Iberdomide Versus Observation Off Therapy After Idecabtagene Vicleucel CAR-T for Multiple Myeloma

Study Overview
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Brief Summary
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This phase II trial compares iberdomide maintenance therapy to disease monitoring for improving survival in patients who have received idecabtagene vicleucel (a type of chimeric antigen receptor T-cell [CAR-T] therapy) for multiple myeloma. The usual approach after treatment with idecabtagene vicleucel is to monitor the multiple myeloma without giving myeloma medications. There is currently no medication approved specifically for use after idecabtagene vicleucel treatment. Upon administration, iberdomide modifies the immune system and activates immune cells called T-cells, which could enhance the effectiveness of idecabtagene vicleucel. Iberdomide may keep multiple myeloma under control for longer than the usual approach (disease monitoring) after idecabtagene vicleucel, and may help multiple myeloma patients live longer.

Detailed Description
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PRIMARY OBJECTIVES: I. To establish and confirm the safety and dose of iberdomide as maintenance after idecabtagene vicleucel (ide-cel) CAR-T. (Safety run-in) II. To assess whether iberdomide maintenance therapy after idecabtagene vicleucel CAR-T cell therapy increases progression-free survival (PFS) relative to observation without additional therapy. (Randomized phase II) SECONDARY OBJECTIVES: I. To demonstrate anti-tumor activity, defined as conversion from non-minimal residual disease (MRD) complete response (CR)/stringent CR (sCR) status to MRD-negative CR/sCR, as well as improvement in PFS in the safety run-in cohort. (Safety run-in) II. To estimate the rate of conversion from MRD-positive at baseline to MRD-negative at any time point post-initiation of iberdomide maintenance or observation without additional therapy. (Key secondary objective; Randomized phase II) III. To estimate overall survival (OS) distribution post-initiation of iberdomide maintenance or observation without additional therapy. (Key secondary objective; Randomized phase II) IV. To estimate the minimal residual disease (MRD)-negativity rate at pre-registration and at one year post-initiation of iberdomide maintenance or observation without additional therapy. (Randomized phase II) V. To estimate rate of deepening hematological response among patients with measurable multiple myeloma (MM) post-initiation of iberdomide maintenance or observation without additional therapy. (Randomized phase II) VI. To evaluate the safety profile of iberdomide maintenance. (Randomized phase II) VII. To evaluate the peripheral blood immunophenotype before and during iberdomide maintenance or observation without additional therapy. (Randomized phase II) VIII. To evaluate persistence of CAR-T cells with iberdomide maintenance or observation without additional therapy. (Randomized phase II) CORRELATIVE SCIENCE OBJECTIVES: I. To estimate the minimal residual disease (MRD)-negativity rate at start of maintenance and at one year post-initiation of maintenance or observation. II. To estimate the sustained MRD-negativity rate. III. To estimate the rate of conversion from MRD-positive to MRD-negative. (Key objective) IV. To evaluate the peripheral blood immunophenotype before and during maintenance therapy or observation. V. To evaluate the persistence of CAR-T cells. VI. To evaluate B-cell maturation antigen (BCMA) protein expression by immunohistochemistry on myeloma cells from patients that have relapsed/recurrent disease. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP 1: Patients undergo disease monitoring at monthly clinic visits until disease progression. Patients also undergo bone marrow aspiration and biopsy throughout the trial, undergo collection of blood samples at screening and on study, and undergo positron emission tomography (PET)/computed tomography (CT) and/or skeletal survey x-ray, CT, or magnetic resonance imaging (MRI) at screening and then as clinically indicated. GROUP 2: Patients receive iberdomide orally (PO) once daily (QD) on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy throughout the trial, undergo collection of blood samples at screening and on study, and undergo PET/CT and/or skeletal survey x-ray, CT, or MRI at screening and then as clinically indicated. After completion of study treatment, patients are followed up within 30 days, then every 3-6 months until 4 years following registration.

Official Title
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Randomized Phase 2 Study of Iberdomide Maintenance Therapy Following Idecaptagene Vicleucel CAR-T in Multiple Myeloma Patients

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Aspiration
* Procedure: Bone Marrow Biopsy
* Procedure: Computed Tomography
* Drug: Iberdomide
* Procedure: Magnetic Resonance Imaging
* Procedure: Patient Monitoring
* Procedure: Positron Emission Tomography
* Procedure: Skeletal Survey X-Ray


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0): All patients must be pre-registered in order to submit the required bone marrow and blood specimens Note: Bone marrow aspirate for patients who consent to biobanking should also be submitted at this time as outlined Please ensure patient has suspected diagnosis of multiple myeloma and meets on study guidelines prior to informed consent and biospecimen collection In cases where the bone marrow aspiration may be inadequate at Step 0 registration, the patient may still register on study ELIGIBILITY CRITERIA (STEP 1): Patients must have diagnostically confirmed MM in response status of stable disease or better by International Myeloma Working Group (IMWG) criteria at day 80-110 post-infusion of ide-cel All subjects are required to have received ide-cel CAR-T within 80-110 days of registration Adverse events related to ide-cel are required to have resolved to grade =< 1 except fatigue, alopecia, and other events that are unlikely to interfere with study assessments or pose a safety risk to participants Prior therapy with iberdomide is permitted but prior iberdomide refractoriness is prohibited. Refractoriness is defined as per published IMWG criteria; progression while on iberdomide or within 60 days of stopping iberdomide Subjects who have received MM-directed therapy since ide-cel infusion are not eligible, with the exception of short-course steroids for managing ide-cel toxicity as described below Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Absolute neutrophil count (ANC) ≥ 1,500/mm^3 Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria Platelet count ≥ 75,000/mm^3 Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria Calculated (calc.) creatinine clearance > 30 mL/min by Modification of Diet in Renal Disease (MDRD) Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria Total bilirubin ≤ 1.5 x upper limit of normal (ULN) Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x upper limit of normal (ULN) Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effect on the developing fetus and newborn are unknown. FCBP (female of childbearing potential) is a female who: 1) has achieved menarche (first menstrual cycle) at some point, 2) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) 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 during the preceding 24 consecutive months). Females of childbearing potential (FCBP): Must use a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with low user dependency during the intervention period and for at least 28 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. The effects of iberdomide on the developing human fetus are unknown. Immunodulatory derivative (IMiD) agents as well as other therapeutic agents used in this trial are known to be teratogenic. Females of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to, and again within 24 hours of starting iberdomide, and must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before she starts taking iberdomide. Examples of highly effective methods are intrauterine device, hormonal contraceptives, tubal ligation, or partner's vasectomy. Examples of barrier method are male condom, diaphragm, or cervical cap. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risk of fetal exposure. Should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, she should inform her treating physician immediately. FCBP must use adequate contraception for at least 28 days after discontinuation from study. Because of the potential for serious adverse reactions in a breastfed child, women are advised not to breastfeed during treatment and for at least 28 days after the last dose. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy. Non-childbearing potential is defined as follows (by other than medical reasons): ≥ 45 years of age and has not had menses for > 1 year Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure Male patients must agree to use an adequate method of contraception for the duration of the study and for 28 days afterwards. Male participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies: Male participants are eligible to participate if they agree to the following during the intervention period and for 28 days after the last dose of study treatment to allow for clearance of any altered sperm: Refrain from donating sperm PLUS, either: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR Must agree to use contraception/barrier as detailed below: Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of <1% per year as when having sexual intercourse with a woman of childbearing potential (including pregnant females) Patients may not have polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome or amyloidosis involving any vital organ; amyloidosis found in skin or lymph nodes (non-vital organs), or incidental observation of amyloidosis on bone marrow biopsy, are both permissible. Plasma cell leukemia is permissible for study enrollment Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load Patients may not have other, active infections at time of study registration. Recent infections are not exclusionary if antibiotics have been completed and infection is considered to be resolved / controlled. (Chronic maintenance antibiotics for prior infections, such as fungal, are permissible.) No known allergy to iberdomide No known medical condition causing an inability to swallow oral formulations of agents Patients receiving other active therapies for MM since ide-cel infusion are prohibited from participating in the study Corticosteroids used for the purpose of managing ide-cel toxicity (often neurotoxicity) soon after ide-cel administration are acceptable, provided that the participant will have been off corticosteroids for > 30 days by cycle 1 day 1. Physiologically dosed chronic steroids are permitted Given the potential for interaction with iberdomide, patients who take strong CYP3A4 inducers or inhibitors may enroll after switching to a different agent and after an appropriate washout period for that particular medication, ideally three half-lives, prior to cycle 1 day 1

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1 (monitoring)<br>Patients undergo disease monitoring at monthly clinic visits until disease progression. Patients also undergo bone marrow aspiration and biopsy throughout the trial, undergo collection of blood samples at screening and on study, and undergo PET/CT and/or skeletal survey x-ray, CT, or MRI at screening and then as clinically indicated. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Computed Tomography<br>* Undergo PET/CT and/or CT<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Patient Monitoring<br>* Undergo disease monitoring<br>* Other names: monitor;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;Procedure: Skeletal Survey X-Ray<br>* Undergo skeletal survey x-ray<br>* Other names: Skeletal Survey;|
| Experimental: Group II (iberdomide)<br>Patients receive iberdomide PO QD on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy throughout the trial, undergo collection of blood samples at screening and on study, and undergo PET/CT and/or skeletal survey x-ray, CT, or MRI at screening and then as clinically indicated. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Computed Tomography<br>* Undergo PET/CT and/or CT<br>* Other names: tomography;Drug: Iberdomide<br>* Given PO<br>* Other names: CC-220;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;Procedure: Skeletal Survey X-Ray<br>* Undergo skeletal survey x-ray<br>* Other names: Skeletal Survey;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (safety run-in) |  | The first 3 months of therapy | 
| Progression-free survival (PFS) (randomized phase II) | Final analyses will use log-rank test statistics to compare the PFS distributions between the treatment arms. Will also evaluate differences in PFS between the treatment arms using a stratified log-rank test. In addition, the methods of Kaplan and Meier will be used to graphically evaluate these distributions as well as to estimate the median PFS and corresponding 95% confidence intervals. Further, will also estimate the 1- and 2-year PFS rates for each treatment arm along with corresponding 95% confidence intervals. Finally, Cox proportional hazards models will be used to evaluate the impact of treatment arm on PFS. | From randomization to the time of progression and/or death, assessed up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Adverse events will be collected and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. For CTCAE data, the maximum grade for each type of adverse will be recorded for each patient, and described using frequency tables. All-cause adverse events will be summarized as well as treatment-related adverse events, with particular focus on grade 3+ non-hematologic adverse events and grade 4+ hematologic events. Frequency tables will be reviewed to identify patterns. The overall adverse event severity will be compared between treatment arms using a chi-square test (or Fisher's exact test if the data in contingency table is sparse). | Up to 4 years | 
| Number of treatment cycles received (tolerability) | Will be summarized. | Up to 4 years | 
| Proportion of patients with dose modifications, omissions, and/or delays (tolerability) | Will be summarized. | Up to 4 years | 
| Proportion of patients who go off treatment due to adverse events | Will be summarized. | Up to 4 years | 
| Overall survival (OS) | The Kaplan-Meier method will be used to estimate OS for each treatment arm, with 1- and 2-year OS estimates and OS medians along with their 95% confidence intervals. For the comparison of the treatment arms, will use a one-sided log-rank test to compare the OS distributions between treatment arms. Will also evaluate the influence of arm on OS using stratified and unstratified multivariable Cox proportional hazards models. | From randomization until death from any cause, assessed up to 4 years | 
| Best response achieved while on study | Will calculate these rates by treatment arm along with corresponding 95% binomial confidence intervals. Logistic regression models may also be used to assess differences in the ability to deepen or convert to a response between treatment arms. Minimal residual disease (MRD) will be assessed as an aspect of response assessment. | Up to 4 years | 
| Proportion of patients who improve their status | Will calculate these rates by treatment arm along with corresponding 95% binomial confidence intervals. Logistic regression models may also be used to assess differences in the ability to deepen or convert to a response between treatment arms. MRD will be assessed as an aspect of response assessment. | After randomization, up to 4 years |