A Study to Learn About the Effects of the Combination of Elranatamab (PF-06863135), Daratumumab, and Lenalidomide Compared With Daratumumab, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Who Are Not Candidates for Transplant

Study Overview
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Brief Summary
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Elranatamab is a bispecific antibody: binding of elranatamab to CD3-expressing T-cells and BCMA-expressing multiple myeloma cells causes targeted T-cell-mediated cytotoxicity. The main purpose of the study is to evaluate if the combination of Elranatamab, Daratumumab and Lenalidomide offers superior clinical benefit compared with the combination of Daratumumab, Lenalidomide and Dexamethasone in people with multiple myeloma. There are 2 parts to this study. Part 1 will characterize the safety and tolerability of elranatamab when administered in combination with daratumumab and lenalidomide and will identify the optimal dose(s) of the combination regimen. Part 2 of the study will evaluate the minimal residual disease (MRD) negativity rate and the progression free survival (PFS) of the combination of elranatamab, daratumumab, and lenalidomide compared with the combination of daratumumab, lenalidomide, and dexamethasone in participants with newly diagnosed transplant-ineligible multiple myeloma.

Official Title
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MAGNETISMM-6: AN OPEN-LABEL, 2-ARM, MULTICENTER, RANDOMIZED PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ELRANATAMAB (PF-06863135) + DARATUMUMAB + LENALIDOMIDE VERSUS DARATUMUMAB + LENALIDOMIDE + DEXAMETHASONE IN TRANSPLANT-INELIGIBLE PARTICIPANTS WITH NEWLY-DIAGNOSED MULTIPLE MYELOMA

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Elranatamab
* Drug: Daratumumab
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of multiple myeloma (MM) as defined by IMWG criteria (Rajkumar et al., 2014) Measurable disease based on IMWG criteria as defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL; Urinary M-protein excretion ≥200 mg/24 hours; Involved FLC ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65). Part 1: Participants with relapsed/refractory multiple myeloma (RRMM) who have received 1-2 prior lines of therapy including at least one immunomodulatory drug and one proteasome inhibitor: or participants with newly-diagnosed multiple myeloma (NDMM) that are transplant-ineligible as defined by age ≥65 years or transplant-ineligible as defined by age <65 years with comorbidities impacting the possibility of transplant. Part 2: participants with newly-diagnosed multiple myeloma that are transplant-ineligible as defined by age ≥65 years or transplant-ineligible as defined by age <65 years with comorbidities impacting the possibility of transplant ECOG performance status ≤2. Not pregnant and willing to use contraception For participants with RRMM: Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1. Exclusion Criteria: Smoldering Multiple Myeloma. Monoclonal gammopathy of undetermined significance. Waldenströms Macroglobulinemia Plasma cell leukemia. Active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) COVID-19/SARS-CoV-2, HBV, HCV, and known HIV or AIDS-related illness. Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ, or Stage 0/1 with minimal risk of recurrence per investigator. For participants with RRMM: Previous treatment with a BCMA-directed therapy or anti-CD38-directed therapy within 6 months preceding the first dose of study intervention in this study. Stem cell transplant ≤3 months prior to first dose of study intervention or active GVHD. For participants with NDMM: Previous systemic treatment for MM except for a short course of corticosteroids (ie, up to 4 days of 40 mg dexamethasone or equivalent before the first dose of study intervention). Live attenuated vaccine administered within 4 weeks of the first dose of study intervention. Administration of investigational product (eg, drug or vaccine) concurrent with study intervention or within 30 days (or as determined by the local requirement) preceding the first dose of study intervention used in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1, Dose Level 1: Elranatamab + Daratumumab + Lenalidomide<br> | Drug: Elranatamab<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>Drug: Daratumumab<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>Drug: Lenalidomide<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>|
| Experimental: Part 1, Multiple Dose Levels, Elranatamab + Daratumumab + Lenalidomide<br> | Drug: Elranatamab<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>Drug: Daratumumab<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>Drug: Lenalidomide<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>|
| Experimental: Part 2 Randomized Arm A: Elranatamab + Daratumumab + Lenalidomide<br> | Drug: Elranatamab<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>Drug: Daratumumab<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>Drug: Lenalidomide<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>|
| Active Comparator: Part 2 Randomized Arm B: Daratumumab + Lenalidomide + Dexamethasone<br> | Drug: Daratumumab<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>Drug: Lenalidomide<br>* Part 1 Dose Level 1 is not randomized. All other cohorts are randomized.<br>Drug: Dexamethasone<br>* Randomized<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 Dose Limiting Toxicity |  | From the first dose of elranatamab/first full dose in combination with EDR until 28 days (+/- visit window) from the first administration of elranatamab 76 with daratumumab and lenalidomide | 
| Part 2: Progression free survival by blinded independent central review |  | From randomization up to 73 months. | 
| Part 2: Sustained minimal residual disease negativity rate |  | For at least 12 months after date of initial MRD-negative status | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | From date of randomization up to 73 months | 
| Overall minimal residual disease negativity rate |  | From date of randomization up to 73 months | 
| Duration of minimal residual disease negativity (Part 2) |  | From date of minimal residual disease negative status up to 73 months | 
| PFS by investigator |  | From date of randomization up to 73 months | 
| PFS2 by investigator (Part 2) |  | From the date of randomization up to 73 months | 
| Objective Response Rate |  | From the date of randomization up to 73 months | 
| Complete Response Rate |  | From the date of randomization up to 73 months | 
| Time to Response |  | From the date of randomization to date of confirmed objective response up to 73 months | 
| Duration of Response |  | From the date of confirmed objective response up to 73 months | 
| Duration of Complete Response |  | From the date of confirmed complete response up to 73 months | 
| Frequency of treatment-emergent adverse events |  | From the date of first dose of study intervention up to 73 months | 
| Frequency of abnormal laboratory results |  | From the date of first dose of study intervention up to 73 months | 
| Elranatamab pharmacokinetics by pre-dose concentrations when used with lenalidomide and daratumumab | Pharmacokinetics of elranatamab (trough concentrations of elranatamab) | From date of first dose of study intervention up to 73 months | 
| Elranatamab pharmacokinetics by post-dose concentrations when used with lenalidomide and daratumumab | Pharmacokinetics of elranatamab (post-dose serum concentrations of elranatamab) | From date of first dose of study intervention up to 73 months | 
| Incidence of Anti-Drug Antibody and Neutralizing Antibody against elranatamab | Immunogenicity of elranatamab | From date of first dose of study intervention up to 73 months | 
| Titers of Anti-Drug Antibody and Neutralizing Antibody against elranatamab | Immunogenicity of elranatamab | From date of first dose of study intervention up to 73 months | 
| Part 2: Health-related quality of life by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire -Myeloma 20 | Higher scores on the functioning subscales (body image, future perspective) represent higher levels of functioning, whereas higher scores on the symptom subscales (disease symptoms, side effects) represent a greater presence of symptoms | From date the informed consent is signed up to 73 months | 
| Part 2: Health-related quality of life by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 | Higher scores on the functional scales represent higher levels of functioning. Higher scores on the global health status/quality of life scale represent higher health status/quality of life. Higher scores on the symptom scales/items represent a greater presence of symptoms. | From date the informed consent is signed up to 73 months | 
| Part 1: Daratumumab and lenalidomide pharmacokinetics by pre-dose concentrations in combination with elranatamab | Pharmacokinetics of daratumumab and lenalidomide (trough concentrations of daratumumab and lenalidomide) | From date of first dose of study intervention up to 73 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PF-06863135, Elranatamab, B-Cell Maturation Antigen, Daratumumab, Lenalidomide, Multiple myeloma, MagnetisMM-6