Safety And Efficacy Of Lenalidomide As Maintenance Therapy In Patients With Newly Diagnosed Multiple Myeloma Following A Tandem Autologous-Allogeneic Transplant
Safety And Efficacy Of Lenalidomide As Maintenance Therapy In Patients With Newly Diagnosed Multiple Myeloma Following A Tandem Autologous-Allogeneic Transplant
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.
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.
Inclusion Criteria:

 1. Newly diagnosed multiple myeloma patients with an HLA identical sibling suitable for
 PBSC donation and treated in induction with thalidomide or bortezomib or lenalidomide
 conteining regimes.

 2. Complete cytogenetic analysis at diagnosis, including FISH analysis for chromosome
 deletions 13 and 17, and translocations (4;14) (11;14) and (14;16).

 3. The patient must have the capacity to give informed consent.

 4. Age >18 and < 65

 5. If female, the patient is either postmenopausal since at least 24 consecutive months
 or surgically sterilized or she agrees to practice sexual abstinence or to use two
 reliable methods for contraception (e.g. a hormonal contraceptive, intra-uterine
 device, diaphragm with spermicide, condom with spermicide) for the duration of study

 6. If male, the patient agrees to practice sexual abstinence or to use a latex condom
 during any sexual contact with women of childbearing potential for the duration of
 study

 7. Negative pregnancy test

 Exclusion Criteria:

 1. Karnofsky score less than 60 (see appendix C), unless due solely to myeloma

 2. Left ventricular ejection fraction less than 40%, or symptomatic coronary artery
 disease or other cardiac failure requiring therapy

 3. Bilirubin greater than 2 X the upper limit of normal, or SGPT and SGOT > 4 X the upper
 limit of normal

 4. DLCO < 40% (corrected) or receiving continuous supplemental oxygen.

 5. Creatinine clearance < 40 cc/min at the time of initial autografting evaluation.

 6. Patients with poorly controlled hypertension

 7. Patients with active non-hematologic malignancies (except non-melanoma skin cancers).

 8. Patients with a history of non-hematologic malignancies (except non-melanoma skin
 cancers) currently in a complete remission, who are less than 5 years from the time of
 complete remission, and have a >20% risk of disease recurrence

 9. Seropositive for HIV

 10. Fertile men or women unwilling to use contraceptive techniques during and for 12
 months following treatment.

 11. To evaluate toxicity and tolerability of lenalidomide after allografting

 12. To evaluate efficacy of lenalidomide in inducing complete remission 12 months after
 allografting