S0833, Bortezomib, Thalidomide, Lenalidomide, Combination Chemotherapy, and Autologous Stem Cell Transplant in Treating Patients With Newly Diagnosed Multiple Myeloma
S0833, Bortezomib, Thalidomide, Lenalidomide, Combination Chemotherapy, and Autologous Stem Cell Transplant in Treating Patients With Newly Diagnosed Multiple Myeloma
RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes
 needed for cell growth. Biological therapies, such as thalidomide and lenalidomide, may
 stimulate the immune system in different ways and stop cancer cells from growing. Drugs used
 in chemotherapy, such as dexamethasone, cisplatin, doxorubicin hydrochloride,
 cyclophosphamide, etoposide, and melphalan, work in different ways to stop the growth of
 cancer cells, either by killing the cells or by stopping them from dividing. Combining
 chemotherapy with autologous stem cell transplant may allow the doctor to give higher doses
 of chemotherapy drugs and kill more cancer cells. Giving bortezomib, thalidomide, and
 combination chemotherapy before and after transplant and lenalidomide after transplant may be
 an effective treatment for multiple myeloma.

 PURPOSE: This phase II trial is studying how well giving bortezomib, thalidomide, and
 lenalidomide together with combination chemotherapy and autologous stem cell transplant works
 in treating patients with newly diagnosed multiple myeloma.
OBJECTIVES:

 Primary

 -  To assess progression-free survival (PFS) at 3 years in patients with newly diagnosed
 multiple myeloma (MM) treated with modified Total Therapy 3 (TT3).

 Secondary

 -  To estimate the frequency and severity of toxicities associated with this treatment
 strategy in these patients.

 Correlative

 -  To perform gene expression profiling on CD138+ purified MM cells and unseparated bone
 marrow biopsy samples to identify the bone marrow micro-environment signature.

 -  To determine whether the 70-gene model, developed in the Arkansas Total Therapy 2 (TT2)
 and validated in the Arkansas TT3 study, also applies to the cooperative group setting.

 -  Determine whether the novel finding in TT3 of the prognostically favorable suppression
 of a micro-environment-associated gene, MAG1, also applies to the cooperative group
 setting.

 -  Once in complete remission, determine whether the MAG signatures can return to a normal
 individual's signature as an indication of profound tumor cytoreduction with durable
 PFS.

 OUTLINE: This is a multicenter study.

 -  Induction therapy: Patients receive bortezomib IV on days 1, 4, 8, and 11; oral
 thalidomide and oral dexamethasone on days 1-4; and cisplatin IV continuously,
 doxorubicin hydrochloride IV continuously, cyclophosphamide IV continuously, and
 etoposide IV continuously on days 1-4.

 -  Peripheral blood stem cell (PBSC) collection: Beginning within 2 months after completion
 of induction therapy, patients undergo PBSC collection until an adequate number of cells
 are collected. Patients with persistent disease after completion of induction therapy
 proceed to bridging therapy after adequate stem cells are collected. Patients not
 requiring bridging therapy proceed directly to transplant.

 -  Bridging therapy: Patients receive oral thalidomide on days 1-21 and oral dexamethasone
 on days 1, 8, and 15. Treatment repeats every 21 days for 1-2 courses in the absence of
 disease progression or unacceptable toxicity. Patients then proceed to transplant.

 -  First autologous PBSC transplantation: Beginning within 6 weeks to 3 months after
 completion of induction therapy (or ≥ 1 week after completion of bridging therapy),
 patients receive bortezomib IV on days -4 and -1 and melphalan IV, oral thalidomide, and
 oral dexamethasone on days -4 to -1. Patients undergo autologous PBSC transplantation on
 day 0.

 -  Inter-transplant bridging therapy: Patients with persistent disease after completion of
 the first autologous PBSC transplant receive bridging therapy as above and then proceed
 to the second transplant. Patients not requiring bridging therapy proceed directly to
 the second transplant.

 -  Second autologous PBSC transplantation: Beginning within 6 months after the first PBSC
 transplant, patients receive bortezomib, melphalan, thalidomide, and dexamethasone and
 undergo autologous PBSC as in the first transplant. Patients who skip the second
 transplant (due to medical or insurance reasons or refusal) proceed to consolidation
 therapy.

 -  Consolidation therapy: Beginning within 6 months after the last transplant, patients
 receive bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin hydrochloride,
 cyclophosphamide, and etoposide as in induction therapy.

 -  Post-consolidation bridging therapy: Patients with persistent disease after completion
 of consolidation therapy receive oral thalidomide on days 1-21 and oral dexamethasone on
 days 1, 8, and 15. Patients then proceed to maintenance therapy. Patients not requiring
 bridging therapy proceed directly to maintenance therapy.

 -  Maintenance therapy: Beginning within 4 months after completion of consolidation therapy
 or post-consolidation bridging therapy, patients receive bortezomib IV and oral
 dexamethasone on days 1, 8, 15, and 22 and oral lenalidomide on days 1-20. Courses
 repeat every 28 days for up to 3 years in the absence of disease progression or
 unacceptable toxicity.

 Blood and bone marrow samples may be collected at baseline and periodically during study for
 gene expression profile analysis.

 After completion of study therapy, patients are followed up periodically for up to 7 years.
DISEASE CHARACTERISTICS:

 -  Newly diagnosed active multiple myeloma (MM)

 -  Measurable disease

 -  Non-secretory disease allowed provided patient has ≥ 20% plasmacytosis or
 multiple (> 3) focal plasmacytomas on skeletal survey and/or MRI

 PATIENT CHARACTERISTICS:

 -  Zubrod performance status (PS) 0-2 (Zubrod PS 3-4 allowed if based solely on bone
 pain)

 -  ANC ≥ 1,500/mm^3*

 -  Platelet count ≥ 150,000/mm^3*

 -  Serum creatinine clearance of ≥ 60 mL/min

 -  Patients with creatinine clearance of < 60 mL/min receive a lower dose of
 melphalan

 -  No patients receiving or planning to receive dialysis

 -  Total bilirubin ≤ 1.5 times upper limit of normal

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  Must be fully aware of the teratogenic potential of thalidomide

 -  Must be willing to comply with the FDA-mandated S.T.E.P.S. program

 -  Ejection fraction > 40% as measured by MUGA scan or two-dimensional ECHO

 -  No peripheral neuropathy ≥ grade 2 per CTCAE v. 4.0

 -  No known hypersensitivity to bortezomib, boron, or mannitol

 -  No uncontrolled diabetes defined as fasting glucose level > 200 mg/dL on at least more
 than two occasions or more that two serum random blood levels > 300 mg/dL despite
 adequate treatment

 -  Patients with a history of diabetes mellitus requiring treatment should be on a
 stable regimen and have their blood glucose closely monitored

 -  No other malignancy within the past 5 years except for adequately treated basal cell
 or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the
 patient has not received treatment within the past year NOTE: *Unless myeloma-related
 marrow infiltration is documented, defined as ≥ 30% marrow cellularity with 50% of the
 cells being malignant plasma cells.

 PRIOR CONCURRENT THERAPY:

 -  At least 4 weeks since prior chemotherapy or radiotherapy

 -  No more than 1 prior course of chemotherapy for MM

 -  Prior chemotherapy must not have included melphalan

 -  No prior radiotherapy to large area of the pelvis (more than half of the pelvis)

 -  Prior radiotherapy for symptomatic localized bone lesions or impending cord
 compression allowed