Multiple Myeloma
Conditions
Keywords
Stage II Multiple Myeloma, Stage III Multiple Myeloma, Refractory Plasma Cell Neoplasm
Brief summary
The study is designed as a Phase III, multi-center trial of tandem autologous transplants versus the strategy of autologous followed by Human Leukocyte Antigen (HLA)-matched sibling non-myeloablative allogeneic transplant. Study subjects will be biologically assigned to the appropriate arm depending on the availability of an HLA-matched sibling. There is a nested randomized phase III trial of observation versus maintenance therapy following the second autologous transplant for patients on the tandem autologous transplant arm.
Detailed description
Multiple myeloma (MM), characterized by malignant plasma cell proliferation, bone destruction, and immunodeficiency, is a disease with a median age at diagnosis of approximately 65 years. It is responsible for about 1 percent of all cancer-related deaths in Western Countries. Conventional treatments with chemotherapy and radiation therapy are non-curative but improve quality of life and duration of survival. Attempts to cure myeloma through high-dose therapy followed by autografting or allografting have largely failed due to a combination of relapsed disease or transplant related mortality (TRM). High-dose therapy with autologous transplantation is safe and has low TRM (less than 5%), but is associated with a continuing and nearly universal risk of disease progression and relapse. Even so, autologous transplantation is superior to continued conventional chemotherapy. Recent data indicate that tandem autologous transplants are superior to a single procedure. Even with this approach, patients remain at risk of relapse and additional approaches are needed. DESIGN NARRATIVE: The overall study design is that of biologic assignment, based on the availability of an HLA-matched sibling, to one of two treatment strategies for MM patients. Patients without an HLA-matched sibling will undergo tandem autologous transplants. Patients with an HLA-matched sibling will undergo an autologous transplant followed by a non-myeloablative allogeneic transplant. In addition, the tandem autologous transplant recipients will be randomized to either observation or one year of maintenance therapy to begin following the second autologous transplant. The large number of MM patients without an HLA-matched sibling enables us to evaluate the role of maintenance therapy following tandem autologous transplants.
Interventions
PROCEDUREOne Autologous Transplant
Melphalan will be administered at a dose of 200 mg/m2. Melphalan will be given in one dose infused on Day -2. Melphalan dose is based on ideal body weight (IBW) for patients who weigh 100-120% of their IBW. All patients will receive an autologous graft with a minimum cell dose of 2.0 x 106 CD34+ cells/kg patient weight. Patients will receive \ 5 ug/kg/day of Granulocyte-Colony Stimulating Factor (G-CSF) subcutaneously from Day 5 post-transplant until absolute neutrophil count (ANC) \> 500/mm3 for two days.
PROCEDURENon-Myeloablative Allogeneic Transplant
Upon recovery and at least Day 60 post-autograft, patients with an available 6/6 HLA matched sibling will receive an allograft after non-myeloablative conditioning. Day 0 patients will receive Total Body Irradiation (TBI) 2.0 Gy from a linear accelerator ≤ 20 cGy/min, followed by allogeneic peripheral blood stem cell (PBSC) infusion. Commence cyclosporine (CSA) on Day -3 at 5 mg/kg bid PO for a daily dose of 10 mg/kg/day through Day +84 based on actual body weight. Starting on Day 84, patients in partial or complete response with the absence of graph versus host disease (GVHD) will have CSA tapered so the patient will be off CSA by Day 180. Oral administration of Mycophenolate Mofetil will be at a daily dose of 30 mg/kg/day from the evening of Day 0 until Day 27 post-transplant.
PROCEDURESecond Autologous Transplant
Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients without an HLA-matched sibling donor will receive a second autograft, also conditioned with melphalan 200 mg/m2.
DRUGThalidomide
Patients will be initiated on a starting dose of 50 mg/day. The dose will be increased weekly by 50 mg as tolerated to achieve a target dose of 200 mg/day. Patients will be treated for 12 months with thalidomide.
DRUGDexamethasone
Patients will receive dexamethasone at a dose of 40 mg per day during Days 1-4 of each month for 12 months. The first dose of dexamethasone to be given the same day the patient starts thalidomide.
BEHAVIORALObservation
One year of observation post-transplants.
Sponsors
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 70 Years
Healthy volunteers
No
Inclusion criteria
* Meeting the Durie and Salmon criteria for initial diagnosis of MM * Stage II or III MM at diagnosis or anytime thereafter * Symptomatic MM requiring treatment at diagnosis or anytime thereafter * Received at least three cycles of initial systemic therapy and are within 2-10 months of initiation of the initial therapy (this time frame excludes the time for mobilization therapy) * If receiving chemotherapy-based mobilization regimens, must be able to receive high-dose melphalan between 2 and 8 weeks after the initiation of mobilization therapy whether delivered at the transplant center or at a referring center * Adequate organ function as measured by: 1. Cardiac: Left ventricular ejection fraction at rest greater than 40% 2. Hepatic: Bilirubin less than 2 times the upper limit of normal and alanine transaminase (ALT) and aspartate transaminase (AST) less than 3 times the upper limit of normal 3. Renal: Creatinine clearance greater than 40 ml/min (measured or calculated/estimated) 4. Pulmonary: Carbon monoxide diffusion (DLCO), Volume forcibly exhaled in one second (FEV1), and Forced Vital Capacity (FVC) greater than 50% of predicted value (corrected for hemoglobin), or O2 saturation greater than 92% of room air * An adequate autologous graft defined as a cryopreserved PBSC graft containing at least 4.0 x 106 CD34+ cells/kg patient weight; if prior to enrollment it is known that a patient will be on the auto-allo arm (i.e., a consenting, eligible HLA-matched sibling donor is available), the required autograft must contain at least 2.0 x 10\^6 CD34+ cells/kg patient weight; the graft may not be CD34+ selected or otherwise manipulated to remove tumor or other cells; the graft can be collected at the transplanting institution or by a referring center; for patients without an HLA-matched sibling donor, the autograft must be stored so that there are two products each containing at least 2 x 10\^6 CD34+ cells/kg patient weight
Exclusion criteria
* Never advanced beyond Stage I MM since diagnosis * Non-secretory MM (absence of a monoclonal protein \[M protein\] in serum as measured by electrophoresis and immunofixation and the absence of Bence Jones protein in the urine defined by use of conventional electrophoresis and immunofixation techniques) * Plasma cell leukemia * Karnofsky performance score less than 70%, unless approved by the Medical Monitor or one of the Protocol Chairs * Uncontrolled hypertension * Uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) * Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Medical Monitor or one of the Protocol Chairs; cancer treated with curative intent more than 5 years previously will be allowed * Pregnant or breastfeeding * Seropositive for the human immunodeficiency virus (HIV) * Unwilling to use contraceptive techniques during and for 12 months following treatment * Prior allograft or prior autograft * Received mid-intensity melphalan (more than 50 mg IV) as part of prior therapy * Prior organ transplant requiring immunosuppressive therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Year 3 | Patients are considered a failure for this endpoint if they die or if they progress or relapse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) for High Risk | Year 3 | The event is death from any cause, patients alive at the time of last observation are considered censored. |
| Cumulative Incidence of Progression/Relapse | Year 3 | Patients are considered experiencing an event when they progress. Deaths without progression are considered as a competing risk. Patients initiating non-protocol anti-myeloma therapy are considered to have progressed on this protocol. |
| Cumulative Incidence of Treatment Related Mortality (TRM) | Year 3 | TRM is defined as death occurring in a patient from causes other than relapse or progression. |
| Overall Survival (OS) for Standard Risk | Years 1, 2, and 3 | The event is death from any cause, patients alive at the time of last observation are considered censored. |
| Incidences of Graft Versus Host Disease (GVHD) | Day 100 | Incidence and severity of GVHD will be scored according to the BMT clinical trials network Manual of Procedures. |
| Incidences of Chronic GVHD | Years 1 and 2 | Incidence and severity of chronic GVHD will be scored according to the BMT clinical trials network Manual of Procedures. |
| Interval From First to Second Transplantation | Year 1 | Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients will receive a second transplant according to treatment assignments. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled between December 2003 and March 2007 from 37 different transplant centers.
Participants by arm
| Arm | Count |
|---|---|
| Auto-Auto Standard Risk Tandem autologous transplant plus thalidomide/dexamethasone (Thal-Dex) or observation (Obs) for standard risk patients
PFS and OS did not differ between the Thal-Dex and the Obs arms and were thus pooled for analysis. | 436 |
| Auto-Allo Standard Risk Autologous transplant plus non-myeloablative allogeneic transplant for standard risk patients | 189 |
| Auto-Auto High Risk Tandem autologous transplant plus thalidomide/dexamethasone (Thal-Dex) or observation (Obs) for high risk patients
PFS and OS did not differ between the Thal-Dex and the Obs arms and were thus pooled for analysis. | 48 |
| Auto-Allo High Risk Autologous transplant plus non-myeloablative allogeneic transplant for high risk patients | 37 |
| Total | 710 |
Baseline characteristics
| Characteristic | Auto-Auto Standard Risk | Auto-Allo Standard Risk | Auto-Auto High Risk | Auto-Allo High Risk | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55 years | 53 years | 57 years | 51 years | 53.2 years |
| Disease status CR | 41 participants | 24 participants | 1 participants | 3 participants | 69 participants |
| Disease status MR | 31 participants | 17 participants | 10 participants | 3 participants | 61 participants |
| Disease status Near CR | 65 participants | 22 participants | 1 participants | 2 participants | 90 participants |
| Disease status Not Evaluable | 30 participants | 12 participants | 8 participants | 4 participants | 54 participants |
| Disease status PR | 158 participants | 76 participants | 21 participants | 14 participants | 269 participants |
| Disease status SD | 21 participants | 6 participants | 6 participants | 4 participants | 37 participants |
| Disease status Unknown | 11 participants | 0 participants | 0 participants | 0 participants | 11 participants |
| Disease status Very Good PR | 79 participants | 32 participants | 1 participants | 7 participants | 119 participants |
| Durie-Salmon Stage III | 294 participants | 130 participants | 38 participants | 28 participants | 490 participants |
| Durie-Salmon Stages I-II | 142 participants | 59 participants | 10 participants | 9 participants | 220 participants |
| Interval from diagnosis to transplantation | 7 months | 7 months | 7 months | 7 months | 7 months |
| Karnofsky Performance score 100 - 90 | 344 participants | 148 participants | 27 participants | 26 participants | 545 participants |
| Karnofsky Performance score < 90 | 92 participants | 41 participants | 21 participants | 11 participants | 165 participants |
| Race/Ethnicity, Customized African American | 77 participants | 18 participants | 8 participants | 3 participants | 106 participants |
| Race/Ethnicity, Customized Caucasian | 335 participants | 161 participants | 38 participants | 33 participants | 567 participants |
| Race/Ethnicity, Customized Other | 24 participants | 10 participants | 2 participants | 1 participants | 37 participants |
| Sex: Female, Male Female | 176 Participants | 78 Participants | 21 Participants | 16 Participants | 291 Participants |
| Sex: Female, Male Male | 260 Participants | 111 Participants | 27 Participants | 21 Participants | 419 Participants |
| β-2 Microglobulin | 2.0 mg/L | 2.0 mg/L | 4.4 mg/L | 3.7 mg/L | 3.025 mg/L |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 436 | 1 / 189 | 0 / 48 | 0 / 37 |
| serious Total, serious adverse events | 15 / 436 | 10 / 189 | 2 / 48 | 5 / 37 |
Outcome results
Primary
Progression-Free Survival (PFS)
Patients are considered a failure for this endpoint if they die or if they progress or relapse.
Time frame: Year 3
Population: Patients that completed second transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Auto-Auto Standard Risk | Progression-Free Survival (PFS) | 46 percentage of patients |
| Auto-Allo Standard Risk | Progression-Free Survival (PFS) | 43 percentage of patients |
| Auto-Auto High Risk | Progression-Free Survival (PFS) | 33 percentage of patients |
| Auto-Allo High Risk | Progression-Free Survival (PFS) | 40 percentage of patients |
Secondary
Cumulative Incidence of Progression/Relapse
Patients are considered experiencing an event when they progress. Deaths without progression are considered as a competing risk. Patients initiating non-protocol anti-myeloma therapy are considered to have progressed on this protocol.
Time frame: Year 3
Population: Patients that completed second transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Auto-Auto Standard Risk | Cumulative Incidence of Progression/Relapse | 50 percentage of patients |
| Auto-Allo Standard Risk | Cumulative Incidence of Progression/Relapse | 46 percentage of patients |
| Auto-Auto High Risk | Cumulative Incidence of Progression/Relapse | 57 percentage of patients |
| Auto-Allo High Risk | Cumulative Incidence of Progression/Relapse | 38 percentage of patients |
Secondary
Cumulative Incidence of Treatment Related Mortality (TRM)
TRM is defined as death occurring in a patient from causes other than relapse or progression.
Time frame: Year 3
Population: Patients that completed second transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Auto-Auto Standard Risk | Cumulative Incidence of Treatment Related Mortality (TRM) | 4 percentage of participants |
| Auto-Allo Standard Risk | Cumulative Incidence of Treatment Related Mortality (TRM) | 11 percentage of participants |
| Auto-Auto High Risk | Cumulative Incidence of Treatment Related Mortality (TRM) | 11 percentage of participants |
| Auto-Allo High Risk | Cumulative Incidence of Treatment Related Mortality (TRM) | 22 percentage of participants |
Secondary
Incidences of Chronic GVHD
Incidence and severity of chronic GVHD will be scored according to the BMT clinical trials network Manual of Procedures.
Time frame: Years 1 and 2
Population: GVHD was only assessed on the Auto-Allo arm for standard risk patients that completed second transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Auto-Auto Standard Risk | Incidences of Chronic GVHD | 1 year | 47 percentage of patients |
| Auto-Auto Standard Risk | Incidences of Chronic GVHD | 2 years | 54 percentage of patients |
Secondary
Incidences of Graft Versus Host Disease (GVHD)
Incidence and severity of GVHD will be scored according to the BMT clinical trials network Manual of Procedures.
Time frame: Day 100
Population: GVHD was only assessed on the Auto-Allo arm for standard risk patients that completed second transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Auto-Auto Standard Risk | Incidences of Graft Versus Host Disease (GVHD) | Grades II-IV | 26 percentage of patients |
| Auto-Auto Standard Risk | Incidences of Graft Versus Host Disease (GVHD) | Grades III-IV | 9 percentage of patients |
Secondary
Interval From First to Second Transplantation
Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients will receive a second transplant according to treatment assignments.
Time frame: Year 1
Population: Patients that completed second transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Auto-Auto Standard Risk | Interval From First to Second Transplantation | 98 days |
| Auto-Allo Standard Risk | Interval From First to Second Transplantation | 105 days |
| Auto-Auto High Risk | Interval From First to Second Transplantation | 101 days |
| Auto-Allo High Risk | Interval From First to Second Transplantation | 111 days |
Secondary
Overall Survival (OS) for High Risk
The event is death from any cause, patients alive at the time of last observation are considered censored.
Time frame: Year 3
Population: Patients that completed second transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Auto-Auto Standard Risk | Overall Survival (OS) for High Risk | 67 percentage of participants |
| Auto-Allo Standard Risk | Overall Survival (OS) for High Risk | 59 percentage of participants |
Secondary
Overall Survival (OS) for Standard Risk
The event is death from any cause, patients alive at the time of last observation are considered censored.
Time frame: Years 1, 2, and 3
Population: Patients that completed second transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Auto-Auto Standard Risk | Overall Survival (OS) for Standard Risk | 1 year | 95 percentage of patients |
| Auto-Auto Standard Risk | Overall Survival (OS) for Standard Risk | 2 years | 89 percentage of patients |
| Auto-Auto Standard Risk | Overall Survival (OS) for Standard Risk | 3 years | 80 percentage of patients |
| Auto-Allo Standard Risk | Overall Survival (OS) for Standard Risk | 1 year | 91 percentage of patients |
| Auto-Allo Standard Risk | Overall Survival (OS) for Standard Risk | 2 years | 85 percentage of patients |
| Auto-Allo Standard Risk | Overall Survival (OS) for Standard Risk | 3 years | 77 percentage of patients |