Trial Information

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

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.