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

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.

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