Minimal Residual Disease-Adapted Strategy in Multiple Myeloma: Evaluation of Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone in Transplant-Eligible Patients
- Trial ID
- 2024-513889-19-00
- Protocol
- MIDAS:IFM 2020-02
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of treatment strategies in patients with **Multiple Myeloma** based on their minimal residual disease (MRD) status post-induction. For patients who are MRD negative after induction, the study aims to increase the rate of MRD negativity by 15% before maintenance therapy, comparing high-dose therapy and autologous stem cell transplantation (ASCT) in Arm B to additional cycles of Isa-KRD in Arm A, targeting 85% MRD negativity in Arm B versus 70% in Arm A. For patients who are MRD positive after induction, the objective is to increase the rate of MRD negativity by 20% before maintenance, comparing tandem ASCT in Arm D to single ASCT in Arm C, with a goal of achieving 45% MRD negativity in Arm D versus 25% in Arm C. This is clinically relevant as achieving MRD negativity is associated with improved patient outcomes and survival rates.
Secondary objectives include:
- Assessing MRD status post-induction and post-consolidation, and response rates according to the International Myeloma Working Group (IMWG) 2016 criteria.
- Evaluating progression-free survival (PFS) and overall survival (OS).
- Monitoring safety on an ongoing basis.
- Determining sustained MRD negativity annually since the start of the maintenance phase.
- Evaluating patient-reported outcomes (PRO) for Arms C and D annually since the start of maintenance.
- Assessing near complete response (nCR) rates according to the National Cancer Institute (NCI) and German Multicenter Myeloma Group (GMMG) definitions.
Participants
The clinical trial involves participants diagnosed with **Multiple Myeloma**, specifically targeting both male and female subjects aged 18 to 65 years. The study population is characterized by individuals who are newly diagnosed and eligible for high-dose therapy and autologous stem cell transplantation. Participants are required to have a documented symptomatic condition satisfying the CRAB and/or SLIM criteria, with measurable disease. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group performance status of 2 or lower, indicating a relatively stable general health status. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial. Key inclusion criteria include specific laboratory values and reproductive health requirements for both men and women, ensuring the safety and integrity of the study outcomes.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a **minimal residual disease** (MRD) adapted strategy in patients with **multiple myeloma** who are eligible for autologous stem cell transplantation. This is a randomized, open-label, active control, parallel group, multicenter, Phase 3 study. The trial aims to increase the rate of MRD negativity before maintenance therapy, comparing different treatment arms based on MRD status after induction therapy. The trial is expected to conclude by September 2028, with recruitment having started in December 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented symptomatic multiple myeloma, and specific laboratory values. The trial includes multiple follow-up visits to monitor treatment response and safety, with the primary endpoint being the MRD negative rate before maintenance therapy. Secondary endpoints include sustained MRD rate at years 2, 3, and 4 post-inclusion, overall survival, and progression-free survival.
The expected duration of participant involvement varies depending on the treatment arm, with a maximum treatment period of up to 48 months. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or failure to meet protocol requirements. The trial employs a chi-square test for primary endpoint analysis and uses logistic regression and Cox regression models for secondary endpoints, ensuring robust statistical evaluation of treatment effects.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. **SARCLISA** (isatuximab) is provided as a 20 mg/mL concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 10 mg/kg and a total dose not exceeding 620 mg/kg over a treatment period of up to 48 weeks. Isatuximab is a humanized monoclonal antibody targeting CD38, produced by SANOFI WINTHROP INDUSTRIE.
Another formulation of **Isatuximab** is used as a solution for injection, administered subcutaneously. The maximum daily dose is 1400 mg, with a total dose limit of 50400 mg over a 36-week period. This formulation utilizes an On Body Delivery System (OBDS) for subcutaneous administration, which includes a user-filled syringe and an elastomeric balloon reservoir.
**Kyprolis** (carfilzomib) is provided as a 60 mg powder for solution for infusion, administered intravenously. The maximum daily dose is 56 mg/m², with a total dose not exceeding 2016 mg/m² over a 12-week period. Carfilzomib is a chemical compound produced by AMGEN EUROPE B.V.
**DECTANCYL** (dexamethasone acetate) is administered orally in tablet form, with a maximum daily dose of 40 mg and a total dose of 1920 mg over a 12-week period. This chemical compound is produced by SANOFI WINTHROP INDUSTRIE.
**Iberdomide** is administered orally in capsule form, with two dosing regimens: 0.75 mg daily with a total dose of 567 mg over 36 weeks, and 1 mg daily with a total dose of 756 mg over the same period. Iberdomide, a chemical compound, is produced by CELGENE CORPORATION.
**Revlimid** (lenalidomide) is available in hard capsule form with three dosing options: 5 mg, 10 mg, and 25 mg. The maximum daily doses are 5 mg, 10 mg, and 25 mg, with total doses of 4935 mg, 10080 mg, and 6300 mg, respectively, over treatment periods ranging from 12 to 48 weeks. Lenalidomide is a chemical compound produced by BRISTOL-MYERS SQUIBB PHARMA EEIG.
**Neofordex** (dexamethasone) is administered orally in tablet form, with a maximum daily dose of 40 mg and a total dose of 1920 mg over a 12-week period. This chemical compound is produced by THERAVIA.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these treatments in achieving minimal residual disease negativity in patients eligible for autologous stem cell transplantation.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of the **Minimal Residual Disease (MRD)** negativity rate, utilizing next-generation sequencing (NGS) at a sensitivity of 10-6. The primary endpoint involves comparing the MRD negative rate before maintenance therapy between different treatment arms. This comparison will be conducted using the chi-square test within the intention-to-treat (ITT) population. The observed MRD negative rate will be reported alongside a 2-sided 95% confidence interval (CI). The treatment effect will be quantified by an Odds Ratio, with its 2-sided 95% confidence interval, derived from a logistic regression model adjusted for stratification variables.
Secondary endpoints include the sustained MRD rate at years 2, 3, and 4 post-inclusion, which will be analyzed similarly to the primary endpoint. Overall Survival (OS) will be estimated using the Kaplan-Meier method, with comparisons between arms made via the log-rank test. The treatment effect on OS will be described by a Hazard Ratio, with 2-sided 95% confidence intervals estimated using a Cox regression model. This model will be adjusted for stratification variables, including high-risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects, and center as a random effect for specific arm comparisons. Progression-Free Survival (PFS), defined as the time from randomization to either progression or death, will be analyzed in a similar manner.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female subjects, 18 years of age or older, younger than 66 years (< 66 years).
- Voluntary written informed consent must be given before performance of any study-related procedure not part of normal medical care, with the understanding that the subject may withdraw consent at any time without prejudice to future medical care.
- Subject must have documented symptomatic multiple myeloma satisfying the CRAB and/or SLIM criteria and measurable disease as defined by: • Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma AND any one or more of the following myeloma defining events: - Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than 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 LLN or hemoglobin < 10 g/dL - Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT - Clonal bone marrow plasma cell percentage ≥ 60% - Involved: uninvolved serum free light chain ratio ≥ 100 - More than 1 focal lesion on MRI studies • Measurable disease as defined by the following: Serum M-component ≥ 5g/L and/or urine M-component ≥ 200 mg/24h and/or serum FLC ≥ 100 mg/L between screening and C1D1.
- Newly diagnosed subjects eligible for high dose therapy and autologous stem cell transplantation
- Eastern Cooperative Oncology group performance status (ECOG score) ≤ 2 (Karnofsky performance status score ≥ 50%)
- Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase (Lab tests should be repeated if done more than 15 days before C1D1): a- Hemoglobin ≥ 7.5 g/dL (≥ 5mmol/L). Prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted; b- Absolute neutrophil count (ANC) ≥ 1.0 Giga/L (G-CSF use is permitted); c- ASAT ≤ 3 x ULN; d- ALAT ≤ 3 x ULN; e- Total bilirubin ≤ 3 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤ 1.5 x ULN); f- eGFR≥ 40 mL/min/1.73 m²; g- Albumin corrected serum calcium ≤ 14 mg/dL (< 3.5 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤ 1.6 mmol/L); h- Platelet count ≥ 50 Giga/L for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count > 30 Giga/L (platelets transfusions performed less than 15 days before C1D1 are not permitted).
- Women of childbearing potential must have a negative serum or urine pregnancy test 10 to 14 days prior to therapy and repeated within 24 hours before starting study drug. They must commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control (one highly effective method and one additional effective method) used at the same time, beginning at least 4 weeks before initiation of Lenalidomide treatment and continuing for at least 90 days after the last dose of Lenalidomide, Iberdomide and 5 months after last dose of Isatuximab. Women must also agree to notify pregnancy during the study.
- Men must agree to not father a child and agree to use a latex condom during therapy and during dose interruptions and for at least 90 days after the last dose of study drug including Lenalidomide and Iberdomide and 5 months after last dose of Isatuximab, even if they have had a successful vasectomy, if their partner is of childbearing potential. Patient must also refrain from donating sperm during this period.
Exclusion Criteria
- Subjects must not have been treated previously with any systemic therapy for multiple myeloma. Prior treatment with corticosteroids or radiation therapy does not disqualify the subject (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of Dexamethasone over a period of 14 calendar days ).Enrolment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy.
- Subject with a current diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.
- Subject has a diagnosis of Waldenström’s macroglobulinemia, or other conditions in which IgM Mprotein is present in the absence of a clonal plasma cell infiltration with ly
- Subject has had plasmapheresis within 14 days of C1D1
- Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
- Myocardial infarction within 4 months prior to enrolment according to NYHA Class III or IV heart failure, uncontrolled angina, PAH, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
- Uncontrolled hypertension
- Subjects with a history of moderate or severe persistent asthma within the past 2 years, or with uncontrolled asthma of any classification at the time of Screening (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study, please refer to Appendix 4).
- Intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
- Subject has plasma cell leukemia (according to 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).
- Any clinically significant, uncontrolled medical conditions that, in the Investigator’s opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results.
- 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, phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before the first dose of study treatment.
- Known intolerance to steroid therapy, mannitol, pregelatinized starch, odium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study intervention that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
- History of allergy to any of the study medications, their analogues, or excipients in the various formulations
- Subject has had major surgery within 2 weeks before study Inclusion (informed consent signature) or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or vertebroplasty are not considered major surgery.
- Clinically relevant active infection or serious co-morbid medical conditions.
- Subject has had any prior or concurrent invasive malignancy (other than multiple myeloma, and adequately treated basal cell or squamous cell carcinoma of the skin) within 5 years of study start, except breast ductal carcinoma in situ, carcinoma in situ of the cervix, localized prostate adenocarcinoma diagnosed for more than 3 years and without evidence of disease.
- Female subject who is pregnant or breast-feeding.
- Serious medical or psychiatric illness likely to interfere with participation in study
- Uncontrolled diabetes mellitus.
- Known HIV infection; Known active hepatitis A, B or C viral infection
- Uncontrolled or active HBV infection: patients with positive HbsAg and/or HBV DNA. Of note: • Patient can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) but HbsAg and HBV DNA are negative. o If anti-HBV therapy in relation with prior infection was started before initiation of IMP, the anti-HBV therapy and monitoring should continue throughout the study treatment period. • Patients with negative HbsAg and positive HBV DNA observed during Screening period will be evaluated by a specialist for start of anti-viral treatment: study treatment could be proposed if HBV DNA becomes negative and all the other study criteria are still met.
- Active HCV infection: positive HCV RNA and negative anti-HCV. Of note: Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion. Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible.
- Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics.
- Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
- Subjects unable or unwilling to undergo antithrombotic prophylactic treatment.
- Person under guardianship, trusteeship or deprived of freedom by a judicial or administrative decision.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Yet Recruiting | 08 Dec 2021 | 39 |
 France | Not Yet Recruiting | 08 Dec 2021 | 752 |
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 |
|---|---|---|---|---|---|---|
Kyprolis 60 mg powder for solution for infusion | Test | POWDER FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 56 | 12 | PRD3418796 |
Revlimid 5 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 5 | 47 | PRD9264284 |
Iberdomide | Test | CAPSULE | ORAL USE | 0.75 | 36 | PRD10086310 |
Revlimid 25 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 12 | PRD9264271 |
SARCLISA 20mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 10 | 48 | PRD8132765 |
Neofordex 40 mg tablets | Other | TABLETS | ORAL | 40 | 12 | PRD3861554 |
DECTANCYL 0,5 mg, comprimé | Other | COMPRIMÉ | ORAL | 40 | 12 | PRD425675 |
Revlimid 10 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 10 | 48 | PRD9264283 |
Isatuximab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 1400 | 36 | PRD10653408 |
Iberdomide | Test | CAPSULE | ORAL USE | 1 | 36 | PRD10086311 |