This phase II trial studies how well mezigdomide/carfilzomib/dexamethasone (MeziKD) works in treating patients with multiple myeloma (MM) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory) and have tumors from myeloma cells outside the bone marrow in the soft tissues or organs of the body (extramedullary disease \[EMD\]). Mezigdomide blocks important processes in myeloma cells and may lead to modulation of the immune system, including activation of T-lymphocytes, and downregulation of the activity of other proteins, some of which play key roles in the proliferation of certain cancer cell types. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Dexamethasone is a type of corticosteroid and is used to kill myeloma cells. It is used with other drugs to treat multiple myeloma. Giving MeziKD may kill more cancer cells in patients with relapsed/refractory multiple myeloma (RRMM) with EMD.
Age ≥ 18 years of age
Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
RRMM patients with one or more prior lines of therapy with at least one ES or PS lesion that is accessible to a biopsy. Accessibility will be assessed by the MM tumor board
Serum M-protein ≥1 g/dL
Participant has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, pomalidomide (including ≥ grade 3 rash during prior thalidomide, lenalidomide, or pomalidomide therapy), carfilzomib or dexamethasone, any cereblon E3 ligase modulators (CELMoD) agents, or the excipients contained in the formulations, or participant has any contraindications per local prescribing information
Administration of strong CYP3A modulators or proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) within 2 weeks of starting study intervention
Participant is unable or unwilling to undergo protocol required thromboembolism prophylaxis
Patient has evidence of mucosal or internal bleeding and/or is platelet transfusion refractory
Single group
Mezigdomide
Biological/VaccineGiven PO
Carfilzomib
DrugGiven IV
Dexamethasone
DrugGiven PO
Echocardiography
Procedure/SurgeryUndergo ECHO
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Computed Tomography
Procedure/SurgeryUndergo PET/CT
Computed Tomography Assisted Biopsy
Procedure/SurgeryUndergo CT guided tumor Biopsy
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration biopsy
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood and saliva sample collection
Overall Response Rate
Will be assessed in patients with serologically measurable disease. Will be defined as the percentage of patients with an objective response of partial response (PWR) or better by International Myeloma Working Group criteria on 2 consecutive evaluations among the eligible patients who began protocol treatment. Will be evaluated using a one-sided Binomial test and a 90% credible region for the overall response rate will be constructed using Jeffrey's prior method
Clinical benefit rate
Will be assessed in patients with non- or oligo-secretory disease. Clinical benefit rate is the percentage of patients who remain progression-free and on protocol treatment for at least 6 months among the eligible patients who began protocol treatment. A 90% binomial credible region will be constructed for the clinical benefit rate using Jeffrey's prior method.
Incidence of Adverse Events (AEs)
As per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0: type, frequency, seriousness, severity and relationship of AEs to mezigdomide and carfilzomib/dexamethasone. For each patient cohort, the AEs reported will be graded and an attribution assigned using CTCAE v5.0. For each patient, the maximum grade of each AE will be determined and the frequency of each AE by max grade will be tabulated for each cohort.
Duration of response
For those with and without serologically measurable disease, the DOR will be estimated by Kaplan-Meier method. Estimates of the median will be obtained with 90% confidence intervals
Progression Free survival
At screening, after 3 cycles of treatment (or progression, whichever occurs first), after 6 cycles of treatment, and then every 6 months for 3 years or until progression, start of a new therapy, or death (whichever occurs first)
Overall Survival
At screening, after 3 cycles of treatment (or progression, whichever occurs first), after 6 cycles of treatment, and then every 6 months for 3 years or until progression, start of a new therapy, or death (whichever occurs first)
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