Multiple Myeloma
Conditions
Keywords
Recurrent multiple myeloma, NK cells, cell therapy, NKAE, Relapsed multiple myeloma
Brief summary
The purpose of this study is to determine wether activated and expanded autologous Natural Killer cells (NKAEs) are effective in the treatment of patients with multiple myeloma on second or later relapse. NKAEs are used in combination with anti-myeloma drugs such as lenalidomide or bortezomib.
Detailed description
It is expected to enroll 10 to 15 patients within 18 months. Patients have to achieve stable disease after induction therapy. Peripheral blood from patients will be collected every cycle (n=4) to produce NKAEs under Good Manufacturing Practice (GMP) conditions peripheral blood mononuclear cell (PBMCs) will be co-cultured with a genetically modified cell line (K562-mb15-41BBL) and 100 IU/ml interleukin-2. Treatment consists of 4 cycles of anti-myeloma consolidation treatment with two infusions of NKAEs every day 1 and 8 of each cycle. Usually, chosen treatment regime will be bortezomib (Velcade) or lenalidomide (Revlimid). These treatments are used to be combined with corticosteroid medications which needs to be suspended before NKAEs infusions. A washout period of 2 weeks is required. NKAEs dose of cells will be constant, 7.5x106/kg. There will be an interim analysis intra-cohort one week after the first batch of two infusions. If at the analysis no grade IV adverse effect is observed we will proceed to the second cycle and the inclusion of other patients.
Interventions
PROCEDURENKAE cells infusion
Expanded and activated autologous NK cells infusion. Each patient will receive two infusions of 7.5 x 106 expanded and activated autologous NK cells/kg/cycle.
DRUGLenalidomide
Lenalidomide, 10 mg oral/day during 21 days (cycle). Patients will receive 4 cycles.
DRUGBortezomib
Bortezomib, 1.3 mg/m2, s.c., days 1, 4, 8 and 11/cycle. Patients will receive 4 cycles.
Sponsors
Hospital Infantil Universitario Niño Jesús, Madrid, Spain
Joaquín Martínez López, MD, PhD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Subjects between 20 and 80 years old * With multiple myeloma in 2nd or later relapse or showing resistance after 2 treatment lines * Eastern Cooperative Oncology Group (ECOG) ≤ 2 * Life expectancy greater than six months * Creatinine clearance rate more than 30 ml / min * Subjects who have received at least 4 cycles of rescue treatment under the procedures of the 12 de Octubre Hospital (rescue treatment will vary depending on previous anti-myeloma treatment). After treatment, patients must have shown chemosensitivity and disease stabilization. * Will be included subjects with partial response or stable disease (for at least 2 cycles) after 75% of planned rescue treatment or patients at subclinical progression (defined as an increase of monoclonal component ≥ 25%) at any time of rescue treatment. Subjects have to show tolerance to rescue treatment, without G3/4 adverse effects, if G1/2 adverse effects exist they must be analyzed immediately before starting reinfusion program. * Subjects have to agree to participate in the trial and they have to sign informed consent.
Exclusion criteria
* Subjects with clinical progression or complete response will not be included. * Any of the following abnormal laboratory results: Absolute Neutrophil Count \< 1000/ µL Platelets Count \< 50000/ µL in those patients with bone marrow infiltration lower than 50% Measured creatinine clearance \<30 ml/min Hemoglobin level ≤ 8 g/dL Peripheral neuropathy ≥ Grade 2 * Subjects have received allogeneic stem cell transplant. * Subjects with heart disease which compromises patient's life or protocol accomplishment. * Subjects with past clinical history of malignant disease within 3 years (exceptions are squamous or basal cell carcinoma). * Subjects receiving another investigational drug or having received investigational drug within 30 days before screening. * Subjects who require chronic steroid or immunosuppressive treatment. * Any condition, including abnormally laboratory results, that might compromise the patient´s life if he participate in this study. * Any concurrent medical condition, abnormally laboratory results or any psychological disorder that prevent the patient to sign the informed consent. * Pregnant or fertile women. * Patients known to be seropositive for human immunodeficiency virus (VIH) or having active hepatitis A, B or C.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events During NKAE Treatment | 16 months | Toxicity will be assessed by adverse events count during NKAE treatment monitoring peripheral blood absolute neutrophil count (cells/μl). Toxicity will be evaluated monthly during NKAE treatment (4 months). During follow-up, it will be assessed monthly the first 6 months. After that, quarterly until one year of follow-up, based on Common Toxicity Criteria for Adverse Events of the National Cancer Institute (CTCAE) to v.4.03. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Peripheral Blood Monoclonal Protein Reduction or Stabilization | 16 months | Efficacy will be assessed monthly during NKAE treatment (4 months) by peripheral blood monoclonal protein monitoring. During follow-up, efficacy will be evaluated monthly the first 6 months. After that, quarterly until one year of follow-up. |
Countries
Spain
Participant flow
Recruitment details
Recruitment was performed between march 2013 and october 2014 at Hospital 12 de Octubre in Madrid.
Participants by arm
| Arm | Count |
|---|---|
| NKAE Cells Infusion + Chemotherapy Expanded and activated autologous NK cells (NKAEs) + chemotherapy (lenalidomide OR bortezomib).
NKAE cells infusion: Expanded and activated autologous NK cells infusion. Each patient will receive: two infusions of 7.5 x 106 expanded and activated autologous NK cells/kg/cycle.
Lenalidomide: Lenalidomide, 10 mg oral/day during 21 days (cycle). Patients will receive 4 cycles.
Bortezomib: bortezomib, 1.3 mg/m2, s.c., days 1, 4, 8 and 11/cycle. Patients will receive 4 cycles. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
Baseline characteristics
| Characteristic | NKAE Cells Infusion + Chemotherapy |
|---|---|
| Age, Continuous | 62 years |
| Region of Enrollment Spain | 5 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 5 |
| serious Total, serious adverse events | 2 / 5 |
Outcome results
Primary
Number of Participants With Adverse Events During NKAE Treatment
Toxicity will be assessed by adverse events count during NKAE treatment monitoring peripheral blood absolute neutrophil count (cells/μl). Toxicity will be evaluated monthly during NKAE treatment (4 months). During follow-up, it will be assessed monthly the first 6 months. After that, quarterly until one year of follow-up, based on Common Toxicity Criteria for Adverse Events of the National Cancer Institute (CTCAE) to v.4.03.
Time frame: 16 months
Population: Analysis per protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NKAE Cells Infusion + Chemotherapy | Number of Participants With Adverse Events During NKAE Treatment | 2 participants |
Secondary
Number of Participants With Peripheral Blood Monoclonal Protein Reduction or Stabilization
Efficacy will be assessed monthly during NKAE treatment (4 months) by peripheral blood monoclonal protein monitoring. During follow-up, efficacy will be evaluated monthly the first 6 months. After that, quarterly until one year of follow-up.
Time frame: 16 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NKAE Cells Infusion + Chemotherapy | Number of Participants With Peripheral Blood Monoclonal Protein Reduction or Stabilization | 5 participants |