Mezigdomide, Carfilzomib, and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma in Patients With Extramedullary Disease

Phase II Clinical Trial of Mezigdomide/Carfilzomib/Dexamethasone (MeziKD) in Patients With Relapsed or Refractory Multiple Myeloma (MM) With Extramedullary Disease (EMD)

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.

Study Overview

• Status: Recruiting
• Conditions: Refractory Multiple Myeloma; Recurrent Multiple Myeloma; Extramedullary Disease in Multiple Myeloma
• Intervention / Treatment: Drug: Dexamethasone; Procedure: Echocardiography; Procedure: Computed Tomography; Procedure: Positron Emission Tomography; Drug: Carfilzomib; Procedure: Biospecimen Collection; Procedure: Bone Marrow Biopsy; Biological: Mezigdomide; Procedure: Computed Tomography Assisted Biopsy; Procedure: Bone Marrow Aspiration

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: ASK RPCI; Phone Number: 8772757724; Email: askroswell@roswellpark.org

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Recruiting
      • Roswell Park Cancer Institute
      • Contact: Ask RPCI; Phone Number: 800-767-9355; Email: ASKRPCI@roswellpark.org
      • Principal Investigator: Jens Hillengass

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

• Measurable disease meeting at least one of the following:

  • Serum M-protein ≥1 g/dL
  • Urine M-protein ≥200 mg/24 h
  • Serum FLC assay: involved FLC level ≥10 mg/dL provided serum FLC ratio is abnormal
  • Up to 10 patients without measurable disease can be enrolled but screening imaging and/or bone marrow biopsy have to confirm RRMM. Follow-up response assessment will be performed with imaging using RECIST 1.1 and Deauville Criteria and bone marrow biopsies
• Absolute neutrophil count: ≥ 1 x 10^9/L
• Platelets: ≥ 75 x 10^9/L
• Total bilirubin: ≤ 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]): ≤ 3 x ULN
• Renal function: Estimated creatinine clearance ≥ 30 mL/min (Cockroft-Gault)
• Adequate cardiac pump function with a left ventricular ejection fraction of ≥ 40%
• Women of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for at least 28 days after the last dose of mezigdomide or 6 months after the last dose of carfilzomib. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Male patients (non-vasectomized) must agree to use contraception during the treatment period and for at least 28 days after the last dose of mezigdomide or 3 months after the last dose of carfilzomib and refrain from donating sperm during this period
• Participant must understand the investigational nature of this study and sign an independent ethics committee/institutional review board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

• 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
• Any medical conditions that, in the investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participation in this study
• Known active infection requiring parenteral or oral anti-infective treatment within the past 14 days

• Participant has a history of prior malignancy other than MM, except if the participant has been free of disease for ≥ 3 years or the participant had 1 of the following noninvasive malignancies treated with curative intent without known recurrence:

  • Basal or squamous cell carcinoma of the skin
  • Carcinoma in situ of the cervix or breast
  • Stage 1 bladder cancer
  • Incidental histological findings of localized prostate cancer such as tumor stage 1a or 1b (T1a or T1b) using the tumor, nodes, and metastasis (TNM) classification of malignant tumors OR prostate cancer that has been treated with curative intent
• Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to patient registration
• Pregnant or breast-feeding females
• Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation
• Known active HIV or hepatitis B or C viral infection
• Known history of HIV infection
• Systemic amyloidosis or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein] and skin changes)
• Prior peripheral stem cell transplant within 12 weeks of study enrollment
• Radiotherapy within 14 days prior to cycle 1 day 1. However, if the radiation portal covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy
• Known intolerance to steroid therapy
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, severe cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Carfilzomib-refractory in the most recent line of therapy
• Prior treatment with mezigdomide
• Contraindication against conscious sedation
• Unwilling or unable to follow protocol requirements
• Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment - MeziKD; Patients receive mezigdomide PO QD on days 1-21 of each cycle, carfilzomib IV over 30 minutes on days 1, 8, and 15 of each cycle, and dexamethasone PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After 6 cycles of study treatment, patients showing a response to therapy may continue the treatment regimen as part of standard of care per physician's discretion. Additionally, patients undergo ECHO, PET/CT, MRI, CT guided tumor biopsy, bone marrow aspiration and biopsy, and blood and saliva sample collection throughout the study,

Drug: Dexamethasone; Given PO; Other Names: Decadron; Adexone; Baycadron; Cortidexason; Dekacort; Fortecortin; Gammacorten; Hexadecadrol; Loverine; Millicorten; Orgadrone; Spersadex; TaperDex; Visumetazone; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Computed Tomography; Undergo PET/CT; Other Names: CAT; CAT Scan; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: PET; PET scan; Drug: Carfilzomib; Given IV; Other Names: CFZ; Procedure: Biospecimen Collection; Undergo blood and saliva sample collection; Other Names: Biological Sample Collection; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Biological: Mezigdomide; Given PO; Other Names: CC-92480; BMS 986348; Procedure: Computed Tomography Assisted Biopsy; Undergo CT guided tumor Biopsy; Other Names: CT Assisted Biopsy; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	At the end of cycle 6 (each cycle is 28 days).
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.	At the end of cycle 6 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 30 days after last dose of study drug
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	From the first documentation of response (≥ PR) to the first documentation of progressive disease or death, assessed up to 3 years
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)	Time from first dose of mezigdomide to disease progression or death from any cause, whichever occurs first, assessed up to 3 years
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)	Time from first dose of mezigdomide to death from any cause, assessed up to 3 years
Imaging Response	Will be assessed in those without serologically measurable disease using positron emission tomography/computed tomography and magnetic resonance imaging. Will be assessed using Response Evaluation Criteria in Solid Tumors v1.1 and Deauville criteria.	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)

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Investigators: Principal Investigator: Jens Hillengass, MD, Roswell Park Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2025
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2030

Study Registration Dates

• First Submitted: October 2, 2024
• First Submitted That Met QC Criteria: October 3, 2024
• First Posted (Actual): October 4, 2024

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: January 9, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hemic and Lymphatic Diseases; Multiple Myeloma; Sulfur Compounds; Organic Chemicals; Investigative Techniques; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Benzene Derivatives; Chemistry Techniques, Analytical; Sulfonic Acids; Sulfur Acids; Spectrum Analysis; Pregnadienetriols; Benzenesulfonates; Arylsulfonates; Arylsulfonic Acids; Dexamethasone; Calcium Dobesilate; Magnetic Resonance Spectroscopy; carfilzomib; dexamethasone 21-phosphate; dexamethasone acetate
• Other Study ID Numbers: I-3576824

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes