Phase III Trial Comparing Extended Lenalidomide-Bortezomib-Dexamethasone with Early Rescue vs. Isatuximab-Lenalidomide-Bortezomib-Dexamethasone vs. Isatuximab-Lenalidomide-Iberdomide-Dexamethasone in Newly Diagnosed Multiple Myeloma Candidates for Autologous Stem Cell Transplantation
- Trial ID
- 2024-517008-12-00
- Protocol
- GEM21menos65
- Sponsor
- Fundacion PETHEMA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III trial is to compare the **efficacy** of extended VRD (Lenalidomide-Bortezomib-Dex) plus ASCT (autologous stem cell transplantation) with Early Rescue Intervention (ERI) using Iberdomide-Isatuximab (Arm B) against Isatuximab-VRD plus ASCT (Arm A). The comparison is based on the proportion of patients achieving minimal residual disease (MRD)-negative status by next-generation flow cytometry (NGF) after 18 treatment cycles, including ASCT. This objective is clinically relevant as achieving MRD-negative status is associated with improved outcomes in patients with newly-diagnosed multiple myeloma (NDMM).
Secondary objectives include:
- Assessing the safety of Isatuximab-VID (Iberdomide-Bortezomib-Dex) plus ASCT (Arm C).
- Exploring preliminary efficacy comparisons of Arm C versus Arm A and Arm C versus Arm B in terms of the proportion of patients reaching NGF MRD-negative status.
- Evaluating progression-free survival (PFS), overall response rate (ORR), complete response rate (CRR), time to response (TTR), duration of response (DoR), PFS2, and overall survival (OS).
Participants
The clinical trial involves participants diagnosed with **newly-diagnosed multiple myeloma (NDMM)**. The study population includes both male and female subjects, with an age range of up to 65 years. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not include a vulnerable population. Participants must have adequate organ function and a measurable secretory disease, as defined by specific serum or urine monoclonal protein levels. The sponsor has not provided information regarding the total number of participants. Selection criteria ensure that participants are willing and able to comply with the protocol requirements, and all prior treatment-related toxicities must be at or below Grade 1, except for alopecia. Lifestyle considerations such as contraceptive use are consistent with local regulations for clinical studies. The trial population was selected based on the 2014 International Myeloma Working Group (IMWG) criteria, which include specific myeloma-defining events and biomarkers. The sponsor has not disclosed any additional information regarding the selection process or lifestyle considerations beyond those mentioned.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of different treatment regimens for **newly-diagnosed multiple myeloma** (NDMM) in patients eligible for autologous stem cell transplantation (ASCT). This is a Phase III, randomized, double-blind, controlled trial comparing three arms: Arm A involves Isatuximab combined with VRD (Lenalidomide, Bortezomib, and Dexamethasone) plus ASCT; Arm B includes extended VRD plus ASCT with early rescue intervention (ERI) using Iberdomide and Isatuximab; and Arm C consists of Isatuximab combined with VRD and Iberdomide. The primary objective is to assess the proportion of patients achieving minimal residual disease (MRD) negativity after 18 cycles plus ASCT, using next-generation flow cytometry.
The trial is expected to last until May 2029, with recruitment starting in November 2022. Participants will be involved for a maximum of 24 months, depending on their assigned treatment arm. The study includes several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as age, performance status, and organ function; regular follow-up visits to monitor treatment response and adverse events; and an end-of-study visit to assess final outcomes. Participants may be withdrawn from the study early if they experience unacceptable toxicity, fail to comply with the protocol, or withdraw consent.
Inclusion criteria require participants to have measurable secretory disease and adequate organ function, among other factors. The trial excludes individuals with prior treatment-related toxicities above Grade 1, except for alopecia. The primary endpoints focus on the improvement and non-inferiority of MRD negativity rates between the treatment arms. The study is not classified as low intervention and involves the use of both chemical and protein-based investigational products, administered orally or subcutaneously, depending on the specific treatment regimen.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Revlimid** (lenalidomide) is provided in the form of 25 mg hard capsules. It is administered orally with a maximum daily dose of 25 mg. The treatment period extends up to 24 months. Revlimid is a chemically derived substance and is utilized as a comparator in the study.
**Isatuximab** is administered as a solution for infusion, with a maximum daily dose of 1400 mg. The route of administration is subcutaneous, facilitated by a sterile, single-use, disposable elastomeric device. This protein-based medication is used as a test treatment in the trial, with a treatment duration of up to 24 months.
**Velcade** (bortezomib) is provided as a 3.5 mg powder for solution for injection. It is administered subcutaneously with a maximum daily dose of 1.3 mg/m². The treatment period is up to 24 months. Velcade is a chemically derived substance and serves as a comparator in the study.
**Iberdomide** is administered in the form of 1 mg capsules, taken orally. The maximum daily dose is 1 mg, with a treatment period extending up to 24 months. Iberdomide is a chemically derived substance and is used as a test treatment in the trial.
Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these treatments in patients with newly diagnosed multiple myeloma who are candidates for autologous stem cell transplantation.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the proportion of patients who achieve **Minimal Residual Disease (MRD)** negativity. The primary endpoints focus on comparing the percentage of MRD-negative patients between two treatment arms: Arm A (Isatuximab-VRD plus Autologous Stem Cell Transplantation (ASCT)) and Arm B (Extended VRD plus ASCT with Early Rescue Intervention (ERI)). The B1 endpoint will assess the impact of VRD extension alone, considering any patient requiring ERI before completing 18 cycles plus ASCT as MRD-positive. The B2 endpoint will evaluate the combined impact of VRD extension and ERI, considering patients achieving MRD negativity with ERI as MRD-negative.
Inclusion and Exclusion Criteria
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 study-related 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 table 2 in protocol.
- Female patient: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- Male patient: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- 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: • Myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV). • Uncontrolled cardiac arrhythmia. • Screening 12-lead ECG showing a baseline interval QTcF> 470 msec (exception: subjects with pacemaker). • Patients with uncontrolled hypertension.
- 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.
- 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 seropositive for hepatitis B defined by a positive test for hepatitis B surface antigen (HBsAg). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time PCR measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Subjects who were positive only for HBsAg and had a valid vaccination certificate for hepatitis B could be included in the stutjdy, without the need to determine an undetectable HBV viral load.
- 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.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 09 Nov 2022 | 480 |
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 |
|---|---|---|---|---|---|---|
Revlimid 15 mg hard capsules | Comparator | HARD CAPSULES | ORAL | 25 | 12 | PRD9264282 |
VELCADE 3.5 mg powder for solution for injection | Comparator | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 1.3 | 24 | PRD3349073 |
Isatuximab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 1400 | 12 | PRD10653408 |
Iberdomide | Test | CAPSULE | ORAL USE | 1 | 24 | PRD10086311 |
Revlimid 10 mg hard capsules | Comparator | HARD CAPSULES | ORAL | 10 | 12 | PRD9264283 |
Iberdomide | Test | CAPSULE | ORAL | 0.45 | 12 | PRD10086308 |
ISATUXIMAB | Test | — | SUBCUTANEOUS | 1400 | 24 | SUB187359 |
Revlimid 5 mg hard capsules | Comparator | HARD CAPSULES | ORAL | 5 | 12 | PRD9264284 |
Revlimid 25 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 25 | 24 | PRD9264271 |
Iberdomide | Test | CAPSULE | ORAL | 0.75 | 12 | PRD10086310 |