Bortezomib, Thalidomide, and Dexamethasone After Melphalan and Stem Cell Transplant in Treating Patients With Stage I-III Multiple Myeloma

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Study of Maintenance Treatment With Sequential Bortezomib, Thalidomide and Dexamethasone Following Autologous Peripheral Blood Stem Cell Transplant in Patients With Multiple Myeloma

Conditions
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Multiple Myeloma and Plasma Cell Neoplasm, Neurotoxicity

Intervention / Treatment
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* Drug: bortezomib
* Drug: dexamethasone
* Drug: melphalan
* Drug: thalidomide
* Genetic: cytogenetic analysis
* Genetic: fluorescence in situ hybridization
* Other: laboratory biomarker analysis
* Other: questionnaire administration
* Procedure: autologous hematopoietic stem cell transplantation
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (stem cell transplant, maintenance treatment)<br>Patients receive high-dose melphalan IV over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation on day 0. Patients receive filgrastim IV or SC beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising 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 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 oral thalidomide once daily until disease progression. | Drug: bortezomib<br>* Given IV<br>Drug: dexamethasone<br>* Given orally<br>Drug: melphalan<br>* Given IV<br>Drug: thalidomide<br>* Given orally<br>Genetic: cytogenetic analysis<br>* Performed on baseline and post transplant bone marrow specimens<br>Genetic: fluorescence in situ hybridization<br>* Performed on baseline and post transplant bone marrow specimens<br>Other: laboratory biomarker analysis<br>* 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.<br>Other: questionnaire administration<br>* 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.<br>Procedure: autologous hematopoietic stem cell transplantation<br>* Minimum dose of 2 X 10(6) CD34 + cells/kg day 0 after two days of treatment with Melphalan<br>Procedure: peripheral blood stem cell transplantation<br>* Minimum dose of 2 X 10(6) CD34 + cells/kg day 0 after two days of treatment with Melphalan<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | All grade 3 and above treatment-related adverse events (AEs) during bortezomib/dexamethasone treatment cycles. | After 4 months of maintenance therapy | 
| 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. | From date of treatment initiation until death from any cause, assessed up to one year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Post-Thalidomide at 1 year. | 
| 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. | From start of treatment initiation until disease progression, relapse or death from any cause, assessed up to 1 year. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neurotoxicity, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma