Lenalidomide + Azacitidine for Adaptive Immunotherapy -> Auto SCT in Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. An autologous stem cell transplant may be able to replace blood-forming cells that were destroyed by lenalidomide and azacitidine. Giving autologous lymphocytes after the transplant may help destroy any remaining cancer cells. PURPOSE: This pilot trial is studying how well giving lenalidomide together with azacitidine works when followed by autologous stem cell transplant and autologous lymphocyte infusion in treating patients with multiple myeloma.

Detailed Description
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OBJECTIVES: Primary Determine the feasibility of mobilizing and infusing autologous lymphocytes (ALI) following immunomodulatory therapy comprising azacitidine and lenalidomide in patients with multiple myeloma. Secondary Determine the ability to proceed with autologous stem cell transplantation in these patients. Determine the complete response rate at 6 months following transplant in patients treated with this regimen. Determine the progression-free survival and overall survival of patients treated with this regimen. Determine the time to progression in patients treated with this regimen. Monitor the toxicity of post-autologous stem cell infusion of autologous lymphocytes. Measure the pre- and post-ALI immune response to cancer testis antigens (CTA) (CTA-specific Ig and T-cell repertoire). Study the expression of CTA in multiple myeloma before and after azacitidine therapy. OUTLINE: Immunomodulatory therapy: Patients receive azacitidine subcutaneously on days 1-5 and oral lenalidomide on days 6-21. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Lymphapheresis: Patients undergo autologous lymphocyte harvest on day 22 of courses 2 and 3. Autologous stem cell transplantation (ASCT): Patients undergo single or tandem ASCT using standard protocols. Autologous lymphocyte infusion (ALI): Patients undergo ALI approximately 28-60 days after ASCT. Blood samples are collected at baseline and periodically during study for correlative laboratory studies, including CTA-specific immune monitoring by RT-PCR, ELISPOT assays, and flow cytometry. Tissue samples from bone marrow aspirates are also collected at baseline, during course one, and after course three for CTA expression and methylation studies. After completion of study therapy, patients are followed periodically.

Official Title
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Lenalidomide and Azacitidine for Adaptive Immunotherapy in Multiple Myeloma: Pilot Study of Autologous Lymphocyte Mobilization Following Immuno-modulatory Therapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with a diagnosis of multiple myeloma, who have residual measurable disease (in partial remission or with stable disease) and are eligible to undergo an autologous stem cell transplant will be able to participate in this trial; measurable disease will comprise of either, quantifiable serum or urinary, M protein or free light chains in the presence of a positive immunofixation or bone marrow plasma cells > 5% Patients who have received prior lenalidomide therapy will be eligible if >= partial response (PR) was observed on a prior lenalidomide containing regimen and patients did not progress while receiving lenalidomide; isolated bone lytic lesions in the absence of measurable para-proteins will not be considered measurable disease A minimum period of two weeks must have elapsed following the prior myeloma therapy; this does not include therapy with bisphosphonates Eastern Cooperative Oncology Group (ECOG) performance status =< 2 No clinical evidence of uncontrolled viral, fungal, bacterial infection Negative serology for human immunodeficiency virus (HIV) Serum bilirubin =< 1.5 times upper limit of normal (ULN) Serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT) =< 3x ULN Calculated creatinine clearance >= 60ml/min by Cockcroft-Gault formula; creatinine clearance >= 60 ml/min or serum creatinine =< 2.0 mg/dL Absolute neutrophil count (ANC) >= 1500/uL Platelet count >= 100,000/ uL Hemoglobin (Hgb) >= 10 g/dL following recovery from last therapy Cardiac and pulmonary function adequate for transplant Ability to sign informed consent All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy Exclusion criteria: Known or suspected hypersensitivity to azacitidine or mannitol Patients with multiple myeloma refractory to therapy with lenalidomide; progression following discontinuation of prior therapy with lenalidomide is allowed as long as patients have not failed rechallenge with lenalidomide Pregnant or breast feeding Other concomitant malignancies Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form Concurrent use of other anti-cancer agents or treatments Known hypersensitivity to thalidomide or lenalidomide

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 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: Aza Len Lymphapheresis SCT ALI<br>Azacitidine will be administered to all the patients subcutaneously at a dose of 75 mg/m2 daily for five days(day 1-5). These cycles will be repeated at 28 day intervals depending on hematopoietic recovery. Starting on day 6 patients will receive lenalidomide 15 mg PO daily until day 21. No drug will be administered from day 22 to day 28. Lymphapheresis will occur after cycles 2 and 3.Patients will undergo a stem cell collection approximately two weeks after complete myeloid recovery from the third cycle of therapy. Stem Cell Transplant (SCT) will occur per transplant center protocols. Post-transplant single or tandem autologous lymphocyte infusions (ALI) will be performed no earlier than 30 days post-transplant and no later than 40 days. | Drug: Azacitidine<br>* Subject will receive Vidaza (azacitidine) and Revlimid (lenalidomide) as treatment for their multiple myeloma. The Vidaza will be given for 5 days as an injection. On day 6 they will receive Revlimid taken by mouth every day for 16 days followed by 7 days of rest. The drug cycle will be repeated 0, 1 or 2 more times depending on how their blood counts recover.<br>* Other names: Revlimid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility to Mobilize and Infuse Autologous Lymphocytes (ALI) After Immunomodulatory Therapy and After Stem Cell Transplant Engraftment | Time frame is post 2nd and 3rd cycles of rev/aza and after stem cell transplant engraftment. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate at 6 Months | 16 of 17 patients proceeded to transplant. 6 month CR rate post transplant was 8/16 (50%). | 6 months | 
| Toxicity as Assessed by NCI CTCAE v3.0 | Time frame includes after stem cell transplant engraftment. Toxicity post ALI infusion: 1 patient grade 1 hypertension 90 min post infusion. Toxicity post Rev maintenance: 1 patient not tolerated, 1 patient dose decreased due to counts. | 6 months | 
| Time to Progression Post Transplant | Time to progression post transplant: For patients not in Complete Response (CR), progressive disease requires one or more: >25% increase in the level of the serum monoclonal paraprotein(absolute increase of at least 0.5 g/dL); > 25% increase in 24-hour urinary light chain excretion(absolute increase of at least 200m/24 hours). Increase plasma cells in a bone marrow aspirate( absolute increase of at least 10%). Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of new bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum Ca > 11.5 mg/dL or > 2.65 mmol/L) not attributable to any other cause. All relapse categories require two consecutive assessments made any time before classification as relapse or progressive disease. | 28 months | 
| Progression-free and Overall Survival | Survival and event-free survival curves (any event of fatality, relapse, acute or chronic GVHD) with Kaplan-Meier curves. The incidence curve for relapse - accounting for the competing risk of fatality - is plotted with step-wise curves. The R statistical software (version 2.15) was used for all time-to-event analyses, with the survival package used for survival curves, and the cmprsk package used for all competing risk curves. Results: The one-year survival rate is 93.3% (SE = 0.4%), and the two-year survival rate is 86.1% (SE = 0.9%). | 1 year to 2 years | 
| Pre- and Post-ALI Immune Response to Cancer Testis Antigens (CTA) | Not able to obtain outcome data. | 6 months | 
| CTA Expression Before and After Azacitidine Therapy | Six patients tested have demonstrated CTA up-regulation in either unfractionated bone marrow (n = 4) or CD138+ cells (n = 2). CTA (CTAG1B)-specific T cell response has been observed in all three patients tested and persists following SCT. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma