This phase Ib trial tests the safety, side effects, and best dose of CC-92480 in combination with elotuzumab and dexamethasone in treating patients with multiple myeloma that has come back after a period of improvement (relapsed) or that does not respond to treatment or has not responded to previous treatment (refractory). Multiple myeloma (MM) remains the second most common hematologic malignancy in the United States. A number of therapies have been approved for patients with MM, including CD38- and B-cell maturating antigen (BCMA)-targeted therapies (antibody and plasma cell treatments that help the body's immune system to kill cancer cells); however, patients will often relapse and become refractory to these therapies. Because of this, it is important to identify effective treatment options for patients progressing on anti-CD38 therapy and BCMA-directed therapies. Elotuzumab is a humanized IgG1 monoclonal antibody, which is a type of protein that can bind to other target cells to prevent them from working the way they should or cause them to act differently. Elotuzumab works by targeting a protein called SLAMF7, which is present on myeloma cells, and makes it easier for the immune system to target the cancer. CC-92480 works by binding to a protein called CRBN that triggers the breakdown of proteins: Ikaros and Aiolos, leading to cell death in multiple myeloma cells. Dexamethasone is a synthetic adrenocortical steroid, or steroid normally naturally made by the adrenal gland in the brain which has been produced in a laboratory, that helps to regulate the amount of different chemicals and water that are being processed by the kidneys. It is also used in patients with myeloma to help treat their disease. The combination of CC-92480 with elotuzumab and dexamethasone may be a safe and effective treatment when given to patients with relapsed or recurrent MM.
PRIMARY OBJECTIVE: I. To evaluate the safety and tolerability of elotuzumab, mezigdomide (CC-92480), and dexamethasone (E480d) in patients with relapsed/refractory multiple myeloma (RRMM) who have received \>= 2 prior regimens including CD38- and BCMA-targeted therapies. SECONDARY OBJECTIVES: I. Determine the time to response (TTR), the duration of response (DOR), very good partial response \[VGPR\] or better and complete response \[CR\] rates, progression free survival (PFS) at 1 year, and overall survival (OS) at 1 year. II. Check minimal residual disease (MRD) negativity rates by next generation sequencing in patients who are suspected of attaining a complete response (CR). III. Correlative studies will include changes in lymphocyte subsets with therapy, immunophenotype of MM cells, and expression of CRBN, Ikaros, and Aiolos. IV. Quality of life (QOL) will be assessed. OUTLINE: This is a dose-escalation study of CC-92480, followed by a dose-expansion study. Patients receive elotuzumab intravenously (IV) on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 orally (PO) on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an echocardiography (ECHO) during screening and undergo magnetic resonance imaging (MRI), computed tomography (CT), or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study. After completion of study treatment, patients are followed up at 30 and 60 days and then every 12 weeks for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Undergo blood sample collection
Undergo bone marrow biopsy and aspiration
Undergo bone marrow biopsy and aspiration
Undergo CT
Given IV or PO
Undergo ECHO
Given IV
Undergo MRI
Given PO
Undergo x-ray imaging
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
The recommended phase 2 dose of mezigdomide (CC-92480) in combination with elotuzumab and dexamethasone
The dose limiting toxicity (DLT) will be defined as one or more of the following toxicities considered to be at least possibly related to the study drug, occurring during cycle 1 of therapy. Furthermore, inability to take \>= 75% of the planned CC-92480 doses, or receive cycle 2 day 1 doses due to a drug-related adverse event occurring in cycle 1 will be considered a DLT.
Time frame: Up to 28 days (Cycle 1)
Incidence of adverse events
Adverse events and toxicities of the combination regimen will be summarized using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Toxicities will be assessed overall, as well as by dose level. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. The incidence of severe (grade 3+) adverse events or toxicities will be described. Will also assess tolerability of the regimen through assessing the number of patients who required dose modifications and/or dose delays. In addition, will capture the proportion of patients who go off treatment due to adverse reactions. All patients who have received at least one dose of any of the study regimen will be evaluable for toxicity.
Time frame: Up to 2 years
Time to progression (TTP)
Primary evaluation of antitumor activity of study treatment will be assessed according to IMWG response criteria. For TTP, cumulative incidence rates will be calculated and compared using Gray's test accounting for competing risks.
Time frame: From start of treatment until objective tumor progression; with death as a competing risk, assessed at 1 year
Time to response (TTR)
Primary evaluation of antitumor activity of study treatment will be assessed according to IMWG response criteria. For TTR, cumulative incidence rates will be calculated and compared using Gray's test accounting for competing risks
Time frame: From start of treatment until measurement criteria are first met for PR, very good partial response (VGPR), or complete response (CR) (whichever status is recorded first), assessed at 1 year
Duration of response (DOR)
DOR will be computed for subjects whose best response is either PR, VGPR, or CR. Primary evaluation of antitumor activity of study treatment will be assessed according to IMWG response criteria. DOR will be analyzed using the Kaplan-Meier method. The probability of survival and median DOR will be calculated together with 95% CIs, and log-rank test will be used for the comparison between patient subgroups.
Time frame: From the time measurement criteria are first met for partial response or better (whichever status is recorded first) until the first date of progressive disease or death, assessed at 1 year
Very good partial response (VGPR) or better rates
Primary evaluation of antitumor activity of study treatment will be assessed according to IMWG response criteria. VGPR will be analyzed using the Kaplan-Meier method. The probability of survival and median DOR will be calculated together with 95% CIs, and log-rank test will be used for the comparison between patient subgroups.
Time frame: From start of treatment until disease progression or death, assessed at 1 year
Complete Response (CR)
Primary evaluation of antitumor activity of study treatment will be assessed according to IMWG response criteria. CR will be analyzed using the Kaplan-Meier method. The probability of survival and median DOR will be calculated together with 95% CIs, and log-rank test will be used for the comparison between patient subgroups.
Time frame: From start of treatment until disease progression or death, assessed at 1 year
Progression free survival (PFS)
Primary evaluation of antitumor activity of study treatment will be assessed according to IMWG response criteria. PFS will be analyzed using the Kaplan-Meier method. The probability of survival and median PFS will be calculated together with 95% CIs, and log-rank test will be used for the comparison between patient subgroups.
Time frame: From start of treatment until disease progression or death, assessed at 1 year
Overall survival (OS)
Primary evaluation of antitumor activity of study treatment will be assessed according to IMWG response criteria. OS will be analyzed using the Kaplan-Meier method. The probability of survival and median OS will be calculated together with 95% CIs, and log-rank test will be used for the comparison between patient subgroups.
Time frame: From start of treatment to the date of his or her death, assessed at 1 year
Minimal residual disease (MRD)
Planned for patients suspected of attaining CR. MRD negativity is associated with superior outcomes compared to MRD positivity.
Time frame: At final study visit, up to 2 years
Changes in lymphocyte subsets with therapy
Changes in expression of these markers across time will be explored by dose level graphically. Relationships between changes in lymphocyte subsets, total number and ratio of regulatory T cells will be explored graphically (e.g. side-by-side boxplots) and with quantitative summaries, compared using Mann-Whitney test or Fisher exact test depending on the data type of expression data.
Time frame: Up to 2 years
Changes in immunophenotype of multiple myeloma cells
Correlative studies including the changes in expression of these markers across time will be explored by dose level graphically.
Time frame: Up to 2 years
Changes in expression of CRBN, Ikaros, and Aiolos with therapy
Changes in expression of these markers across time will be explored by dose level graphically.
Time frame: Up to 2 years
Quality of life (QOL)
Measured with the Patient-Reported Outcomes Measurement Information System Global 10 Quality of Life Survey and The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Multiple Myeloma20. A repeated measures linear mixed model will be fit to all QOL scores. The model will include all time points (baseline as reference session 0 and 1-6 or higher for each monthly measure), and a patient-level random effect. A p-value for the difference between baseline QOL and QOL at the end of the study will be obtained from the model, and if the positive difference with p-value is \< 0.05 QOL will be seen as improved.
Time frame: At baseline and monthly until study completion, up to 2 years
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