A Study of Bortezomib, Lenalidomide and Dexamethasone (VRd) followed by Cilta-cel, a CAR-T Therapy Directed Against BCMA versus VRd followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants with Newly Diagnosed Multiple Myeloma for Whom ASCT is Not Planned as Initial Therapy

JRCT ID: jRCT2011210025

Registered date:30/07/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Multiple Myeloma
• Date of first enrollment: 29/10/2021
• Target sample size: 650
• Countries of recruitment: Australia,Japan,Austria,Japan,Belgium,Japan,Brazil,Japan,Canada,Japan,Germany,Japan,Denmark,Japan,Spain,Japan,Finland,Japan,United Kingdom Of Great Britain,Japan,Greece,Japan,Israel,Japan,Italy,Japan,Korea,Japan,Netherlands,Japan,Poland,Japan,Sweden,Japan,United States Of America,Japan
• Study type: Interventional

Intervention(s)

Arm A
Participants will receive bortezomib, lenalidomide, and dexamethasone (VRd) regimen for 6 cycles before randomization.
Following randomization, participants in Arm A will receive 2 more cycles of VRd.
After 8 cycles of VRd, treatment will continue with lenalidomide and dexamethasone (Rd) maintenance therapy.
Participants will continue to receive Rd until confirmed progressive disease or unacceptable toxicity.

<VRd regimen> Cycles 1-8 (21 days of each cycle)
Bortezomib 1.3 mg/m^2 (SC) day1, 4, 8, 11 days of each cycle
Lenalidomide 25 mg (oral) day1 to 14 days of each cycle
Dexamethasone 20 mg (oral) days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle
<Rd regimen> Cycle 9 and beyond (28 days of each cycle)
Lenalidomide 25 mg (oral) day1 to 21 days of each cycle
Dexamethasone 20 mg (oral) days 1, 8, 15, and 22 of each cycle

Arm B
Participants will receive VRd regimen for 6 cycles before randomization.
Following randomization, participants in Arm B will undergo apheresis and receive two more cycles of VRd as bridging therapy.
After 8 cycles of VRd, participants will receive a conditioning regimen (cyclophosphamide 300 mg/m^2 intravenous [IV] and fludarabine 30 mg/m^2 IV daily for 3 days) and Cilta-cel infusion 0.75X10^6 chimeric antigen receptor (CAR)-positive viable T cells/kilogram (kg).

<VRd regimen> Cycles 1-8 (21 days of each cycle)
Bortezomib 1.3 mg/m^2 (SC) day1, 4, 8, 11 days of each cycle
Lenalidomide 25 mg (oral) day1 to 14 days of each cycle
Dexamethasone 20 mg (oral) days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle

Outcome(s)

• Primary Outcome: Progression Free Survival (PFS):Up to 4 years and 5 months:Progression-free survival is defined as the time from the date of randomization to the date of first documented Progressive Disease (PD), as defined in the International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first.

Secondary Outcome

Sustained Minimal Residual Disease (MRD) Negative CR:Up to 12 years and 5 months:Sustained MRD negative complete response (CR) as determined by next generation sequencing (NGS) with sensitivity of 10^-5, and defined by MRD negative CR plus at least 12 months durability of the MRD negative CR status.
MRD Negative CR at 9 Months:9 months:MRD negative CR rate at 9 months is defined as the percentage of participants who achieve MRD negative CR status at 9+-3 months after the randomization date.
Overall MRD Negative CR:Up to 12 years and 5 months:Overall MRD negative is defined as the percentage of participants who achieve MRD negativity at any time after the date of randomization before initiation of subsequent therapy.
Overall Survival (OS):Up to 12 years and 5 months:Overall survival is measured from the date of randomization to the date of the participants death.
Complete Response or Better:Up to 12 years and 5 months:CR or better is defined as percentage of participants who achieve a CR response or Stringent Complete Response (sCR) response according to the IMWG criteria.
Time to Subsequent Anti-myeloma Therapy:Up to 12 years and 5 months:Time to subsequent anti-myeloma therapy is defined as the time from randomization to the start of subsequent anti-myeloma therapy.
Progression Free Survival on Next-line Therapy (PFS2):Up to 12 years and 5 months:PFS2 is defined as the time interval between the date of randomization and date of event, which is defined as PD as assessed by investigator that starts after the next line of subsequent therapy, or death from any cause, whichever occurs first.
Number of Participants with Adverse Events (AEs), Abnormalities in Laboratory Parameters, 12-Lead Electrocardiogram (ECG), Physical Examination, and Vital Signs:Up to 12 years and 5 months:Number of participants with AEs, abnormalities in laboratory parameters (complete blood count [CBC] with differential, coagulation, chimeric antigen receptor T cell [CAR-T] chemistry, full metabolic panel etc.), 12-lead ECG, physical examination, and vital signs will be reported.
Arm B: Systemic Cytokine Concentrations:Up to Day 112:Serum or plasma proteomic profiling of cytokines (such as interleukin [IL] 6, IL-15, and IL 10) concentrations will be measured for biomarker assessment.
Arm B: Levels of Chimeric Antigen Receptor T cell (CAR-T) Cell Activation Markers:Up to 12 years and 5 months: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), single cell RNA sequencing (scRNAseq) or similar technologies and be correlated with response.
Arm B: Levels of Soluble B-cell Maturation Antigen (BCMA):Up to 1 year:Levels of soluble BCMA will be reported.
Arm B: Levels of Cilta-cel Expansion (proliferation), and Persistence:Up to 12 years and 5 months:Levels of cilta-cel expansion (proliferation),and persistence via monitoring CAR-T positive cell counts and CAR transgene level will be reported.
Arm B: Number of Participants with Anticilta-cel Antibodies:Up to 12 years and 5 months:Number of participants with anti-cilta-cel
antibodies will be reported.
Arm B: Number of Participants with Presence of Replication Competent Lentivirus:Up to 12 years and 5 months:Number of participants with presence of replication competent lentivirus will be reported.
Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC-QLQ-C30)Scale Score:Baseline up to 12 years and 5 months:The EORTC QLQ-C30 includes 30 items in 5 functional scales (physical, role,emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, nausea/vomiting), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). 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.
Change from Baseline in Health-Related Quality of Life as Assessed by MySIm-Q Scale Score:Baseline up to 12 years and 5 months:The MySIm-Q is a disease-specific PRO assessment complementary to the EORTCQLQ-C30. It includes 17 items with recall period of "7 days" and responses are reported on a 5-point verbal rating scale. Item responses are scored from 0 to 4.Higher scores indicate greater severity/impact.
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:Baseline up to 12 years and 5 months: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. Each of the 5 dimensions is divided into 5 levels of perceived problems, where Level 1: no problem, Level 2: slight problems,Level 3: moderate problems, Level 4: severe problems and Level 5: extreme problems, plus a visual analog scale rating "health today"with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).
Change from Baseline in Health-Related Quality of Life as Assessed by Patient Global Impression of Symptom Severity (PGIS) Scale Score:Baseline up to 12 years and 5 months:The PGIS uses 2 items to assess the participants perception of the severity of their disease symptoms and impact using a 5-point verbal rating scale. Score ranges from 1 (None) to 5 (Very Severe).
Patient-reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Items:Up to 161 days:The National Cancer Institute's PROCTCAE is an item library of common adverse events experienced by people with cancer that are appropriate for selfreporting. Each symptom selected for inclusion can be rated by up to 3 attributes characterizing the presence/frequency, severity, and/or interference that ranges from 0 to 4 with higher scores indicating higher frequency or greater severity/impact.
Time to Worsening of Symptoms,Functioning and Overall Well-being:Up to 12 year and 5 months:Time to worsening is measured as the interval from the date of randomization to the start date of worsening in MySIm-Q symptom, impact, or total scores.

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

- Documented diagnosis of multiple myeloma (MM) according to International Myeloma Working Group (IMWG) diagnostic criteria
- Measurable disease at screening as defined by any of the following: Serum monoclonal paraprotein (M-protein) level greater than or equal to (>=)1.0 gram per deciliter (g/dL) or urine M-protein level >=200 milligram (mg)/24 hours; or Light chain MM in whom only measurable disease is by serum free light chain (FLC) levels: Serum immunoglobin (Ig) free light chain >=10 milligrams per deciliter (mg/dL) and abnormal serum Ig kappa/lambda FLC ratio
- Eastern Cooperative Oncology Group Performance Status grade of 0 or 1
-Not considered for high-dose chemotherapy with Autologous Stem Cell Transplant (ASCT) due to: Ineligible due to advanced age; or Ineligible due to presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT; or Deferral of high-dose chemotherapy with ASCT as initial treatment
-A woman of childbearing potential (WOCBP) must have 2 negative highly sensitive serum or urine pregnancy tests (beta-human chorionic gonadotropin) prior to starting Bortezomib, Lenalidomide and Dexamethasone (VRd) and must agree to further testing during the study.
-Clinical laboratory values meeting the following criteria during the screening phase: hemoglobin greater than or equal to (>=) 8.0 g/dL (>=5 millimoles per liter [mmol/L]), recombinant human erythropoietin use is permitted; platelets >=75 *10^9/L; absolute lymphocyte count >=0.3 *10^9/L; absolute neutrophil count (ANC) >=1.0 x10^9/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to (<=) 3.0 * upper limit of normal (ULN); estimated glomerular filtration rate >=40 milliliter per minute/1.73 meter square (mL/min/1.73 m^2) based upon modified diet in renal disease formula (MDRD-4) calculation or a 24-hour urine collection; total bilirubin <=2.0 * ULN; except in participants with congenital hyperbilirubinemia, such as Gilbert syndrome (in which case direct bilirubin <=2.0 * ULN is required)

Exclude criteria

-Frailty index of >=2 according to Myeloma Geriatric Assessment score
-Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5
-Known active, or prior history of central nervous system (CNS) involvement or clinical signs of meningeal involvement of MM
-Stroke or seizure within 6 months of signing Informed Consent Form (ICF)
-Seropositive for human immunodeficiency virus (HIV)
-Vaccinated with live, attenuated vaccine within 4 weeks prior to first dose of VRd
-Participant must not require continuous supplemental oxygen
-Hepatitis B infection
-Hepatitis C infection
-Prior treatment with chimeric antigen receptor T (CAR-T) therapy directed at any target
-Any therapy that is targeted to B-cell maturation antigen (BCMA)

Related Information

• Primary Sponsor: Fujikawa Ei
• Secondary ID(s): NCT04923893