MInimal residual Disease Adapted Strategy / IFM 2020-02

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Intergroupe Francophone Du Myelome

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

BMS/CELGENE · Sanofi Aventis · Amgen · Intergroupe Francophone du Myélome

External identifiers

EU CT number

2024-513889-19-00

EudraCT number

2020-005216-21

ClinicalTrials.gov

NCT04934475

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

For patients MRD negative after induction : Increase by 15% the rate of MRD negativity (NGS, 10-6) before maintenance with high-dose therapy and ASCT (Arm B) vs additional cycles of Isa-KRD (Arm A), i.e., 85% MRD negativity in Arm B vs 70% in Arm A.
For patients MRD positive after induction : Increase by 20% the rate of MRD negativity (NGS,10-6) before maintenance with tandem ASCT (Arm D) vs single ASCT (Arm C), i.e., 45% MRD negativity in Arm D vs 25% in Arm C.

Secondary objectives 6

1. MRD post-induction, MRD post-Consolidation, responses rate according to IMWG 2016 criteria,
2. PFS and OS
3. Safety (ongoing basis)
4. Sustained MRD negativity (every year since the start of Maintenance phase),
5. PRO for Arms C and D (every year since the start of Maintenance).
6. nCR responses rate according to NCI and GMMG definition,

Conditions and MedDRA coding

Multiple Myeloma

Study design 1 period

Regulatory references

Plan to share IPD

Yes

IPD plan description

All safety data (The data safety Reports: adverse events that are serious, unlisted/unexpected, annual safety reports containing line listings of safety data, SAEI) will be shared with the compagnies (SANOFI, AMGEN and BMS/CELGENE) in order to capture any security element related to the other projects they are sponsoring. The companies (SANOFI, AMGEN and BMS/CELGENE) may also have access to the study data and may use this information to implement a file requesting authorization to market the drug in certain countries. All data processing is MR001 compliant. Sharing will be securely performed.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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 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.
4. Newly diagnosed subjects eligible for high dose therapy and autologous stem cell transplantation
5. Eastern Cooperative Oncology group performance status (ECOG score) ≤ 2 (Karnofsky performance status score ≥ 50%)
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): 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).
7. 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.
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 27

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 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.
2. Subject with a current 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 Mprotein is present in the absence of a clonal plasma cell infiltration with ly
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, PAH, 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, please refer to Appendix 4).
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. 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.
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. 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.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 4

1. Sustained MRD rate at year 2, 3, 4 post inclusion will be analyzed similarly to the primary endpoint.
2. 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.
3. Treatment effect will be described by Hazard Ratio and its 2-sided 95% confidence intervals are 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).
4. Progression Free survival, defined as time from randomization to either progression or death will be analyzed similarly

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Intergroupe Francophone Du Myelome

Sponsor organisation

Intergroupe Francophone Du Myelome

Address

75 Avenue Parmentier

City

Paris Cedex 11

Postcode

75544

Country

France

Scientific contact point

Organisation

Intergroupe Francophone Du Myelome

Contact name

Pr Philippe MOREAU - Medical Project Coordinator

Public contact point

Organisation

Intergroupe Francophone Du Myelome

Contact name

Lydia ZERROUK- Project Manager Lead

Third parties 4

Locations

2 EU/EEA countries · 72 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications