Extramedullary Disease in Multiple Myeloma, Recurrent Multiple Myeloma, Refractory Multiple Myeloma
Conditions
Brief summary
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.
Interventions
BIOLOGICALMezigdomide
Given PO
DRUGCarfilzomib
Given IV
DRUGDexamethasone
Given PO
PROCEDUREEchocardiography
Undergo ECHO
PROCEDUREPositron Emission Tomography
Undergo PET/CT
PROCEDUREComputed Tomography
Undergo PET/CT
PROCEDUREComputed Tomography Assisted Biopsy
Undergo CT guided tumor Biopsy
PROCEDUREBone Marrow Aspiration
Undergo bone marrow aspiration biopsy
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy
PROCEDUREBiospecimen Collection
Undergo blood and saliva sample collection
Sponsors
Roswell Park Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | At the end of cycle 6 (each cycle is 28 days). | 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 | At the end of cycle 6 (each cycle is 28 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free survival | Time from first dose of mezigdomide to disease progression or death from any cause, whichever occurs first, assessed up to 3 years | 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) |
| Incidence of Adverse Events (AEs) | Up to 30 days after last dose of study drug | 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. |
| Imaging Response | 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) | 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. |
| Overall Survival | Time from first dose of mezigdomide to death from any cause, assessed up to 3 years | 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) |
| Duration of response | From the first documentation of response (≥ PR) to the first documentation of progressive disease or death, assessed up to 3 years | 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 |
Countries
United States
Contacts
Primary ContactASK RPCI
Outcome results
None listed