Clinical Trials /

Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma

NCT01572480

Description:

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.

Related Conditions:
  • Smoldering Plasma Cell Myeloma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma
  • Official Title: Carfilzomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma: a Clinical and Correlative Pilot Study

Clinical Trial IDs

  • ORG STUDY ID: 120107
  • SECONDARY ID: 12-C-0107
  • NCT ID: NCT01572480

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
CarfilzomibA - (closed)
RevlimidA - (closed)
DexamethasoneA - (closed)

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.

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.

        -  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:

      - To assess the response rate of CRd in patients with high-risk SMM, focusing on the MRD(-)
      CR rate

      ELIGIBILITY:

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

             -  Serum M-protein greater than or equal to 3 g/dl and/or bone marrow plasma cells
                greater than or equal to 10 % and less than 60%,

             -  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

             -  Involved/un-involved light chain ratio must be less than 100

        -  Measurable disease as defined in the protocol

        -  'High-risk SMM' per Mayo Clinic, Spanish PETHEMA, or the Rajkumar, Landgren Mateos
           criteria

        -  Age greater than or equal to 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 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 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. 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.
    

Trial Arms

NameTypeDescriptionInterventions
A - (closed)ExperimentalCarfilzomib (IV, Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (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)
  • Carfilzomib
  • Revlimid
  • Dexamethasone
BExperimentalCarfilzomib (IV, Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (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)
  • Carfilzomib
  • Revlimid
  • Dexamethasone

Eligibility Criteria

        -  INCLUSION CRITERIA:

        Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma
        confirmed by the Laboratory of Pathology, NCI or the Department of Laboratory Medicine, CC
        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% and <60%

          -  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 on X-ray, CT, or PET/CT and not more than 1 lesion on
             spinal MRI. (NOTE: At the discretion of the investigator, PET/CT may replace MRI in
             patients who have a contraindication to MRI.)

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

        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

        NOTE: As of Amendment L (version date 05/17/2018), the primary endpoint is MRD(-) CR rate;
        therefore, per the discretion of the Principal Investigator, patients without measurable
        disease (e.g., M-spike <1) may also be enrolled. This is in line with the most recent IMWG
        MM response criteria.

        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 (ANC) greater than or equal to1.0 K/uL

        NOTE: At the discretion of the investigator, patients with an ANC of 0.5 K/uL <1.0 K/uL may
        also be enrolled if clinically appropriate (e.g., patients with a baseline neutropenia that
        is chronic and that does not cause complications)

          -  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

          -  Serum creatinine less than or equal to 1.5 X institutional ULN. If serum creatinine is
             above 1.5 X ULN, Creatinine Clearance (CrCl) or eGFR (estimated glomerular filtration
             rate) must be greater than or equal to 50 ml/min.

               -  CrCl will be calculated by Cockcroft-Gault method. CrCl (calculated) = (140 -
                  Age) x Mass (in kilograms) x [0.85 if Female] 72 x Serum Creatinine (in mg/dL).

               -  eGFR will be calculated by either of the following well established formulas:
                  modification of diet in renal disease (MDRD) or the chronic kidney disease
                  (CKD)-epidemiology collaboration (EPI)(institutional standard) equations

          -  CrCl may also be determined by measuring a 24 hour urine collection. The measured CrCl
             must be greater than or equal to 50 ml/min.

        In addition to having SMM, patients must also be classified as 'high-risk SMM' per Mayo
        Clinic or Spanish PETHEMA criteria.

        Criteria set forward by Rajkumar, Landgren, Mateos[14] may also be used to define high risk
        disease, namely clonal bone marrow plasma cells greater than or equal to 10% and any one or
        more of the following:

          -  Serum M protein greater than or equal to 30g/L

          -  IgA SMM

          -  Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes

          -  Serum involved/uninvolved FLC ratio greater than or equal to 8 (but less than 100)

          -  Progressive increase in M protein level (evolving type of SMM; increase in serum M
             protein by greater than or equal to 25% on 2 successive evaluations within a 6-month
             period)

          -  Clonal BMPCs 50%-60%

          -  Abnormal PC immunophenotype (greater than or equal to 95% of BMPCs are clonal) and
             reduction of greater than or equal to 1 uninvolved immunoglobulin isotypes

          -  t(4;14) or del(17p) or 1q gain

          -  Increased circulating PCs

          -  MRI with diffuse abnormalities or 1 focal lesion

          -  PET-CT with focal lesion with increased uptake without underlying osteolytic bone
             destruction

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

        The effects of carfilzomib and lenalidomide on the developing human fetus are unknown. The
        immunomodulatory agents used in this trial (i.e., lenalidomide) 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. In
        regard to carfilzomib, FCBP and their male partners must agree to use at least one method
        of effective contraception for at least 30 days after the

        last dose of carfilzomib and males must agree to use contraception and not to donate sperm
        for at least 90 days after the last dose of carfilzomib.

        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 a diagnosis of MM as defined by the 2014 IMWH diagnostic criteria.

        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, in addition to patients with known allergy to sulfobutyl ether <=-
        cyclodextrin (Captisol ).

        Uncontrolled hypertension or diabetes

        Pregnant or lactating females. Pregnant women are excluded from this study. The effects of
        carfilzomib on a developing human fetus are unknown. Lenalidomide is teratogenic with
        unknown potential for abortifacient effects. Breastfeeding women and women planning on
        breastfeeding may not participate. No studies of carfilzomib have

        been conducted on breast feeding women and it is not known if it is excreted in milk.
        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.

        Significant cardiovascular disease with NYHA Class II, 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 2 years or if, at the clinical discretion of the investigator, the risks of
        this study do not outweigh the potential benefits on a case to case basis.

        Major surgery within 1 month prior to enrollment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response Rate
Time Frame:8 months
Safety Issue:
Description:VGPR decline/response rate will be assessed using simple two-sided 90% confidence intervals at the evaluation time points

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:at time of disease progression
Safety Issue:
Description:The time of study entry to progression or death.
Measure:Duration of Response
Time Frame:at time of disease progression
Safety Issue:
Description:The time from response to disease progression or death

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Proteasome Inhibitor
  • Immunomodulatory Agents
  • Combination Therapy
  • Anti-Myeloma Activity

Last Updated

July 16, 2021