Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma
Conditions
Multiple Myeloma
Conditions: official terms
Multiple Myeloma - Neoplasms, Plasma Cell
Conditions: Keywords
Proteasome Inhibitor, Anti-Myeloma Inhibitor, Immunomodulatory Agents, Combination Therapy, Smoldering Multiple Myeloma, SMM
Study Type
Interventional
Study Phase
Phase 2
Study Design
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Intervention
Name: Carfilzomib Type: Drug
Name: Revlimid Type: Drug
Name: Dexamethasone Type: Drug
Overall Status
Recruiting
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:

- SMM is a precursor condition to MM defined by the clinical parameters of M-protein greater than or equal to 3.0 g/dL or bone marrow plasma cells greater than or equal to 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.1-2

- The current standard of care for SMM is close follow-up without treatment until symptomatic

MM develops. However, 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:

Primary Endpoints:

- The primary objective of the study is to assess the response rate of CRd in patients with high-risk SMM.

Secondary Endpoints:

- To determine progression free survival (PFS)

- To determine duration of response (DOR)

- To evaluate toxicity of combination therapy (carfilzomib, lenalidomide, and

dexamethasone).

- To evaluate biological activity of carfilzomib and correlate to clinical outcomes (gene expression profiling (GEP) on pre and post carfilzomib exposure bone marrow samples)

ELIGIBILITY:

- SMM according to the International Myeloma Working Group definition 3 i.e.:

- Serum M-protein greater than or equal to3 g/dl and/or bone marrow plasma cells greater than or equal to10 %,

- Absence of anemia: Hemoglobin > 10 g/dl

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

Ca < 10.5 mg/dl or 2.65 mmol/L

- Absence of lytic bone lesion

- Measurable disease within the past 4 weeks defined by any one of the following:

- Serum monoclonal protein greater than or equal to 1.0 g/dl

- Urine monoclonal protein > 200 mg/24 hour

- Serum immunoglobulin free light chain > 10 mg/dL AND abnormal kappa/lambda ratio

(reference 0.26-1.65)

- High-risk SMM per Mayo Clinic2 or Spanish PETHEMA criteria

- Age > 18 years

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

- Male or female patient who accepts and is able to use recognised effective contraception (oral contraceptives, IUCD, barrier method of contraception in conjunction with spermicidal jelly) throughout the study when relevant

- Absolute neutrophil count (ANC) greater than or equal to1.0 K/uL, hemoglobin greater than or equal to8 g/dL, and platelet count greater than or equal to 75 K/microL

- Adequate hepatic function, with bilirubin < 1.5 x the ULN, and AST and ALT < 3.0 x

ULN

- Calculated creatinine clearance > 60 mL/min as determined by the Cockcroft-Gault formula: CrCl = (140 Age) x Mass (in kilograms) x [0.85 if Female] 72 x Serum Creatinine (in mg/dL). If calculated CrCl based on Cockcroft-Gault method is < 60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min.

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 will 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 SPEP and free light chains monthly

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

- Patients will also undergo evaluation for minimal residual disease at regular interval time points, using multi-parametric flow cytometry and FDG PET-CT

- This single arm pilot study will plan on initially enrolling 12 evaluable patients to detect a 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.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: - INCLUSION CRITERIA:

Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma confirmed by the Laboratory of Pathology, NCI based on the International Myeloma Working Group Criteria:

- Serum M-protein greater than or equal to 3 g/dl and/or bone marrow plasma cells greater than or equal 10 %

- Absence of anemia: Hemoglobin > 10 g/dl

- Absence of renal failure: serum creatinine < 2.0 mg/dL Absence of hypercalcemia: Ca < 10.5 mg/dl

- Absence of lytic bone lesion

Measurable disease within the past 4 weeks defined by any one of the following:

- Serum monoclonal protein greater than or equal to 1.0 g/dl

- Urine monoclonal protein > 200 mg/24 hour

- Serum immunoglobulin free light chain > 10 mg/dL AND abnormal kappa/lambda ratio

Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of carfilzomib in combination with lenalidomide in patients < 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.

ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).

Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to1.0 K/uL

- platelets greater than or equal to75 K/uL

- hemoglobin greater than or equal to 8 g/dL(transfusions are permissible)

- total bilirubin less than or equal to 1.5 times institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 3.0 times institutional upper limit of normal

- Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated by Cockcroft Gault method. CrCl (calculated) = (140 Age) times Mass (in kilograms) times [0.85 if Female] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on Cockcroft-Gault method is < 60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min.

High-risk SMM per Mayo Clinic or Spanish PETHEMA criteria

All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist.

The effects of carfilzomib and lenalidomide on the developing human fetus are unknown. For this reason and because immunomodulatory agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 10 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. 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.

Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Patients who are receiving any other investigational agents.

Concurrent systemic treatment or prior therapy within 4 weeks for SMM

- Treatment with corticosteroids for other indications is permitted

- Patients with prior proteasome inhibitor therapy will be excluded

Patients with a diagnosis of MM

Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy

History of allergic reactions attributed to compounds of similar chemical or biologic composition to carfilzomib or lenalidomide agents used in study, such as bortezomib or thalidomide.

Uncontrolled hypertension or diabetes

Pregnant or lactating females. Pregnant women are excluded from this study because Carfilzomib/Lenalidomide are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Carfilzomib/Lenalidomide, breastfeeding should be discontinued if the mother is treated with Carfilzomib/Lenalidomide. These potential risks may also apply to other agents used in this study

Significant cardiovascular disease with NYHA Class III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia

Active hepatitis B or C infection

Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption

Significant neuropathy > Grade 2 at the time of first dose or within 14 days of enrollment

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations within 2 weeks that would limit compliance with study requirements.

History of other malignancy (apart from basal cell carcinoma of the skin, or in situ cervix carcinoma) except if the patient has been free of symptoms and without active therapy during at least 5years

Major surgery within 1 month prior to enrollment
Location
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Status: Recruiting
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office - 888-624-1937
Start Date
March 2012
Completion Date
April 2018
Sponsors
National Cancer Institute (NCI)
Source
National Institutes of Health Clinical Center (CC)
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page