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

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 hours (h) * Serum free light chain (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 Response Evaluation Criteria in Solid Tumors (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)
• Hemoglobin: ≥ 8 g/dL
• Adequate cardiac pump function with a left ventricular ejection fraction of ≥ 40%
• Females of childbearing potential (FCBP) must: * Have two negative pregnancy tests as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after discontinuation of mezigdomide. This applies even if the subject practices true abstinence from heterosexual contact. ** True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and coitus interruptus (withdrawal) are not acceptable methods of contraception. * 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, two reliable forms of contraception as defined in the Pregnancy Prevention Plan (PPP) and provided to the subject at the time of informed consent, without interruption, 28 days prior to starting mezigdomide, during the study therapy (including during dose interruptions), and for 184 days after the last dose of mezigdomide (or carfilzomib). ** True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and coitus interruptus (withdrawal) are not acceptable methods of contraception. Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point and, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 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 subjects must: * Practice true abstinence (which must be reviewed on a monthly basis) or agree to use of a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study (even during dose interruptions) and for at least 94 days following mezigdomide (or carfilzomib) last dose in accordance with the Pregnancy Prevention Plan (PPP) provided to the subject at the time of informed consent, even if he has undergone a successful vasectomy. ** True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and coitus interruptus (withdrawal) are not acceptable methods of contraception
• Males must agree to refrain from donating sperm while on mezigdomide for 94 days after the last dose of mezigdomide. Females must agree to refrain from donating ova while on mezigdomide for 184 days after last dose
• 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