Phase 3 Randomized Study of Iberdomide, Daratumumab, and Dexamethasone vs. Daratumumab, Bortezomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma
- Trial ID
- 2024-510800-35-00
- Protocol
- CC-220-MM-002
- Sponsor
- Celgene Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of the combination of iberdomide, daratumumab, and dexamethasone (IberDd) with that of daratumumab, bortezomib, and dexamethasone (DVd) in subjects with **relapsed or refractory multiple myeloma (RRMM)**. The comparison focuses on achieving minimal residual disease (MRD) negative complete response (CR) at any time and progression-free survival (PFS). This is clinically relevant as achieving MRD negativity and extending PFS are critical indicators of treatment success in RRMM, potentially leading to improved patient outcomes.
Secondary objectives include:
- Determining the dose of iberdomide in combination with dexamethasone and daratumumab to continue in Stage 2 of the study.
- Assessing the pharmacokinetics (PK) of iberdomide in combination with daratumumab and dexamethasone.
- Evaluating overall survival in subjects treated with IberDd compared to DVd.
- Evaluating the sustainability of MRD negativity in subjects treated with IberDd compared to DVd.
- Evaluating additional efficacy parameters in subjects treated with IberDd compared to DVd.
- Evaluating the safety of IberDd compared to DVd in subjects with RRMM.
- Evaluating cancer-related symptoms and health-related quality of life (HRQoL) using the European Organization for Research and Treatment of Cancer – Quality of Life C30 questionnaire (EORTC QLQ-C30) and the European Quality of Life Multiple Myeloma Module (EORTC QLQ-MY20) in subjects treated with IberDd compared to DVd.
Participants
The clinical trial involves a total of **470 participants** diagnosed with **Relapsed or Refractory Multiple Myeloma (RRMM)**. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2, indicating they are ambulatory and capable of all self-care. Participants were selected based on their documented diagnosis of multiple myeloma and measurable disease, having received one to two prior lines of anti-myeloma therapy, and having achieved a response of partial remission or better to at least one prior regimen. The trial includes individuals who have experienced disease progression during or after their last anti-myeloma regimen. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraception requirements and agree to refrain from donating blood or sperm during the study. The trial population includes vulnerable subjects, ensuring comprehensive monitoring and adherence to ethical standards.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the efficacy of two treatment regimens in patients with **relapsed or refractory multiple myeloma** (RRMM). The trial compares the combination of **iberdomide**, **daratumumab**, and **dexamethasone** (IberDd) against **daratumumab**, **bortezomib**, and **dexamethasone** (DVd). The primary objective is to assess progression-free survival (PFS) and the achievement of minimal residual disease (MRD) negative complete response (CR) at any time. The study is expected to conclude by September 2028, with recruitment having commenced in June 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and prior treatment history. The trial will include regular follow-up visits to monitor treatment response, safety, and adherence to the protocol. The end-of-study visit will evaluate the final outcomes and any long-term effects of the treatment. The expected duration of participant involvement is contingent upon individual response and disease progression, with the possibility of early termination if significant adverse events occur or if the disease progresses despite treatment.
Key elements of the research methodology include the use of **oral** and **subcutaneous** administration routes for the investigational products, with **iberdomide** administered in capsule form, **daratumumab** as a solution for injection, and **dexamethasone** in tablet form. The trial will adhere to rigorous safety and efficacy assessments, including pharmacokinetic and pharmacodynamic evaluations, to determine the recommended dose for subsequent stages. Participants will be monitored for overall survival, sustainability of MRD negativity, and other secondary endpoints such as time to response and duration of response.
Inclusion criteria require participants to have a documented diagnosis of multiple myeloma with measurable disease and to have received one to two prior lines of anti-myeloma therapy. Exclusion criteria include prior treatment with CD38-directed therapy in certain stages and progression during or shortly after previous bortezomib therapy. The trial will ensure compliance with a pregnancy prevention program and other safety measures to protect participants throughout the study duration.
Treatment
The clinical trial involves the administration of several treatments to evaluate their efficacy in subjects with **relapsed or refractory multiple myeloma**. The experimental medication **Iberdomide** is provided in a **capsule** form, with a maximum daily dose of 1.6 mg. It is administered orally, and the treatment period can extend up to 999 days. Iberdomide, also known by its sponsor product code CC-220, is a chemical compound developed by Celgene Corporation. Participant compliance with the dosing schedule is monitored throughout the trial.
**Daratumumab**, marketed as **DARZALEX 1800 mg solution for injection**, is a biological treatment administered subcutaneously. The maximum daily dose is 1800 mg, and the treatment duration is also up to 999 days. This medication is produced by Janssen-Cilag International NV and is designated as an orphan drug for this study.
**Dexamethasone** is utilized in two formulations: **Dexamethasone 2mg Tablets** and **Dexamethason-ratiopharm® 4 mg Tabletten**. Both are chemical compounds administered orally, with a maximum daily dose of 40 mg. The treatment period for dexamethasone is up to 999 days. The 2mg tablets are provided by Aspen Pharma Trading Limited, while the 4 mg tablets are produced by Ratiopharm GmbH.
**Bortezomib** is included as a comparator treatment in the trial. It is provided as a **powder for solution for injection** and is administered orally. The maximum daily dose is 1.3 mg/m², with a treatment period of up to 999 days. Bortezomib is a chemical compound, and its administration is closely monitored to ensure participant compliance.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating two primary endpoints: **Progression-Free Survival (PFS)** and **Minimal Residual Disease (MRD) negative Complete Response (CR)**. PFS is defined as the time from randomization to the first documentation of progressive disease according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma 2016 or death due to any cause, whichever occurs first. MRD negative CR is defined as achieving MRD negativity, which is less than 1 in 10^5 nucleated cells, as determined by next-generation flow cytometry in bone marrow aspirate for subjects who achieve CR or better at any time after randomization.
Secondary endpoints include the recommended iberdomide dose for Stage 2 based on safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) data; overall survival; sustainability of MRD negativity; overall response; time to response; duration of response; time to progression; time to next treatment; progression-free survival 2; safety; and patient-reported outcomes using the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires. The schedule for measuring these endpoints will be aligned with the trial protocol, ensuring systematic data collection and analysis throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 1.Subject is ≥ 18 years of age at the time of signing the ICF.
- 2.Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
- 3.Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
- 4.Subject has documented diagnosis of MM and measurable disease, defined as any of the following: a.M-protein quantities ≥ 1 g/dL by sPEP or ≥ 200 mg/24-hour urine collection by uPEP; or b.Light chain MM without measurable disease in serum or urine: serum FLC levels ≥ 100 mg/L (10 mg/dL) involved light chain and an abnormal kappa/lambda FLC ratio
- 5.Subject has received one to 2 prior lines of anti-myeloma therapy.
- 6.Subject achieved a response (PR or better) to at least 1 prior anti-myeloma regimen.
- 7.Subject must have documented disease progression during or after their last anti-myeloma regimen.
- Prior treatment with CD38-directed therapy: In Stage 1, subjects with prior CD38-directed- containing therapy are not eligible. In Stage 2, prior treatment with CD38-directed therapy is permitted only if all the following are fulfilled: a. Best response achieved during CD38-directed-containing therapy was ≥ PR. b.Subject did not progress while receiving CD38-directed therapy or within 60 days of last dose of therapy. c.Subject did not discontinue CD38-directed therapy due to a related AE. d.Last dose of daratumumab was ≥ 3 months prior to randomization.
- 9.Prior treatment with bortezomib therapy is permitted, if all the following are fulfilled: a.Best response achieved during bortezomib- containing therapy was at least a minimal response (MR). b.Subject did not progress while receiving bortezomib therapy or within 60 days of last dose of therapy.
- 10.Subject has an ECOG performance status score of 0, 1 or 2.
- Individuals of childbearing potential (IOCBP) must: a.Have two negative pregnancy tests as verified by the Investigator prior to starting study treatment. They 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, 2 forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting study treatment, during the study treatment (including dose interruptions), and for at least 28 days after the last dose of iberdomide, 3 months after the last dose of daratumumab or 7 months after the last dose of bortezomib, whichever is longest.
- Individuals assigned male at birth must: a. Practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to use a condom during sexual contact with a pregnant partner or an individual of childbearing potential while participating in the study, during dose interruptions and for at least 28 days after the last dose of iberdomide, 3 months after the last dose of daratumumab, or 4 months after the last dose of bortezomib, whichever is longer even if he has undergone a successful vasectomy. Contraception requirements are detailed in APPENDIX E and local PI of bortezomib and daratumumab
- Male (as assigned at birth) subjects must agree to refrain from donating sperm while receiving iberdomide, during dose interruptions and for at least 28 days following last dose of iberdomide, 3 months after the last dose of daratumumab or 4 months after the last dose of bortezomib whichever is later.
- 14.Subjects must agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment.
- All subjects must follow all requirements defined in the Pregnancy Prevention Program (v8.0). See APPENDIX E and local PI of bortezomib and daratumumab (see current version of PI, SmPC, or equivalent document for the specific country/region).
Exclusion Criteria
- 1.Subject has any significant medical condition
- Coronavirus Disease 2019 (COVID-19) within 7 days for mild or asymptomatic infections or 14 days for moderate/severe infections prior to initiating study treatment. A longer duration may be needed based on the investigator’s clinical judgment.
- 3.Subject has any condition that confounds the ability to interpret data from the study.
- 4.Subject has any of the following laboratory abnormalities: a.ANC <1,000 cells/µL. It is not permissible to administer GCSF to achieve minimum ANC levels. b. Platelet count: < 50,000 cells/µL. It is not permissible to transfuse subjects to achieve minimum platelet counts c.Hemoglobin <8 g/dL (<4.9 mmol/L) d.eGFR <30 mL/min or requiring dialysis. e.Corrected serum calcium >13.5 mg/dL (>3.4 mmol/L). f.Serum AST or ALT >2.5 × ULN g.Serum total bilirubin >1.5 × ULN or >3.0 mg/dL for subjects with documented Gilbert's syndrome.
- 5.Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia or POEMS syndrome, or clinically significant amyloidosis
- 6.Subject has peripheral neuropathy Grade 3, 4 or 2 with pain.
- 7.Subject has gastrointestinal disease that may significantly alter the absorption of iberdomide and/or other oral study treatment.
- 8.Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥3 years with the exception of some noninvasive malignancies.
- 9.Subject with known central nervous system involvement with MM.
- 10.Subject has received immunosuppressive medication within the last 14 days of initiating study treatment .
- 11.Subject has impaired cardiac function or clinically significant cardiac disease.
- 12.Subject received prior therapy with iberdomide.
- 13.Subject received any of the following a.Plasmapheresis within the last 28 days of initialting study treatment b.Major surgery within 28 days of initialting study treatment c.Radiation therapy, other than local palliative therapy, for myeloma associated bone lesions within 14 days of initialting study treatment d.Use of any systemic anti-myeloma drug therapy within 14 days of initialting study treatment
- 14.Subject received any investigational agent within 28 days.
- 15.Subject has previously received a live vaccine within 3 months of of initialting study treatment.
- 16.Concurrent administration of a strong inhibitor or inducer of CYP450 (including within 14 days of initialting study treatment).
- 17.Subject is unable or unwilling to undergo protocol required thromboembolism or herpes zoster prophylaxis.
- 18.Subject has previously received allogeneic stem cell transplantation at any time during prior therapy or received autologous stem cell transplantation within 12 weeks of initialting study treatment.
- 19.Subject has known COPD with a FEV1 <50% of predicted normal.
- 20.Subject has known moderate or severe persistent asthma within the last 2 years, or currently has uncontrolled asthma of any classification.
- 21.Subject is an individual of childbearing potential who is pregnant, nursing or breastfeeding, or who intends to become pregnant during participation in the study.
- 22.Subject is positive for human immunodeficiency virus, chronic or active hepatitis B, A or C.
- 23.Subject has prior history of systemic or clinically significant allergies, hypersensitivity, or intolerance to boron or mannitol, hyaluronidase, sorbitol, corticosteroids, monoclonal antibodies or human proteins, cereblon modulating agents or their excipients or known sensitivity to mammalian-derived products.
- 24.Subject has any contraindications to daratumumab, bortezomib or dexamethasone, per local PI.
- Vulnerable, under judicial protection, people without freedom by administrative or judicial decision, people with psychiatric conditions without their consent, people accepted in a health or social institution for other purposes than the research, adults under legal guardianship, curatorship, and people incapable of giving consent personally.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 11 Jun 2021 | 24 |
 Belgium | Not Recruiting | 11 Jun 2021 | 11 |
 Czechia | Not Recruiting | 11 Jun 2021 | 10 |
 Denmark | Not Recruiting | 11 Jun 2021 | 11 |
 Finland | Not Recruiting | 11 Jun 2021 | 10 |
 France | Not Recruiting | 11 Jun 2021 | 72 |
 Germany | Not Recruiting | 11 Jun 2021 | 24 |
 Greece | Not Recruiting | 11 Jun 2021 | 48 |
 Ireland | Not Recruiting | 11 Jun 2021 | 10 |
 Italy | Not Recruiting | 11 Jun 2021 | 32 |
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 |
|---|---|---|---|---|---|---|
Dexamethasone 2mg Tablets | Comparator | TABLETS | ORAL | 40 | 999 | PRD4219381 |
Iberdomide | Test | CAPSULE | ORAL USE | 1.6 | 999 | PRD10086310 |
Iberdomide | Test | CAPSULE | ORAL USE | 1.6 | 999 | PRD10519000 |
BORTEZOMIB | Comparator | — | SUBCUTANEOUS | 1.3 | 999 | SUB20020 |
Dexamethason-ratiopharm® 4 mg Tabletten | Comparator | TABLETTEN | ORAL | 40 | 999 | PRD668856 |
DARZALEX 1800 mg solution for injection | Comparator | SOLUTION FOR INJECTION | SUBCUTANEOUS | 1800 | 999 | PRD8157846 |
Iberdomide | Test | CAPSULE | ORAL USE | 1.6 | 999 | PRD10086322 |
Iberdomide | Test | CAPSULE | ORAL USE | 1.6 | 999 | PRD10086311 |