Lenalidomide After Reduced-intensity Allogeneic Stem Cell Transplantation for Relapsed Multiple Myeloma

Study Overview
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Brief Summary
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Allogeneic stem cell transplantation (Allo-SCT) in multiple myeloma (MM) remains a controversial topic because of a high risk of relapse and a significant transplant-related mortality (TRM). In an effort to reduce the TRM, most allogeneic transplants in MM are now performed after reduced-intensity conditioning regimens. In these conditions, TRM usually range from 10 to 20%. However, reducing the intensity of the conditioning invariably increases the incidence of relapse to 45 to 60%. As a consequence, post-transplant strategies to reduce the incidence of relapse after reduced-intensity Allo-SCT should be considered and evaluated.

Detailed Description
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Lenalidomide has a significant clinical activity in patients with relapsed or refractory MM and in patients relapsing after Allo-SCT. The mechanisms of action involve immunomodulation, anti-angiogenesis activity, direct anti tumor activity and effects on microenvironment. So far, the experience with lenalidomide after Allo-SCT has been limited to patients with progressive disease. In such patients, some responses are observed but most of them are transient with median progression-free survivals of less than one year. Lenalidomide used as maintenance therapy in patients with persistent rather than progressive disease might be a better approach. Lenalidomide is interesting in the Allo-SCT setting also because some recent studies focusing on its immunological properties have suggested that the molecule could stimulate the graft versus myeloma effect. First, it has been demonstrated in vitro that lenalidomide can inhibit the proliferation and the suppressor function of regulatory T cells. Secondly, a clinical study using lenalidomide as salvage therapy after Allo-SCT demonstrated an increase of activated T cells and NK cells. Finally, a case report described a patient's response to lenalidomide associated with the development of an acute graft versus host disease. Taken together, these data suggest that patients with MM who have a persistent disease after a reduced-intensity Allo-SCT might benefit from a post-transplant maintenance strategy with lenalidomide by a direct anti-tumor effect and a stimulation of the graft versus myeloma effect. The primary objective of this study is to evaluate the safety of such a strategy.

Official Title
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Safety of a Maintenance Therapy With Lenalidomide After Reduced-intensity Allogeneic Stem Cell Transplantation for Chemosensitive Relapsed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18 to 65 years Multiple Myeloma in 2nd or 3rd complete or partial response* Disease never refractory to lenalidomide Lenalidomide treatment ≤ 9 months HLA related or unrelated donor (matched 10/10 or mismatched 9/10 HLA-C high resolution level or HLA-DQ high or low resolution level) Insured under Social Security Information and consent signed Exclusion Criteria: Stable or progressive disease Hypersensitivity to lenalidomide or excipients Lenalidomide treatment > 9 months Absence of efficient contraception in women or men Cardiac insufficiency (ejection fraction < 50% by echocardiography) Pulmonary disease characterized by DLCO < 60% Severe renal insufficiency (clearance of creatinin < 30 ml/min) Hepatic disease characterized by ASAT and/or ALAT and/or total bilirubin > 2 times the upper normal value except in case of Gilbert's disease Bacterial, Viral or Fungal uncontrolled infections No contraceptive method for Female subjects of childbearing potential No use of condoms for males subjects Pregnant or breast feeding woman History of previous cancer (other than myeloma) except if the patient is in complete remission for more than 5 years.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lenalidomide<br> | Drug: Lenalidomide<br>* Start between Day+100 and Day+120 post-transplant - Initial dose: 5 mg/day every day In the absence of thrombocytopenia < 75000/mm3 or neutropenia < 1000/mm3 (with or without G-CSF), increase to the upper level than the ongoing one every third month up to the maximal dose of 15 mg/day every day. - Duration until persistent stringent complete response for 3 months or progression defined by IMWG criteria12 or unacceptable toxicity or one year after transplant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of lenalidomide | The main judgement criteria will be the occurrence of adverse events (AE) requiring the definitive interruption of lenalidomide : Grade 3 or 4 adverse event according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 occurring at the lowest dose of lenalidomide or Steroid-refractory acute (Seattle criteria) or chronic (National Institutes of Health (NIH) criteria) graft versus host disease or Transplant-related death | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year Progression-Free Survival | Progression defined according to International Myeloma Working Group (IMWG) criteria | one year | 
| One-year Overall Survival | all-cause death | one year | 
| One-year Transplant Related Mortality |  | one year | 
| One-year incidence of Relapse/Progression | Progression defined according to IMWG criteria | one year | 
| Incidences of acute and chronic Graft versus Host Disease | Acute graft versus host disease according to Seattle criteria. Chronic graft versus host disease according to NIH criteria. | one year | 
| Immunophenotypic analysis of blood B, T, NK and dendritic cells |  | one year | 
| Chimerism analysis |  | one year | 
| safety of lenalidomide | all adverse events, graded according to NCI-CTCAE v3 | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lenalidomide