Multiple Myeloma and Plasma Cell Neoplasm
Conditions
Keywords
stage II multiple myeloma, stage III multiple myeloma
Brief summary
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
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.
Interventions
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hematopoietic Engraftment | Up to 1 year | Days to absolute neutrophil count \> 500 cells per microliter. |
| Disease Response | Up to 2 years | 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. |
| Feasibility of MILs Generation as Assessed by Percentage of Participants With Successful MIL Generation | Up to 1 year | Success rate of expanding MILs in vitro and obtaining a protocol-specified product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC) | Days 14, 28, 60, 180, and 360 | ALC counts trending over time. |
| Anti-tumor Immune Responses | At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant | Myeloma lysate response that measures the T-cell response quantified as %CD3+/CFSE-low/IFN-gamma+. |
| Survival | Up to 129 months | 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. |
| Pneumococcal-specific Vaccine Responses | At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant | CRM-197 Prevnar-specific vaccine responses that measure the T-cell response of the vaccine quantified as %CD3+/CFSE-low/IFN-gamma+. |
Countries
United States
Participant flow
Pre-assignment details
There was one screen failure.
Participants by arm
| Arm | Count |
|---|---|
| MILs in Patients Undergoing an Autologous Peripheral SCT therapeutic autologous lymphocytes
therapeutic tumor infiltrating lymphocytes
melphalan
autologous hematopoietic stem cell transplantation | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Administration of ASCT+MILs | Death | 10 |
| Administration of ASCT+MILs | Lack of Efficacy | 8 |
| Collection of MILs | Relapsed | 1 |
| Collection of MILs | Withdrawal by Subject | 1 |
| Generation of MILs Product | Relapsed | 1 |
Baseline characteristics
| Characteristic | MILs in Patients Undergoing an Autologous Peripheral SCT |
|---|---|
| Age, Continuous | 56 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 22 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 22 |
| other Total, other adverse events | 21 / 22 |
| serious Total, serious adverse events | 1 / 22 |
Outcome results
Primary
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.
Time frame: Up to 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MILs in Patients Undergoing an Autologous Peripheral SCT | Disease Response | Complete Response | 7 Participants |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Disease Response | Partial Response | 6 Participants |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Disease Response | Stable Disease | 6 Participants |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Disease Response | Progressive Disease | 3 Participants |
Primary
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.
Time frame: Up to 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MILs in Patients Undergoing an Autologous Peripheral SCT | Feasibility of MILs Generation as Assessed by Percentage of Participants With Successful MIL Generation | 100 percentage of participants |
Primary
Hematopoietic Engraftment
Days to absolute neutrophil count \> 500 cells per microliter.
Time frame: Up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MILs in Patients Undergoing an Autologous Peripheral SCT | Hematopoietic Engraftment | 17.9 days |
Secondary
Anti-tumor Immune Responses
Myeloma lysate response that measures the T-cell response quantified as %CD3+/CFSE-low/IFN-gamma+.
Time frame: At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MILs in Patients Undergoing an Autologous Peripheral SCT | Anti-tumor Immune Responses | At time of bone marrow harvest | 1.58 %CD3+/CFSE-low/IFN-gamma+ |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Anti-tumor Immune Responses | Day 60 post-transplant | 14.1 %CD3+/CFSE-low/IFN-gamma+ |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Anti-tumor Immune Responses | Day 180 post-transplant | 18.1 %CD3+/CFSE-low/IFN-gamma+ |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Anti-tumor Immune Responses | Day 360 post-transplant | 12.7 %CD3+/CFSE-low/IFN-gamma+ |
Secondary
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+.
Time frame: At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MILs in Patients Undergoing an Autologous Peripheral SCT | Pneumococcal-specific Vaccine Responses | Day 60 post-transplant | 14.4 %CD3+/CFSE-low/IFN-gamma+ |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Pneumococcal-specific Vaccine Responses | At time of bone marrow harvest | 21.5 %CD3+/CFSE-low/IFN-gamma+ |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Pneumococcal-specific Vaccine Responses | Day 180 post-transplant | 23.4 %CD3+/CFSE-low/IFN-gamma+ |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Pneumococcal-specific Vaccine Responses | Day 360 post-transplant | 20.1 %CD3+/CFSE-low/IFN-gamma+ |
Secondary
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.
Time frame: Up to 129 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MILs in Patients Undergoing an Autologous Peripheral SCT | Survival | Overall survival | 112.1 months |
| MILs in Patients Undergoing an Autologous Peripheral SCT | Survival | Progression-free survival | 12.3 months |
Secondary
T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC)
ALC counts trending over time.
Time frame: Days 14, 28, 60, 180, and 360
Population: Data was not collected on one participant at the Day 28 and 180 timepoints, and data was not collected for eight participants at the Day 360 timepoint. Data was not collected on CD3+/CD4+/CD8+ cells for all participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MILs in Patients Undergoing an Autologous Peripheral SCT | T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC) | Day 28 | 1768 cells per microliter |
| MILs in Patients Undergoing an Autologous Peripheral SCT | T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC) | Day 60 | 1700 cells per microliter |
| MILs in Patients Undergoing an Autologous Peripheral SCT | T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC) | Day 14 | 756 cells per microliter |
| MILs in Patients Undergoing an Autologous Peripheral SCT | T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC) | Day 180 | 1430 cells per microliter |
| MILs in Patients Undergoing an Autologous Peripheral SCT | T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC) | Day 360 | 1660 cells per microliter |