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Multiple Myeloma

Neoplasms, Plasma Cell

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Smoldering Multiple Myeloma

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Immunoglobulins

Evaluation of initial safety and tolerability of the step-up regimen leading up to the start of full dose linvoseltamab.

Linvoseltamab monotherapy according to the same dosing schedule established in the safety run-in part.

Administration by intravenous (IV) infusion

Linvoseltamab

Clinical Trials Administrator

Clinical Trial Management

This study is researching an investigational drug called linvoseltamab ("study drug") in participants at high risk of developing multiple myeloma (MM), a group commonly labeled as high-risk smoldering multiple myeloma (HR-SMM).

The aim of the study is to understand the safety and tolerability (how your body reacts to linvoseltamab) as well as the effectiveness (how well linvoseltamab eliminates plasma cells and prevents the development of MM) of the study drug. There are 2 parts to the study.

* In Part 1, linvoseltamab will be given to a small number of participants to study the early side effects (safety) of the study drug and make sure the treatment is acceptable.
* In Part 2, linvoseltamab will be given to more participants to continue to assess the side effects of the study drug and to evaluate the ability of linvoseltamab to treat HR-SMM and prevent progression to MM.

The study is looking at several other research questions, including:

* How many participants treated with linvoseltamab (study drug) have improvement of their HR-SMM?
* What side effects may happen from taking the study drug?
* How much study drug is in your blood at different times?
* Whether the body makes antibodies against the study drug (which could make the drug less effective or could lead to side effects)

A Proof-of-Concept Trial to Study the Safety and Activity of Linvoseltamab in Participants With Smoldering Multiple Myeloma at High Risk of Developing Multiple Myeloma

Phase 2 Study of Linvoseltamab in Patients With Smoldering Multiple Myeloma at High Risk of Progression to Multiple Myeloma

All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing

AESI include grade 2 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS)

As assessed by the NCI-CTCAE grading system version 5 (for all grades)

Regeneron Pharmaceuticals

Participants in this group will be administered a fixed duration of Linvoseltamab for four to six 28-day cycles, depending on minimal residual disease (MRD) conversion status. After four cycles, participants that are MRD-negative will no longer receive study treatment. Participants that are MRD-positive will receive an additional two cycles of Linvoseltamab.

Total participation duration is up to 3 years.

Participants will be administered Linvoseltamab intravenously (IV), using a step-up dosing schedule as follows:

* Cycle 1, Day 1: 5mg
* Cycle 1, Day 8: 25mg
* Cycle 1, Days 15 and 22: 200mg
* Cycles 2 and 3, Days 1, 8, 15 and 22: 200mg
* Cycle 4, Days 1 and 15: 200mg.

For participants who are MRD-positive after four (4) cycles of study treatment:

* Cycles 5 and 6, Days 1 and 15: 200 mg

Dickran Kazandjian, MD

The purpose of this study is to determine whether Linvoseltamab therapy in patients with newly diagnosed multiple myeloma will convert the disease status from minimal residual disease (MRD)-positive to MRD-negative, and increase the length of time that the disease is controlled. The researchers also want to find out the effects (good and bad) that Linvoseltamab has on participants and the condition.

IMMUNOPLANT for Newly Diagnosed Multiple Myeloma

Immuno-consolidation for Newly Diagnosed Multiple Myeloma Using Lack of MRD Negativity After Initial cOmbination Therapy to Pursue Deeper Responses With Linvoseltamab ANd Delay Transplant

The rate of MRD-negativity among participants. Defined by rate of MRD negativity using clonoSEQ MRD® assay at sensitivities of 10\^-5 and 10\^-6. MRD negativity is defined as 0 residual clonal cells in a bone marrow biopsy sample

The sustained rate of MRD-negativity among participants will be reported. The duration of time in months measured from the first time the participant achieves an MRD-negative bone marrow (BM) biopsy result until the time the participant has relapsed from MRD-negativity objectively documented with an MRD-positive BM result.

Progression-free survival among study participants will be assessed during treatment and clinical follow-up. PFS is defined as the time from start of treatment until disease progression or death.

Overall survival (OS) among study participants will be assessed during treatment and clinical follow-up. OS is defined from start of treatment until death from any cause.

The number of participants experiencing treatment-related adverse events will be reported. Adverse events will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Professor of Clinical

Muromonab-CD3

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

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

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

Linvoseltamab will be administered by intravenous (IV) infusion

This study is researching an experimental drug called linvoseltamab (called "study drug"). The study is focused on participants with newly diagnosed multiple myeloma (NDMM) who are eligible for high dose chemotherapy with autologous stem cell transplantation (transplant-eligible) or ineligible for autologous stem cell transplantation (transplant-ineligible).

The aim of this clinical trial is to study the safety, tolerability (how the body reacts to the drug), and effectiveness (tumor shrinkage) of linvoseltamab in study participants with NDMM as a first step in determining if the study drug has a role in the treatment of NDMM.

This study consists of 2 phases:

* In Phase 1, the study drug will be given to participants to study the side effects of the study drug and to establish the regimen (initial doses and full dose) of the study drug to be given to participants in Phase 2.
* In Phase 2, the study drug will be given to more participants to continue to assess the side effects of the study drug and to evaluate the ability of the study drug to shrink the tumor (multiple myeloma) in participants with NDMM.

The study is looking at several research questions, including:

* What side effects may happen from taking linvoseltamab?
* What the right dosing regimen is for linvoseltamab?
* How many participants treated with linvoseltamab have improvement of their disease and for how long?
* The effects of linvoseltamab study treatment before and after transplant
* How much linvoseltamab is in the blood at different times?
* Whether the body makes antibodies against linvoseltamab (which could make the drug less effective or could lead to side effects).

Note: Phase 1 part B will be randomized 1:1. All other participants will be non-randomized.

A Window of Opportunity Trial to Learn if Linvoseltamab is Safe and Well Tolerated, and How Well it Works in Adult Participants With Recently Diagnosed Multiple Myeloma Who Have Not Already Received Treatment

Phase 1/2 Study of Linvoseltamab (Anti-BCMA X Anti-CD3 Bispecific Antibody) in Previously Untreated Patients With Symptomatic Multiple Myeloma

Phase 1 has two parts. Part 1, consists of REGN5458/linvoseltamab intravenous (IV) dose escalation and Part 2, consists of subcutaneous (SC) administration.

Note: subcutaneous (SC) administration is not applicable for US.

Low Dose of REGN5458/linvoseltamab IV monotherapy.

High Dose of REGN5458/linvoseltamab IV monotherapy.

Anti-interleukin (IL)-6 receptor (R) prophylactic therapy followed by high dose of IV dose of REGN5458 monotherapy.

Note: Cohort 3 is not applicable for US.

Clinical Trial Administrator

Ka Lung Wu, MD

Marie-Christiane Vekemans, MD

Toshiki Uchida

Shinsuke Lida

Hiroshi Handa

Kunihiro Tsukasaki

Tadao Ishida

Mitsuo Hori

Junya Kuroda

Shuji Ozaki

Hyeon Seok Eom

Ja Min Byun, MD

Jin Seok Kim, MD

Chang Ki Min, MD

Paula Rodriguez Otero

Jordi Lopez Pardo, MD

Adrian Alegre Amor

Ana Jimenez Ubieto, MD

Joaquin Martinez Lopez, MD

Maria Victoria Mateos Manteca, MD

Martin Kaiser, MD

The main purpose of this study is to learn about the safety of REGN5458 and to find out what is the best dose of REGN5458 to give to patients with multiple myeloma. An additional purpose is to look for any signs that REGN5458 can treat cancer.

The study is looking at several other research questions, including:

* Side effects that may be experienced by people receiving REGN5458
* How REGN5458 works in the body
* How much REGN5458 is present in the blood
* How REGN5458 may work to treat cancer

Phase 1/2 Study of REGN5458 in Adult Patients With Relapsed or Refractory Multiple Myeloma

Phase 1/2 FIH Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) in Patients With Relapsed or Refractory Multiple Myeloma

All IPD that underlie results in a publication.

Phase 1 and Phase 2 for Japanese cohort only

Phase 1 Note: Phase 1, part 2 is not applicable for US.

Phase 1, part 2 and Phase 2, for Japanese cohort only

Phase 2, cohort 3 Note: Phase 2, Cohort 3 is not applicable for US.

Phase 1 part 1 and Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.

Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US.

Phase 1 and Phase 2, cohorts 1 and 2 Note: Phase 1, part 2 is not applicable for US.

Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.

Phase 2

The EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Participants rate items on a 4-point scale, with 1 as "not at all" and 4 as "very much."

Note: Phase 2, Cohort 3 is not applicable for US.

Phase 2

The EORTC QLQ-MY20 is a self -administered instrument to assess QoL in persons with MM. This 20-item questionnaire measures the following domains: symptom scales, including disease symptoms (6 items) and symptoms related to side effects of treatment (10 items); function scale and future perspective (3 items); and body image (1 item). A high score represents a high level of symptoms or problems.

Note: Phase 2, Cohort 3 is not applicable for US.

Phase 2

The EQ-5D-3L is a self-administered generic standardized health status measure, consisting of an EQ-5D descriptive system and an EQ visual analog scale. The EQ-5D-3L descriptive system assesses 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 3-level scale: no problems, some problems, and extreme problems. The EQ visual analog scale component is a vertical visual analog scale used by patients to rate their health.

Note: Phase 2, Cohort 3 is not applicable for US.

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

Antibodies, Monoclonal

Dexamethasone

Lenalidomide

Pomalidomide

Dexamethasone acetate

BB 1101

Elotuzumab

Proteasome Inhibitors

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

REGN5458 will be administered by intravenous (IV) infusion

Elotuzumab will be administered by IV infusion

Pomalidomide capsules will administered by mouth (PO)

Dexamethasone tablets/capsules will be administered PO and/or by IV infusion

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

A Trial to Learn How Well Linvoseltamab Works Compared to the Combination of Elotuzumab, Pomalidomide and Dexamethasone for Adult Participants With Relapsed/Refractory Multiple Myeloma

An Open-label, Randomized, Phase 3 Study of Linvoseltamab (REGN5458; Anti- BCMA x Anti-CD3 Bispecific Antibody) Versus the Combination of Elotuzumab, Pomalidomide, and Dexamethasone (EPd), in Patients With Relapsed/Refractory Multiple Myeloma (LINKER-MM3)

The BPI-SF is a validated, self-administered questionnaire designed to measure a participant's perceived level of pain. The BPI-SF Item 3 uses a numeric rating scale to assess pain severity and pain interference in the past 24 hours. The numeric rating scale ranges from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicate greater intensity of pain.

Defined by at least a 2-point reduction from baseline in the BPI-SF Item 3 without an increase in analgesic use using the modified Analgesic Quantification Algorithm (AQA).

The EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Participants rate items on a 4-point scale, with 1 as "not at all" and 4 as "very much."

The EORTC QLQ-MY20 is a self -administered instrument to assess QoL in persons with MM. This 20-item questionnaire measures the following domains: symptom scales, including disease symptoms (6 items) and symptoms related to side effects of treatment (10 items); function scale and future perspective (3 items); and body image (1 item). A high score represents a high level of symptoms or problems.

The PGIS is a single 1-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time by using a 4-point Likert scale that ranges from (1) = "none (no symptoms)" to (4) = "severe".

The global anchor, PGIS will be used for interpretation of EORTC QLQ-C30, EORTC QLQ-MY20, and BPI-SF.

The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change since starting treatment as rated on a 5-point Likert scale anchored by (1) "much better" to (5) "much worse", with (4) = "no change".

The global anchor, PGIC will be used for interpretation of EORTC QLQ-C30, EORTC QLQ-MY20, and BPI-SF.

The EQ-5D-5L consists of EQ-5D descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems.

Monoclonal Gammopathy of Undetermined Significance

Immunomodulating Agents

Immunoglobulins, Intravenous

Myeloma Proteins

Paraproteins

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.

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

The primary purpose of the study is to understand how well the study drug can eliminate abnormal plasma cells and laboratory signs of high-risk monoclonal gammopathy of undetermined significance (HR-MGUS) and non high-risk smoldering multiple myeloma (NHR-SMM). This requires understanding the safety and tolerability of the study drug (how the body reacts to linvoseltamab) as well as the effectiveness of the study drug (how well linvoseltamab eliminates plasma cells). All participants will start treatment with gradually increasing doses of linvoseltamab (step-up doses) before they start receiving the assigned full dose.

The study is split into 2 parts:

* In Part 1, separate groups of 3-6 patients will receive different full doses of linvoseltamab to evaluate the short-term side effects (safety) and tolerability of the study drug within the first 5 weeks after starting treatment. The data collected will help to make a decision about the dosing regimens chosen for Part 2.
* In Part 2, a larger number of participants will be randomized to different dosing regimens to further assess the side effects of linvoseltamab, and to evaluate the ability of linvoseltamab to eliminate abnormal plasma cells in HR-MGUS and NHR-SMM.

The study is looking at several other research questions, including:

* How many participants treated with linvoseltamab have improvement of their HR-MGUS or NHR-SMM?
* What side effects may happen from taking the study drug?
* How much study drug is in the blood at different times?
* Whether the body makes antibodies against the study drug (which could make the drug less effective or could lead to side effects).

A Proof-of-Concept Study to Learn Whether Linvoseltamab Can Eliminate Abnormal Plasma Cells That May Lead to Multiple Myeloma in Adult Patients With High-Risk Monoclonal Gammopathy of Undetermined Significance or Non-High-Risk Smoldering Multiple Myeloma

Phase 2 Dose-Ranging and Interception Study of Linvoseltamab in Patients With High-Risk Monoclonal Gammopathy of Undetermined Significance or Non-High-Risk Smoldering Multiple Myeloma

All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing.

Part 1 As assessed by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading system version 5 (for all grades). AESI include grade 2 or higher cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), grade 3 or higher tumor lysis syndrome (TLS), infusion-related reaction (IRR), allergic reactions, infections and hepatitis B virus (HBV) reactivation

Part 1 As assessed by the NCI-CTCAE grading system version 5 (for all grades)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Proof-of-Concept Trial to Study the Safety and Activity of Linvoseltamab in Participants With Smoldering Multiple Myeloma at High Risk of Developing Multiple Myeloma	NCT05955508	Smoldering Mult...	Linvoseltamab	18 Years -	Regeneron Pharmaceuticals
IMMUNOPLANT for Newly Diagnosed Multiple Myeloma	NCT06376526	Multiple Myelom...	Linvoseltamab	18 Years -	University of Miami
A Window of Opportunity Trial to Learn if Linvoseltamab is Safe and Well Tolerated, and How Well it Works in Adult Participants With Recently Diagnosed Multiple Myeloma Who Have Not Already Received Treatment	NCT05828511	Multiple Myelom...	Linvoseltamab	18 Years -	Regeneron Pharmaceuticals
Phase 1/2 Study of REGN5458 in Adult Patients With Relapsed or Refractory Multiple Myeloma	NCT03761108	Multiple Myelom...	Linvoseltamab	18 Years -	Regeneron Pharmaceuticals
A Trial to Learn How Well Linvoseltamab Works Compared to the Combination of Elotuzumab, Pomalidomide and Dexamethasone for Adult Participants With Relapsed/Refractory Multiple Myeloma	NCT05730036	Relapsed Refrac...	Linvoseltamab Elotuzumab Pomalidomide Dexamethasone	18 Years -	Regeneron Pharmaceuticals
A Trial to Learn How Well Linvoseltamab Works Compared to the Combination of Elotuzumab, Pomalidomide and Dexamethasone for Adult Participants With Relapsed/Refractory Multiple Myeloma	NCT05730036	Relapsed Refrac...	Linvoseltamab Elotuzumab Pomalidomide Dexamethasone	18 Years -	Regeneron Pharmaceuticals
A Proof-of-Concept Trial to Study the Safety and Activity of Linvoseltamab in Participants With Smoldering Multiple Myeloma at High Risk of Developing Multiple Myeloma	NCT05955508	Smoldering Mult...	Linvoseltamab	18 Years -	Regeneron Pharmaceuticals
A Proof-of-Concept Study to Learn Whether Linvoseltamab Can Eliminate Abnormal Plasma Cells That May Lead to Multiple Myeloma in Adult Patients With High-Risk Monoclonal Gammopathy of Undetermined Significance or Non-High-Risk Smoldering Multiple Myeloma	NCT06140524	Monoclonal Gamm... Smoldering Mult...	Linvoseltamab	18 Years -	Regeneron Pharmaceuticals
A Window of Opportunity Trial to Learn if Linvoseltamab is Safe and Well Tolerated, and How Well it Works in Adult Participants With Recently Diagnosed Multiple Myeloma Who Have Not Already Received Treatment	NCT05828511	Multiple Myelom...	Linvoseltamab	18 Years -	Regeneron Pharmaceuticals

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