2 trial, this study offers participants the opportunity to be among the first to receive a promising new treatment and contribute to determining its effectiveness.

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 mentions a washout period (time without taking certain medications) for prior corticosteroid use. It's best to discuss your specific medications with the trial team.

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

Research has shown that linvoseltamab has been tested for safety in people with multiple myeloma, a type of blood cancer. In other studies, patients treated with linvoseltamab experienced generally manageable side effects. Common side effects included tiredness, nausea, and low blood cell counts, typically mild to moderate.

Importantly, linvoseltamab was studied in patients who had already tried other treatments without success. Despite this, the drug demonstrated an acceptable safety profile. Although some patients experienced more serious side effects, these were uncommon.

As linvoseltamab is being studied in early stages for newly diagnosed multiple myeloma, understanding its safety in this context is still developing. However, its testing in other situations provides some insight into what new patients might expect regarding safety. ^{1 2 3 4 5}

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

Linvoseltamab is unique because it targets multiple myeloma cells through a novel approach. Unlike traditional treatments like chemotherapy or proteasome inhibitors, Linvoseltamab is a bispecific antibody designed to engage the immune system directly to attack the cancer cells. Researchers are excited because this method could offer a more precise treatment option with potentially fewer side effects and improved effectiveness, especially for those who are newly diagnosed or cannot undergo transplants. This innovative mechanism gives hope for better outcomes in managing multiple myeloma.

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

Research shows that linvoseltamab may help treat multiple myeloma, especially in patients whose disease has returned or hasn't responded to other treatments. In earlier studies, many patients responded strongly to linvoseltamab, with significant tumor shrinkage. One study found that the positive effects of linvoseltamab lasted an average of 29.4 months. Additionally, most patients tolerated the treatment well, experiencing manageable side effects. In this trial, participants will receive linvoseltamab in different cohorts, including those who are transplant-eligible and transplant-ineligible, to further evaluate its effectiveness and safety. These results suggest that linvoseltamab could be a good option for managing multiple myeloma, even in challenging cases. ^{6 7 8 9 10}

Who Is on the Research Team?

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults under 70 with newly diagnosed symptomatic multiple myeloma who haven't had treatment, except possibly short-term steroids or emergency radiation. They should be fit enough for a transplant and have good heart, liver, kidney, and lung function.

Inclusion Criteria

I am under 70 and my liver, kidneys, lungs, and heart are healthy enough for a transplant.

I have multiple myeloma and haven't received treatment, except possibly emergency radiation or short-term steroids.

My blood, liver, kidney, and heart are functioning well.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive linvoseltamab to study side effects and establish dosing regimen

Up to 28 days

Multiple visits for dose escalation and monitoring

Phase 2 Treatment

Participants receive linvoseltamab to assess side effects and tumor shrinkage

Up to 5 years

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 90 days post-last dose

Follow-up visits for safety assessments

What Are the Treatments Tested in This Trial?

Interventions

• Linvoseltamab

Trial Overview The study tests Linvoseltamab's safety and optimal dosing in Phase 1. In Phase 2, it evaluates its effectiveness against multiple myeloma. It also examines how the drug moves in the body and its impact on immune response and blood markers like BCMA.

How Is the Trial Designed?

Group I: Phase 2 - transplant ineligible cohort Experimental Treatment 1 Intervention

Transplant-ineligible participants, enrolled in dose expansion, will receive selected Linvoseltamab regimen until disease progression as per protocol.

Group II: Phase 2 - transplant eligible cohort Experimental Treatment 1 Intervention

Transplant-eligible participants, enrolled in dose expansion, will receive selected linvoseltamab regimen for a fixed duration of treatment as per protocol

Group III: Phase 1 cohort Experimental Treatment 1 Intervention

Linvoseltamab dose escalation (part A) and dose expansion (part B) for participants with NDMM who are treatment-naïve.

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

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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-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]

Citations

1. 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 ...

2. 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, ...

3. 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 ( ...

4. 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) ...

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/140/Supplement%201/4444/492326/Trial-in-Progress-REGN5458-a-BCMAxCD3-Bispecific

REGN5458, a BCMAxCD3 Bispecific Antibody, in a Phase Ib ... A global, Phase Ib, open-label, multi-cohort study exploring REGN5458 in combination with other cancer treatments in patients with relapsed/refractory multiple ...

8. 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.

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

Linvoseltamab Shows Durable Efficacy, Manageable ... ... data on the efficacy and safety of linvoseltamab in patients with heavily pretreated, relapsed/refractory (R/R) multiple myeloma.

10. 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 ...