Clinical trial NCT01055301: S0833, Bortezomib, Thalidomide, Lenalidomide, Combination Chemotherapy, and Autologous Stem Cell Transplant in Treating Patients With Newly Diagnosed Multiple Myeloma
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 type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Multiple Myeloma
Plasma Cell Myeloma
Keywords: stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
Lead sponsor: SWOG Cancer Research Network
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-01-25
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression-free survival at 3 years
timeFrame: 3 years
Secondary outcomes:
measure: Overall survival
timeFrame: 3 years
measure: Frequency and severity of toxicities
timeFrame: 3 years
measure: Gene expression profiling analysis of CD138+ purified plasma cells
timeFrame: 3 years
Other outcomes:
Locations:
city: Alexandria
country: United States
facility: Tulane Cancer Center Office of Clinical Research
state: Louisiana
city: Baton Rouge
country: United States
facility: Hematology-Oncology Clinic
state: Louisiana
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Cancer Clinic
state: Mississippi
city: Anacortes
country: United States
facility: Island Hospital Cancer Care Center at Island Hospital
state: Washington
city: Bellingham
country: United States
facility: St. Joseph Cancer Center
state: Washington
city: Bremerton
country: United States
facility: Olympic Hematology and Oncology
state: Washington
city: Burien
country: United States
facility: Highline Medical Center Cancer Center
state: Washington
city: Kennewick
country: United States
facility: Columbia Basin Hematology
state: Washington
city: Mount Vernon
country: United States
facility: Skagit Valley Hospital Cancer Care Center
state: Washington
city: Poulsbo
country: United States
facility: Harrison Poulsbo Hematology and Onocology
state: Washington
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Minor and James Medical, PLLC
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Seattle
country: United States
facility: Group Health Central Hospital
state: Washington
city: Seattle
country: United States
facility: Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
state: Washington
city: Seattle
country: United States
facility: University Cancer Center at University of Washington Medical Center
state: Washington
city: Sedro-Woolley
country: United States
facility: North Puget Oncology at United General Hospital
state: Washington
city: Spokane
country: United States
facility: Cancer Care Northwest - Spokane South
state: Washington
city: Spokane
country: United States
facility: Evergreen Hematology and Oncology, PS
state: Washington
city: Wenatchee
country: United States
facility: Wenatchee Valley Medical Center
state: Washington
Study officials:
affiliation: Barbara Ann Karmanos Cancer Institute
name: Muneer H. Abidi, MD
role: PRINCIPAL_INVESTIGATOR
References: