Phase II Multicenter Study of Iberdomide and Dexamethasone, Alone or with Daratumumab, in Transplant-Ineligible Newly Diagnosed Multiple Myeloma Patients
- Trial ID
- 2024-518870-15-00
- Protocol
- GEM-IBERDARAX
- Sponsor
- Fundacion PETHEMA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **efficacy** of iberdomide in combination with dexamethasone (IBERDEX cohort 1) and also in combination with daratumumab and dexamethasone (IBERDARADEX cohort 2) in transplant ineligible newly diagnosed multiple myeloma (NDMM) patients. This will be measured by the overall response rate (ORR) and other response categories, with particular emphasis on the complete response rate (CRR) according to the International Myeloma Working Group (IMWG) response criteria 2016. The clinical relevance of this objective lies in its potential to improve treatment outcomes for NDMM patients who are not eligible for transplant, offering insights into the effectiveness of these combination therapies.
Secondary objectives include:
- Evaluating the efficacy in terms of minimal residual disease (MRD), focusing on the proportion of patients achieving MRD negativity at 12 months and sustaining it over time.
- Assessing time to event data, including Progression Free Survival (PFS) and Overall Survival (OS) in the overall, frail, and non-frail populations.
- Evaluating changes in immune profiling to better understand outcomes in different patient subgroups.
- Assessing quality of life evolution using EQ-5D/5L, QLQ-C30, and MY20 questionnaires at specified intervals.
- Assessing the safety of the combination therapies involving iberdomide, dexamethasone, and daratumumab.
- Evaluating Time to Progression (TTP) and time from start of therapy to second disease progression or initiation of third-line therapy (PFS2).
- Overall survival (OS).
Participants
The clinical trial focuses on patients diagnosed with **Multiple Myeloma** who are newly diagnosed and non-transplant eligible. The study population includes both male and female participants aged 18 years and older. Participants must have a measurable secretory disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. The trial does not include a vulnerable population. Participants are required to have adequate organ function and must be either non-frail or frail as defined by the modified-IMWG scale, with a target of 30% frail participants. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the ability to comply with study procedures and the provision of informed consent. Lifestyle considerations such as diet and physical activity are not specified. The trial population was selected based on specific medical and health criteria, ensuring participants are suitable for the study's objectives.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, phase II study to evaluate the efficacy of **iberdomide** in combination with **dexamethasone** and **daratumumab** in patients with newly diagnosed **multiple myeloma** who are ineligible for transplant. The trial aims to assess the overall response rate (ORR) and complete response rate (CRR) according to the International Myeloma Working Group (IMWG) response criteria. The study is expected to run from October 3, 2022, to March 20, 2025, with recruitment having started on December 1, 2022. The estimated end date for the trial is December 28, 2029.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, including age, performance status, and organ function. Following the screening, participants will be randomized into one of the treatment cohorts. Regular follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and ensure compliance with the study protocol. The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study.
The expected length of participant involvement in the trial is approximately 21 days for the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, disease progression, or withdrawal of consent by the participant. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and are aware of their rights to withdraw from the study at any time without prejudice to their future medical care.
Treatment
The clinical trial involves the administration of **DARATUMUMAB**, marketed as DARZALEX, which is provided as a **solution for injection**. This experimental medication is administered via **IV infusion**. The dosage is set at a maximum of 1800 mg per day, with the total dose not exceeding 1800 mg over a treatment period of 7 days. DARATUMUMAB is a protein-based therapeutic agent developed by Janssen-Cilag International NV. The administration schedule and participant compliance are monitored to ensure adherence to the protocol.
Another experimental medication used in the trial is **IBERDOMIDE**, which is provided in **capsule** form. This medication is administered **orally** with a maximum daily dose of 1 mg and a total dose not exceeding 1.3 mg over a treatment period of 21 days. IBERDOMIDE is a chemical-based immunomodulatory agent developed by Celgene Corporation. The dosing schedule is carefully monitored to ensure participant compliance and to evaluate the efficacy of the treatment regimen.
The trial also includes the use of **DEXAMETHASONE**, a standard-of-care therapy, which is combined with the experimental treatments in different cohorts. The study aims to evaluate the efficacy of IBERDOMIDE in combination with DEXAMETHASONE (IBERDEX cohort 1) and in combination with DARATUMUMAB and DEXAMETHASONE (IBERDARADEX cohort 2) in patients with newly diagnosed multiple myeloma who are ineligible for transplant. The primary objective is to assess the overall response rate and complete response rate according to the International Myeloma Working Group response criteria 2016.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Overall Response Rate (ORR)**, which includes various response categories with a particular focus on the **Complete Response Rate (CRR)**. This is defined as the percentage of participants achieving a confirmed complete response or better, such as stringent complete response. The trial will utilize the International Myeloma Working Group (IMWG) response criteria from 2016 to evaluate these outcomes.
Secondary endpoints for efficacy assessment include the **Minimal Residual Disease (MRD) negativity rate**, determined by next-generation flow cytometry (NGF), PET/CT, and mass spectrometry, following IMWG guidelines. Additional secondary endpoints include **Progression-Free Survival (PFS)**, **Overall Survival (OS)**, and the analysis of immune cell populations such as myeloid suppressor cells, monocytes, macrophages, antigen-presenting cells, NK, B, and T cells from baseline through treatment, remission, and disease progression. Patient-reported outcomes will be collected using the EQ-5D/5L, QLQ-C30, and MY20 questionnaires at baseline and at months 4, 8, 12, 18, and 24.
Data collection will also include the incidence of deaths and primary causes, vital signs, adverse events, therapy discontinuation rates due to adverse events, dose modification percentages, and changes in laboratory analytes from hematology and blood chemistry panels. The trial will also measure **Time to Progression (TTP)** and **PFS2**, which is the time from start of therapy to second disease progression or initiation of third-line therapy.
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 nor 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 ≥ 65 years or younger but non-transplant eligible who requires start active treatment according to the IMWG published in 2014.
- 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 is defined as non-frail or frail using the modified-IMWG scale. Frailty score according to the modified-IMWG scale will be collected before starting the treatment in order to ensure 30% of the patients are frail.
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
- Patient must be ≥ 18 years of age.
- Patient must have adequate organ function, defined as follows (see Table 3 in the protocol).
- Female childbearing potential patient (FCBP) criteria: 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 female of childbearing potential (FNCBP) OR • Is a FCBP and ✓ She understands the potential teratogenic risk to the unborn child. ✓ She understands the need for effective contraception, without interruption, 28 days before starting study treatment, throughout the entire duration of study treatment, during dose interruptions and for at least 3 months after the last dose of study treatment. ✓ She understands and agrees to inform the Investigator if a change or stop of method of contraception is needed. ✓ She must be capable of complying with effective contraceptive measures. ✓ She is informed and understands the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy. ✓ She understands the need to commence study treatment as soon as it is dispensed following a negative pregnancy test. ✓ She understands and accepts the need to undergo pregnancy testing based on the frequency outlined in this plan and in the Informed Consent. ✓ She acknowledges she understands the hazards study drugs can cause to an unborn fetus and the necessary precautions associated with the use of study drugs. ✓ She understands and accepts the need to undergo pregnancy testing based on the frequency outlined in this plan and in the Informed Consent. ✓ She acknowledges she understands the hazards study drugs can cause to an unborn fetus and the necessary precautions associated with the use of study drugs. The Investigator must ensure that a FCBP: Complies with the conditions of the pregnancy prevention plan, including confirmation that she has an adequate level of understanding. Acknowledges the aforementioned requirements. A FCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 24 hours before the first dose of study drug(s). Non-childbearing potential is defined as follows (by other than medical reasons): o Has not achieved menarche at some point. o Has undergone a hysterectomy or bilateral oophorectomy. o Has been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has not had menses at any time in the preceding 24 consecutive months).
- 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 during dose interruptions and for at least 3 months following the last dose of iberdomide to allow for clearance of any altered sperm: • Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a FCBP. • Understand the need for the use of a condom even if he has had a vasectomy, if engaged in sexual activity with a pregnant female or a FCBP. • Understand the potential teratogenic risk if the subject donates semen or sperm. • Understand that the effects on fertility are currently unknown, therefore all family planning options and/or alternatives should be thoroughly discussed with the study doctor prior to receiving study drugs.
- All prior treatment-related toxicities (defined by National Cancer Institute - Common Toxicity Criteria for Adverse Events), 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.
- Patient has invasive malignancies other than disease under study, unless the second malignancy has been medically stable for at least 2 years and, in the opinion of the principal investigators, will not affect the evaluation of the effects of clinical trial treatments on the currently targeted malignancy. Participants with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction.
- 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 lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment.
- Pregnant or breastfeeding females.
- Patient is simultaneously enrolled in other interventional clinical trial.
- Received plasmapheresis within 7 days prior to the first dose of study drug.
- Patient has received prior radiotherapy 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. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
- Patients has used any anti-myeloma drug therapy, except for steroid pulses in case of emergency (40 mg of dexamethasone for 4 days), the administration of bisphosphonates or antialgic radiotherapy or due to the presence of plasmacytomas requiring some emergency.
- Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to iberdomide or drugs chemically related to iberdomide, or any of the excipients contained in the formulation of the study treatment.
- Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to daratumumab or drugs chemically related to daratumumab, or any of the excipients contained in the formulation of the study treatment.
- Participant has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to other monoclonal antibodies.
- Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to dexamethasone or drugs chemically related to dexamethasone, or any of the excipients contained in the formulation of the study treatment.
- Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
- Patient has peripheral neuropathy or neuropathic pain grade ≥2, as defined by the National Cancer Institute Terminology Criteria for Adverse Events (NCI CTC AE) Version 5.0.
- Patient evidence of cardiovascular risk including any of the following: • QTcF interval QTcF > 480 msec (the QT interval values must be corrected for heart rate by Fridericia’s formula [QTcF]). • Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Type II) or 3rd degree atrioventricular (AV) block. • History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening. • Class III or IV heart failure as defined by the New York Heart Association functional classification system [NYHA, 1994]. • Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg despite optimal treatment.
- Patient has 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).
- Patients with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
- Patients 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.
- Patient has an active infection requiring antibiotic, antiviral, or antifungal treatment.
- Participant has known HIV infection.
- Patient has presence of 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 to also undergo Hepatitis C RNA testing.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 28 Apr 2022 | 140 |
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 |
|---|---|---|---|---|---|---|
Iberdomide | Test | CAPSULE | ORAL | 0.45 | 21 | PRD10086308 |
DARZALEX 1800 mg solution for injection | Test | SOLUTION FOR INJECTION | IV INFUSION | 1800 | 7 | PRD8157846 |
Iberdomide | Test | CAPSULE | ORAL | 1 | 21 | PRD10086311 |
Iberdomide | Test | CAPSULE | ORAL | 0.75 | 21 | PRD10086310 |