Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma

Phase 2

Completed

Conditions: Multiple Myeloma

Interventions: Drug: Carfilzomib
Drug: Revlimid
Drug: Dexamethasone

Registration Number: NCT01572480

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

* Multiple myeloma is a blood cancer that affects the plasma cells. These cells help produce antibodies and fight infection. Smoldering multiple myeloma (SMM) is a related condition that may develop into multiple myeloma. The current standard of care for SMM is close follow-up without treatment until multiple myeloma develops. However, researchers are studying possible treatments for SMM itself. One possible treatment involves a combination of cancer treatment drugs.

* Lenalidomide is a drug that may help reduce or prevent the growth of cancer cells. Dexamethasone is a steroid that is often given with other anti-cancer drugs. These two drugs are an approved treatment for multiple myeloma that has not responded to at least one other treatment. Carfilzomib is an experimental drug that has been effective in treating multiple myeloma. Researchers want to combine these three drugs to see if they are a safe and effective treatment for SMM.

Objectives:

- To see if carfilzomib, lenalidomide, and dexamethasone are a safe and effective treatment for smoldering multiple myeloma.

Eligibility:

- Individuals at least 18 years of age who have SMM that is likely to progress to multiple myeloma.

Design:

* Participants will be screened with a physical exam and medical history. They will also have blood and urine tests, and baseline bone marrow scans. Bone marrow samples will also be collected.

* Participants will have eight 28-day cycles of treatment with the three study drugs. The drugs will be given as tablets or as infusions. Treatment will be monitored with frequent blood tests and study visits.

* After the first four cycles, participants who are eligible for a stem cell transplant will have their stem cells collected and stored for future use.

* At the end of eight cycles, participants whose disease has not progressed will have up to 12 more cycles of treatment with lenalidomide tablets alone.

Detailed Description: Background:

Smoldering multiple myeloma (SMM) is a precursor condition to multiple myeloma (MM) defined by the clinical parameters of M-protein \>= 3.0 g/dL or bone marrow plasma cells \>= 10% and absence of end organ disease.

Risk of progression of high risk SMM at 5 years is 72-75% with median time to progression \< 2 years.

The current standard of care for SMM is close follow-up without treatment until symptomatic MM develops. However, International Myeloma Working Group (IMWG) states "Preventive clinical trials need to be considered for patients with high risk smoldering myeloma".

Carfilzomib is a new proteasome inhibitor with potent anti-MM effects

Objectives:

To assess the response rate of cyclophosphamide, lenalidomide, and dexamethasone (CRd) in patients with high-risk SMM, focusing on the

Minimal residual disease (MRD(-) Complete Response (CR) rate

Eligibility:

SMM according to the International Myeloma Working Group definition; i.e.:

Serum M-protein \>=3 g/dl and/or bone marrow plasma cells \>=10 % and \< 60%

Absence of anemia: Hemoglobin \>10 g/dl

Absence of renal failure: serum creatinine \< 2.0 mg/dL.

Absence of hypercalcemia: Calcium (Ca) \< 10.5 mg/dl or 2.65 mmol/L

Absence of lytic bone lesion

Involved/un-involved light chain ratio must be \< 100

Measurable disease

High-risk SMM per Mayo Clinic, Spanish Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA), or the Rajkumar, Landgren, Mateos criteria

Age \>=18 years

Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Adequate laboratory parameters as defined in the protocol

Design:

Single arm pilot trial of combination therapy (carfilzomib, lenalidomide, and dexamethasone) for high risk smoldering multiple myeloma

Patients will receive 8 cycles of induction combination therapy of CRd

Each cycle consists of 28-days

After 4 cycles of therapy, transplant eligible patients may choose to undergo stem cell collection

After 8 cycles of CRd, patients will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year.

Patients will have routine blood work with serum protein electrophoresis (SPEP) and free light chains monthly during the induction phase. Laboratory evaluations may be spread out to every 3 months during the maintenance and follow-up phases.

Pre-treatment, post-treatment and follow-up bone marrow biopsies will be obtained for confirmation of diagnosis, response and correlative studies

Patients will also undergo evaluation for minimal residual disease at regular interval time points, using multi-parametric flow cytometry and fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT)

This single arm pilot study will plan on initially enrolling 12 evaluable patients to detect a very good partial response (VGPR) from baseline. A replicate cohort of 16 evaluable patients will then be enrolled in order to more precisely define the response rate to the CRd regimen in this population. Accrual will then be extended to a total of 50 evaluable patients in order to estimate the MRD(-) CR rate with reasonable precision. To allow for a number of inevaluable patients and screen failures, the accrual ceiling will be set at 63.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 55

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Group A - (closed) - Carfilzomib with Revlimid and Dexamethasone	Revlimid	Carfilzomib (intravenous (IV), Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (by mouth (PO), Days 1-21 of the 28-day cycle; exception: not given on cycle 1 day 1); and Dexamethasone (PO or IV, Days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycle; exception: not given on cycle 1 day 1)
Group B - Carfilzomib with Revlimid and Dexamethasone	Revlimid	Carfilzomib (intravenous (IV), Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (by mouth (PO), Days 1-21 of the 28-day cycle); and Dexamethasone (PO or IV, Days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycle)
Group A - (closed) - Carfilzomib with Revlimid and Dexamethasone	Carfilzomib	Carfilzomib (intravenous (IV), Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (by mouth (PO), Days 1-21 of the 28-day cycle; exception: not given on cycle 1 day 1); and Dexamethasone (PO or IV, Days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycle; exception: not given on cycle 1 day 1)
Group A - (closed) - Carfilzomib with Revlimid and Dexamethasone	Dexamethasone	Carfilzomib (intravenous (IV), Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (by mouth (PO), Days 1-21 of the 28-day cycle; exception: not given on cycle 1 day 1); and Dexamethasone (PO or IV, Days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycle; exception: not given on cycle 1 day 1)
Group B - Carfilzomib with Revlimid and Dexamethasone	Carfilzomib	Carfilzomib (intravenous (IV), Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (by mouth (PO), Days 1-21 of the 28-day cycle); and Dexamethasone (PO or IV, Days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycle)
Group B - Carfilzomib with Revlimid and Dexamethasone	Dexamethasone	Carfilzomib (intravenous (IV), Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (by mouth (PO), Days 1-21 of the 28-day cycle); and Dexamethasone (PO or IV, Days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycle)

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Minimal Residual Disease (MRD)Negative Complete Response (CR) Per International Myeloma Working Group (IMWG) Criteria	8 months	MRDnegative Complete Response (CR) per the IMWHG criteria is defined as absence of phenotypically aberrant clonal plasma cells by flow cytometry on bone marrow aspirates using the eight-color two tube approach with a minimum sensitivity of 1 in 10\^5 nucleated cells or higher.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Date treatment consent signed to date off study, approximately 117 months and 1 day.	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Clinical Progression Free Survival	time from enrollment in the study until development of overt clinical multiple myeloma (end organ damage or myeloma-defining event) or death, up to 5 years	Clinical progression was assessed by the International Myeloma Working Group Criteria for Multiple Myeloma. Progression is any one of the following: Increase of ≥25% from lowest response value in the following on 2 consecutive measurements: Serum M-component and/or (the absolute increase must be ≥0.5g/dl). The serum M-component increases of ≥1 gm/dl are sufficient to define relapse if starting M-component is ≥0.5g/dl. Urine M-component and/or (the absolute must be ≥200mg/24h. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels. The absolute increase must be \>10mg/dl. Bone marrow plasma cell percentage: the absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia that can be attributed solely to the plasma cell proliferative disorder.
Duration of Response	time from partial response to disease progression, up to 5 years	Duration of response is defined as the time from partial response to disease progression. Response was assessed by the International Myeloma Working Group Criteria for Multiple Myeloma. Partial Response is ≥50% reduction if serum M-protein and reduction in 24-hour(h) urinary M-protein by ≥90% or to \<200mg per 24h. If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria. Progression is any one of the following: Increase of ≥25% from lowest response value in the following on 2 consecutive measurements: Serum M-component and/or (the absolute increase must be ≥0.5g/dl). The serum M-component increases of ≥1 gm/dl are sufficient to define relapse if starting M-component is ≥0.5g/dl. Urine M-component and/or (the absolute must be ≥200mg/24h.
Overall Response Rate	time measurement criteria are met for best response until the first date that recurrent or progressive disease is met, up to 5 years	Overall response is defined as the percentage of participants who have a partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) defined by the International Myeloma Working Group Criteria for Multiple Myeloma out of all evaluable participants. PR is ≥50% reduction if serum M-protein and reduction in 24-hour(h) urinary M-protein by ≥90% or to \<200mg per 24h. If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria. VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis. CR is negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≥5% plasma cells in bone marrow. sCR is complete response plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.
Percentage of Participants That Have Minimal Residual Disease (MRD)-Negative Complete Response (CR) for a Minimum of 1 Year	1 year	Percentage of participants that have Minimal Residual Disease (MRD)-negative Complete Response (CR) for a minimum of 1 year estimated along with a 95% two-sided confidence interval. MRDnegative Complete Response (CR) is defined as absence of phenotypically aberrant clonal plasma cells by flow cytometry on bone marrow aspirates using the eight-color two tube approach with a minimum sensitivity of 1 in 10\^5 nucleated cells or higher.
Biochemical Progression Free Survival	time from enrollment in the study until development of overt clinical multiple myeloma (end organ damage or myeloma-defining event) or death, and progressive disease by IMWG criteria, up to 5 years	Biochemical progression free survival is defined as the time from enrollment in the study until development of overt clinical multiple myeloma (end organ damage or myeloma-defining event) or death, and progressive disease by International Myeloma Working Group (IMWG) criteria. Progression is any one of the following: Increase of ≥25% from lowest response value in the following on 2 consecutive measurements: Serum M-component and/or (the absolute increase must be ≥0.5g/dl). The serum M-component increases of ≥1 gm/dl are sufficient to define relapse if starting M-component is ≥0.5g/dl. Urine M-component and/or (the absolute must be ≥200mg/24h. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels. The absolute increase must be \>10mg/dl. Bone marrow plasma cell percentage: the absolute % must be ≥10%.