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Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Dickran Kazandjian, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01572480
First received: April 5, 2012
Last updated: March 28, 2017
Last verified: March 2017
  Purpose

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.

Condition Intervention Phase
Multiple Myeloma Drug: Carfilzomib Drug: Revlimid Drug: Dexamethasone Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Carfilzomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma: A Clinical and Correlative Study

Resource links provided by NLM:


Further study details as provided by Dickran Kazandjian, M.D., National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Response at 8 Cycles Induction -Treatment Interval [ Time Frame: 8 cycles after induction, approximately 7.5 months ]
    Response is defined by the International Myeloma Working Group Criteria for Multiple Myeloma. Stringent complete response (sCR) is normal free light chain (FLC) ration and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. Complete response (CR) is negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow. Minimal residual disease (MRD) neg complete response (CR) is patients who meet criteria for CR and on bone marrow biopsy assessment have no evidence of residual aberrant plasma cells based on flow cytometry with a resolution of 10-5. . Near complete response (nCR) is defined as absence of myeloma protein on electrophoresis, independent of immunofixation status. Very good partial response (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24h.

  • Response at 1 Year Maintenance Treatment Interval [ Time Frame: 1 year ]
    Response is defined by the International Myeloma Working Group Criteria for Multiple Myeloma. Stringent complete response (sCR) is normal free light chain (FLC) ration and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. Complete response (CR) is negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow. Minimal residual disease (MRD) neg complete response (CR) is patients who meet criteria for CR and on bone marrow biopsy assessment have no evidence of residual aberrant plasma cells based on flow cytometry with a resolution of 10-5. Near complete response (nCR) is absence of myeloma protein on electrophoresis, independent of immunofixation status. Very good partial response (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine

  • Response at 2 Years Maintenance Treatment Interval [ Time Frame: 2 years ]
    Response is defined by the International Myeloma Working Group Criteria for Multiple Myeloma. Stringent complete response (sCR) is normal free light chain (FLC) ration and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. Complete response (CR) is negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow. Minimal residual disease (MRD)neg complete response (CR) is patients who meet criteria for CR and on bone marrow biopsy assessment have no evidence of residual aberrant plasma cells based on flow cytometry with a resolution of 10-5. Near complete response (nCR) is defined as absence of myeloma protein on electrophoresis, independent of immunofixation status. Very good partial response (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24h.


Secondary Outcome Measures:
  • Percentage of Participants With Progression Free Survival [ Time Frame: 36 months ]
    Progression free survival is defined as time of study entry to progression or death. Progressive disease requires one or more 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 ≥5g/dl. Urine M-component and/or (the absolute increase must be ≥200mg/24h. Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain 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.

  • Percentage of Responders Still in Response. [ Time Frame: 36 months ]
    Duration of response is defined as time from response to disease progression or death. Progressive disease requires one or more 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 ≥5g/dl. Urine M-component and/or (the absolute increase must be ≥200mg/24h. Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain 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.

  • Number of Participants With Adverse Events [ Time Frame: 2 years, 9 months and 16 days ]
    Here is the number of participants with adverse events assessed by the Common Terminology Criteria in Adverse Events v4. For the detailed list of events, see the adverse event module.


Enrollment: 18
Actual Study Start Date: June 28, 2012
Estimated Study Completion Date: September 1, 2020
Primary Completion Date: September 1, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Carfilzomib, Revlimid & Dexamethasone
Carfilzomib, Revlimid and Dexamethasone in Multiple Myeloma (MM)
Drug: Carfilzomib
Cycle 1 ONLY: Carfilzomib 20 mg/m(2) per dose, days 1 and 2; Carfilzomib 36 mg/m(2) per dose, days 8, 9, 15, and 16 Cycles 2-8: Carfilzomib 36 mg/m(2) per dose, days 1, 2, 8, 9, 15, and 16
Other Name: Kyprolis
Drug: Revlimid
Cycles 1-8: 25 mg/day, days 1 - 21 every 28 days (exception: lenalidomide is NOT given on cycle 1, day 1) Cycles 9 and beyond: 25 mg/day, days 1 - 21 every 28 days
Other Name: Lenalidomide
Drug: Dexamethasone
20 mg/dose, days 1, 2, 8, 9, 15, 16, 22, and 23 (exception: dexamethasone is NOT given on cycle 1, day 1)
Other Name: Decadron

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma confirmed by the Laboratory of Pathology, National Cancer Institute (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: Calcium (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.

Eastern Cooperative Oncology Group (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
  • Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase(SGOT)/ alanine aminotransferase (ALT) serum glutamic pyruvic transaminase(SGPT) less than or equal to 3.0 times institutional upper limit of normal
  • Creatinine Clearance (CrCl) 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 smoldering multiple myeloma (SMM) per Mayo Clinic or Spanish Programa Espanol de Tratamientos en Hematologia (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 multiple myeloma (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 New York Heart Association (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 gastrointestinal (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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01572480

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Dickran Kazandijian, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Dickran Kazandjian, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT01572480     History of Changes
Other Study ID Numbers: 120107
12-C-0107
Study First Received: April 5, 2012
Results First Received: November 28, 2016
Last Updated: March 28, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Dickran Kazandjian, M.D., National Institutes of Health Clinical Center (CC):
Proteasome Inhibitor
Anti-Myeloma Inhibitor
Immunomodulatory Agents
Combination Therapy
Smoldering Multiple Myeloma
SMM

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Lenalidomide
Thalidomide
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 21, 2017