['smoldering multiple myeloma']
['carfilzomib', 'lenalidomide', 'dexamethasone', 'melphalan']

        Inclusion Criteria:

          -  In the investigator's opinion, the patient must be able to fulfill all the clinical
             trial requirements.

          -  The patient must voluntarily sign the informed consent before any study procedure that
             is not part of the standard of care for these patients is performed, with the
             patient's knowledge that he/she may withdraw from the study at any time, without
             prejudice to his/her future care.

          -  The patient must be aged between 18 and 70 years, and eligible to receive high-dose
             therapy and autologous peripheral blood stem cell transplant.

          -  The patient must be diagnosed with smoldering multiple myeloma at high risk of
             progressing to symptomatic multiple myeloma, or at ultra high risk of progression to
             symptomatic disease, defined by:

          -  smoldering multiple myeloma at high risk of progression to symptomatic disease:

        Bone marrow infiltration with plasma cells (PCs) greater than or equal 10% and presence of
        a monoclonal component, immunoglobulin G (IgG) greater than3 g/dL or IgA greater than 2
        g/dL or Bence Jones proteinuria greater than 1 g/24h and absence of lytic lesions,
        hypercalcemia, renal failure (creatinine less than 2 mg/dL) and anemia (hemoglobin greater
        than 10 gr/dL or not 2 gr/dL below the lower limit of normal).

        Bone marrow infiltration with PCs greater than or equal 10% OR IgG greater than 3 g/dL or
        immunoglobulin A (IgA) greater than 2 g/dL or Bence Jones proteinuria greater than 1g/24h
        (but not both together) and always in the absence of lytic lesions, hypercalcemia, renal
        failure and anemia. These patients may be included in the study if they meet the following
        additional criteria: A percentage of phenotypically aberrant plasma cells (PCs) within the
        bone marrow (BM) PC compartment (aPC/ BM PC) greater than or equal 95% and immunoapheresis,
        defined as a reduction in the levels of 1 or 2 immunoglobulin (Igs) of more than 25%
        compared with the normal values of the corresponding Ig.

        - smoldering multiple myeloma at ultra high risk of progression to symptomatic disease:

        Presence of more than 1 focal lesion in MRI (ideally whole body MRI).

        Infiltration in the BM equal or higher than 60%.

        Ratio of involved/uninvolved serum Friend leukemia cell (FLC) higher than 100.

          -  The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status
             less than 2.

          -  The patient must be able to attend the scheduled visits.

          -  Women of childbearing potential must have a negative pregnancy test (serum or urine)
             within the 14 days before the starting the study drug. In addition, sexually active
             women must agree to use contraceptive methods (hormone contraceptives [oral,
             injectable or implanted], tubal ligation, intrauterine device, barrier contraceptives
             with spermicide or have a vasectomised partner) while receiving the study drug. Women
             of childbearing potential must agree to undergo pregnancy tests every 4 weeks while
             receiving the study drug (every 14 days for women with irregular menstrual cycles) and
             4 weeks after the last dose of study drug.

        Exclusion Criteria:

          -  Any physical condition or psychiatric disorder that would prevent the patient from
             signing or understanding the informed consent form.

          -  Previous treatment for smoldering multiple myeloma.

          -  Pregnancy or breastfeeding.

          -  Presence of lytic lesions, anemia, renal failure or hypercalcemia.

          -  Any of the following laboratory abnormalities:

        Absolute neutrophil count (ANC) less than 1,000/mm3

        Platelet count less than 75,000/mm3.

        Serum GOT or glutamic pyruvic transaminase (GPT) greater than 3 x upper limit of normal

        Serum total bilirubin greater than 2 x upper limit of normal

          -  Prior history of neoplasm other than multiple myeloma (except for basal cell or
             squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast)
             unless the patient has been disease-free for > 5 years.

          -  Major surgery within 4 weeks before inclusion in the study.

          -  Known active infection by human acquired immunodeficiency virus, B or C hepatitis
             virus.

          -  Any investigational drug within 30 days before inclusion in the study.

          -  Acute active infection requiring treatment (systemic antibiotics, antivirals, or
             antifungals) within 14 days prior to enrolment.

          -  Unstable angina or myocardial infarction within 6 months prior to enrollment, New York
             Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, history
             of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick
             sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3
             conduction system abnormalities unless subject has a pacemaker.

          -  Uncontrolled hypertension or uncontrolled diabetes.

          -  Significant neuropathy (Grades 3?4, or Grade 2 with pain) within 14 days prior to
             enrollment.

          -  Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize
             carfilzomib).

          -  Contraindication to any of the required concomitant drugs or supportive treatments,
             including intolerance to hydration due to pre-existing pulmonary or cardiac
             impairment.

          -  Left ventricular ejection fraction (LVEF) less than 40

          -  Pulmonary hypertension
      