Phase III Randomized Trial of Iberdomide vs. Iberdomide Plus Isatuximab Post-Autologous Hematopoietic Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma
- Trial ID
- 2023-507402-13-00
- Protocol
- GMMG-HD9/DSMM XVIII
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized phase III trial is to demonstrate the superiority of **iberdomide** plus **isatuximab** compared to iberdomide alone in achieving bone marrow minimal residual disease (MRD) negativity rates, with a sensitivity of 2x10^-6, as assessed by next-generation flow cytometry (NGF) after two years of maintenance therapy in patients with newly diagnosed **multiple myeloma**. Achieving MRD negativity is clinically significant as it is associated with improved long-term outcomes and survival rates in multiple myeloma patients.
Secondary objectives include demonstrating the superiority of iberdomide plus isatuximab compared to iberdomide alone with respect to progression-free survival (PFS). This is clinically relevant as prolonged PFS is indicative of delayed disease progression, which can enhance the quality of life and overall survival in patients.
Participants
The clinical trial involves participants diagnosed with **multiple myeloma**, focusing on both male and female subjects. The study population includes adults aged 18 years and older, with a **World Health Organization (WHO) performance status** of 0, 1, or 2, indicating a range from fully active to capable of self-care but unable to carry out any work activities. Participants must have previously been included and treated in the GMMG-HD8/DSMM XIX trial, with a confirmed diagnosis of multiple myeloma and measurable disease prior to induction therapy. They must have received at least one cycle of high-dose melphalan therapy and autologous stem cell transplantation, achieving at least a partial response according to the International Myeloma Working Group (IMWG) criteria. The trial does not include a vulnerable population. Lifestyle considerations include adherence to specific contraceptive measures for both male and female participants, as outlined in the Pregnancy Prevention Program. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **randomized**, phase III study to evaluate the efficacy of **iberdomide** versus iberdomide plus **isatuximab** as maintenance therapy following autologous hematopoietic stem-cell transplantation in patients with newly diagnosed **multiple myeloma**. The trial aims to demonstrate the superiority of the combination therapy in achieving bone marrow minimal residual disease (MRD) negativity rates after two years of maintenance therapy. The study is double-blind and controlled, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thus minimizing bias.
The trial is expected to commence recruitment on January 29, 2024, and is estimated to conclude by July 31, 2029. Participants will be involved in the study for a maximum treatment period of 36 months. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as prior inclusion in the GMMG-HD8/DSMM XIX trial, age, and performance status. Following the screening, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, with assessments including MRD status via next-generation flow cytometry. The end-of-study visit will occur after the completion of the maintenance therapy period or upon early termination.
Participants may be withdrawn from the study early if they experience disease progression, unacceptable toxicity, or if they withdraw consent. Additionally, adherence to the study protocol, including the use of contraception and abstinence from blood donation, is mandatory to ensure participant safety and data integrity. The primary endpoint of the trial is the rate of NGF-MRD negativity after two years, while secondary endpoints include progression-free survival (PFS), defined as the time from randomization to disease progression or death from any cause.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Dexamethasone**, marketed as Dexamethason TAD® 20 mg Tabletten, is provided in tablet form. The active substance, dexamethasone, is of chemical origin. The maximum daily dose is 20 mg, with a total maximum dose of 80 mg over a treatment period of up to 4 weeks. The tablets are administered orally.
**Iberdomide** is another experimental medication used in this trial. It is available in capsule form and is administered orally. The active substance, iberdomide, is also of chemical origin. The maximum daily dose is 1 mg, with a total maximum dose of 819 mg over a treatment period of up to 36 months. Iberdomide is a Cereblon E3 Ubiquitin Ligase Modulating Drug (CELMoD®) with structural similarities to Lenalidomide.
**Isatuximab** is administered as a solution for injection. The active substance, isatuximab, is a protein of other origin, specifically a monoclonal CD38 antibody. The maximum daily dose is 1400 mg, with a total maximum dose of 61600 mg over a treatment period of up to 36 months. The solution is delivered subcutaneously using the On Body Delivery System (OBDS), a sterile, single-use, disposable, elastomeric device designed for subcutaneous delivery.
In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the prescribed treatment regimens.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of bone marrow **minimal residual disease (MRD)** negativity rates. The sensitivity of this assessment is set at 2x10^-6, utilizing next-generation flow cytometry (NGF) after two years of maintenance therapy. This primary endpoint aims to demonstrate the superiority of the combination of iberdomide plus isatuximab compared to iberdomide alone in patients with newly diagnosed multiple myeloma following autologous hematopoietic stem-cell transplantation.
Secondary efficacy endpoints include progression-free survival (PFS), which is defined as the time from randomization to disease progression or death from any cause, whichever occurs first. The collection and analysis of these endpoints will be conducted at specified intervals throughout the trial duration, ensuring a comprehensive evaluation of the treatment's efficacy. The trial is designed to provide robust data on the effectiveness of the treatment regimens under investigation.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients meeting all of the following criteria will be considered for admission to the trial: Prior inclusion and treatment within the GMMG-HD8/DSMM XIX trial (including confirmation of diagnosis of MM with myeloma-defining events [end-organ damage or biomarker of malignancy] and measurable disease prior to initiation of induction therapy as outlined in the IMWG criteria)
- Received at least one cycle high dose melphalan therapy (HDM) and autologous stem cell transplantation (ASCT)
- At least Partial Response (PR) according to IMWG criteria at inclusion in the trial
- Age of 18 years or higher at trial inclusion
- WHO performance status of 0, 1, or 2 (see Appendix II)
- A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) and must: a) Have two negative serum or urine pregnancy tests as verified by the Investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact. b) Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting investigational product, during the study treatment (including dose interruptions), and for at least 28 days after the last dose of iberdomide.
- Male subjects must practice complete abstinence (True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [e.g. calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of contraception) or agree to use a condom during sexual contact with a pregnant female or a FCBP while taking iberdomide, during dose interruptions and for at least 28 days following the last dose of iberdomide even if he has undergone a successful vasectomy.
- Males must agree to refrain from donating sperm while on study treatment, during dose interruptions and for at least 28 days following last dose of study treatment.
- All male and female subjects must follow all requirements defined in the Pregnancy Prevention Program (see section 7.1.7 and Appendix IV).
- All patients must agree to abstain from donating blood while taking study treatment and for 28 days following discontinuation of study treatment
- Ability of patient to understand character and individual consequences of the clinical trial
- Written informed consent (must be available before enrolment in the trial)
Exclusion Criteria
- Patients presenting with any of the following criteria will not be included in the trial: Subjects with gastrointestinal disease that may significantly alter the absorption of iberdomide
- Patients with severe renal insufficiency (Creatinine Clearance < 30 mL/min) or requiring hemodialysis
- Patients with peripheral neuropathy or neuropathic pain, grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0, see Appendix V)
- Patients with a history of any active malignancy during the past 5 years with the exception of following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy. A history of an early stage malignancy during the past 5 years may be acceptable, however, in this case the GMMG or DSMM study office has to be consulted prior to study inclusion
- Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
- Autoimmune haemolytic anaemia with positive indirect Coombs test or immune thrombocytopenia
- Platelet count < 75 x 10^9/L
- Haemoglobin ≤ 8.0 g/dL, unless related to MM
- Absolute neutrophil count (ANC) < 1.0 x 10^9/L (the use of colony stimulating factors within 14 days before the test is not allowed)
- Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L)
- Unable or unwilling to undergo thromboprophylaxis
- Patient has known hypersensitivity or contraindication to any of the components of study therapy (e.g. known intolerance or hypersensitivity to iberdomide, isatuximab, infused proteins products, sucrose, histidine, and polysorbate 80 as well as intolerance to arginine and Poloxamer 188)
- Pregnancy and lactation
- Participant has any concurrent severe and/or uncontrolled medical condition or psychiatric disease that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study or that confounds the ability to interpret data from the study
- Participation in other interventional clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months
- Systemic AL amyloidosis (except for localized AL amyloidosis limited to the skin or the bone marrow) or plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential blood count) or polyneuropathy, organomegaly, endocrinopathy, monoclonal-protein and skin abnormalities (POEMS syndrome); or Waldenström macroglobulinemia.
- Previous systemic anti-myeloma treatment other than administered within the GMMG-HD8 / DSMM XIX trial (including up to two cycles cycle high dose melphalan therapy (HDM) and autologous stem cell transplantation (ASCT). Local, consolidative radiotherapy for myeloma disease is permitted unless performed in case of progressive disease (PD) according to IMWG criteria
- Severe cardiac dysfunction (NYHA classification III-IV; see Appendix II)
- Significant hepatic dysfunction (ASAT and/or ALAT ≥ 3 times normal level and/or serum bilirubin ≥ 1.5 times normal level if not due to hereditary abnormalities as Gilbert’s disease), unless related to MM or HDM/ASCT
- Patients with active or uncontrolled hepatitis B or C or detectable liver disease due to hepatitis B or C. In case of history of hepatitis B or C, it must be clarified whether it has been overcome and negative circulating HBV-DNA or HCV-RNA with sensitive PCR blood tests must be provided. Positive hepatitis B status may only be acceptable in absence of circulating HBV-DNA or signs of chronic or acute infection and if an adequate prophylaxis is being implemented during the course of the study. Prophylaxis for patients with history of hepatitis B or C should be set on a patient individual basis
- HIV positivity
- Patients with active, uncontrolled infections
- Patients with a history of serious allergic reaction to another immunomodulatory agent (thalidomide, lenalidomide, or pomalidomide), as angioedema and severe dermatologic reactions, including Grade 4 rash and exfoliative or bullous rash
- Patients currently being treated with medically indispensable strong inhibitors or inducers of CYP3A4/5
- Subjects, who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Yet Recruiting | 29 Jan 2024 | 40 |
 Germany | Recruiting | 29 Jan 2024 | 411 |
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 |
|---|---|---|---|---|---|---|
Dexamethason TAD® 20 mg Tabletten | Other | TABLETTEN | ORAL | 20 | 4 | PRD4709328 |
Iberdomide | Test | CAPSULE | ORAL | 1 | 36 | PRD10086310 |
Iberdomide | Test | CAPSULE | ORAL | 1 | 36 | PRD10086308 |
Iberdomide | Test | CAPSULE | ORAL | 1 | 36 | PRD10086311 |
Iberdomide | Test | CAPSULE | ORAL | 1 | 36 | PRD10086309 |
Isatuximab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 1400 | 36 | PRD10653408 |