Pom-dex Versus Pom-Cyclo-dex in MM Patients With Biochemical or Clinical Relapse, During Lena Maintenance Treatment
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Recurrence
Intervention: Pomalidomide; Cyclophosphamide; Dexamethasone
Intervention description: 4 mg/daily as oral administration (PO) on days 1-21.; 50 mg every other day as oral administration (PO) on days 1-28; 40 mg as oral administration (PO) on days 1, 8, 15, 22.
Intervention MeSH terms: Dexamethasone; Cyclophosphamide; Pomalidomide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: This is a 2x2 factorial randomized study.
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: biochemical relapse

Summary:

      The combination lenalidomide plus low-dose dexamethasone (Rd) is an active treatment for
      Multiple Myeloma (MM) patients, both at diagnosis and at relapse.

      Pomalidomide, is an immunomodulatory molecule (IMID), derivative of thalidomide, developed to
      improve the efficacy and reduce the toxicity of the parent molecule. Pomalidomide and
      dexamethasone (pom-dex) proved to be an effective and safe treatment in MM patients
      refractory to lenalidomide and refractory/intolerant to bortezomib.

      The addition of chemotherapy to novel drugs has been evaluated both at diagnosis and at
      relapse. The combination of pomalidomide-cyclophosphamide-prednisone proved to be safe and
      effective in relapsed/refractory MM patients. The combination
      pomalidomide-cyclophosphamide-dexamethasone (pom-cyclo-dex) was tested in a phase II study in
      patients with relapsed and refractory MM, demonstrating a good tolerability using
      pomalidomide at the dose of 4 mg. Pom-cyclo-dex resulted in a superior response rate and
      Progression-Free Survival (PFS) compared to pom-dex. The increased hematologic toxicities, as
      a result of the addition of oral cyclophosphamide, were manageable. With an overall response
      rate of 65% the combination demonstrated a promising efficacy.The first aim of our trial, is
      to compare the combination of pom-cyclo-dex vs pom-dex.

      Relapsed myeloma is defined as previously treated myeloma that progresses and requires the
      initiation of salvage therapy.

      According to International Myeloma Working Group (IMWG) recommendation, biochemical relapse
      is defined as an increase of ≥ 25% of tumor burden from lowest value, without any CRAB
      feature (CRAB is defined as the onset of clinical symptoms: hypercalcemia, renal failure,
      anemia and bone lesions) and detected in 2 consecutive determinations.

      Clinical relapse requires one or more direct indicators of progressive disease and end organ
      dysfunction (CRAB features).

      Treatment at relapse should start in case of clinical relapse or a significant paraprotein
      increase (doubling of M-component in 2 months).

      In case of biochemical relapse the standard is observation only, as in case of asymptomatic
      MM at diagnosis.

      However, a recently published trial, showed improved PFS and OS for newly diagnosed
      asymptomatic patients treated with lenalidomide and dexamethasone in comparison with
      observation only. Our hypothesis is that similarly, in the relapse setting, patients may
      benefit from an early intervention, meaning a treatment at biochemical relapse and not only
      in case of clinical relapse or rapid increase of M-component.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients >18 years and <80 years.

          -  Patient is, in the investigator(s) opinion, willing and able to comply with the
             protocol requirements.

          -  Patient has given voluntary written informed consent before performance of any
             study-related procedure not part of normal medical care, with the understanding that
             consent may be withdrawn by the patient at any time without prejudice to their future
             medical care.

          -  Male patient agrees to use an acceptable method for contraception (i.e. condom or
             abstinence) for the duration of the study.

        Female of childbearing potential agrees to use two acceptable methods for contraception
        [implant, levonorgestrel-releasing intrauterine system (IUS), medroxyprogesterone acetate
        depot, tubal sterilization, sexual intercourse with a vasectomised male partner only
        (vasectomy must be confirmed by two negative semen analyses), ovulation inhibitory
        progesterone-only pills (i.e. desogestrel)] or absolute and continuous sexual abstinence.

          -  Patient has measurable disease, defined as follows: any quantifiable serum monoclonal
             protein value (generally, but not necessarily, ≥ 0.5 g/dL of M-protein) and, where
             applicable, urine light-chain excretion of >200 mg/24 hours; only in patients without
             measurable serum and urine M-protein levels: the difference between involved and
             uninvolved Free Light Chain (FLC) levels must be > 10 mg/dL. Less than 10% of oligo-
             or non-secretory MM patients with free light chains will be admitted to this study in
             order to maximize interpretation of benefit results.

          -  Patient receiving lenalidomide maintenance therapy as part of first line treatment
             (concomitant use of prednisone is accepted) and has experienced a biochemical relapse,
             with evidence of progressive disease defined as an increase of 25% from lowest
             response value in any one or more of the following: serum M-component (absolute
             increase must be ≥0.5 g/100 ml) and/or urine M-component (absolute increase must be
             ≥200 mg per 24 hours) only in patients without measurable serum and urine M-protein
             levels: the difference between involved and uninvolved FLC levels must be >10 mg/dL
             (35).

          -  Patient who received as first line treatment a bortezomib-based therapy, including
             lenalidomide maintenance during the same line of therapy, can be included in the
             trial.

          -  Patient has a life-expectancy > 3 months

          -  Patient has not a currently active malignancy, other than non melanoma skin cancer and
             carcinoma in situ of the cervix, and has not invasive malignancies within the past 5
             years.

          -  No history of allergic reactions attributed to study agents

          -  Patient has the following laboratory values within 28 days before baseline day 1 of
             the cycle 1:

               1. absolute neutrophil count (ANC) > 1 x 10^9/L

               2. platelet count > 75 x 10^9/L

               3. haemoglobin > 8 g/dl.

               4. aspartate transaminase (AST): < 2 x the upper limit of normal (ULN).

               5. alanine transaminase (ALT): < 2 x the ULN.

        Exclusion Criteria:

          -  Pregnant or lactating females.

          -  Patient with Creatinine Clearance (CrCl) < 45 mL/minute

          -  Patient with peripheral neuropathy ≥ Grade 2

          -  Subject with any one of the following:

          -  Congestive heart failure (NY Heart Association Class III or IV)

          -  Myocardial infarction within 12 months prior to starting study treatment

          -  Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina
             pectoris

          -  Any significant medical disease or conditions (e.g. pulmonary disease, infection)
             that, in the investigator's opinion, may interfere with protocol adherence or
             subject's ability to give informed consent or could place the subject at unacceptable
             risk.

          -  Clinical active infectious hepatitis type A, B, C or HIV Acute active infection
             requiring antibiotics or infiltrative pulmonary disease

          -  Contraindication to any of the required drugs or supportive treatments.

          -  Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations