Isatuximab, Carfilzomib, Pomalidomide, and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This phase II trial studies the effect of isatuximab, carfilzomib, pomalidomide, and dexamethasone in treating patients with multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Isatuximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Carfilzomib may stop the growth of cancer cells by blocking some of the proteins needed for cell growth. Pomalidomide may help shrink or slow the growth of mutliple myeloma. Anti-inflammatory drugs, such as dexamethasone lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Giving isatuximab, carfilzomib, pomalidomide, and dexamethasone may kill more cancer cells.

Detailed Description
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OUTLINE: INDUCTION: Patients receive isatuximab intravenously (IV) on days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of subsequent cycles carfilzomib IV over 30 minutes on days 1, 8, and 15, pomalidomide orally (PO) once daily (QD) on days 1-21, and dexamethasone PO or IV on days 1,8, 15, and 22. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive isatuximab IV days 1 and 15, carfilzomib IV over 30 minutes on days 1 and 15, pomalidomide PO QD on days 1-21, and dexamethasone PO or IV on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then for up to 5 years.

Official Title
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Isatuximab, Carfilzomib, Pomalidomide, and Dexamethasone (Isa-KPd) for Patients With Relapsed/Refractory Multiple Myeloma

Conditions
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Recurrent Multiple Myeloma, Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Dexamethasone
* Biological: Isatuximab
* Drug: Pomalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with relapsed or refractory multiple myeloma, with >= 1 prior therapy Must have received prior lenalidomide therapy Must have measurable disease, as defined by International Myeloma Working Group criteria, having one or more of the following: Serum M protein >= 0.5 g/dL Urine M protein >= 200 mg/24 hours Involved serum free light chain level >= 10 mg/dL with abnormal kappa/lambda ratio Measurable biopsy-proven plasmacytomas (>= 1 lesion has a single diameter >= 2 cm) Bone marrow plasma cells >= 30% Age 18 years and older, and have the capacity to give informed consent Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Subjects should have resolution of any toxicities from prior therapy to grade =< 1 or baseline prior to enrollment (with the exception of peripheral neuropathy) Subjects are required to have grade =< 2 peripheral neuropathy to enroll Prior autologous stem cell transplant is allowed; patients must be >= 6 months post- autologous stem cell transplantation to enroll Estimated glomerular filtration rate (eGFR) >= 20 ml/min Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) Total bilirubin =< 2 x ULN Absolute neutrophil count (ANC) >= 1,000/uL Platelets >= 50,000/uL Hemoglobin >= 8 g/dL Growth factor use or transfusions may be used to meet the eligibility requirement for ANC, platelets, and hemoglobin Female patients of childbearing potential and male patients must agree to use 2 effective forms of contraception or continuously abstain from heterosexual intercourse during the period of therapy, and for 6 months after discontinuation of study treatment for females and 3 months after discontinuation of study treatment for males Exclusion Criteria: History of clinically significant cardiovascular disease, including congestive heart failure New York Heart Association (NYHA) class 3-4, symptomatic ischemia, left ventricular ejection fraction < 40%, uncontrolled conduction abnormalities, myocardial infarction in last 6 months Uncontrolled hypertension as determined by the principal investigator (PI) or designee Active plasma cell leukemia or systemic amyloid light-chain (AL) amyloidosis History of another primary malignancy that has not been in remission for at least 1 year (with the exception of non-melanoma skin cancer, curatively treated localized prostate cancer, curatively treated superficial bladder cancer and cervical carcinoma in site on biopsy or a squamous intraepithelial lesion on papanicolaou [PAP] smear) For patients with chronic hepatitis B viral infection, the hepatitis B virus (HBV) polymerase chain reaction (PCR) must be undetectable on suppressive therapy Patients with a history of Hepatitis C viral infection must have been treated and cured. For patients on treatment for hepatitis C, they are eligible if they have an undetectable hepatitis C virus (HCV) viral load Subjects with active uncontrolled infection Concurrent use of other anticancer agents or experimental treatments Treatment with anti-CD38 monoclonal antibody therapy in the last 90 days

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (isatuximab, carfilzomib, pomalidomide, steroid)<br>INDUCTION: Patients receive isatuximab IV on days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of subsequent cycles carfilzomib IV over 30 minutes on days 1, 8, and 15, pomalidomide PO QD on days 1-21, and dexamethasone PO or IV on days 1,8, 15, and 22. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive isatuximab IV days 1 and 15, carfilzomib IV over 30 minutes on days 1 and 15, pomalidomide PO QD on days 1-21, and dexamethasone PO or IV on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. | Drug: Carfilzomib<br>* Given IV<br>* Other names: CFZ;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Biological: Isatuximab<br>* Given IV<br>* Other names: SAR-650984;Drug: Pomalidomide<br>* Given PO<br>* Other names: CC4047;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Responses will be based on the International Myeloma Working Group criteria for response in multiple myeloma. | Up to 5 years post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS will be calculated using assessments by investigators. Kaplan-Meier methodology will be used to estimate event-free curves and corresponding quartiles (including the median). | From first study drug administration to the first occurrence of disease progression or death from any cause, assessed up to 5 years | 
| Overall survival | Kaplan-Meier methodology will be used to estimate the event-free curves. | From the first study drug administration to death from any cause, assessed up to 5 years | 
| Time to progression |  | Up to 5 years post treatment | 
| Incidence of adverse events | Will be measured by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. | Up to 30 days post treatment | 
| Rates of minimal residual disease negativity | Measured by next-generation sequencing of immunoglobulin genes in the bone marrow. | Up to 5 years post treatment |