Phase III Evaluation of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone Versus Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma
- Trial ID
- 2024-513422-38-00
- Protocol
- EMN24
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III study is to compare the rate of **Minimal Residual Disease (MRD)** negativity by next-generation sequencing (NGS) between the treatment regimens of Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) and Carfilzomib-Lenalidomide-Dexamethasone (KRd) in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplantation. Achieving MRD negativity is clinically significant as it is associated with improved patient outcomes and can serve as a surrogate marker for long-term remission and survival in multiple myeloma.
The secondary objectives include:
- Assessing the rate of MRD negativity after induction by NGS.
- Comparing progression-free survival (PFS) between the two treatment arms.
- Evaluating the rate of 1-year sustained MRD negativity by NGS from post-autologous stem cell transplantation (ASCT) consolidation to post-light consolidation.
- Determining the overall response rate, very good partial response (VGPR), complete response (CR), and stringent complete response (sCR) rate after induction, ASCT, post-ASCT consolidation, and light consolidation in the two treatment arms.
- Determining the duration of response, duration of MRD negativity, and the rate of sustained 1-year MRD negativity.
- Evaluating the time to progression, overall survival, and time to next therapy in the two treatment arms.
- Assessing whether tumor response and outcome may change in subgroups with different prognoses according to current prognostic factors.
- Evaluating the safety of the two treatment arms.
- Determining the success of stem cell harvest and engraftment after ASCT.
- Assessing the quality of life of patients.
Participants
The clinical trial involves participants diagnosed with **newly diagnosed multiple myeloma**. The study population includes both male and female subjects, aged between 18 and 70 years, who are eligible for autologous stem cell transplantation. Participants are required to have a life expectancy of at least 3 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. The trial population was selected based on their diagnosis and eligibility for autologous stem cell transplantation, with a focus on those for whom standard treatment is not deemed the best available option by the investigator. Participants must have measurable disease and meet specific clinical laboratory criteria, including adequate hepatic function and creatinine clearance. The trial also considers lifestyle factors such as compliance with a pregnancy prevention plan for females of childbearing potential and contraception requirements for male subjects. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy in patients with **newly diagnosed multiple myeloma** who are eligible for autologous stem cell transplantation. This is a Phase III, randomized, double-blind, controlled trial comparing the combination of Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) versus Carfilzomib-Lenalidomide-Dexamethasone (KRd). The trial aims to assess the rate of Minimal Residual Disease (MRD) negativity post-autologous stem cell transplantation (ASCT) consolidation treatment. The trial is expected to run until April 2030, with recruitment having started in July 2020.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, disease status, and laboratory values. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of MRD status, progression-free survival, and overall survival, among other endpoints. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement is up to 24 months, depending on individual response and treatment tolerance. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Participants will be monitored closely throughout the trial to ensure adherence to the protocol and to manage any adverse events that may arise.
Treatment
The clinical trial involves the administration of several experimental medications, including **Revlimid** in various dosages. **Revlimid** is provided in hard capsule form and contains the active substance **lenalidomide**. The dosages used in the trial are 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg. These capsules are administered orally, with a maximum daily dose ranging from 5 mg to 25 mg, depending on the specific capsule strength. The total maximum dose for each strength varies, with the highest being 4200 mg for the 25 mg capsules. The treatment period for **Revlimid** is up to 24 months, and the capsules are specifically labeled for clinical trial use.
**Isatuximab** is another experimental medication used in the trial. It is a concentrate for solution for infusion, administered intravenously. The active substance is **isatuximab**, a protein-based compound. The maximum daily dose is 10 mg/kg, with a total maximum dose of 300 mg/kg over the treatment period. The infusion is labeled for clinical trial use, and the treatment duration is up to 24 months.
**Kyprolis**, containing the active substance **carfilzomib**, is provided as a powder for solution for infusion. It is administered intravenously with a maximum daily dose of 56 mg/m² and a total maximum dose of 2652 mg/m². The treatment period is up to 24 months, and the drug is labeled and provided with secondary packaging for clinical trial use.
**Dexsol** is an oral solution containing **dexamethasone**. It is administered orally with a maximum daily dose of 40 mg and a total maximum dose of 1760 mg over the treatment period. The solution is labeled for clinical trial use, and the treatment duration is up to 24 months.
**Soldesam** is another oral solution used in the trial, containing **dexamethasone sodium phosphate**. It is administered orally with a maximum daily dose of 40 mg and a total maximum dose of 1760 mg. The treatment period is up to 24 months, and the solution is not specifically labeled for clinical trial use.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these medications in the treatment of newly diagnosed multiple myeloma in patients eligible for autologous stem cell transplantation.
Efficacy
The efficacy of the clinical trial will be assessed primarily by evaluating the rate of **Minimal Residual Disease (MRD)** negativity. This will be determined as the proportion of patients achieving MRD negativity at a sensitivity level of 10^-5 after autologous stem cell transplantation (ASCT) consolidation treatment. The assessment will follow the intention-to-treat (ITT) principle, and patients who withdraw or are lost to follow-up before completing four post-ASCT consolidation cycles will have their best MRD assessment considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.
Secondary efficacy endpoints include the rate of MRD negativity after induction and light consolidation phases, progression-free survival (PFS), and overall survival (OS). PFS will be measured from the date of randomization to the first observation of disease progression or death from any cause. OS is defined as the time between randomization and death, regardless of the cause. Additional secondary endpoints include the rate of 1-year sustained MRD negativity, response rate according to the International Myeloma Working Group (IMWG) criteria, time to progression (TTP), duration of response (DOR), and time to next treatment (TNT). Quality of life will be assessed using the EORTC QLQ-C30, EORTC QLQ-MY20, and EQ5D5L instruments.
The trial will employ next-generation sequencing (NGS) for MRD assessment, and the schedule for measuring these parameters will be aligned with the different phases of treatment, including induction, ASCT, post-ASCT consolidation, and light consolidation. The trial aims to provide a comprehensive evaluation of the efficacy of the drug combinations in newly diagnosed multiple myeloma patients eligible for ASCT.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 1.Patient with newly diagnosed multiple myeloma and eligible to ASCT, for whom the standard treatment it is not, according to investigator, the best treatment available.
- 2.Patient is, in the investigators opinion, willing and able to comply with the study visits and procedures required per protocol.
- 3.Patient has provided written informed consent in accordance with federal, local, and institutional guidelines prior to initiation of any study specific activities or procedures. Subject does not have kind of conditionthat, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent and patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements.
- 4.Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria: CRAB criteria: - Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL) - Renal insufficiency: creatinine clearance <40mL/min or serum creatinine >177 μmol/L (>2 mg/dL) - Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL - Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT Biomarkers of Malignancy: - Clonal bone marrow plasma cell percentage ≥60% - Involved: uninvolved serum FLC ratio ≥100 - >1 focal lesion on magnetic resonance imaging (MRI) studies
- 5.Patient is 18 - 70 years old and is eligible for autologous stem cell transplantation
- 6.Patient has measurable disease as defined by any one of the following: - Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine Mprotein level ≥200 mg/24 hours; or - Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
- 7.Life expectancy ≥ 3 months
- 8.ECOG status ≤2
- 9.Clinical laboratory values meeting the following criteria during the Screening Phase: -Adequate hepatic function, with serum (alanine aminotransferase) ALT≤ 2.5 times the upper limit of normal (ULN), AST (aspartate transaminase) ≤ 2.5 x the ULN -Serum direct bilirubin ≤ 1.5 ULN) (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubinemia ≤ 1.5 ULN) -Absolute neutrophil count (ANC) ≥1.0 10^9/L -Platelet count≥ 75 10^9/L (≥ 50 10^9/L if myeloma involvement in the bone marrow is > 50%) and no platelet infusion in the 1 week prior to screening platelet count -Creatinine clearance (CrCl) ≥ 30 mL/minute. Creatinine clearance should be calculated using eGFR (Modified Diet in Renal Disese [MDRD]) -Corrected serum calcium ≤ 13.5 mg/dL (3.4 mmol/L) -LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
- 10.Females of childbearing potential (FCBP)* complies with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding and must agree to ongoing pregnancy testing and to practice contraception or true abstinence. FCBP must use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for 5 months after the last dose of study drugs.
- 11.Male subjects must agree to practice contraception if sexually active with FCBP during the treatment and for at least 5 months after the last dose of study drugs. Males must agree to refrain from donating sperm for at least 90 days after the last dose of carfilzomib and for at least 5 months after the last dose of isatuximab.
Exclusion Criteria
- 1.Previous treatment with anti-myeloma therapy (does not include radiotherapy, biphosphonates, or a single short course of steroid ≤ to the equivalent of dexamethasone 40 mg/day for 4 days).
- 10.Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg despite optimal treatment (measured following European Society of Hypertension/European Society of Cardiology 2013 guidelines), in the last 5 years pulmonary embolia, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
- 11.Non-hematologic or hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
- 12.Significant neuropathy (Grades 3b4, or Grade 2 with pain) within 14 days prior to randomization as defined by National Cancer Institute Common Toxicity Criteria (NCI CTCAE) 5.0
- 13.Known history of allergy to CaptisolB. (a cyclodextrin derivative used to solubilize carfilzomib) and to PS80; prior hypersensitivity to sucrose, histidine (as base and hydrochloride salt), or known intolerance or hypersensitivity to infused protein products or any of the components (active substance or excipients) of study treatments that are not amenable to premedication with steroids, or H2 blockers, that would prohibit further treatment with these agents.
- 14.Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
- 15.Any other clinically significant medical disease or condition that, in the Investigators opinion, may interfere with protocol adherence or a subjects ability to give informed consent
- 2.Patients with non-secretory MM unless serum free light chains are present and the ratio is abnormal or a plasmacytoma with minimum largest diameters of > 2 cm.
- 3.Patients with plasma cell leukemia, amyloidosis, Waldenstrom Disease, POEMS syndrome
- 4.Meningeal involvement of multiple myeloma
- 5.Patient ineligible for autologous transplantation
- 6.Pregnant or lactating females
- 7.Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization
- 8.Known human immunodeficiency virus infection (HIV)
- 9.Active hepatitis A, B or C infection. Hepatitis C infection (subjects with hepatitis C that achieve a sustained virologic response after antiviral therapy are allowed), or hepatitis B infection (subjects with hepatitis B surface antigen or core antibody that achieve sustained virologic response with antiviral therapy are allowed). Tests to be performed if required per local country regulations (in Czech Republic testing for HIV and hepatitis B and C is required at screening). In fact it is not possible to avoid the risk of virological reactivation with the study treatments. Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA Active HCV infection: positive HCV RNA and negative anti-HCV
- 16.Received any investigational drug within 14 days or 5 half-lives of the investigational drug, prior to initiation of study intervention, whichever is longer.
- 17.Pregnant or breastfeeding woman or woman who intends to become pregnant during the participation in the study. FCBP unwilling to prevent pregnancy by the use of 2 reliable methods of contraception for ≥4 weeks before the start of study treatment, during treatment (including dose interruptions), and for at least 28 days following discontinuation of study lenalidomide, or 30 days following discontinuation of carfilzomib or for 5 months after discontinuation of isatuximab treatment, whichever occurs last
- 18.Male participants who disagree to practice true abstinence or disagree to use a condom during sexual contact with a pregnant woman or a FCBP while participating in the study, during dose interruptions, and for at least 28 days following discontinuation of study lenalidomide, or 3 months following discontinuation of carfilzomib, or for 5 months after discontinuation of isatuximab treatment, whichever occurs last, even if he has undergone a successful vasectomy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Jul 2020 | 11 |
 Czechia | Not Recruiting | 01 Jul 2020 | 28 |
 Germany | Not Recruiting | 01 Jul 2020 | 12 |
 Greece | Not Recruiting | 01 Jul 2020 | 32 |
 Italy | Not Recruiting | 01 Jul 2020 | 58 |
 The Netherlands | Not Recruiting | 01 Jul 2020 | — |
 Norway | Not Recruiting | 01 Jul 2020 | 9 |
 Spain | Not Recruiting | 01 Jul 2020 | 63 |
| Netherlands | — | — | 89 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SOLDESAM 0,2% gocce orali, soluzione | Test | GOCCE ORALI, SOLUZIONE | ORAL USE | 40 | 24 | PRD362173 |
Revlimid 20 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 20 | 24 | PRD9264267 |
Revlimid 25 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 24 | PRD9264271 |
ISATUXIMAB | Test | — | INTRAVENOUS USE | 10 | 24 | SUB187359 |
Revlimid 15 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 15 | 24 | PRD9264282 |
ISATUXIMAB | Test | — | INTRAVENOUS USE | 10 | 24 | SUB187359 |
Dexsol 2mg/5ml Oral Solution | Test | ORAL SOLUTION | ORAL USE | 40 | 24 | PRD4134499 |
Revlimid 10 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 10 | 24 | PRD9264283 |
Kyprolis 60 mg powder for solution for infusion | Test | POWDER FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 56 | 24 | PRD3374183 |
Revlimid 5 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 5 | 24 | PRD9264284 |