KRDI in Transplant-Eligible MM

Study Overview
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Brief Summary
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This research study is testing the efficacy of an experimental drug combination for people with newly diagnosed multiple myeloma that are eligible for a stem cell transplant. The names of the study drugs involved in this study are: Carfilzomib Isatuximab Lenalidomide Dexamethasone

Detailed Description
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This is a phase II study to evaluate the efficacy of once weekly carfilzomib, lenalidomide, dexamethasone, and isatuximab (KRDI) in patients with newly diagnosed, transplant-eligible multiple myeloma. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. The study treatment portion of this study is comprised of an induction phase and a maintenance phase. Induction Phase : All participants will receive the same study drugs (carfilzomib, isatuximab, lenalidomide, and dexamethasone) for up to 8 cycles. Each cycle is 28 days in length. All participants will perform stem cell collection after 4 cycles of therapy. Based on the recommendation participants may or may not proceed to an autologous stem cell transplant (SCT) as part of induction therapy. Maintenance Phase: During maintenance, participants will receive the study treatment for up to two years after induction until progressive disease or unacceptable toxicity It is expected that about 50 people will take part in this research study. This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease. Investigational means that the drug combination is being studied. The U.S. Food and Drug Administration (FDA) has approved carfilzomib or isatuximab as a treatment for relapsed/refractory multiple myeloma. The FDA has also approved lenalidomide and dexamethasone as a treatment option for transplant-eligible multiple myeloma. However, the FDA has not approved the combination of isatuximab, carfilzomib, lenalidomide, and dexamethasone as an approved regimen. The combination is considered to be investigational for the treatment of individuals with newly diagnosed multiple myeloma.

Official Title
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A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Isatuximab
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be at least 18 years of age. Subject must have documented multiple myeloma satisfying the CRAB criteria and measurable disease defined as: Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy-proven Plasmacytoma. Measurable disease as defined by any of the following: IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥.5 g/dL or urine M-protein level ≥200 mg/24 hours; or IgA, IgM, or IgD multiple myeloma: serum M-protein level ≥0.25 g/dL or urine M-protein level ≥200 mg/24 hours; or Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio. Sixty percent or greater clonal plasma cells on bone marrow examination. Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved free light chain is at least 100 mg/L (a patient's involved free light chain - either kappa or lambda - is the one that is above the normal reference range; the uninvolved light chain is the one that typically is in, or below, the normal range). More than one focal lesion on magnetic resonance image (MRI) that is at least 5 mm or greater in size. Newly diagnosed and considered candidate for high-dose chemotherapy with stem cell transplant. Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase: hemoglobin ≥ 7.5 g/dL (≥ mmol/L; prior RBC transfusion or recombinant human erythropoietin use is permitted); absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor [GCSF] use is permitted); platelet count ≥70 x 109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count >50 × 109/L (transfusions are not permitted to achieve this minimum platelet count) aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN); alanine aminotransferase (ALT) ≤2.5 x ULN; total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN) creatinine clearance ≥30 mL/min corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L); or free ionized calcium <6.5 mg/dL (<1.6 mmol/L). Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy. A man who is sexually active with a woman of childbearing potential must agree to use a latex or synthetic condom, even if they had a successful vasectomy. All men must also not donate sperm during the study, for 4 weeks after the last dose of lenalidomide, for 90 days after the last dose of carfilzomib, and for 4 months after the last dose of isatuximab. A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing. Each subject (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF. Exclusion Criteria: Any potential subject who meets any of the following criteria will be excluded from participating in the study. Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less. Smoldering multiple myeloma is defined as asymptomatic MM with absence of related organ or tissue impairment end organ damage. Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions Subject has prior or current systemic therapy or SCT for MM, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment. Subject has a history of malignancy (other than MM) within 5 years before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years). Subject has had radiation therapy within 14 days of enrollment. Subject has had plasmapheresis within 28 days of enrollment. Subject is exhibiting clinical signs of meningeal involvement of MM. Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Subjects with known or suspected COPD or asthma must have a FEV1 test during screening. Subject is known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C. Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study. Subject has clinically significant cardiac disease, including: myocardial infarction within 1 year before enrollment, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV; uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥2) or clinically significant ECG abnormalities; screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec. uncontrolled hypertension Subject has known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or IB) or known sensitivity to mammalian-derived products. Subject has plasma cell leukemia (according to World Health Organization [WHO] criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol specified assessments. Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study within 30 days after the last dose of lenalidomide or carfilzomib, or within 4 months after the last dose of isatuximab. Or, subject is a man who plans to father a child while enrolled in this study, within 4 weeks after the last dose of lenalidomide, within 90 days of the last dose of carfilzomib, or within 4 months after the last dose of isatuximab. Subject has had major surgery within 2 weeks before enrollment or has not fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery. Subject has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before enrollment or is currently enrolled in an interventional investigational study. Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism. Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs. Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobartital), or use of Ginkgo biloba, St. John's wort within 14 days before the first dose of study treatment.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction<br>All participants will receive 4 cycles of induction therapy. Based on the recommendation of investigators, participants may or may not proceed to an autologous stem cell transplant (SCT) after cycles 1-4. Each cycle is 28 days in length (see dosing details below.) For patient undergoing upfront stem cell transplant (SCT): 4 cycles followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 cycles (called consolidation). For patients deferring SCT following collection: 4 cycles followed by stem cell collection followed by 4 additional cycles. Carfilzomib: 56 mg/m2 IV on days 1, 8,15 Lenalidomide 25 mg orally (PO) on Days 1-21 Isatuximab: 10 mg/kg IV weekly for cycles 1-2 (days 1, 8, 15, 22), then every 2 weeks for cycles 3-6 (days 1 and 15), and monthly (day 1) thereafter Dexamethasone: 20 mg orally (PO) administered day of and day after carfilzomib and isatuximab (days 1, 2, 8, 9, 15, and 16; days 22 and 23 during cycles 1-2 only). | Drug: Carfilzomib<br>* Induction: protocol determine dose,via IV on 3 days per cycle up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: protocol determine dose,via IV on 2 days per cycle- Maintenance Cycle until progressive disease (PD) or unacceptable toxicity<br>* Other names: Kyprolis;Drug: Isatuximab<br>* Induction: At predetermined dose, via IV up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination: -- Cycles 1 and 2 once per week, Cycles 3-4 every other week, Cycles 5 and 6 every other week, Cycles 7 and 8 once every 4 weeks. Maintenance: At predetermined dose, via IV, once per cycle, Maintenance Cycle until progressive disease (PD) or unacceptable toxicity<br>* Other names: Sarclisa;Drug: Lenalidomide<br>* - Induction Predetermined Dose, oral, days 1-21 of up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: At predetermined dose, oral days 1-21 per cycle until progressive disease (PD) or unacceptable toxicity<br>* Other names: REVLIMID;Drug: Dexamethasone<br>* Induction: Predetermined dosage, oral, Predetermined times per cycle up to 8 cycles dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: orally or IV will be administered as a preinfusion medication prior to isatuximab dosing<br>* Other names: Decadron;|
| Experimental: Maintenance-High Risk<br>Only patients that have achieved a partial response (PR) or better after induction therapy with or without stem cell transplant will continue on to maintenance therapy. The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk. High Risk: subjects with high risk cytogenetics (deletion (del 17, translocation (t)(4:14), t(14;16), t(14;20), 1q duplications) will receive the following study treatment for up to two years (24 28-day cycles) until progressive disease (PD) or unacceptable toxicity: Lenalidomide 10 mg orally (PO) Day 1-21 Carfilzomib 56 mg/m2 or last tolerated dose IV Days 1, 15 Isatuximab 10 mg/kg IV Day 1 | Drug: Carfilzomib<br>* Induction: protocol determine dose,via IV on 3 days per cycle up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: protocol determine dose,via IV on 2 days per cycle- Maintenance Cycle until progressive disease (PD) or unacceptable toxicity<br>* Other names: Kyprolis;Drug: Isatuximab<br>* Induction: At predetermined dose, via IV up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination: -- Cycles 1 and 2 once per week, Cycles 3-4 every other week, Cycles 5 and 6 every other week, Cycles 7 and 8 once every 4 weeks. Maintenance: At predetermined dose, via IV, once per cycle, Maintenance Cycle until progressive disease (PD) or unacceptable toxicity<br>* Other names: Sarclisa;Drug: Lenalidomide<br>* - Induction Predetermined Dose, oral, days 1-21 of up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: At predetermined dose, oral days 1-21 per cycle until progressive disease (PD) or unacceptable toxicity<br>* Other names: REVLIMID;Drug: Dexamethasone<br>* Induction: Predetermined dosage, oral, Predetermined times per cycle up to 8 cycles dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: orally or IV will be administered as a preinfusion medication prior to isatuximab dosing<br>* Other names: Decadron;|
| Experimental: Maintenance- Standard Risk<br>Only patients that have achieved a partial response (PR) or better after induction therapy with or without stem cell transplant will continue on to maintenance therapy. The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk. Standard Risk: subjects without high risk cytogenetics (deletion (del 17, translocation (t)(4:14), t(14;16), t(14;20), 1q duplications) will receive the following study treatment for up to two years (24 28-day cycles) until progressive disease (PD) or unacceptable toxicity: - Lenalidomide 10 mg orally (PO) Day 1-21 | Drug: Lenalidomide<br>* - Induction Predetermined Dose, oral, days 1-21 of up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: At predetermined dose, oral days 1-21 per cycle until progressive disease (PD) or unacceptable toxicity<br>* Other names: REVLIMID;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR + Stringent CR) Rate | Percentage of patients who achieved a complete response (CR) or stringent CR (sCR) per International Myeloma Working Group (IMWG) Uniform Response criteria after 4 cycles of of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI). IMWG criteria define a CR as Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow and an sCR as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. | 112 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate After 4 Cycles Induction Therapy | Overall response rate will be the percentage of patients who achieve at least partial response (PR) per International Myeloma Working Group (IMWG) Uniform Response criteria after 4 cycles of of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI). The IMWG response criteria define a PR as: > 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or to < 200 mg/24 h, OR If the serum and urine M-protein are unmeasurable, a > 50% decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria, OR If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, > 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was > 30%. In addition to the above listed criteria, if present at baseline, a > 50% reduction in the size of soft tissue plasmacytomas is also required for a partial response. | 112 days (4 cycles) | 
| Minimal Residual Disease (MRD) Rate After 4 Cycles Induction Therapy | MRD is the small number myeloma cells surviving in the bone marrow after a clinical response has been measured and the patient is in remission. MRD negativity will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA). The MRD rate after 4 cycles of of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI) is the percentage of patients who are MRD negative at 10^(-5) and 10^(-6), meaning that no MRD was detected in samples of 100,000 cells and 1,000,000 cells, respectively. | 112 Days (4 Cycles) | 
| Minimal Residual Disease (MRD) Rate at 10^(-5) in Patients Receiving Upfront Stem Cell Transplant | MRD is the small number myeloma cells surviving in the bone marrow after a clinical response has been measured and the patient is in remission. MRD negativity will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA). The MRD rate is the percentage of patients who are MRD negative at 10^(-5), meaning that no MRD was detected in a sample of 100,000 cells. MRD status was assessed after 4 cycles of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI) induction, stem cell transplant, and 2 cycles of KRDI consolidation therapy (6 cycles total.) | 168 Days (6 cycles, upfront transplant) | 
| Minimal Residual Disease (MRD) Rate at 10^(-5) in Patients Deferring Stem Cell Transplant | MRD is the small number myeloma cells surviving in the bone marrow after a clinical response has been measured and the patient is in remission. MRD negativity will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA). The MRD rate is the percentage of patients who are MRD negative at 10^(-5), meaning that no MRD was detected in a sample of 100,000 cells. MRD status was assessed after 4 cycles of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI) induction, stem cell collection, and 4 additional cycles of KRDI (8 cycles total). | 224 Days (8 cycles transplant-deferred) | 
| Progression Free Survival at 12 Months | Progression free survival (PFS) is defined as the time between the start of treatment and disease progression or death due to any cause. PFS at 12 months is the percentage of patients who were alive and without disease progression 12 months after initiating treatment with of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI). | 12 months | 
| Overall Survival at 12 Months | Overall survival (OS) is defined as the time between the start of treatment and death due to any cause. OS at 12 months is the percentage of patients who were alive 12 months after initiating treatment with of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI). | 12 months | 
| Complete Response Rate in Patients With Upfront Stem Cell Transplant | Percentage of patients who achieved a complete response (CR) or stringent CR (sCR) per International Myeloma Working Group (IMWG) Uniform Response criteria after 4 cycles of of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI), stem cell transplant, and 2 cycles of KRDI consolidation (6 cycles total). IMWG criteria define a CR as Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow and an sCR as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. | 168 Days | 
| Complete Response Rate in Patients Deferring Stem Cell Transplant | Percentage of patients who achieved a complete response (CR) or stringent CR (sCR) per International Myeloma Working Group (IMWG) Uniform Response criteria after 4 cycles of of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (KRDI), stem cell collection, and 4 additional cycles of KRDI after deferring stem cell transplant (8 cycles total). IMWG criteria define a CR as Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow and an sCR as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. | 224 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma