Refractory Plasma Cell Myeloma
Conditions
Brief summary
This phase II trial studies the side-effects and anti-cancer effects of giving an autologous or syngeneic stem cell transplant followed by an allogeneic donor stem cell transplant and bortezomib. Patients treated on this trial have newly diagnosed high-risk, relapsed, or refractory multiple myeloma (MM). Giving chemotherapy before an autologous stem cell transplant slows or stops the growth of cancer cells by preventing them from dividing or killing them. Stem cells that were harvested earlier from the patient's blood and frozen are then returned to the patient to replace the blood-forming cells that were destroyed by chemotherapy. Giving chemotherapy and total-body irradiation before an allogeneic donor stem cell transplant also prevents the patient's immune system from rejecting the donor's stem cells. Undergoing an autologous or syngeneic stem cell transplantation followed by an allogeneic donor stem cell transplant and bortezomib may be overall more effective in killing cancer cells.
Detailed description
PRIMARY OBJECTIVES: I. Progression-free survival (PFS) at 2 years after the autograft (=\< 50% in historic controls). SECONDARY OBJECTIVES: I. Overall survival (OS) at 2 years after the autograft. II. Non-relapse mortality (NRM) at 200 days and 1 year after allograft. III. Incidence of grades II-IV acute graft-versus-host-disease (GVHD) and chronic extensive GVHD. IV. Safety of bortezomib maintenance therapy after stem cell transplantation. OUTLINE: PERIPHERAL BLOOD STEM CELL (PBSC) MOBILIZATION: Patients undergo PBSC mobilization and collection using the preferred regimens at the participating institution. CONDITIONING CHEMOTHERAPY AND AUTOLOGOUS OR SYNGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT): Patients receive high-dose melphalan intravenously (IV) on day -2 followed by an autologous or syngeneic HSCT on day 0. NON-MYELOABLATIVE ALLOGENEIC HSCT: Beginning 40-180 days after autologous HSCT, patients receive 1 of the following regimens: 1. HLA-IDENTICAL RELATED DONOR: Patients receive cyclosporine IV or orally (PO) twice daily (BID) starting on days -3 to 56, and taper until day 180. Patients then undergo total-body irradiation (TBI) and non-myeloablative allogeneic HSCT on day 0. Four to six hours after completion of allogeneic HSCT, patients receive mycophenolate mofetil (MMF) PO BID on days 0-27. 2. HLA-UNRELATED DONOR: Patients receive fludarabine phosphate IV on days -4 to -2. Patients also receive cyclosporine IV or PO BID starting on days -3 to 100 and taper until day 180. Patients then undergo TBI and non-myeloablative allogeneic HSCT on day 0. Four to six hours after completion of allogeneic HSCT, patients receive MMF PO thrice daily (TID) on days 0-27 and then BID on days 27-40 with taper of MMF on days 40-96. MAINTENANCE THERAPY: Beginning 60-120 days after allogeneic HSCT, patients receive bortezomib subcutaneously (SC) on days 1 and 4 of 14-day cycles for 9 months or for up to 18 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year and then annually for up to 5 years.
Interventions
PROCEDUREAutologous Hematopoietic Stem Cell Transplantation
Undergo transplantation
DRUGBortezomib
Given SC
DRUGCyclosporine
Given IV
DRUGFludarabine Phosphate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMelphalan
Given IV
DRUGMycophenolate Mofetil
Given PO
PROCEDURENonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo transplantation
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo transplantation
Undergo transplantation
RADIATIONTotal-Body Irradiation
Undergo radiotherapy
Sponsors
Millennium Pharmaceuticals, Inc.
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
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
* Newly diagnosed patients must have received induction therapy (e.g., vincristine, doxorubicin, dexamethasone \[VAD\], thalidomide/dexamethasone) for a minimum of 4 cycles * Must have the capacity to give informed consent * Must have an human leukocyte antigen (HLA) genotypically identical sibling or a phenotypically matched relative or, at a minimum, a high likelihood of identifying an HLA-matched unrelated donor; the determination of availability of a suitable unrelated donor may be based on a World-Book search * In addition, patients must meet at least one of the criteria A-I (A-G at time of diagnosis or pre-autograft): * A) Any abnormal karyotype by metaphase analysis except for isolated t(11,14) and constitutional cytogenetic abnormality * B) Fluorescence in situ hybridization (FISH) translocation 4;14 * C) FISH translocation 14;16 * D) FISH deletion 17p * E) Beta2-microglobulin \> 5.5 mg/L * F) Cytogenetic hypodiploidy * G) Plasmablastic morphology (\>= 2%) * DONOR: HLA genotypically identical sibling or phenotypically matched relative OR * DONOR: HLA phenotypically matched unrelated donor (according to Standard Practice HLA matching criteria, Grade #2.1) * Matched HLA-A, B, C, DRB1, and DQB1 alleles by high resolution typing. * Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
Exclusion criteria
* Recurrent or non-responsive (less than partial response \[PR\]) MM after at least two different lines of conventional chemotherapy * Progressive MM after a previous autograft * Life expectancy severely limited by disease other than malignancy * Seropositive for the human immunodeficiency virus (HIV) * Females who are pregnant or breastfeeding * Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment * Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy * Patients with fungal infection and radiological progression after receipt of amphotericin B or active triazole for greater than 1 month * Patients with the following organ dysfunction: * Symptomatic coronary artery disease or ejection fraction \< 40% or other cardiac failure requiring therapy; myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities * Ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease * Diffusing lung capacity for carbon monoxide (DLCO) \< 50%, forced expiratory volume in 1 second (FEV) \< 50% and/or receiving supplementary continuous oxygen; the Fred Hutchinson Cancer Research Center (FHCRC) principle investigator (PI) of the study must approve of enrollment of all patients with pulmonary nodules * Liver function abnormalities: Patient with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; the patient will be excluded if he/she is found to have fulminant liver failure; cirrhosis of the liver with evidence of portal hypertension; alcoholic hepatitis; esophageal varices; a history of bleeding esophageal varices; hepatic encephalopathy; uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time ascites related to portal hypertension; bacterial or fungal liver abscess; biliary obstruction; chronic viral hepatitis with total serum bilirubin \> 3 mg/dL; and symptomatic biliary disease; * Karnofsky score \< 70% for adult patients * Patient with poorly controlled hypertension and on multiple antihypertensives * Patients with current \>= grade 2 peripheral neuropathy * Patient has an active bacterial or fungal infection unresponsive to medical therapy * DONOR: Identical twin * DONOR: Donors unwilling to donate PBSC * DONOR: Pregnancy * DONOR: Infection with HIV * DONOR: Inability to achieve adequate venous access * DONOR: Known allergy to G-CSF * DONOR: Current serious systemic illness * DONOR: Failure to meet FHCRC criteria for stem cell donation * DONOR: Age \< 12 years * DONOR: A positive anti-donor cytotoxic crossmatch * DONOR: Patient and donor pairs must not be homozygous at mismatched allele
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Surviving Progression-free | At 2 years after the autograft | Number of subjects surviving without progressive disease post-transplant. Progressive disease criteria: 1. Greater than 25% increase in serum (absolute increase must be ≥0.5 g/dL) or urine (absolute increase must be ≥200 mg/24h) M proteins compared to best response status after autologous transplant. 2. Appearance of new lytic bone lesions or plasmacytomas. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grade II-IV Acute GVHD | 100 days post allo transplant | Number of patients who developed acute GVHD post allogeneic transplant. aGVHD Stages Skin: 1. \- a maculopapular eruption involving \< 25% BSA 2. \- a maculopapular eruption involving 25 - 50% BSA 3. \- generalized erythroderma 4. \- generalized erythroderma w/ bullous formation and often w/ desquamation Liver: 1. \- bilirubin 2.0 - 3.0 mg/100 mL 2. \- bilirubin 3 - 5.9 mg/100 mL 3. \- bilirubin 6 - 14.9 mg/100 mL 4. \- bilirubin \> 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death |
| Number of Patients With Chronic GVHD | 1 year post allo | Number of subjects with classic chronic or chronic extensive GVHD post allogeneic transplant. |
| Number of Patients With Toxicities Related to Bortezomib Maintenance Therapy | Up to 100 days after the autograft or allograft | Number of subjects with toxicities related to bortezomib maintenance therapy post-transplant. |
| Number of Patients With Non-relapse Mortality | 200 and 365 days after allo | Number of subjects with non-relapse mortalities post allogeneic transplant. |
| Number of Patients Surviving Overall | At 2 years after the autograft | Number of subjects surviving two years post autologous transplant. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy See Detailed Description
Autologous Hematopoietic Stem Cell Transplantation: Undergo transplantation
Bortezomib: Given SC
Cyclosporine: Given IV
Cyclosporine: Given PO
Fludarabine Phosphate: Given IV
Laboratory Biomarker Analysis: Correlative studies
Melphalan: Given IV
Mycophenolate Mofetil: Given PO
Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo transplantation
Peripheral Blood Stem Cell Transplantation: Undergo transplantation
Syngeneic Bone Marrow Transplantation: Undergo transplantation
Total-Body Irradiation: Undergo radiotherapy | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Age, Continuous | 49.2 years |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 32 |
| serious Total, serious adverse events | 16 / 32 |
Outcome results
Primary
Number of Patients Surviving Progression-free
Number of subjects surviving without progressive disease post-transplant. Progressive disease criteria: 1. Greater than 25% increase in serum (absolute increase must be ≥0.5 g/dL) or urine (absolute increase must be ≥200 mg/24h) M proteins compared to best response status after autologous transplant. 2. Appearance of new lytic bone lesions or plasmacytomas.
Time frame: At 2 years after the autograft
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy | Number of Patients Surviving Progression-free | 14 Participants |
Secondary
Number of Patients Surviving Overall
Number of subjects surviving two years post autologous transplant.
Time frame: At 2 years after the autograft
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy | Number of Patients Surviving Overall | 21 Participants |
Secondary
Number of Patients With Chronic GVHD
Number of subjects with classic chronic or chronic extensive GVHD post allogeneic transplant.
Time frame: 1 year post allo
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy | Number of Patients With Chronic GVHD | 10 Participants |
Secondary
Number of Patients With Grade II-IV Acute GVHD
Number of patients who developed acute GVHD post allogeneic transplant. aGVHD Stages Skin: 1. \- a maculopapular eruption involving \< 25% BSA 2. \- a maculopapular eruption involving 25 - 50% BSA 3. \- generalized erythroderma 4. \- generalized erythroderma w/ bullous formation and often w/ desquamation Liver: 1. \- bilirubin 2.0 - 3.0 mg/100 mL 2. \- bilirubin 3 - 5.9 mg/100 mL 3. \- bilirubin 6 - 14.9 mg/100 mL 4. \- bilirubin \> 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death
Time frame: 100 days post allo transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy | Number of Patients With Grade II-IV Acute GVHD | 14 Participants |
Secondary
Number of Patients With Non-relapse Mortality
Number of subjects with non-relapse mortalities post allogeneic transplant.
Time frame: 200 and 365 days after allo
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy | Number of Patients With Non-relapse Mortality | 200 days post allo | 1 Participants |
| Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy | Number of Patients With Non-relapse Mortality | 1 Year post allo | 1 Participants |
Secondary
Number of Patients With Toxicities Related to Bortezomib Maintenance Therapy
Number of subjects with toxicities related to bortezomib maintenance therapy post-transplant.
Time frame: Up to 100 days after the autograft or allograft
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy | Number of Patients With Toxicities Related to Bortezomib Maintenance Therapy | 1 Participants |