Hospital Universitario La Zarzuela | Clinical Research Unit
Status and phase
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About
This is a Phase III open-label, 3-arm, parallel, randomized, controlled trial. The allocation ratio 1:1:1 and outcome assessment are blind to group allocation. Patients will be randomized from 3 arms. Patients will receive VRD extended + ASCT plus ERI or Isatuximab-VRD + ASCT or Isatuximab-VID + ASCT.
Full description
Patients will receive induction treatment, which will consist: arm A (Isatuximab-VRD + ASCT) or arm B (VRD extended + ASCT plus ERI) or arm C (Isatuximab-VID + ASCT). After ASTC, patients will start consolidation which will be 2 cycles of similar treatment to induction.
Continuous treatment will follow after consolidation and patients will receive:
The primary objective is to compare the efficacy of extended VRD + ASCT plus ERI (Arm B) vs. Isatuximab-VRD + ASCT (Arm A) in terms of proportion of patients who are MRD-negative by next generation flow cytometry (NGF) after 18 cycles + ASCT.
The primary endpoint, the MRD rate, takes as a reference the evaluation after the last extended VRD cycle, this is: 6 cycles for induction, 6 months for transplantation, 2 cycles for consolidation and 10 cycles until completing the 18 cycles of VRD, (in total about 24 months). For this reason,the primary endpoint in Arms A and C are established after a similar treatment time, which includes 4 cycles of induction, ASCT, 2 cycles of consolidation and 12 cycles of continuous treatment with Iberdomide plus Isatuximab (Dexamethasone to be determined).In patients of Arm B included in ERI, due to the great variability of the possible moments of incorporation in this therapeutic program, only rules are established for the moment and the realization or not of the transplant. The evaluation of the results will be carried out separately in the patients included, butalso in conjunction with the rest of the patients in Arm B to know the effect of the global strategy.
After the evaluation of the primary endpoint, continuous/maintenance treatment continues in Arms A, B and C, including patients in ARM B assigned to the ERI program. Obtaining conventional CR in either arm will require a BM analysis for MRD. In the case of stable response or improvement without RC, MRD controls have been pre-established. Due to the lack of data on tolerance and adherence to long-term treatment with Isatuximab and Iberdomide, changes in the therapeutic programs, for this reason, a complete revision of the therapeutic program has been predetermined at the moment in which the last patient included in the clinical trial reaches 36 months of treatment. At this point, taking into account the updated knowledge about continuous or maintenance treatments, the strategies for a second clinical trial or an extension of this clinical trial will be defined.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.
Patient must be able to understand the study procedures.
Patient has given voluntary written informed consent before performance of any studyrelated procedure non part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
Newly diagnosed multiple myeloma patient who requires start active treatment according to the 2014 IMWG criteria, namely clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcaemia, Anaemia, Renal Insufficiency, or Bone lesions (one or more osteolytic lesions on skeletal radiography, CT, or PET-CT), and any one or more of the following biomarkers: clonal BMPC% ≥60%, i/u free light ratio ≥100 or > 1 focal lesions on MRI or PET/CT) [Lancet Oncol. 2014;15(12): e538-e548].
Patient must have a measurable secretory disease defined as either serum monoclonal protein of ≥ 0,5 g/dl or urine monoclonal (light chain) protein ≥ 200 mg/24 h. For patients whose disease is only measurable by serum FLC, the involved FLC should be ≥ 10mg/dL (100 mg/L), with an abnormal serum FLC ratio.
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
Patient must be ≤ 65 years of age.
Patient must have adequate organ function, defined as follows:
Female patient: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female patient is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
Is not a woman of childbearing potential (WOCBP), i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy OR
Is a WOCBP and
The Investigator must ensure that a WOCBP: i) Complies with the conditions of the pregnancy prevention plan, including confirmation that she has an adequate level of understanding. ii) Acknowledges the aforementioned requirements.
A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 72 hours before the first dose of study drug.
Nonchildbearing potential is defined as follows (by other than medical reasons):
Male patient: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Male patient is eligible to participate if he agrees to the following from the time of first dose of study until 6 months after the last dose of iberdomide or lenalidomide to allow for clearance of any altered sperm:
All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0 must be ≤ Grade 1 at the time of enrolment except for alopecia.
Exclusion criteria
Patient has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia or active POEMS syndrome at the time of screening.
Patient has had clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS multiple myeloma.
Prior history of malignancies, other than multiple myeloma (except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or the breast), unless the patient has been free of the disease for ≥ 5 years.
Any serious medical condition that places the subject at an unacceptable risk if he or she participates in this study; subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and/or lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment.
Pregnant or breastfeeding females.
Men and women of reproductive potential who are not using effective contraceptive methods (double barrier method, intrauterine device, oral contraception).
Patient is simultaneously enrolled in other interventional clinical trial.
Patient has used an investigational drug within 28 days or five half-lives, whichever is longer, preceding the first dose of study drug.
Patient must not have received prior radiotherapy (except localized palliative radiotherapy for pain, palliation or fracture) within 2 weeks of start of study therapy. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
Patient has peripheral neuropathy or neuropathic pain grade 1 with pain or ≥2, as defined by the National Cancer Institute Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
Patient evidence of cardiovascular risk including any of the following:
Patients who have current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria.
Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect patient's safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil inclusion criteria.
Evidence of active mucosal or internal bleeding.
Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.
Uncontrolled endocrine diseases (i.e. diabetes mellitus, hypothyroidism or hyperthyroidism) (i.e. requiring relevant changes in medication within the last month, or hospital admission within the last 3 months).
Patient with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
Patient with severe chronic obstructive pulmonary disease (COPD) or asthma with forced expiratory volume in the first minute (FEV1) less than 50%.
History of interstitial lung disease or ongoing interstitial lung disease.
Subject has gastrointestinal disease that may significantly alter the absorption of iberdomide and/or other oral study treatment.
Patient has an active infection requiring systemic antibiotic, antiviral, or antifungal treatment at the time of starting treatment.
Patient has known HIV infection.
Patient has positive hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb) at screening or within 3 months prior to first dose of study treatment.
Patient has positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. Note: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. Note: Hepatitis RNA testing is optional and participants with negative Hepatitis C antibody test are not required.
Patient require concurrent administration of a strong inhibitor or inducer of cytochrome P450 (CYP3A4/5) (including within 14 days of initiating study treatment).
Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to iberdomide or drugs chemically related to iberdomide.
Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to isatuximab or drugs chemically related to isatuximab, hypersensitivity reactions, or idiosyncratic reactions to other molecular antibodies.
Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to lenalidomide or dexamethasone or drugs chemically related to lenalidomide or dexamethasone.
Primary purpose
Allocation
Interventional model
Masking
480 participants in 3 patient groups
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Central trial contact
Roberto Maldonado; Carmen López-Carrero
Data sourced from clinicaltrials.gov
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