Activated White Blood Cells With ASCT for Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Activating white blood cells in the laboratory may help them kill more cancer cells when they are put back in the body. This may be an effective treatment for patients undergoing a stem cell transplant for multiple myeloma. PURPOSE: This phase I/II trial is studying the side effects of activated white blood cells and to see how well they work in treating patients who are undergoing a stem cell transplant for newly diagnosed stage II or stage III multiple myeloma.

Detailed Description
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OBJECTIVES: Primary Evaluate the safety and response rate of activated marrow infiltrating lymphocytes (aMILs) in patients undergoing autologous peripheral blood stem cell transplantation for newly diagnosed, stage II-III multiple myeloma. Determine the overall in vitro fold-expansion and assess pre- and post-expansion for myeloma T-cell specificity in assessing the feasibility of generating aMILs from myeloma patients. Assess the toxicity of aMILs. Evaluate the effect of aMILs on hematopoietic engraftment, including neutrophil engraftment, platelet engraftment, and primary graft failure (if failure occurs). Evaluate response rates utilizing the Blade criteria, including the complete response (CR) rate, near complete response (nCR) rate, very good partial response (VGPR) rate, partial response (PR) rate, minimal response (MR) rate, and overall response rate (CR, VGPR, PR, MR). Secondary Evaluate T-cell reconstitution, including absolute lymphocyte counts, CD3+, CD4+, and CD8+ T-cell counts. Evaluate progression-free survival and overall survival. Evaluate anti-tumor immune response. Determine pneumococcal-specific vaccine responses. Determine delayed-type hypersensitivity (DTH) responses. OUTLINE: Patients undergo collection of marrow infiltrating lymphocytes (MILs)* either at diagnosis prior to the initiation of induction therapy or upon completion of induction therapy. The MILs bone marrow product undergo ex vivo activation and expansion of T cells for 7-8 days to produce activated marrow infiltrating lymphocytes (aMILs). Patients then undergo stem cell mobilization and leukapheresis to collect the peripheral blood stem cells 12 days after mobilization. Patients receive melphalan IV over 20-30 minutes on days -2 and -1 and undergo a peripheral blood stem cell transplantation on day 0 as planned. Patients receive aMILs infusion on day 3. Patients receive pneumococcal polyvalent vaccine on day 21. NOTE: *Patients who have completed induction therapy receive pneumococcal polyvalent vaccine approximately 2 weeks prior to MILs collection; patients undergoing MILs collection prior to starting induction therapy do not receive a pre-transplantation vaccine. Blood and bone marrow samples are collected periodically for laboratory correlative studies. After completion of study treatment, patients are followed periodically for up to 1 year.

Official Title
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Adoptive Immunotherapy Utilizing Activated Marrow Infiltrating Lymphocytes in the Autologous Transplant Setting in Multiple Myeloma

Conditions
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Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Biological: MILs
* Drug: Melphalan
* Biological: PCV13


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of multiple myeloma Newly diagnosed disease Durie-Salmon stage II or III disease Measurable disease, defined by any of the following: Measurable serum and/or urine M-protein levels documented and available prior to induction therapy Positive serum free light chain assay Must have completed a minimum of 3 courses of myeloma specific therapy Candidate for autologous stem cell transplantation Patients who have achieved a complete remission at the time of bone marrow harvest for marrow infiltrating lymphocytes (MILs) expansion are not eligible No evidence of spinal cord compression Diagnosis of the following cancers are not allowed: POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) Non-secretory myeloma (no measurable protein on serum free light chain assay) Plasma cell leukemia No amyloidosis PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 6 months Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and up to day 180 Corrected serum calcium < 11 mg/dL and no evidence of symptomatic hypercalcemia Total bilirubin ≤ 2.0 times upper limit of normal (ULN) ALT ≤ 2.0 times ULN Serum creatinine < 2.0 mg/dL No history of other malignancy within the past 5 years, except adequately treated basal cell or squamous cell skin cancer No history of autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus) requiring systemic treatment Hypothyroidism without evidence of Graves' disease or Hashimoto thyroiditis is allowed No infection requiring treatment with antibiotics, antifungal, or antiviral agents within the past 7 days No HIV infection No major organ system dysfunction including, but not limited to, the following: New York Heart Association class III or IV congestive heart failure Pulmonary disease requiring the use of inhaled steroids or bronchodilators Renal, hepatic, gastrointestinal, neurologic, or psychiatric dysfunction that would impair ability to participate in the study PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior hematopoietic stem cell transplantation At least 3 weeks since prior corticosteroids (i.e., glucocorticoids) At least 3 weeks since prior myeloma-specific therapy At least 4 weeks since participation in any clinical trial that involved an investigational drug or device No concurrent therapy with any of the following: Corticosteroids (e.g., hydrocortisone, prednisone, prednisolone, dexamethasone [Decadron]) Inhaled steroids used for treatment of allergic rhinitis or pulmonary disease allowed Thalidomide Interferon Growth factors, interleukins, or other cytokines (except filgrastim [G-CSF] as outlined in the protocol, or erythropoietin) Cytotoxic chemotherapy agents (except cyclophosphamide for stem cell mobilization and high-dose melphalan) Immunosuppressive drugs Experimental therapies Radiotherapy

Ages Eligible for Study
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Minimum Age: 18 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: ASCT+MILs<br>Autologous stem cell transplant with a conditioning regimen of melphalan 100 mg/m^2 on each of Days -2 and -1. Infusion of activated marrow infiltrating lymphocytes (MILs) on Day 3. PCV13 vaccine will be given before and/or after Day 0 depending on when participants are enrolled. | Biological: MILs<br> <br> * Other names: aMILs;Drug: Melphalan<br> <br> * Other names: Alkeran;Biological: PCV13<br> <br> * Other names: Prevnar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematopoietic Engraftment | Days to absolute neutrophil count > 500 cells per microliter. | Up to 1 year | 
| Disease Response | Percentage of participants with partial or complete response by Bladé criteria. Partial response is defined as a >= 50% decrease in serum paraprotein or 90% decrease in urinary light chains (for participants without measurable serum paraprotein). Complete response is defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells. | Up to 2 years | 
| Feasibility of MILs Generation as Assessed by Percentage of Participants With Successful MIL Generation | Success rate of expanding MILs in vitro and obtaining a protocol-specified product. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC) | ALC counts trending over time. | Days 14, 28, 60, 180, and 360 | 
| Survival | Survival in months for participants who are alive (Overall Survival) and alive without disease progression (Progression-free survival). Disease progression is defined as a change from negative to positive on immunofixation or electrophoresis for participants previously in complete remission or a 25% increase in serum electrophoresis for participants not previously in complete remission. Partial response is defined as a >= 50% decrease in serum paraprotein or 90% decrease in urinary light chains (for participants without measurable serum paraprotein). Complete response is defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells. | Up to 129 months | 
| Pneumococcal-specific Vaccine Responses | CRM-197 Prevnar-specific vaccine responses that measure the T-cell response of the vaccine quantified as %CD3+/CFSE-low/IFN-gamma+. | At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant | 
| Anti-tumor Immune Responses | Myeloma lysate response that measures the T-cell response quantified as %CD3+/CFSE-low/IFN-gamma+. | At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant | 

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