Lenalidomide for Multiple myeloma|Newly diagnosed multiple myeloma

Stratification factors

• ISS Stage (I vs II vs III)
• Cytogenetic risk by FISH (high-risk vs standard risk/missing based on presence of t(4;14), t(14;16), and/or del 17p)

Inclusion criteria

• {"criterion_text":"- 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.\n- 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.\n- 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.\n- 2.Patient is, in the investigators opinion, willing and able to comply with the study visits and procedures required per protocol.\n- 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.\n- 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\n- 5.Patient is 18 - 70 years old and is eligible for autologous stem cell transplantation\n- 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.\n- 7.Life expectancy ≥ 3 months\n- 8.ECOG status ≤2\n- 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."}

Exclusion criteria

• {"criterion_text":"- 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).\n- 4.Meningeal involvement of multiple myeloma\n- 5.Patient ineligible for autologous transplantation\n- 6.Pregnant or lactating females\n- 7.Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization\n- 8.Known human immunodeficiency virus infection (HIV)\n- 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\n- 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.\n- 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\n- 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.\n- 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\n- 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\n- 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\n- 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.\n- 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\n- 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\n- 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.\n- 3.Patients with plasma cell leukemia, amyloidosis, Waldenstrom Disease, POEMS syndrome"}

Primary endpoints

• {"endpoint_text":"- The rate of MRD negativity is determined as the proportion of patients with MRD negativity (≥10 -5 sensitivity level) after ASCT consolidation treatment using ITT principle. For patients who withdraw from the study or are lost to follow up before four post ASCT consolidation cycles, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.","definition_or_measurement_approach":"Proportion of patients with MRD negativity assessed by NGS at sensitivity level ≥10^-5 after ASCT consolidation, analysed using the intent-to-treat (ITT) principle; best MRD assessment used for patients who withdraw or are lost to follow-up before four post-ASCT consolidation cycles; patients without assessment or only MRD-positive results classified as MRD positive."}

Secondary endpoints

• {"endpoint_text":"- The rate of MRD negativity after induction is determined as the proportion of patients with MRD negativity after the induction phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate.","definition_or_measurement_approach":"Proportion of patients with MRD negativity by NGS after induction phase using ITT; patients without assessment or only MRD-positive results classified as MRD positive; inadequate samples considered MRD positive."}
• {"endpoint_text":"- PFS will be measured from the date of randomization to the date of first observation of PD, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to FU will also be censored at the time of last complete disease assessment.","definition_or_measurement_approach":"Progression-free survival measured from randomization to first observation of disease progression (PD) or death from any cause; censoring at last complete disease assessment for those without progression or withdrawn/lost to follow-up."}
• {"endpoint_text":"- The rate of MRD negativity after light consolidation is determined as the proportion of patients with MRD negativity after light consolidation phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate. Patients who withdraw from the study or are lost to follow up before MRD evaluation, the best MRD assessment will be considered.","definition_or_measurement_approach":"Proportion with MRD negativity by NGS after light consolidation using ITT; best MRD assessment considered for early withdrawals; classification rules as above."}
• {"endpoint_text":"- Rate of 1 year sustained MRD negativity by NGS will be also evaluated.","definition_or_measurement_approach":"Proportion of patients with sustained MRD negativity for 1 year measured by NGS."}
• {"endpoint_text":"- Response rate will be evaluated according to IMWG Response criteria after induction, ASCT, post ASCT consolidation and light consolidation.","definition_or_measurement_approach":"Overall response rate and categories (VGPR, CR, sCR) determined per IMWG response criteria at specified treatment phases."}
• {"endpoint_text":"- The description of this secondary endpoint exceeds the number of allowed characters in this field. Please refer to the protocol enclosed in this application","definition_or_measurement_approach":""}
• {"endpoint_text":"- TTP will be measured from the date of randomization to the date of first observation of PD, or deaths for PD. Subjects who have not progressed or who withdraw from the study or die from causes other than PD will be censored at the time of the last complete disease assessment. Subjects lost to FU will also be censored at the time of last complete disease assessment.","definition_or_measurement_approach":"Time to progression measured from randomization to first PD; censoring rules as described."}
• {"endpoint_text":"- DOR is defined as time between first documentation of response and PD with deaths owning to causes other than progression not counted, but censored. Responders without disease progression at the cut-off date of final analysis will be censored either at the time of lost to FU, at the time of death due to other cause than PD, or at the at the time of last contact.","definition_or_measurement_approach":"Duration of response defined from first documented response to PD; censoring for death due to other causes, lost to follow-up, or last contact."}
• {"endpoint_text":"- OS is defined as the time between randomization and death, regardless cause of death. Subjects who withdraw consent will be censored at the time of withdrawal. Subjects who are still alive at the cut-off date of final analysis will be censored at the cut-off date. Subjects lost to FU will also be censored at the time of last contact.","definition_or_measurement_approach":"Overall survival measured from randomization to death from any cause; censoring rules as specified."}
• {"endpoint_text":"- TNT will be measured from the date of randomization to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects lost to FU will also be censored at the time of last contact.","definition_or_measurement_approach":"Time to next therapy measured from randomization to start of next anti-myeloma therapy; death before therapy is an event; censoring rules described."}
• {"endpoint_text":"- Determine safety in the 2 treatment arms in the different phases.","definition_or_measurement_approach":"Safety assessments across phases; adverse events and other safety data to be collected and compared between arms."}
• {"endpoint_text":"- Determine whether tumor response and outcome may change in subgroups with different prognosis according to current prognostic factors.","definition_or_measurement_approach":"Subgroup analyses by prognostic factors to assess differences in tumor response and outcomes."}
• {"endpoint_text":"- The rate of MRD negativity after ASCT is determined as the proportion of patients with MRD negativity , NGS using ITT principle. For patients who withdraw from the study or are lost to follow up before ASCT, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.","definition_or_measurement_approach":"Proportion with MRD negativity by NGS after ASCT using ITT; best assessment for early withdrawals; classification rules as above."}
• {"endpoint_text":"- The rate of MRD negativity after induction, ASCT, post ASCT consolidation and light consolidation are determined as the proportion of patients with MRD negativity after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.","definition_or_measurement_approach":"Phase-specific MRD negativity rates by NGS using ITT; classification and best-assessment rules apply."}
• {"endpoint_text":"- The duration of MRD Negativity is defined as time between first MRD Negativity and first MRD positivity. Patients without MRD positivity will be censored at last complete assessment.","definition_or_measurement_approach":"Time from first MRD negative result to first MRD positive result; censoring at last complete assessment if no MRD positivity."}
• {"endpoint_text":"- Determine the rate of sustained for 1-year MRD negativity.","definition_or_measurement_approach":"Rate of patients maintaining MRD negativity for 1 year."}
• {"endpoint_text":"- Determine the success of stem cell harvest according to baseline characteristics; stem cells will be harvested at a minimum of 4 x 10^6 CD34+ cells/kg.","definition_or_measurement_approach":"Stem cell harvest success assessed relative to baseline; target minimum yield ≥4 x 10^6 CD34+ cells/kg."}
• {"endpoint_text":"- Determine the success of engraftment after ASCT, defined by the time needed to achieve: Absolute Neutrophil Count (ANC) and Platelet count","definition_or_measurement_approach":"Time to hematologic engraftment measured by ANC and platelet count recovery after ASCT."}
• {"endpoint_text":"- Quality of life defined by EORTC QLQ-C30, EORTC QLQ-MY20 and EQ5D5L.","definition_or_measurement_approach":"Quality of life assessed with EORTC QLQ-C30, EORTC QLQ-MY20 and EQ-5D-5L instruments."}

Germany

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

18-06-2025

Processing Time Days

309

Number Of Sites

3

Number Of Participants

12

Czechia

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

16-06-2025

Processing Time Days

307

Number Of Sites

4

Number Of Participants

28

Belgium

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

16-06-2025

Processing Time Days

307

Number Of Sites

1

Number Of Participants

11

Spain

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

18-06-2025

Processing Time Days

309

Number Of Sites

6

Number Of Participants

63

Netherlands

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

17-06-2025

Processing Time Days

308

Number Of Sites

12

Number Of Participants

89

Italy

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

17-06-2025

Processing Time Days

308

Number Of Sites

12

Number Of Participants

58

Norway

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

16-06-2025

Processing Time Days

307

Number Of Sites

2

Number Of Participants

9

Greece

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

17-06-2025

Processing Time Days

308

Number Of Sites

2

Number Of Participants

32

Primary sponsor

Full Name

European Myeloma Network B.V.

Organisation Type

Patient organisation/association

Country Of Registered Address

Netherlands

Contract research organisations

Name

Health Data Specialists Consulting Services Organization And Conduct Of Studies Single Member S.A.

Responsibilities

SponsorDuties codes include 1 and 12 (organization and conduct of studies roles as listed in third-party entry)

Name

Emn Trial Office S.r.l. Impresa Sociale

Responsibilities

Trial office responsibilities including central lab duties and correlative evaluations (sponsorDuties codes: 15, 4)

Third parties

• {"country":"Belgium","full_name":"Clinigen Clinical Supplies Management","duties_or_roles":"Labelling of IMP, secondary packaging, distribution and return of the IMPs, IMPs destruction (sponsorDuties codes: 14, 15)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Adaptive Biotechnologies Corp.","duties_or_roles":"MRD by NGS (sponsorDuties codes include 15 and 4)","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"Health Data Specialists Consulting Services Organization And Conduct Of Studies Single Member S.A.","duties_or_roles":"Roles include code 1 and 12 (as listed in sponsorDuties)","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)","duties_or_roles":"FISH, MRD by NGF and related duties (sponsorDuties codes: 15, 4)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Ireland","full_name":"Health Data Specialists Ireland Limited","duties_or_roles":"Duties include code 12 and financial/site contracts related roles (codes 12, 15, 8 as listed)","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Emn Trial Office S.r.l. Impresa Sociale","duties_or_roles":"Correlative evaluation of the humoral and cellular immune response to SARS-CoV-2 (sponsorDuties codes: 15, 4)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Netherlands","full_name":"Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting","duties_or_roles":"Roles include trial coordination and financial contracts with sites (sponsorDuties codes: 1, 12, 15)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Spain","full_name":"Hospital Universitario De Salamanca","duties_or_roles":"Routine clinical pathology testing (sponsorDuties codes: 15, 4)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Italy","full_name":"Mipharm S.p.A.","duties_or_roles":"Sponsor duty code 14 (as listed)","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Labospace S.r.l.","duties_or_roles":"Routine Clinical Pathology Testing (sponsorDuties codes: 15, 4)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Italy","full_name":"Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino (as third party listed)","duties_or_roles":"Routine clinical pathology testing (sponsorDuties codes: 15, 4)","organisation_type":"Hospital/Clinic/Other health care facility"}

Co-sponsors

• Emn Trial Office S.r.l. Impresa Sociale