S0833, Bortezomib, Thalidomide, Lenalidomide, Combination Chemotherapy, and Autologous Stem Cell Transplant in Treating Patients With Newly Diagnosed Multiple Myeloma

Sponsor

Southwest Oncology Group (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01055301

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Patients Per Site

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma Plasma Cell Myeloma	Drug: bortezomib Drug: cisplatin Drug: cyclophosphamide Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: etoposide Drug: lenalidomide Drug: melphalan Drug: thalidomide Genetic: gene expression analysis Genetic: microarray analysis Other: laboratory biomarker analysis Procedure: autologous-autologous tandem hematopoietic stem cell transplantation	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

S0833, Modified Total Therapy 3 (TT3) for Newly Diagnosed Patients With Multiple Myeloma (MM): A Phase II SWOG Trial for Patients Aged ≤ 65 Years

Study Start Date :

Jul 1, 2011

Actual Primary Completion Date :

Jul 1, 2011

Actual Study Completion Date :

Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: treatment Ind (1cycle): bort 1mg/m2 IV/SQ D1,4,8,11 D1-4: thalid 200mg/d & dex 20mg/d PO; cisplatin & dox 10mg/m2/d, cyclophos 400mg/m2/d, etoposide 40mg/m2/d contIV; enoxaparin 40mg/d SQ prn. PBSC Coll: at recovery per local standard Bridging (before/between trans/after Cons): thal 50mg/d D1-21 & dex 20mg D1,8,15 PO Tandem Trans (x2): bort 1mg/m2 IV/SQ D-4,-1 D-4to-1: mel 50 mg/m2 IV, thal 200mg/d & dex 40mg/d PO PBSC >/=200x10^6 cells Cons (1cycle): same as Ind except cis/dox 7.5mg/m2/d, cyclo 300mg/m2/d, no enox Maint(</= 3 yrs): D1,8,15,22:bort 1mg/m2 IV/SQ, dex 20mg/d PO; len 20mg/d PO D1-20	Drug: bortezomib Other Names: bort Drug: cisplatin Drug: cyclophosphamide Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: etoposide Drug: lenalidomide Drug: melphalan Drug: thalidomide Genetic: gene expression analysis Genetic: microarray analysis Other: laboratory biomarker analysis Procedure: autologous-autologous tandem hematopoietic stem cell transplantation

Arm

Intervention/Treatment

Experimental: treatment

Ind (1cycle): bort 1mg/m2 IV/SQ D1,4,8,11 D1-4: thalid 200mg/d & dex 20mg/d PO; cisplatin & dox 10mg/m2/d, cyclophos 400mg/m2/d, etoposide 40mg/m2/d contIV; enoxaparin 40mg/d SQ prn. PBSC Coll: at recovery per local standard Bridging (before/between trans/after Cons): thal 50mg/d D1-21 & dex 20mg D1,8,15 PO Tandem Trans (x2): bort 1mg/m2 IV/SQ D-4,-1 D-4to-1: mel 50 mg/m2 IV, thal 200mg/d & dex 40mg/d PO PBSC >/=200x10^6 cells Cons (1cycle): same as Ind except cis/dox 7.5mg/m2/d, cyclo 300mg/m2/d, no enox Maint(</= 3 yrs): D1,8,15,22:bort 1mg/m2 IV/SQ, dex 20mg/d PO; len 20mg/d PO D1-20

Drug: bortezomib

Other Names:

bort

Drug: cisplatin

Drug: cyclophosphamide

Drug: dexamethasone

Drug: doxorubicin hydrochloride

Drug: etoposide

Drug: lenalidomide

Drug: melphalan

Drug: thalidomide

Genetic: gene expression analysis

Genetic: microarray analysis

Other: laboratory biomarker analysis

Procedure: autologous-autologous tandem hematopoietic stem cell transplantation

Outcome Measures

Primary Outcome Measures

Progression-free survival at 3 years [3 years]

Secondary Outcome Measures

Overall survival [3 years]
Frequency and severity of toxicities [3 years]
Gene expression profiling analysis of CD138+ purified plasma cells [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tulane Cancer Center Office of Clinical Research	Alexandria	Louisiana	United States	71315-3198
2	Hematology-Oncology Clinic	Baton Rouge	Louisiana	United States	70809
3	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
4	University of Mississippi Cancer Clinic	Jackson	Mississippi	United States	39216
5	Island Hospital Cancer Care Center at Island Hospital	Anacortes	Washington	United States	98221
6	St. Joseph Cancer Center	Bellingham	Washington	United States	98225
7	Olympic Hematology and Oncology	Bremerton	Washington	United States	98310
8	Highline Medical Center Cancer Center	Burien	Washington	United States	98166
9	Columbia Basin Hematology	Kennewick	Washington	United States	99336
10	Skagit Valley Hospital Cancer Care Center	Mount Vernon	Washington	United States	98274
11	Harrison Poulsbo Hematology and Onocology	Poulsbo	Washington	United States	98370
12	Harborview Medical Center	Seattle	Washington	United States	98104
13	Minor and James Medical, PLLC	Seattle	Washington	United States	98104
14	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
15	Group Health Central Hospital	Seattle	Washington	United States	98112
16	Swedish Cancer Institute at Swedish Medical Center - First Hill Campus	Seattle	Washington	United States	98122-4307
17	University Cancer Center at University of Washington Medical Center	Seattle	Washington	United States	98195
18	North Puget Oncology at United General Hospital	Sedro-Woolley	Washington	United States	98284
19	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
20	Evergreen Hematology and Oncology, PS	Spokane	Washington	United States	99218
21	Wenatchee Valley Medical Center	Wenatchee	Washington	United States	98801-2028