Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Smoldering Multiple Myeloma
Intervention: Carfilzomib; Revlimid; Dexamethasone
Intervention description: Carfilzomib intravenous (IV) 20-36 mg/m^2 per dose on days 1, 2, 8, 9, 15, and 16 of each cycle based on arm; until disease progression or unacceptable toxicity.; Revlimid by mouth (PO) 25 mg/day, days 1-21 every 28 days of each cycle based on arm; until disease progression or unacceptable toxicity.; Dexamethasone by mouth (PO) 20 mg per dose on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle based on arm; until disease progression or unacceptable toxicity.
Intervention MeSH terms: Dexamethasone; Lenalidomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Proteasome Inhibitor; Immunomodulatory Agents; Combination Therapy; Anti-Myeloma Activity

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma
        confirmed by the Laboratory of Pathology, national Cancer Institute (NCI) or the Department
        of Laboratory Medicine, Clinical Center (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: Calcium (Ca) <10.5 mg/dl

          -  Absence of lytic bone lesion on X-ray, computed tomography (CT), or positron-emission
             tomography (PET)/CT and not more than 1 lesion on spinal magnetic resonance imaging
             (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 minimal residual
        disease (MRD(-) Complete Response (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 International Myeloma Working Group (IMWG) multiple
        myeloma (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.

        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 (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 to 75 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

          -  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 estimated glomerular filtration rate
             (eGFR) (estimated glomerular filtration rate) must be greater than or equal to 50
             ml/min.

               -  Creatinine clearance (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 Smoldering Multiple Myeloma (SMM), patients must also be classified
        as 'high-risk SMM' per Mayo Clinic or Spanish Programa de Estudio y Tratamiento de las
        Hemopatías Malignas (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

          -  Immunoglobulin A (IgA) SMM

          -  Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes

          -  Serum involved/uninvolved free light chain (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 bone marrow plasma cells (BMPCs) 50%-60%

          -  Abnormal plasma cells (PCs) 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 Risk Evaluation and Mitigation Strategy
        (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 New York Heart Association (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 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 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.