Multiple Myeloma and Plasma Cell Neoplasm, Neurotoxicity
Conditions
Keywords
neurotoxicity, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma
Brief summary
RATIONALE: Bortezomib and thalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. Bortezomib may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving bortezomib together with thalidomide and dexamethasone may kill any cancer cells that remain after high-dose melphalan and stem cell transplant in patients with multiple myeloma. PURPOSE: This phase II trial is studying the side effects of giving bortezomib together with thalidomide and dexamethasone after melphalan and stem cell transplant and to see how well it works in treating patients with stage I-III multiple myeloma.
Detailed description
OBJECTIVES: Primary * To assess the feasibility and toxicities of maintenance therapy with sequential bortezomib, thalidomide, and dexamethasone after high-dose melphalan and autologous peripheral blood stem cell transplantation in patients with multiple myeloma. * To assess whether administration of sequential bortezomib, thalidomide, and dexamethasone can improve progression-free survival of these patients. Secondary * To assess whether administration of sequential bortezomib, thalidomide, and dexamethasone can increase complete remission rate and duration of response in these patients. * To assess the impact of maintenance therapy with sequential bortezomib, thalidomide, and dexamethasone after transplantation on overall survival of these patients. * To evaluate the influence of cytogenetic abnormalities (e.g., chromosome 13 deletion, 14 q32 abnormality, t \[4;14\], chromosome 1 q21 amplification, and chromosome 17 deletion) on outcome by performing conventional cytogenetic study and fluorescence in situ hybridization (FISH) studies on baseline and post-transplant bone marrow specimens. OUTLINE: * High-dose melphalan and autologous peripheral blood stem cell transplantation (PBSCT): Patients receive high-dose melphalan IV over 30 minutes on days -2 and -1 and undergo autologous PBSCT on day 0. Patients receive filgrastim (G-CSF) IV or subcutaneously beginning on day 5 and continuing until blood counts recover. * Maintenance therapy: Beginning 4-8 weeks after transplantation, patients receive bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral dexamethasone on days 1-4; treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive oral thalidomide once daily until disease progression. Patients complete the FACT-GOG neurotoxicity questionnaire periodically. Bone marrow samples are collected at baseline and post-transplant for cytogenetic analysis by FISH.
Interventions
DRUGbortezomib
Given IV
DRUGdexamethasone
Given orally
DRUGmelphalan
Given IV
DRUGthalidomide
Given orally
GENETICcytogenetic analysis
Performed on baseline and post transplant bone marrow specimens
GENETICfluorescence in situ hybridization
Performed on baseline and post transplant bone marrow specimens
OTHERlaboratory biomarker analysis
Baseline, post transplant and prior to start of bortezomib, every 3 months post transplant for the first year, after 6 cycles of bortezomib, every year after transplant for 2-4 years.
OTHERquestionnaire administration
Completed at baseline (within 6 weeks prior to enrollment) and at 2 months post transplant and once a month after that for the first year. For the second year the questionnaire will be completed every 3 months as long as on thalidomide for the duration of the study.
PROCEDUREautologous hematopoietic stem cell transplantation
Minimum dose of 2 X 10(6) CD34 + cells/kg day 0 after two days of treatment with Melphalan
PROCEDUREperipheral blood stem cell transplantation
Minimum dose of 2 X 10(6) CD34 + cells/kg day 0 after two days of treatment with Melphalan
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 70 Years
Healthy volunteers
No
Inclusion criteria
* Multiple Myeloma patients with symptomatic disease, stage II or III at diagnosis or progressive stage I requiring chemotherapy and/or radiation therapy (by Salmon-Durie classification), who are not eligible for tandem transplant study using TMI; because of previous radiation or eligibility criteria; documentation of disease staging by both Salmon-Durie classification and International Staging System (ISS) is required * Patients with non-secretory myeloma should have measurable serum free-light chain protein by the Free-lite test or measurable disease such as a soft tissue myeloma * A minimum of 4 x 10\^6 of CD 34 Positive cell/kg has been harvested * A Karnofsky performance status (KPS) of \>= 70% is required unless the KPS is impaired due to bone disease * No contraindication to the collection of a minimum of 4 x 10\^6 CD34+ cells/kg by apheresis * All patients must have signed a voluntary, informed consent in accordance with institutional and federal guidelines * Bilirubin =\< 1.5 mg/dl * Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) \< 2.5 x upper limits of normal * Creatinine clearance of \>= 40cc/min * Absolute neutrophil count of \> 1000/ul * Platelet count of \> 100,000/ul * Cardiac ejection fraction \>= 45% by multigated acquisition (MUGA) scan and/or by echocardiogram * Diffusing capacity of the lung for carbon monoxide (DLCO) \>= 50% of predicted lower limit * Human immunodeficiency virus (HIV) antibody tests negative * No other medical, or psychosocial problems which in the opinion of the primary physician or principal investigator would place the patient at unacceptably high risk from this treatment regimen
Exclusion criteria
* Presence of peripheral neuropathy \>= grade II * Patients with evidence of disease progression (with \>= 25% increase in M protein) on bortezomib and or thalidomide therapy prior to transplant * Pregnant or nursing women, as well as women of child bearing age, who are unwilling to use a dual method of contraception and men who are unwilling to use condom * Patients with history of hypersensitivity to bortezomib, boron or mannitol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | After 4 months of maintenance therapy | All grade 3 and above treatment-related adverse events (AEs) during bortezomib/dexamethasone treatment cycles. |
| One Year Overall Survival | From date of treatment initiation until death from any cause, assessed up to one year. | One year overall survival estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients alive at year one after starting treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Count of Response in Patients Started on Maintenance Therapy | Post-Thalidomide at 1 year. | Complete Response (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100mg per 24-h. Partial Response (PR): \> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by \> 90% or to \< 200mg per 24-h In addition to the above listed criteria, if present at baseline, a . 50% reduction in the size of soft tissue plasmacytomas is also required. Stable Disease (SD): Not meeting criteria for CR, VGPR, PR or progressive disease. Relapse: Any of the following: Reappearance of serum or urine M-protein by immunofixation or electrophoresis Development of \> 5% plasma cells in the bone marrow. Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion) |
| One Year Progression-free Survival (PFS) | From start of treatment initiation until disease progression, relapse or death from any cause, assessed up to 1 year. | PFS estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients progression-free at year one after starting treatment. International Myeloma Working Group uniform response criteria for disease progression: Increase of \> 25% from baseline in Serum M-component and/or (the absolute increase must be \> 0.5 g/dl); Urine M-component and/or (the absolute increase must be \> 200 mg/24 h; Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be \>l0mg/dl. Bone marrow plasma cell percentage: the absolute % must be \> 10%C; Definite development of new bone lesions or soft tissue plasmacytomas. or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium \>11.5 mg/dl or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Stem Cell Transplant, Maintenance Treatment) Patients receive high-dose melphalan IV 200mg/m\^2 over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation (Minimum dose of 2 X 10(6) CD34 + cells/kg ) on day 0. Patients receive filgrastim 5ug/kg IV or SQ beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising 1.3 mg/m\^2 of bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive 40mg of oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive 50mg/day of oral thalidomide once daily until disease progression. | 45 |
| Total | 45 |
Baseline characteristics
| Characteristic | Treatment (Stem Cell Transplant, Maintenance Treatment) |
|---|---|
| Age, Continuous | 55 years |
| Region of Enrollment United States | 45 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 40 / 45 |
| serious Total, serious adverse events | 9 / 45 |
Outcome results
Primary
Number of Participants With Adverse Events
All grade 3 and above treatment-related adverse events (AEs) during bortezomib/dexamethasone treatment cycles.
Time frame: After 4 months of maintenance therapy
Population: Five patients did not start the maintenance phase of the study because of neurotoxicity (n=3), thrombocytopenia (n=1), or withdrawal of consent (n=1).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Leukopenia | 1 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Lymphopenia | 13 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Neutropenia | 2 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Fatigue | 2 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Upper respiratory infection | 1 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Anxiety | 1 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Pain in extremity | 1 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Sinus bradycardia | 1 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Hyperglycemia | 4 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Hypophosphatemia | 3 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Thrombocytopenia | 1 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Number of Participants With Adverse Events | Cataract | 1 Participants |
Primary
One Year Overall Survival
One year overall survival estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients alive at year one after starting treatment.
Time frame: From date of treatment initiation until death from any cause, assessed up to one year.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Stem Cell Transplant, Maintenance Treatment) | One Year Overall Survival | 95 percentage of participants |
Secondary
Count of Response in Patients Started on Maintenance Therapy
Complete Response (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100mg per 24-h. Partial Response (PR): \> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by \> 90% or to \< 200mg per 24-h In addition to the above listed criteria, if present at baseline, a . 50% reduction in the size of soft tissue plasmacytomas is also required. Stable Disease (SD): Not meeting criteria for CR, VGPR, PR or progressive disease. Relapse: Any of the following: Reappearance of serum or urine M-protein by immunofixation or electrophoresis Development of \> 5% plasma cells in the bone marrow. Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion)
Time frame: Post-Thalidomide at 1 year.
Population: Five patients did not start the maintenance phase of the study because of neurotoxicity (n=3), thrombocytopenia (n=1), or withdrawal of consent (n=1).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Count of Response in Patients Started on Maintenance Therapy | PR | 3 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Count of Response in Patients Started on Maintenance Therapy | CR | 20 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Count of Response in Patients Started on Maintenance Therapy | VPR | 2 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Count of Response in Patients Started on Maintenance Therapy | Relapsed | 6 Participants |
| Treatment (Stem Cell Transplant, Maintenance Treatment) | Count of Response in Patients Started on Maintenance Therapy | Not Assessed | 9 Participants |
Secondary
One Year Progression-free Survival (PFS)
PFS estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients progression-free at year one after starting treatment. International Myeloma Working Group uniform response criteria for disease progression: Increase of \> 25% from baseline in Serum M-component and/or (the absolute increase must be \> 0.5 g/dl); Urine M-component and/or (the absolute increase must be \> 200 mg/24 h; Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be \>l0mg/dl. Bone marrow plasma cell percentage: the absolute % must be \> 10%C; Definite development of new bone lesions or soft tissue plasmacytomas. or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium \>11.5 mg/dl or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder.
Time frame: From start of treatment initiation until disease progression, relapse or death from any cause, assessed up to 1 year.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Stem Cell Transplant, Maintenance Treatment) | One Year Progression-free Survival (PFS) | 88 percentage of participants |