Safety And Efficacy Of Lenalidomide As Maintenance Therapy In Patients With Newly Diagnosed Multiple Myeloma Following A Tandem Autologous-Allogeneic Transplant
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      Rationale: We recently reported a study where overall and event free survivals in newly
      diagnosed myeloma patients receiving an autologous transplant followed by an allograft from
      an HLA-identical sibling were superior as compared to those undergoing a double autologous
      transplant. A larger multicenter study by the Gruppo Italiano Trapianti di Midollo (GITMO),
      co-ordinated by our group and recently closed, employing a tandem auto-allo approach in newly
      diagnosed patients confirmed the achievement of prolonged event free and overall survival.
      Importantly, the achievement of at least very good partial remission at the time of
      allografting conferred a significant advantage in both event-free-survival (HR 0,23, CI
      0,11-0,48; p=0,0001) and overall survival (HR 0,26; CI 0,09-0,79; p=0,02). Moreover, recent
      advances in the understanding of the pathogenesis of multiple myeloma have identified
      specific signalling pathways that have become targets for biologically-based drugs such as
      thalidomide, bortezomib and lenalidomide and employed in several trials, including after
      allograft. The aim of the current proposal is to combine the post-transplant efficacy of
      graft-vs.-myeloma with the anti-myeloma effect of lenalidomide in newly diagnosed myeloma
      patients with an HLA-identical sibling treated with a tandem autograft-allograft approach.
      Maintenance/consolidation of the response may be a key factor to further improve rate of
      clinical and molecular (as a prelude to cure) remissions and prolong overall and event free
      survivals after allografting. We would like to investigate the safety and efficacy of
      lenalidomide as consolidation/maintenance therapy in patient undergoing tandem
      autologous-allogeneic transplant.

      Objectives of study: To evaluate 1) toxicity and tolerability of lenalidomide after
      allografting; 2)To evaluate efficacy of lenalidomide in inducing complete remission, defined
      as negative immunofixation, 12 months after allografting; 3) overall-survival; 4) event-free
      survival; 5) molecular remission rate. Furthermore we plan to compare molecular remission
      rate in patients treated with lenalidomide after tandem auto-allo transplant and after double
      autologous transplant and to monitor minimal residual disease in patients achieving clinical
      CR with lenalidomide.

      Patient Selection: Patients with newly diagnosed multiple myeloma with an HLA identical
      sibling suitable for PBSC donation will be included. Complete cytogenetic analysis at
      diagnosis will be required. The patient must have the capacity to give informed consent. Age
      >18 and < 65. Negative pregnancy test and willing to use contraceptive techniques during and
      for 12 months following treatment is required. Only very unfitted patients will be excluded.

      Treatment plan: Lenalidomide will be started at 6 months post-allotransplant at the dose of
      10 mg/day continuously in all patients (unless in molecular CR), if the following conditions
      are present:

        -  absolute neutrophil count > 1 x 109/L without the use of growth factors;

        -  platelet count > 75 x 109/L without transfusion support;

        -  calculated or measured creatinine clearance: ≥ 20 mL/minute;

        -  total bilirubin < 2 x the upper limit of normal,

        -  AST and ALT < 2.5 x upper limit of normal

        -  less than 1 mg/kg/day of prednisone, and no more than 2 immunosuppressive drugs other
           than steroid to control GVHD (if more immunosuppression is required to control GVHD, the
           maintenance therapy with lenalidomide will be held until this criteria will be
           satisfied) Treatment will be continued without interruption, unless not tolerated, until
           unacceptable adverse events are experienced or progressive disease occurs. Moreover,
           lenalidomide will be discontinued in patients who achieve and maintain molecular
           remission for 2 consecutive controls at least 6 weeks apart.

      Safety section - dose modification plan: During the study patients will be monitored for the
      occurrence of side effects. Toxicity events will be graded according to the NCI toxicity
      criteria. In case of severe toxicity, the lenalidomide dose will be reduced or withheld as
      outlined in the protocols.

      Statistical section: - Total patient sample size: 53. This is a phase 2 study designed
      according to a Simon's two-stage Minimax Design. An early stopping rule will be established
      to interrupt the study in case of futility (a non satisfactory response rate). In stage I 27
      patients will be enrolled; if < 14 complete remissions will be observed, the trial will be
      stopped. In stage II 26 more patients will be enrolled. If ≥ 32 responses will be observed,
      it will be concluded that the lenalidomide maintenance is active in increasing the complete
      remission rate after auto-allograft.

      Analysis plan: Toxicity monitoring will be incorporated into the study design by requiring
      that the trial be terminated after an initial stage if the number of observed toxicities
      (treatment related deaths) is excessive.
    

Detailed description: 
      A. Pre-transplant phase: Induction Therapy

      Patients will start induction treatment with lenalidomide and dexamethasone (RD) for 4 cycles
      every 28 days (as was detailed also in the GIMEMA protocol RV-MM-PI-209):

        -  Lenalidomide will be given orally at the dose of 25 mg/day for 21 days followed by a 7
           day rest period (day 22 to 28),

        -  Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15 and 22 every 28
           days.

      If a patient relapses during RD before the end of the 4th cycle, the induction treatment may
      be held and stem cell collection may be attempted with cyclophosphamide according to
      physician willing.

      For dose reduction during induction therapy see Appendix O. Antithrombotic prophylaxis as per
      protocol RV-MM-PI-209. For patients not previously enrolled in protocol RV-MM-PI-209, we
      recommend prophylaxes with aspirin for patients without additional thrombotic risk factors,
      and low molecular weight heparin (LMWH) 100 U/kg for the others.

      Otherwise, induction schemas are accepted provided thalidomide, lenalidomide or bortezomib,
      alone or in combination, are included.

      B. Peripheral Blood Stem Cell (PBSC) Mobilization and collection

      After 1-2 months from the completion of the last induction course, patients will undergo PBSC
      mobilization with cyclophosphamide 4 g/m2 and G-CSF (10 ug/kg/day starting at day 5 until
      completion of PBSC collection) to collect an adequate number of PBSC (4 to 10 x 106/kg CD 34+
      cells). Patients who fail to collect the minimum of 4 x 106/kg CD 34+ cells will receive a
      second course of cyclophosphamide for a second mobilization attempt. Patients who fails to
      collect a minimum of 4 x 106/kg CD 34+ will be withdrawn from the study.

      C. High-Dose Melphalan / Autologous PBSC Transplant

      High dose melphalan will be given 4 to 8 weeks after high dose cyclophosphamide.

        1. Melphalan will be administered at a cumulative dose of 200 mg/m2. This will be given in
           one dose infused on day -2. Dose will be calculated according to the participating
           institutional standard practice for using body weight. High dose Melphalan is
           administered via a central catheter as per single center procedure.

        2. Peripheral Blood Stem Cell or Bone Marrow Infusion: Infuse > 2 x 106 CD 34+ cells /kg,
           hydration requirements, and pre-medication per guidelines of the institution.

        3. G-CSF: Administer G-CSF 5 ug/kg/day subcutaneously or intravenously from day +3 until
           ANC >1000 for 3 days.

      D. Allogeneic transplant phase: Non-myeloablative PBSC Allografting

      Pre-conditioning Upon recovery from high-dose melphalan, between 40-120 days post
      autografting (preferably within 60 days) patients will proceed to nonmyeloablative allograft.
      If indicated, radiation to high risk skeletal lesions may be given pre-transplant. If
      interval exceeds 120 days, present to PCC for discussion and approval.

      Recovery from high-dose melphalan will be defined by patients achieving the following
      clinical criteria after receiving high dose melphalan:

        1. mucositis and gastrointestinal symptoms resolved, off hyperalimentation and intravenous
           hydration;

        2. have completed steroids for autologous GVHD;

        3. LFT / renal function values within the inclusion criteria for initial autograft;

        4. off IV antibiotics and amphotericin for documented infections;

        5. patients should be CMV antigenemia negative;

        6. if patients have experienced CMV infection post-autograft, they must have completed
           therapy with Ganciclovir or Foscarnet and have been off this therapy for > two weeks and
           remain CMV antigenemia negative;

        7. should have completed administration of any radiotherapy;

        8. any patient who does not fulfill these criteria, can be discussed with the principle
           investigator for recommendations as to the timing of the allograft.
    

Intervention name(s): Lenalidomide
Intervention type(s): Drug
Intervention description(s): Lenalidomide will be started at 6 months post-allotransplant at 10 mg/day continuously in all patients:
absolute neutrophil count >1x109/L without growth factors
platelet count >75x109/L without transfusion support
calculated/measured creatinine clearance: ≥20mL/minute
total bilirubin <2 x the upper limit of normal
AST (SGOT) and ALT (SGPT) <2.5 x upper limit of normal
<1mg/kg/day of prednisone, and no more than 2 immunosuppressive drugs other than steroid to control GVHD
Treatment will be continued without interruption, unless not tolerated, until unacceptable adverse events or progressive disease occur. In case of disease progression occurring before the start of lenalidomide, the patient will be withdrawn from study and treated according to the center preference. Lenalidomide will be discontinued in patients achieving and maintaining molecular remission for 2 consecutive controls at least 6 weeks apart.
Intervention MeSH terms: Lenalidomide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Lenalidomide; Tandem Autologous-Allogeneic Transplant