A Study Comparing JNJ-68284528, a CAR-T Therapy Directed Against B-cell Maturation Antigen (BCMA), Versus Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd) in Participants With Relapsed and Lenalidomide-Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy of JNJ-68284528 (ciltacabtagene autoleucel [cilta-cel]) with standard therapy, either Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd).

Detailed Description
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Multiple myeloma is a malignant plasma cell disorder diagnosed annually in approximately 86,000 participants worldwide. JNJ-68284528 (cilta-cel) is an autologous chimeric antigen receptor T-cell (CAR-T) therapy that targets B-cell maturation antigen (BCMA), a molecule expressed on the surface of mature B lymphocytes and malignant plasma cells. The primary hypothesis for this study is that JNJ-68284528 (cilta-cel) will significantly improve progression free survival (PFS) compared with standard therapy (PVd or DPd), in participants who have previously received 1 to 3 prior line(s) of therapy, that included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and who are refractory to lenalidomide. This study will be conducted in 3 phases: Screening (up to 28 days before randomization), Treatment, and Follow-Up. Assessment like patient-reported outcome(s) (PROs) assessments, electrocardiogram (ECG), vital signs, pharmacokinetic will be performed during the study. Safety evaluations will include review of adverse events, laboratory test results, vital sign measurements, physical examination findings, and assessments of cardiac function, Immune Effector Cell-associated Encephalopathy (only for Arm B) and Eastern Cooperative Oncology Group performance status. Safety data will be periodically reviewed by an Independent Data Monitoring Committee (IDMC). The duration of the study is approximately 6 years.

Official Title
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A Phase 3 Randomized Study Comparing JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against BCMA, Versus Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd) in Subjects With Relapsed and Lenalidomide-Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: JNJ-68284528
* Drug: Pomalidomide
* Drug: Bortezomib
* Drug: Dexamethasone
* Drug: Daratumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Measurable disease at screening as defined by any of the following: (a) Serum monoclonal paraprotein (M-protein) level greater than or equal to (>=) 0.5 gram per deciliter (g/dL) or urine M-protein level >=200 milligram (mg)/24 hours; or (b) Light chain multiple myeloma without measurable M-protein in the serum or the urine: Serum free light chain >=10 mg/dL and abnormal serum free light chain ratio Have received 1 to 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) Have documented evidence of PD by International Myeloma Working Group (IMWG) criteria based on investigator's determination on or within 6 months of their last regimen Be refractory to lenalidomide per IMWG consensus guidelines (failure to achieve minimal response or progression on or within 60 days of completing lenalidomide therapy). Progression on or within 60 days of the last dose of lenalidomide given as maintenance will meet this criterion. For participants with more than 1 prior line of therapy, there is no requirement to be lenalidomide refractory to the most recent line of prior therapy. However, participants must be refractory to lenalidomide in at least one prior line Have clinical laboratory values meeting the following criteria during the Screening Phase (re testing is allowed but the below criteria must be met in the latest test prior to randomization): Hemoglobin >=8 gram per deciliter (g/dL) (without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted); Absolute neutrophil count (ANC) >=1 * 10^9 per liter (L) (without recombinant human granulocyte colony-stimulating factor [G-CSF] within 7 days and without pegylated G-CSF within 14 days of the laboratory test); Platelet count >=75 * 10^9/L (without prior platelet transfusion within 7 days before the laboratory test) in participants in whom less than (<) 50 percent (%) of bone marrow nucleated cells are plasma cells; platelet count >=50 * 10^9/L (without prior platelet transfusion within 7 days before the laboratory test) in participants in whom >=50% of bone marrow nucleated cells are plasma cells; Lymphocyte count >=0.3 * 10^9/L; Aspartate aminotransferase (AST) less than or equal to (<=)3 * upper limit of normal (ULN); Alanine aminotransferase (ALT) <=3 * ULN; Total bilirubin <=2.0 * ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin <=1.5 * ULN is required); Estimated glomerular filtration rate >=40 milliliter per minute (mL/min) per 1.73 meter square (m^2) (to be calculated using the Modification of Diet in Renal Disease [MDRD] formula) Exclusion Criteria: Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy directed at any target Any previous therapy that is targeted to B-cell maturation antigen (BCMA) Ongoing toxicity from previous anticancer therapy that has not resolved to baseline levels or to Grade 1 or less; except for alopecia Participants with Grade 1 peripheral neuropathy with pain or Grade 2 or higher peripheral neuropathy will not be permitted to receive pomalidomide, bortezomib, and dexamethasone (PVd) as standard therapy or bridging therapy; however, participants may receive daratumumab, pomalidomide, and dexamethasone (DPd) as standard therapy or bridging therapy Received a cumulative dose of corticosteroids equivalent to >=70 mg of prednisone within the 7 days prior to randomization Monoclonal antibody treatment within 21 days Cytotoxic therapy within 14 days Proteasome inhibitor therapy within 14 days Immunomodulatory drug (IMiD) therapy within 7 days

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: Arm A: PVd or DPd (Standard Therapy)<br>Participants will receive either PVd or DPd as a standard therapy. In PVd treatment, participants will receive oral pomalidomide 4 mg on Days 1 to 14 in each cycle; bortezomib 1.3 mg/meter square (m^2) SC on Days 1, 4, 8 and 11 (Cycles 1 to 8) and on Days 1 and 8 (Cycle 9 onwards) and oral dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11 and 12 (Cycles 1 to 8) and Days 1, 2, 8 and 9 (Cycle 9 onwards). Each cycle will consist of 21 days. In DPd treatment, participants will receive daratumumab SC 1800 mg weekly on Days 1, 8, 15, and 22 (Cycles 1 and 2), every 2 weeks on Days 1 and 15 (Cycles 3 to 6) and every 4 weeks on Day 1 (Cycle 7 onwards); oral pomalidomide 4 mg on Days 1 to 21 (Cycle 1 onwards); dexamethasone 40 mg oral or IV weekly on Days 1, 8, 15, and 22 (Cycle 1 onwards). Each cycle will consist of 28 days. Participants will continue to receive PVd or DPd until confirmed PD, death, intolerable toxicity, withdrawal of consent, or end of the study, whichever occurs earlier. | Drug: Pomalidomide<br>* Pomalidomide 4 mg will be administered orally.<br>Drug: Bortezomib<br>* Bortezomib 1.3 milligram per meter square (mg/m^2) will be administered subcutaneously (SC).<br>Drug: Dexamethasone<br>* Dexamethasone 20 mg/day (10mg/day for participants >75 years of age) (on bortezomib treatment days and the days following bortezomib treatment) will be administered orally in PVd treatment; and orally or intravenous (IV) at 40 mg weekly (20mg weekly for participants >75 years of age) in DPd treatment.<br>Drug: Daratumumab<br>* Daratumumab 1800 mg will be administered SC.<br>|
| Experimental: Arm B: JNJ-68284528 (Ciltacabtagene Autoleucel [Cilta-cel])<br>Participants will receive at least one cycle of bridging therapy (PVd or DPd) and additional cycles of bridging therapy may be considered based on participant's clinical status and timing of availability of JNJ-68284528 (cilta-cel) along with conditioning regimen (cyclophosphamide 300 milligram [mg]/m^2 intravenous [IV] and fludarabine 30 mg/m^2 IV daily, for 3 days), and JNJ-68284528 (cilta-cel) infusion 0.75 * 10^6 chimeric antigen receptor (CAR)-positive viable T cells/ kilogram (kg). | Drug: JNJ-68284528<br>* Cilta-cel infusion will be administered at a target dose of 0.75 * 10^6 CAR-positive viable T cells/kilogram (kg).<br>* Other names: Cilta-cel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from the date of randomization to the date of first documented disease progression as defined in the IMWG criteria, or death due to any cause, whichever occurs first. | Until end of the study (up to 6 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) or Stringent Complete Response (sCR) Rate | CR or sCR rate is defined as percentage of participants who achieve a CR or sCR response according to the International Myeloma Working Group (IMWG) criteria. | Until end of the study (up to 6 years) | 
| Overall Minimal Residual Disease (MRD) Negative Rate | Overall MRD negativity is defined as the percentage of participants who achieve MRD negativity at any time after the date of randomization before initiation of subsequent therapy. | Until end of the study (up to 6 years) | 
| MRD Negativity Rate in Participants with CR or sCR at 12 Months +/-3 Months | MRD negativity rate in participants with CR or sCR at 12 months +/-3 months is defined as the percentage of participants who achieve MRD-negative status and are in CR or sCR within time window. | Until end of the study (up to 6 years) | 
| Sustained MRD Negative Rate | Sustained MRD negativity rate is defined as the percentage of participants who achieve MRD negativity, confirmed minimum 1 year apart and without any examination showing MRD positive status in between. | Until end of the study (up to 6 years) | 
| Overall Survival (OS) | OS is measured from the date of randomization to the date of the participant's death. If the participant is alive or the vital status is unknown, then the participant's data will be censored at the date the participant was last known to be alive. | Until end of the study (up to 6 years) | 
| Overall response rate (ORR) | ORR is defined as the percentage of participants who achieve a partial response (PR) or better according to the IMWG criteria. | Until end of the study (up to 6 years) | 
| Time to Worsening of Symptoms | Time to worsening of symptoms is measured as the interval from the date of randomization to the start date of worsening in the Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q) total symptom score. The MySIm-Q is a disease-specific PRO assessment complementary to the EORTC-QLQ-C30. It includes 17 items resulting in a symptom subscale and an impact subscale. The recall period is the past 7 days and responses are reported on a 5 point verbal rating scale. | Until end of the study (up to 6 years) | 
| Progression Free Survival on next-line therapy (PFS2) | PFS2 is defined as the time interval between the date of randomization and date of event, which is defined as progressive disease as assessed by investigator that starts after the next line of subsequent therapy, or death from any cause, whichever occurs first. | Until end of the study (up to 6 years) | 
| Incidence and Severity of Adverse Events (AEs) | Incidence and severity of AEs will be reported. | Until end of the study (up to 6 years) | 
| Systemic Cytokine Concentrations | Serum or plasma proteomic profiling of cytokines (such as interleukin [IL] 6, IL-15, and IL 10) concentrations will be measured for biomarker assessment. | Until end of the study (up to 6 years) | 
| Levels of CAR-T Cell Activation Markers | CAR-T cell activation markers including, but not limited to, CD4+, CD8+, CD25+, central memory, effector memory cells will be reported. An evaluation of cell populations may be performed by flow cytometry or cytometry by time of flight (CyTOF) or both and correlated with response. | Until end of the study (up to 6 years) | 
| Levels of JNJ-68284528 T Cell Expansion (proliferation), and Persistence | Levels of JNJ-68284528 T cell expansion (proliferation), and persistence via monitoring CAR-T positive cell counts and CAR transgene level will be reported. | Until end of the study (up to 6 years) | 
| Number of Participants with Anti-JNJ-68284528 Antibodies | Number of participants exhibiting anti-drug antibodies for JNJ-68284528 will be reported. | Until end of the study (up to 6 years) | 
| Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC-QLQ-C30) Scale Score | The EORTC QLQ-C30 includes 30 items in 5 functional scales, 1 global health status scale, 3 symptom scales, and 6 single symptom items. The responses are reported using a verbal rating scale. The item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms. | Until end of the study (up to 6 years) | 
| Change from Baseline in Health-Related Quality of Life as Assessed by MySIm-Q Scale Sore | The MySIm-Q is a disease-specific PRO assessment complementary to the EORTC-QLQ-C30. It includes 17 items resulting in a symptom subscale and an impact subscale. The recall period is the past 7 days and responses are reported on a 5 point verbal rating scale. | Until end of the study (up to 6 years) | 
| Change from Baseline in Health-Related Quality of Life as Assessed by European Quality of Life - 5 Dimensions-5 Levels (EQ-5D-5L) Scale Score | The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating health today with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). | Until end of the study (up to 6 years) | 
| Change from Baseline in Health-Related Quality of Life as Assessed by Patient Global Impression of Symptom Severity (PGIS) Scale Score | The PGIS is a single item to assess the participant's perception in the severity of their overall health status using a 5-point verbal rating scale. Score ranges from 1 (None) to 5 (Very Severe). | Until end of the study (up to 6 years) | 
| Frequency in Health-Related Quality of Life as Assessed by The Patient-reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item | Frequency distributions of the PRO-CTCAE is an item library of common adverse events experienced by people with cancer that are appropriate for self-reporting. Each symptom selected for inclusion can be rated by up to 3 attributes characterizing the presence/frequency, severity, and/or interference of the adverse event. A 5-point verbal rating scale is used for participants to select their experience based on the last 7 days. | Until end of the study (up to 6 years) |