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MInimal Residual Disease Adapted Strategy (MIDAS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04934475
Recruitment Status : Recruiting
First Posted : June 22, 2021
Last Update Posted : February 28, 2023
Sponsor:
Collaborators:
Amgen
Sanofi
Bristol-Myers Squibb
Information provided by (Responsible Party):
Intergroupe Francophone du Myelome

Brief Summary:
IFM 2020-02 will enroll patients eligible for ASCT less than 66 years. All patients will receive induction based on 6 cycles (28-day) of KRD-Isatuximab (Isa-KRD), in order to achieve deep responses and high MRD negativity rates. Patients will be classified at diagnosis according to cytogenetics (standard vs high-risk cytogenetics defined by the LP score including 17p deletion, t(4;14), del(1p32), gain 1q, trisomy 21 and trisomy 5).

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Isatuximab Procedure: ASCT Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 716 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:

All patients will receive ISa-KRD treatment for induction. Depending on MRD status, patients will be randomized :

MRD Standard-risk post induction MRD <10-5,(1:1 Randomization):

Arm A: 6 additional cycles of Isa-KRD Arm B: ASCT followed by 2 cycles of Isa-KRD MRD High-risk (post induction MRD >10-5) (1:1 Randomization) Arm C: ASCT followed by 2 cycles of Isa-KRD Arm D: tandem ASCT

Maintenance:

In arms A/B, patients will receive commercial Lenalidomide, for 3 years. In arms C/D, patients will receive Iberdomide and Isatuximab for 3 years. Treatment allocation A/B to patients: randomization stratified per center according to LP score.

Treatment allocation C/D to patients: randomization stratified per center according to LP score.

For each randomization, primary analysis will evaluate MRD (NGS, 10-6 threshold) after all subjects have completed the post-consolidation response evaluation or have been discontinued from study treatment by this timepoint

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MInimal Residual Disease Adapted Strategy: Frontline Therapy for Patients Eligible for Autologous Stem Cell Transplantation Less Than 66 Years; a Prospective Study
Actual Study Start Date : December 8, 2021
Estimated Primary Completion Date : December 1, 2024
Estimated Study Completion Date : September 1, 2028

Resource links provided by the National Library of Medicine

Drug Information available for: Isatuximab

Arm Intervention/treatment
Experimental: MRD Standard-risk patients (post induction MRD <10-5, MRD SR) (1:1 Randomization) : Arm A

Arm A: consolidation with 6 additional cycles of Isa-KRD (cycles 7 to 12) 6 cycles of Isatuximab Carfilzomib Lenalidomide Dexamethasone (Isa-KRD) (28-day cycle):

  • Isatuximab: 10 mg/kg I.V. on days 1 and 15 (cycles 7 to 12)
  • Carfilzomib: 56 mg/m2 I.V on days 1, 8 and 15 (cycles 7 to 12)
  • Lenalidomide: 25 mg per day orally from days 1 to 21
  • Dexamethasone: 40 mg orally on day 1, 8, 15, 22
Drug: Isatuximab
treatment with Isa-KRD during induction and consolidation , with revlimid or Iberdomide +isatuximab during maintenance phase
Other Names:
  • Carfilzomib
  • Revlimid
  • Dexamesone

Experimental: MRD Standard-risk patients (post induction MRD <10-5, MRD SR) (1:1 Randomization): Arm B

Arm B: consolidation with ASCT followed by 2 cycles of Isa-KRD (cycles 7 and 8) Melphalan 200 mg/m2 followed by autologous stem cell transplantation (please refer to section 6.3.2) 2 cycles of Isatuximab Carfilzomib Lenalidomide Dexamethasone (Isa-KRD) (28-day cycle):

  • Isatuximab: 10 mg/kg I.V. on days 1 and 15 (cycles 7 to 8)
  • Carfilzomib: 56 mg/m2 I.V on days on days 1, 8 and 15 (cycles 7 to 8)
  • Lenalidomide: 25 mg per day orally from days 1 to 21
  • Dexamethasone: 40 mg orally on days 1, 8, 15, 22
Drug: Isatuximab
treatment with Isa-KRD during induction and consolidation , with revlimid or Iberdomide +isatuximab during maintenance phase
Other Names:
  • Carfilzomib
  • Revlimid
  • Dexamesone

Procedure: ASCT
ASCT for ams B, C and D during consolidation

Experimental: MRD High-risk patients (post induction MRD >10-5, MRD HR) (1:1 Randomization): Arm C

Arm C: ASCT followed by 2 cycles of Isa-KRD (cycles 7 and 8) Melphalan 200 mg/m2 followed by autologous stem cell transplantation. 2 cycles of Isatuximab Carfilzomib Lenalidomide Dexamethasone (Isa-KRD) (28-day cycle):

  • Isatuximab: 10 mg/kg I.V. on days 1 and 15 (cycles 7 to 8)
  • Carfilzomib: 56 mg/m2 I.V on days on days 1, 8 and 15 (cycle 7 to 8)
  • Lenalidomide: 25 mg per day orally from day 1 to day 21
  • Dexamethasone: 40 mg orally on days 1, 8, 15, 22
Drug: Isatuximab
treatment with Isa-KRD during induction and consolidation , with revlimid or Iberdomide +isatuximab during maintenance phase
Other Names:
  • Carfilzomib
  • Revlimid
  • Dexamesone

Procedure: ASCT
ASCT for ams B, C and D during consolidation

Experimental: MRD High-risk patients (post induction MRD >10-5, MRD HR) (1:1 Randomization): Arm D
tandem ASCT Melphalan 200 mg/m2 followed by autologous stem cell transplantation.
Procedure: ASCT
ASCT for ams B, C and D during consolidation




Primary Outcome Measures :
  1. Negative MRD rate [ Time Frame: Time Frame: change from post induction baseline MRD at end of consolidation phase (6 months) ]

    For both parts of the trial (A vs B and C vs D), the primary comparison of the 2 strategies will be made with respect to negative MRD rate (10-6 NGS) before maintenance using the chi square test in the ITT population.

    The observed MRD negative rate will be provided along with its 2-sided 95% Confidence interval (CI). Treatment effect will be described by an Odds Ratio, along with its 2-sided 95% confidence interval, by fitting a logistic regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison). In case of missing MRD, data will be imputed as positive in all arms.

    Sensitivity analyses will be performed using best-worst and worst-best case to check for robustness of the results.


  2. Negative MRD rate [ Time Frame: change from post induction baseline MRD at 1 years ]

    For both parts of the trial (A vs B and C vs D), the primary comparison of the 2 strategies will be made with respect to negative MRD rate (10-6 NGS) before maintenance using the chi square test in the ITT population.

    The observed MRD negative rate will be provided along with its 2-sided 95% Confidence interval (CI). Treatment effect will be described by an Odds Ratio, along with its 2-sided 95% confidence interval, by fitting a logistic regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison). In case of missing MRD, data will be imputed as positive in all arms.

    Sensitivity analyses will be performed using best-worst and worst-best case to check for robustness of the results.


  3. Negative MRD rate [ Time Frame: change from post induction baseline MRD at 2 years ]

    For both parts of the trial (A vs B and C vs D), the primary comparison of the 2 strategies will be made with respect to negative MRD rate (10-6 NGS) before maintenance using the chi square test in the ITT population.

    The observed MRD negative rate will be provided along with its 2-sided 95% Confidence interval (CI). Treatment effect will be described by an Odds Ratio, along with its 2-sided 95% confidence interval, by fitting a logistic regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison). In case of missing MRD, data will be imputed as positive in all arms.

    Sensitivity analyses will be performed using best-worst and worst-best case to check for robustness of the results.


  4. Negative MRD rate [ Time Frame: change from post induction baseline MRD at 3 years ]

    For both parts of the trial (A vs B and C vs D), the primary comparison of the 2 strategies will be made with respect to negative MRD rate (10-6 NGS) before maintenance using the chi square test in the ITT population.

    The observed MRD negative rate will be provided along with its 2-sided 95% Confidence interval (CI). Treatment effect will be described by an Odds Ratio, along with its 2-sided 95% confidence interval, by fitting a logistic regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison). In case of missing MRD, data will be imputed as positive in all arms.

    Sensitivity analyses will be performed using best-worst and worst-best case to check for robustness of the results.



Secondary Outcome Measures :
  1. Sustained MRD rate [ Time Frame: change from post induction baseline MRD at end of consolidation phase (6 months) ]
    Sustained MRD rate at after consolidation phase ( 6 months) than year 1, 2, 3 post consolidation phase will be analyzed similarly to the primary endpoint

  2. Sustained MRD rate [ Time Frame: change from post induction baseline MRD at 1 years ]
    Sustained MRD rate at after consolidation phase ( 6 months) than year 1, 2, 3 post consolidation phase will be analyzed similarly to the primary endpoint

  3. Sustained MRD rate [ Time Frame: change from post induction baseline MRD at 2 years ]
    Sustained MRD rate at after consolidation phase ( 6 months) than year 1, 2, 3 post consolidation phase will be analyzed similarly to the primary endpoint

  4. Sustained MRD rate [ Time Frame: change from post induction baseline MRD at 3 years ]
    Sustained MRD rate at after consolidation phase ( 6 months) than year 1, 2, 3 post consolidation phase will be analyzed similarly to the primary endpoint

  5. Overall Survival (OS) [ Time Frame: through study completion, an average of 8 year ]
    For Overall Survival (OS), the distribution of OS since randomization will be estimated using Kaplan Meier method. The comparison of the 2 arms will be made by log-rank test. Treatment effect will be described by Hazard Ratio and its 2-sided 95% confidence intervals will be estimated using a Cox regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison).

  6. Progression Free Survival (PFS) [ Time Frame: through study completion, an average of 8 year ]
    Progression Free Survival, defined as time from randomization to either progression or death will be analyzed similarly to OS

  7. Safety analyses [ Time Frame: until 30 days post last dose of protocol treatment ]
    rate of adverse events that occured during treatment period



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 66 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female subjects, 18 years of age or older, younger than 66 years (< 66 years)
  2. 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.
  3. Subject must have documented multiple myeloma satisfying the CRAB and measurable disease as defined by:

    1. 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 lower limit of normal 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
      • Superior 1 focal lesion on MRI studies
    2. Measurable disease as defined by the following:

      • M-component ≥ 5g/L, and/or urine M-component ≥ 200 mg/24h and/or serum FLC ≥ 100 mg/L
  4. Newly diagnosed subjects eligible for high dose therapy and autologous stem cell transplantation
  5. Karnofsky performance status score ≥ 50% (eastern cooperative oncology group performance status ECOG score ≤ 2)
  6. 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):

    1. Hemoglobin ≥ 7.5 g/dL (≥ 5mmol/L). Prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted;
    2. Absolute neutrophil count (ANC) ≥ 1.0 Giga/L (GCSF use is permitted);
    3. ASAT ≤ 3 x ULN;
    4. ALAT ≤ 3 x ULN;
    5. Total bilirubin ≤ 3 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤ 1.5 x ULN);
    6. Calculated creatinine clearance ≥ 40 mL/min/1.73 m²;
    7. Corrected serum calcium ≤ 14 mg/dL (< 3.5 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤ 1.6 mmol/L);
    8. Platelet count ≥ 50 Giga/L for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count > 50 Giga/L (transfusions are not permitted to achieve this minimum platelet count).
  7. Women of childbearing potential must have a negative serum or urine pregnancy test within 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 30 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.
  8. 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:

  1. 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 in a 2-week period). Two weeks must have elapsed since the date of the last radiotherapy treatment. 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.
  2. Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.
  3. Subject has a diagnosis of Waldenström's macroglobulinemia, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
  4. Subject has had plasmapheresis within 14 days of C1D1.
  5. Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
  6. Myocardial infarction within 4 months prior to enrolment according to NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  7. Uncontrolled hypertension
  8. 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).
  9. Intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
  10. 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).
  11. 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.
  12. 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.
  13. 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.
  14. History of allergy to any of the study medications, their analogues, or excipients in the various formulations
  15. 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.
  16. Clinically relevant active infection or serious co-morbid medical conditions
  17. Prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer free of disease since 5 years.
  18. Female subject who is pregnant or breast-feeding
  19. Serious medical or psychiatric illness likely to interfere with participation in study
  20. Uncontrolled diabetes mellitus
  21. Known HIV infection; Known active hepatitis A, B or C viral infection
  22. 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.
    • 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.
  23. 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.
  24. Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics.
  25. Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs
  26. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment
  27. Person under guardianship, trusteeship or deprived of freedom by a judicial or administrative decision

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04934475


Contacts
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Contact: chanaz louni +331 40 21 42 01 c.louni@myelome.fr
Contact: lydia zerrouk +331 40 21 42 01 l.zerrouk@myelome.fr

Locations
Show Show 65 study locations
Sponsors and Collaborators
Intergroupe Francophone du Myelome
Amgen
Sanofi
Bristol-Myers Squibb
Investigators
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Principal Investigator: Philippe Moreau, Professor CHU de Nantes
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Intergroupe Francophone du Myelome
ClinicalTrials.gov Identifier: NCT04934475    
Other Study ID Numbers: IFM2020-02
2020-005216-21 ( EudraCT Number )
First Posted: June 22, 2021    Key Record Dates
Last Update Posted: February 28, 2023
Last Verified: February 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Intergroupe Francophone du Myelome:
Younger patients
First line of treatment
Autograft
Isa-KRD
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasm, Residual
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Neoplastic Processes
Pathologic Processes
Lenalidomide
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents